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Why don't mosquitoes target the visible blood vessels under the skin?

Why don't mosquitoes target the visible blood vessels under the skin?


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We can see numerous veins under our skin. Why don't mosquitoes suck blood from those vessels?

Why don't they use better option?


For a mosquito, there is really no benefit to targeting those visible blood vessels. Mosquitoes take only a small amount of blood, and their proboscis is going to be a limiting factor anyways.

However, mosquitoes also aren't just blinding sticking their proboscis into the extracellular space. They actually do target individual vessels, and scientists have actually been able to video the process. Capillaries are good targets because they are found in all the tissues, so the mosquito doesn't need to find a surface vein.

See the videos with the original paper here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050464 (in the "Supporting information" section)

There are also versions on YouTube, like here: https://www.youtube.com/watch?v=MbXSPacvuak

Choumet, V., Attout, T., Chartier, L., Khun, H., Sautereau, J., Robbe-Vincent, A.,… & Bain, O. (2012). Visualizing non infectious and infectious Anopheles gambiae blood feedings in naive and saliva-immunized mice. PLoS One, 7(12), e50464.


Anemia

Anemia is defined as a low number of red blood cells. In a routine blood test, anemia is reported as a low hemoglobin or hematocrit. Hemoglobin is the main protein in your red blood cells. It carries oxygen, and delivers it throughout your body. If you have anemia, your hemoglobin level will be low too. If it is low enough, your tissues or organs may not get enough oxygen. Symptoms of anemia -- like fatigue or shortness of breath -- happen because your organs aren't getting what they need to work the way they should.

Anemia is the most common blood condition in the U.S. It affects almost 6% of the population. Women, young children, and people with long-term diseases are more likely to have anemia. Important things to remember are:

  • Certain forms of anemia are passed down through your genes, and infants may have it from birth.
  • Women are at risk of iron-deficiency anemia because of blood loss from their periods and higher blood supply demands during pregnancy.
  • Older adults have a greater risk of anemia because they are more likely to have kidney disease or other chronic medical conditions.

There are many types of anemia. All have different causes and treatments. Some forms -- like the mild anemia that happens during pregnancy -- aren’t a major concern. But some types of anemia maymay reflect a serious underlying medical condition


What Are the Causes of Thinning Blood Vessels?

Thinning blood vessels can be caused by a number of conditions in addition to the normal processes of aging. This condition, usually called vasculitis, can be the result of some cancers, some disorders of the immune system, as well as the result of an allergic reaction. Blood vessels get inflamed and can either thicken or thin. The latter can be the underlying cause of a bulge in the blood vessel which can cause a dangerous aneurysm.

If you are experiencing serious medical symptoms, seek emergency treatment immediately.


Side Matters in Colorectal Cancer

CUTTING-EDGE CANCER RESEARCH is often focused with pinpoint precision on tiny variations in the genetic code. It’s akin to working with typos in a phonebook. So last summer, when researchers revealed that there may be a significant difference between colorectal cancer that emerges on the right side of the body versus that arising on the left side, oncologists got very curious about this apparently much more simple discovery.

It has been observed for years that patients with rightsided colorectal cancer had worse outcomes than those with left-sided disease. Nobody knew why, and while there was some evidence of molecular differences based on where a colorectal cancer emerged, the consensus assumption seemed reasonable: Right-sided patients fared worse because their disease was less likely to be caught at an early stage.

Stool is more liquid on the right side, and the bowel is larger. “We assumed that you would need a more advanced cancer on the right side to manifest symptoms,” explains Alan Venook, M.D., a gastrointestinal (GI) oncologist at the UCSF Helen Diller Family Comprehensive Cancer Center, in California. Patients with a right-sided tumor were thus more likely to be diagnosed with later-stage disease. It was serendipity that made Venook rethink left versus right. He was invited to give a memorial lecture at Cornell Medical School in April 2016 in honor of Scott Wadler, a specialist in GI cancers who had died in 2007. While researching his talk, Venook found a 2001 paper that showed a five-month difference in survival between left- and right-handed colorectal cancers. “Now, that blew my mind,” says Venook. Because the therapy regimen in the paper was obsolete, the research never got the attention it deserved.

Venook was motivated to re-examine data he’d helped generate as the lead investigator on Cancer and Leukemia Group B/Southwest Oncology Group 80405, a trial that had studied some combination therapies for metastatic colorectal cancer. As its ponderous name and number suggests, it was one of the thousands of generally anonymous studies that, bit by bit, advance cancer treatment.

Study 80405 had largely wrapped up by 2014, but it had never looked at where the cancer had arisen. “It hadn’t occurred to us that that was relevant,” says Venook. “In almost no study in that era did we capture that information.” For six weeks, a small team combed through more than a thousand patient files, pulling out the primary disease location in the colon.

When they ran the numbers, the differences leapt off the page. To double-check, he scoured other studies. “It just blew my mind. I had no clue that it was this big a difference,” says Venook.

Colleagues were similarly intrigued when Venook presented his analysis in 2016 (it hasn’t been published yet). For patients with metastatic colorectal cancer, he found, the sidedness of the primary tumor within the colon appears to affect both survival and the effectiveness of commonly used biological agents Avastin (bevacizumab) and Erbitux (cetuximab), which are designed to interfere with the formation of blood vessels that feed a tumor, and with growth factor receptor signaling. Patients with left-sided disease enjoyed a median overall survival of 33 months compared with 19.4 months in right-sided disease. And a comparison of Avastin and Erbitux showed that Erbitux might actually be harmful to patients with right-sided tumors.

Because the study was not originally designed to scrutinize sidedness, scientists believe more research is needed for confirmation. But the issue has the attention of GI oncologists. “Most of us believe this finding could be practice-changing,” says Mohamed Salem, M.D., of the Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, D.C.

UNDERSTANDING COLORECTAL CANCER

Anatomically, the colon, or large intestine, seems like a single organ, a unified piece of human plumbing. For years, the primary tool of colorectal cancer screening was a sigmoidoscope, which only views the left side of the colon. The premise: no polyps — potentially precancerous growths — on the left side meant that the right colon would be fine, since more cancers do, in fact, arise in the rectum, or left side of the colon. That was eventually disproven, one reason why colonoscopy, which can examine the entire colon, is now favored by many providers. Flexible sigmoidoscopy is still used for screening, but performed every five years compared to every decade for colonoscopy.

In fact, the two sides of the colon emerge from different parts of embryo. Every cell in the body descends from that first fusion between the egg and the sperm, but as the embryo grows, these cells begin to develop in different directions. Some cells become skin, while other cells become neurons in the brain. Some cells become the right colon, while others become the left colon. The right colon comes from the mid gut while the left colon comes from the hind gut, and they have different blood supplies. The cells on the left and rights sides function slightly differently, and therefore, while they possess the same genes, they may not all be turned on to express the same set of proteins. “That doesn’t mean their gene expression patterns are necessarily different, but it certainly would be believable that they are,” says Venook.

It’s also assumed that the microbiome, which affects the way the body operates, plays a role. The microbiome is composed of all the genes within the collection of microbes (mostly bacteria) that live in and on humans. The vast majority of the GI microbiome resides in the colon, where it interacts constantly with the immune system through the lining of the intestine. It can affect the chemical composition of the colon contents, including what is absorbed into the body, But the microbiome is a moving target: different in different parts of the colon, different in every person and different over time. “The microbiome is very hard to understand in colon cancer,” Venook says. It’s also disrupted by the procedures used to diagnose and treat colorectal cancer. “This is a black box. Undoubtedly this is important, but we just don’t know how.”

While colon cancer is typically a disease of older people, Salem reports “an alarming finding:” over the last 10 to 15 years, an increase in colorectal cancer for patients between the ages of 20 and 49. And while there has been a slight overall decline in colorectal cancer, the frequency of rightsided colon cancer appears to be increasing. But the right/ left divide is more complex than just patients with left-sided disease doing a little better. There is slightly more left-sided disease than right. Patients with right-sided disease also tend to be older and are more likely to be female.

Right-sided disease is also subtly different: more advanced, with larger tumors that look different and have different chemical signatures.

The information about sidedness also comes on the heels of a major upgrade in our understanding of colorectal cancer. As our ability to decode the genetics and molecular biology of tumors has gotten both cheaper and more powerful, colorectal cancer is now recognized as more than one disease. Gene mutations like HER2 and BRAF, which can be targeted with drugs, are just part of the picture, as experts are learning that the overall biology of the tumor is also important when it comes to designing treatment. In 2015, scientists divided the disease into what they call “consensus molecular subtypes:” CM1, CM2, CM3 and CM4.

Between this new classification system and left/right awareness, future clinical trials hold greater promise than ever. Among the first tasks is finding out what the sidedness means. “It’s our job to figure out what it’s a surrogate for,” says Venook. “Is it an independent prognosticator, or some kind of voodoo we don’t understand?”

“Any future clinical trials will stratify patients according to the side,” adds Salem.

APPLYING NEW IDEAS

But can this information be used now? First of all, it’s important to understand that right-sided disease is not a death sentence. “I’ve had patients say ‘Oh, I’ve got right-sided cancer. I’m toast,’” says Venook. “These are generalities, these are averages. There are patients within the group who do fine.” Indeed, if caught early enough, surgery to excise rightsided disease is typically less complicated than that undertaken for left-sided colorectal cancer.

Alternatively, the intel can be comforting to some with left-sided disease. While C. Damon Hecker, a Virginia-based executive, was in the midst of chemo for his stage 3 colorectal cancer, his wife, Karen, did most of the family education, reading journal articles and connecting with Colon Town and other patient communities. When she learned about the right/left difference, she happily conveyed the news to her husband — it was, after all, among the more encouraging statistics in the face of the loss of nearly a foot of his left colon.

“I didn’t give a s***, to be honest,” he confesses — the chemo was hitting him hard. “I was pretty focused on other things, but it helped her.” She agrees: “You’re always looking for an edge.”

Once the disease is metastatic, treatment options change. Salem and Venook now use sidedness as one variable of many, on a case-by-case basis.

First of all, learning that Erbitux is riskier for right-sided patients bodes well in the long term. “As a physician, the first directive is to not harm your patient,” says Salem. The patient’s ideas about quality of life and ambition of treatment are also very important. Often enough — and in the absence of confirmed guidelines suggesting that Erbitux not be used in right-sided colorectal cancers — treatment choice is governed by side effects, like the desire to avoid a rash, or pre-existing medical conditions such as hypertension. Also, Erbitux is not used in colon cancers bearing KRAS mutations.

“We cannot cure most colon cancer patients,” admits Salem. “Yet the median overall survival has increased from six months 20 years ago to almost three years. The main change is that we have more drugs. It is important to receive all lines of therapy. The more options available, the better you do.”

Right-sided disease might also mean choosing clinical trials. “We may treat you more aggressively,” says Venook. The breast cancer drug Herceptin, which targets an overexpression of the protein HER2, is in trial for colorectal cancer now, and immune therapy options are blossoming. And it should not take long for the research community to incorporate left/right dynamics and the new molecular subtypes into a whole raft of new trials.

“This is a reason to make sure that you are in contact with, or actually see, a doctor at a major center,” says Venook. “This is an evolution, and they are the people that know about it.”

Salem agrees: “Clinical trials give you an opportunity for 2018 therapy.”


GERnétic Argini

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Directions

Frequency: 2 to 3 times per week.

  • After a thorough cleaning of the skin, apply the Argini mask in sufficient quantity to uniformly cover the entire face and neck.
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(No information offered on this web site should be considered as medical advice.)

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Book an online consultation.

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(No information offered on this web site should be considered as medical advice.)


Exam #1

- Generation of cells
- Response to underuse, disuse, decreased blood supply, nutritional changes, nerve loss, child development, aging
- Protein catabolism ^^
- Protein synthesis decreases
- Endoplasmic reticulum, mitochondria, microfilaments decrease
- ^^ autophagy (hydrolysis)

implications at the organ level:
- e.g. physiologic hypertrophy (as in enlargement of the heart in athletes, a normal compensatory mechanism)
- e.g. pathologic hypertrophy (as in aortic valve stenosis you must pump against high pressure system of systemic circulation, the left ventricle enlarges to compensate)

Gunshot wounds: entrance and exit wounds

- unstable molecules with unpaired electron
- form bonds with proteins, lipids, CHO's, etc causing cell injury and death

causes:
- air pollution
- UV light
- smoking
- aging (cumulative stress/exposure)

due to:
- lipases breaking down fat
- trauma with ischemia/hypoxia

due to:
- Compromised circulation (hypoxia/ischemia, thrombosis), chronic disease (diabetes- lost sensation due to neuropathy means they don't notice injury, recovery can be harder thereafter due to disease),
- infection
- trauma
(lower extremities, intestines, other)

Vasodilation
- Increased flow, vascular permeability and leakage
- WBC's accumulate at site

- facilitates phagocytosis
- degranulation
- chemotaxis
- cell lysis
(marks foreign bodies so immune system cells can kill them)

coagulation
- fibrin meshwork for clotting
- framework for repair and healing

1. PRRs (pattern recognition receptors)
- recognize molecules expressed by infectious agents or products of cellular damage (PAMPs)

2. TLRs (toll-like receptors)
- recognize molecular patterns on viral, bacterial surfaces and microbial nucleic acid

Secreted by macrophages in response to pathogens and TLR recognition

pro-inflammatory cytokine that promotes the systemic effects of inflammation (e.g. fever, malaise)

- release histamine and chemotactic factors
- key players in inflammation/allergy

triggers inflammatory response

increases permeability of capillaries to WBC's

- binds to H1 receptors in various parts of the body, causing various changes

- *CNS (neurotransmission)
- blood vessels (vasodilation, capillary permeability)
- lungs (bronchoconstriction)
- skin (itching, pain)*

1. Recognition and adherence
2. Engulfment/ phagosome formation
3. Fusion with lysosomal granules to form phagolysosome
4. Destruction of the target

helper:
release cytokines required for the differentiation and proliferation of B cells and cytotoxic T cells
- "CD4 positive"

1. Inflammation (1-2 days)
- Platelets, neutrophils, macrophages,
- Coagulation, bacterial clearing, growth factors

2. Proliferation (3-14 days)
- Fibroblasts
- Collagen, epithelial/granular tissue with capillaries, contraction
- Growth factors

- excessive contraction: exaggerated shrinkage (usually at joints)

2. Adaptation
- ACTH causes release of cortisol from adrenal gland (along with epinephrine and norepinephrine)
- inflammation (cytokines) vs. anti-inflammatory effects
- other hormones (endorphins, neuropeptide Y, substance P)

Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system*

a1- postsynaptic smooth muscle

a2- presynaptic neurons, postsynaptic tissues (ocular, adipose, intestinal, hepatic, renal, endocrine, and platelets)

b2- bronchial, uterine, vascular, smooth muscle (relaxation)

increases blood flow to muscles, output of the heart, pupil dilation, and blood sugar (does this by its effects on alpha and beta receptors)

2. norepinephrine
- in PNS
- increases vascular smooth muscle tone

increases heart rate, triggers the release of glucose from energy stores, and increases blood flow to skeletal muscle

HPA is the feedback interactions between the hypothalamus, pituitary gland, and adrenal glands. Part of the neuroendocrine system that regulates the body's response to stress and immunity.

3) adrenal cortex
>> glucocorticoids (cortisol) >>

or adrenal medulla
>> catecholamines (epinephrine and norepinephrine) >>

Anti-inflammatory effects (with high doses in drug therapy)

Immunosuppressive effects (in therapy)

- Dependent on particle concentrations on 2 sides of the membrane

- "draws water"
- Created by proteins (albumin) & other particles glucose, salt

- hypothalamus contains thirst center, stimulated by
1. cellular dehydration - ^ ECF osmolality
2. decreased circulating BV
3. production of Angiotensin II in kidneys

- dryness of mucous membranes

Movement of fluid from the capillaries >> interstitial space
1. Capillary hydrostatic pressure (BP)
2. Interstitial fluid osmotic pressure (protein)

high plasma osmolality or low circulating fluid volume causes this system:

1. Synthesized: hypothalamus
2. Released: posterior pituitary
3. Site of action: distal tubules and collecting ducts of the nephron
4. Effect/Mechanism: reabsorption of water ↓ urine volume ↑ urine concentration

Regulation of sodium balance (SNS and RAAS) measured by osmoreceptors

1. Synthesized: adrenal cortex
2. Released: Angiotensin II which is activated by ↓ circulating blood volume ↑ [K] in plasma
3. Site of action: renal tubules
4. Effect/Mechanism: absorb Na and H2O

↑ aldosterone ↓ urine volume
↓ aldosterone ↑ urine volume

stretch receptors in atria detect high degree of stretch

1. Synthesized: ANP atria of heart BNP ventricles
2. Released: response to stretch of vasculature/vessels
3. Site of action: inhibit renin vasodilate
4. Effect/Mechanism: promote diuresis and natriuresis, decrease BP

a) Neurogenic/central DI: defect in synthesis or release of ADH

b) Nephrogenic DI: inability of kidneys to respond to ADH (common in elderly, can be congenital)

Clinical Manifestations:
- Intense thirst/water craving
- Excretion of large volumes of urine (3-20 L/day)

(ADH secretion continues despite decreased serum osmolality- excess of ADH)*

- Results in water retention and dilutional hyponatremia (dec. Na because it's being diluted by so much H2O)

a) Acute/transient: surgery, pain, stress, severe temperature changes. Some drugs (e.g. lithium)

b) Chronic:
- Tumors (bronchial, lymphoid, prostrate, pancreas) produce/release ADH independent of CNS
- Chest lesions, CNS disorders

Clinical Manifestations: s/s dilutional effects of expanded blood volume. Decreased urine output, urine osmolality is high, while serum osmolality is low.

Extracellular Fluid Volume Excess

Extracellular Fluid Volume Deficit

Intracellular Fluid Volume Excess

Intracellular Fluid Volume Deficit

Extracellular (interstitial) Fluid Volume Excess

1. Increased capillary hydrostatic pressure
- Venous obstruction thrombophlebitis, prolonged standing
- Salt, water retention Heart failure, liver cirrhosis, renal failure

2. Decreased plasma oncotic pressure (maintained by protein, namely albumin) protein leakage from chronic kidney disease, wound drainage, burns, liver cirrhosis

3. Increased capillary permeability

Generalized
-more uniform distribution within ISF
- Dependent

- External loss of Na & water (usually isotonic fluid)

- GI excretion: emesis, overuse of laxatives, diarrhea, gastric suctioning
- Alteration in Na excretion & kidney: adrenal insufficiency, kidney disorders

Etiology: Addition/retention of saline (salt water) in same concentration as plasma.
- Excessive aldosterone renal disease, cushing disease, heart failure, or giving too much IV fluid

Plasma levels: 135-145 mEq/L

Roles
- Maintaining plasma osmolality (concentratedness), neuromuscular irritability, acid-base balance, and cellular chemical reactions and membrane transport

Levels maintained by: kidneys (98% reabsorbed), renin-angiotensin-aldosterone system (RAAS), natriuretic peptides

ECF contains too little water for amount of Na+

Gain of salt: concentrated tube feedings without adequate water, water access

Loss of water: DI, osmotic diuresis (water follows sugar in Diabetes), prolonged emesis, diarrhea

Manifestations:
- Hypovolemia (low BV)
(Tachycardia, weak pulses, and postural hypotension)
- Marked water deficit (relative to Na+)
- Headache, thirst, dry skin and mucous membranes, fever, weight loss, concentrated urine

- Non-specific CNS : confusion, lethargy, convulsions

Etiology: results from factors that cause relative water excess in proportion to salt in ECF

Gain of water over salt:
- Excessive ADH: SIADH or tumors
- Physical stressors: pain, nausea

Loss of Salt (dilutional)
- Diuretics, renal disease, emesis, diarrhea w/o salt replacement

Clinical Manifestations:
- Lethargy, confusion, decreased reflexes, seizures, and coma
- Loss of ECF and hypovolemia, hypotension, tachycardia, decreased urine output

Etiology: excessive loss of hypotonic sodium-containing fluids from body. Ex. gastroenteritis
- ECV deficit + hypernatremia.

Measured in serum: chemistry

- Concentration maintained by Na+/K+ ATPase pump
Regulation of ICF osmolality and fluid balance

Aldosterone, insulin, and catecholamines influence serum potassium levels

Causes: reduced intake of potassium, increased entry of potassium into cells, and increased loss of potassium

Manifestations (depend on rate and severity)
- Membrane hyperpolarization causes a decrease in neuromuscular excitability, skeletal muscle weakness, smooth muscle atony, and cardiac dysrhythmias

Hyperkalemia is rare because of efficient renal excretion

Caused by increased intake, shift of K+ from ICF into ECF, decreased renal excretion, insulin deficiency, or cell injury

Mild
- Increased neuromuscular irritability
- Tingling of lips and fingers, restlessness, intestinal cramping, and diarrhea

Inverse logarithm of the H+ concentration
If the H+ are high in number, the pH is low (acidic) If the H+ are low in number, the pH is high (alkaline)

Determined by relative amounts of acids & bases
- Normal range: 7.35-7.45
pH < 6.8 or > 7.8 = high mortality
- Know the normal ranges for pH!

Acids are formed as end products of protein, carbohydrate, and fat metabolism

Produced continuously in large quantities

Plasma
- Bicarbonate buffer system (ECF) (first buffering system, most important)

ICF
- Hemoglobin
- Phosphate & protein

Carbonic Acid (H2CO3)
- Regulated by lungs

HCO-3 + H+ >><< H2CO3 >> carbonic anhydrase >> CO2 + H2O

During periods of excess acid accumulation in the blood, bicarbonate is released into extracellular fluid where it can take up the extra H+ ions released by the acid and becomes carbonic acid. Carbonic acid is a weak acid and easily gives up H+. Thus, through enzymatic conversion by carbonic anhydrase, H2CO3 cans be dissociated into CO2 and H2O, which can be excreted by the lungs during respiration.

Kidneys can also regenerate H2Co3 from Co2 and H2O

Decreased HCO3- reflects an excess of metabolic acids in the blood.

Excretion of H+ as NH4+ (ammonium)

PaCO2: level of CO2 in blood: 35 - 45 mm Hg

This usually happens only when the underlying disease process is corrected

If the pathology includes the lungs, can the lungs compensate for acid-base imbalance?
If the kidneys are involved in the pathology, can they compensate for acid-base imbalance?

Cause: hyperventilation
- Anxiety, excessive sobbing
- Brainstem stimulation-head trauma, meningitis

S/S: diaphoresis, numbness, tingling

Compensatory response: decreased renal excretion of metabolic acids

Pulmonary diseases: COPD, pneumonia, pulmonary edema, Obstructive Sleep Apnea

Impaired neuromuscular function

Compensation: increased renal excretion of metabolic acids

Compensatory response: hypoventilation (attempt to conserve CO2)

Caused by:
- Chronic renal failure
- Loss of bicarbonate during severe diarrhea
- Ketoacidosis (ex: type 1 diabetes lacking insulin- body breaks down free fatty acids to ketoacids, starvation)
- Methanol and certain medication poisoning

Compensatory Response:
- Respiratory: hyperventilation
- Decreases H2CO3 in attempt to normalize pH when HCO3 is low.

Treatment:
- Correct the underlying cause of acidosis
- Alkalinizing salt (sodium bicarbonate) if severe
- Given oral or IV

S/S: headache, abdominal pain, CNS depression

Relative excess of any acid except carbonic or decrease in base, or both. Decrease in normal 20:1 ration of HCO3 to H2CO3.

- Electroneutrality: concentration of anions (-) should equal the concentration of cations (+) not all normal anions are routinely measured
- The "gap" is unmeasured serum anions phosphate, citrate, sulfate, protein

Sodium: primary measured cation

Bicarbonate & Chloride primary measured anions

Plasma anion gap = [Na] - ([HCO3 + Cl])

Metabolic acidosis with increased anion gap= acid increase: organic anions (ketoacids, lactate, formate, salicylate) accumulate. Decreased HCO3 is offset by increased (but unmeasured) anion. Examples: diabetic acidosis, lactic acidosis, chronic renal failure

Three anatomic compartments
1. Platelets
2. Clotting factors
3. Blood vessel walls

2. formation of platelet plug
- adhesion to damaged surface by Von Willebrand factor (forms bridge b/w 1st layer of platelets and endothelial layer
- platelet aggregation: collagen, ADP, TXA2
- platelet degrangulation/secretion to stimulate the process to continue (activates more platelets)
- procoagulant activity with some platelet inhibition

3. fibrin thrombus and clot retraction
- activation of coagulation cascade (to generate fibrin strands to organize platelets)
- thrombin >> fibrinogen to fibrin

extrinsic- in response to tissue damage and factor VII triggers tissue thromboplastin
- takes seconds

1. Antithrombin III
- inhibits thrombin and factor Xa in the presence of heparin
- decreased activity with inhibition conditions, sepsis

in the presence of heparin there is
- a conformational change
- allows AT-III to bind with and inactivate thrombin

2. Tissue Factor Pathway Inhibitor (TFPI)
- initiates negative feedback on TF:Factor VIIa

2. coagulation
- balanced by Anti Thrombin-III, Protein C & S **know these (and also TFPI)

normal bleeding time 3-10 minutes (single best indicator of platelet function)

PT (prothrombin time) common test (International Normalized Range or INR) examine extrinsic and common pathways
- commonly used to monitor warfarin therapy or to look for vit K deficiency

PTT (Activated Partial Thromboplastin Time)
- evaluates intrinsic and common pathways
- used to monitor heparin therapy

- essential thrombocytosis >> myeloproliferation

usually people are asymptomatic until plt count over 1 million

can occur post splenectomy

or transiently as response to stress, exercise, etc

predisposing conditions
- hereditary
- acquired (venous stasis, e.g. post op)

venous stasis- sluggish flow allows clotting factors to hang out, also there's a slow return of activated factors to spleen

Hemophilia A
- Factor VIII deficiency
- 85% of clinical cases of hemophilia
- sex linked recessive
- most severe

Hemophilia B
- Factor IX deficiency
- sex linked recessive
- less severe than A
- aka Christmas disease

Hemophilia C
- Factor XI deficiency
- not sex linked, autosomal recessive,
- least severe type

easy bleeding/bruising
- hemoarthrosis (bleeding into joints, can lead to degeneration of joints early in life)
- intracranial bleeds, bleeding into the neck (can't stop it in the brain, in neck it affects airway and circulation)
- administer the specific factor that's missing or flash frozen plasma or cryoprecipitate

- always secondary to some other disease process (e.g. circulatory crisis with hypotension and stagnated blood flow leading to activation of coagulation system)
- hypoxemia insults vessel walls
- widespread coagulation in microvasculature leading to anoxia and tissue death
- consumes all clotting factors and platelets leading to diffuse bleeding and hemorrhage

conditions associated with DIC:
- obstetrical complications
- malignancies
- sepsis
- autoimmune reactions
- tissue injuries
- there is a chronic form as well

SUMMARY: widespread fibrin deposition in micro-vasculature >>organ and tissue ischemia triggering more clotting which uses up platelets, clotting factors, increases fibrinolysis >> bleeding

disease: occurs when infection results in change from normal state of heath

relationship with host (symbiosis)
- protective, established colonies prevent overgrowth of harmful microorganisms

resident flora are usually bacteria, re-colonize quickly if disturbed

opportunistic infections
- normal flora may become pathogenic when immune system is compromised

disseminated through enivronment

reproduce
- form spores, detach from parent cell, germinate into new fungi elsewhere, colonize especially when normal flora are disturbed

mycoses
- infections caused by fungi

(prokaryocytes) that have no discrete nucleus (not membrane bound) reactions take place in cytoplasm, target treatments to cell wall

Degrade and break down dead tissue for other organisms

Encapsulation
- Prevents microorganism from being phagocytized- prevents opsonization

Enzymes secreted during bacterial growth, usually act at distinct tissue sites remote from bacterial growth. (Neurotoxins, endotoxins, etc.)

lead to:
- decrease in plasma volume
- increased vascular permeability

Caused by
- Individuals treated with antibiotics taking only part of prescribed dose
- Overprescription of antibiotics

Resistant form may be transmitted to other individuals

Cocci
- Round and nonmotile
- May clump together like bunches of grapes, in pairs, or in long strands

Bacilli
- Rod-shaped
- About ½ are motile

Step 1. Staining with crystal violet.

Step 2. Fixation with iodine stabilizes crystal violet staining. All bacteria remain purple or blue.

Step 3. Extraction with alcohol or other solvent. Decolorizes some bacteria (Gram negative) and not others (Gram positive).

Purposes:
- Destruction of infectious microorganisms that are resistant to inflammation
- Long-term highly effective protection against future exposure to the same microorganism

Inducible-must recognize pathogen/antigen as foreign (nonself)

Specific-unique pathogens identified eliminated

Memory-long-term/permanent protection against pathogen

Immunogens
- bind with antibodies and also induce immune response (production of antibodies, T and B cells)
- Must be foreign to the host and in sufficient quantity
- All are antigens

*She's not gonna ask us the difference between e.g. immunogen or antigen (know the disease process pathogens cause, that's the focus)

Entry route (intravenous, intradermal, oral) stimulates different lymphoid tissue

Cellular: T cells mediated
- Subpopulations (effector T cells)
- - Kill target directly
- - Stimulate other leukocytes

Both produce memory cells

*Autoimmunity (mistaken sensitivity)
- Reacts to "self" antigens causing harm to the body*

Basic mechanism
- Specific antigen-antibody reaction or specific antigen-lymphocyte interaction

Allergy
- Deleterious effects of hypersensitivity to environmental (exogenous) antigens

Autoimmunity
- Disturbance in the immunologic tolerance of self-antigens

*Type I
IgE mediated* (only type when you should know the immunoglobulin involved)

*Type II
Tissue-specific* reactions

*Type III
Immune complex* mediated

- IgE mediated
- sensitivity to environmental antigens (allergens)
- IgE binds to Fc receptors on surface of mast cells - mast cells become "sensitized" and release histamine

*Histamine release : most important mediator
- Causes increased vascular permeability, vasodilation, urticaria, smooth muscle constriction, increased mucus secretion, pruritus, can lead to anaphylactic shock

Mild
*- Hives (urticaria)
- Seasonal allergic rhinitis
- Eczema
- Mild asthma symtoms*

Moderate symptoms
*- Throat constriction
- Localized edema
- Wheezing
- Tachycardia*

When stimulated, release histamine and chemotactic factors

next mechanisms by which Type II responses occur:
1.Cell is destroyed by antibodies and complement
Ex: Erythrocyte destruction in autoimmune hemolytic anemia or Transfusion reaction

2. Cell destruction through phagocytosis
Ex: antibodies against RBC antigens of Rh system e.g., Rh negative mother is sensitized to her fetus's Rh-positive red cell group antigens

3. Soluble antigens (meds, infectious agents) enter the circulation and deposit on tissues tissues destroyed by complement and neutrophil granules.

4. Antibody-dependent cell-mediated cytotoxicity (ADCC)

5. Does not destroy cell causes target cell malfunction (e.g., Graves)

Serum sickness: (systemic) immune complexes in blood-deposited in target tissues (vessels, joints, kidneys). Ex: Raynaud phenomenon temperature-dependent deposition of immune complexes in peripheral capillary beds.

Direct cell-mediated cytotoxicity
- Cytotoxic T cells
- Viral reactions

Immune system recognizes its own cells as foreign and mounts an immune response that injures self tissues.

Failure of self tolerance

Thyroid diseases: Graves Disease & Hypothyroidism

Transplant rejection and transfusion reactions:
- Major histocompatibility complex (MHC)
- Human leukocyte antigens (HLC)

Transfusion reactions
- ABO blood groups

Hallmark: defective cell-mediated immunity
- Decrease in CD4+ T-helper lymphocytes/macrophages

Most common cause of disease in humans

Composed of:
- DNA or RNA surrounded by "capsid"

Totally dependent on host cell
- Do not possess any metabolic organelles
- Lack self-replication "machinery"

Classified by:
- Genetic makeup
- Mode of replication
- Structure of viral capsule (capsid)
- Specific host cell that virus invades

Must enter host cell to replicate/invade:
1.Can adhere to cell membrane, cause phagocytosis. Once inside cell, capsule opens to release viral genetic material.

2. Can stick to cell surface and inject genetic material into host cell.

3. Manufacture envelope to surround viral capsid
- Composed of host cell membrane and viral proteins
- Virus then released by budding from cell surface.

Two Major Categories
a. Contain DNA (ex: herpes simplex)

b. Contain RNA (ex: influenza or HIV)
- Retrovirus
- Replicating virus

- Requires specific enzyme: Reverse Transcriptase for transcription of RNA into DNA.
- Retrovirus

CD4 cells help other cells to battle infections

HIV infection causes a steady decline in CD4 cells

Key enzymes facilitate conversion of RNA to DNA:
Reverse transcriptase
- Allows virus to copy RNA into DNA

Protease
- "Molecular scissors": splits long chains of precursor proteins into smaller, active units

Chemokine co-receptors located on host CD4+ cells
- Required for final binding/entry of virus into host

Early infection: the virus tends to bind to CCR5 co-receptor

2. Fusion: Once HIV particle is bound to both CD4 receptor and chemokine receptor, gp41 implants in the cell membrane, causing lipid bilayer envelope to fuse with host cell and release HIV RNA into cytoplasm of the host cell, producing infection

3. Reverse transcription: HIV RNA transcribed into single-stranded DNA by HIV reverse transcriptase

4. Replication: RT converts single strand HIV DNA into double stranded HIV DNA

5. Integration: HIV DNA integrated into host DNA by HIV integrase

6. Transcription: HIV DNA transcribed into RNA
May become part of genome for new virion or
Is messenger RNA that codes for HIV proteins

7. Translation: mRNA translated into HIV glyco or structural proteins and enzymes

8. Migration/assembly: All components migrate to cell surface and create new virus


Rosacea, Inflammation, And Aging: The Inefficiency Of Stress

Rosacea, or acne rosacea, has been defined as "vascular and follicular dilation involving the nose and contiguous portions of the cheeks . . ." that may involve persistent erythema with hyperplasia of sebaceous glands. Stedman's Medical Dictionary 23rd edition.

Light-skinned people, especially women between the ages of 30 and 50, sometimes develop a persistent redness of their cheeks and nose. It may begin as a tendency to flush excessively, but the blood vessels can become chronically dilated. Similar processes occur in dark-skinned people less frequently.

The eyes are sometimes involved, with redness of the exposed areas (conjuctival hyperemia). New blood vessels develop in the area, and the flow of blood through the affected tissue is greatly increased. The tissues become thickened and fibrotic, with the multiplication of fibroblasts and the increased deposition of collagen.

The cornea normally receives its oxygen from the air, and its nutrients from the aqueous humor. As rosacea of the eye develops, the blood vessels surrounding the cornea become increasingly visible, and, especially on the inner (nasal) side of the eye, the vessels tend to enlarge and become tortuous. Rhinophyma, or potato nose, has been described as a late development of rosacea.
Too often, the medical reaction is to give the condition a name, and to distinguish its variants as if they were different problems, and then to use the most direct means to eliminate the problem they have defined.

A typical attitude is that "Rosacea is an enigmatic disease with multiple exacerbations and remissions, and, unfortunately, treatment is directed toward symptomatic control rather than cure" (Randleman).

Lasers or other radiation, caustic chemical abrasion, surgical planing and dermal shaves, and other forms of surgery may be used to destroy the superficial blood vessels, and to reduce the enlarged nose or other irregularities. A few decades ago, when rosacea was believed to be the result of a local infection, antibiotics were used to treat it, and some of them, including tetracycline, helped. It was discovered that some antibiotics have anti-inflammatory actions, apart from their germicidal effects, and now it is very common to prescribe the chronic use of tetracycline to suppress symptoms.

Rosacea, and the fibrotic changes associated with it (pingueculae and pterygia in the eyes, rhinophyma of the nose, etc.), are much more than "cosmetic" issues, involving the skin and eye surface. If the invasive proliferation of blood vessels can be prevented, it's important to do that, because, for example, pannus/neovascularization of the cornea can seriously impair vision.
But possibly the strangest thing about the relationship of the medical profession to rosacea is that its essential features, invasive neovascularization and fibrotic growth, are of great interest when they occur elsewhere, and many physiological processes are known to regulate the growth of blood vessels and fibroblasts, but nearly all the attention given to rosacea and rhinophyma concerns control of symptoms for cosmetic effect. Rosacea is a physiological problem that deserves consideration in the light of all that's known about physiology and developmental biology.
The increased incidence of rosacea after the age of 30, and the fact that it occurs most commonly in the areas that are most exposed to sunlight (bald men sometimes develop it on the top of the head), indicate that aging and irritation are essential causes. Stress, irritation (such as produced by ultraviolet or ionizing radiation or free radicals), and aging are known to cause disorganized growth of fibrous and vascular tissues in various parts of the body. The occurrence of these processes at the surface, where the changes can be observed immediately, and without invasive procedures, should have aroused wide interest among those who study kidney disease, diabetes, and other degenerative diseases in which fibrosis and neovascularization play important roles.

A localized stress or irritation at first produces vasodilation that increases the delivery of blood to the tissues, allowing them to compensate for the stress by producing more energy. Some of the agents that produce vasodilation also reduce oxygen consumption (nitric oxide, for example), helping to restore a normal oxygen tension to the tissue. Hypoxia itself (produced by factors other than irritation) can induce vasodilation, and if prolonged sufficiently, tends to produce neovascularization and fibrosis.

Sensitivity to the harmful effects of light can be increased by some drugs and by excess porphyrins produced in the body (and by the porphyrin precursor, delta-amino levulinic acid), leading to rosacea, so those factors should be considered, but too often alcohol (which can cause porphyrin to increase) is blamed for rosacea and rhinophyma, without justification. There are many ways in which poor health can increase light sensitivity. Some types of excitation produced by metabolites (or by the failure of inhibitory metabolites) can produce vasodilation, involving the release of nitric oxide (Cardenas, et al., 2000), setting off a series of potentially pathological reactions, including fibrosis. The nitric oxide increases glycolysis while lowering energy production. The excitatory metabolite glutamate, and nitric oxide, are both inhibited by aspirin (Moro, et al., 2000).

When blood flow in skin affected by rosacea was measured, circulation was 3 or 4 times higher than normal (Sibenge & Gawkrodger, 1992), and oxygen tension may be increased. An inability to extract oxygen from the blood, or to use it to produce energy, will produce the same hyperemia that would be produced by a lack of oxygen. These measurements suggest that mitochondrial defects would be the best place to look for a general cause of rosacea.

When mitochondria are damaged, active cells produce increased amounts of lactic acid, even in the presence of adequate oxygen. Otto Warburg identified this kind of metabolism, aerobic glycolysis, as an essential feature of cancer, and showed that it could be produced by stress, ionizing radiation, carcinogenic toxins, and even by a simple oxygen deficiency. Other investigators around the same time showed that lactic acid produces vasodilation (for example, in the cornea), and more recently it has been shown to promote the development of fibrosis, and it has been called a "phlogogen," a promoter of inflammation.

Riboflavin, vitamin B2, is an essential component of the mitochondrial respiratory enzymes, and it is very easily destroyed by light (blue light and especially ultraviolet). When it is excited by high energy light, it can spread the damage to other components of the mitochondria, including the cytochromes and the polyunsaturated fatty acids. The other B vitamins are affected when riboflavin's actions are disturbed.

Vitamin K is also extremely light sensitive, and it interacts closely with coenzyme Q in regulating mitochondrial metabolism. For example, mitochondrial Complex-I, NADH-ubiquinone reductase, is probably the most easily damaged part of the mitochondrion, and it is protected by vitamin K. Vitamin E, coenzyme Q, and the polyunsaturated fatty acids are also light sensitive, and they are more susceptible to free radical damage when vitamin K is deficient.

Niacinamide, one of the B vitamins, provides energy to this mitochondrial system. Under stress and strong excitation, cells waste niacinamide-NADH, but niacinamide itself has a sedative antiexcitatory effect, and some of its actions resemble a hormone. Estrogen tends to interfere with the formation of niacin from tryptophan. Tryptophan, rather than forming the sedative niacin (pyridine carboxylic acid), can be directed toward formation of the excitatory quinolinic acid (pyridine dicarboxylic acid) by polyunsaturated fatty acids. Excitation must be in balance with a cell's energetic resources, and niacinamide can play multiple protective roles, decreasing excitation, increasing energy production, and stabilizing repair systems. The state of excitation and type of energy metabolism are crucial factors in governing cell functions and survival.

The polyunsaturated fatty acids, besides their interactions with estrogen and tryptophan metabolism, promote excitation and decrease energy production in several other ways. For example, they increase the excitatory effects of the glutamate pathways (Yu, et al., 1986 Nishikawa, 1994), and their breakdown products inhibit mitochondrial respiration (Humphries, et al., 1998 Picklo, et al., 1999 Lovell, et al., 2000).

The excess excitation that produces nitric oxide and lactic acid lowers the energy production of vascular cells, possibly enough to lower their contractile ability (Geng, et al., 1992), causing vasodilation. When flushing is caused by a mismatch between energy supply and energy demand, caffeine can decrease the vasodilation (Eikvar & Kirkebøen, 1998), but when vasodilation is caused more physiologically by carbon dioxide, caffeine doesn't have that effect (Meno, et al., 2005). In a study in which drinking hot water or coffee was compared with drinking room-temperature coffee or caffeine, it was found that the hot liquids caused flushing, but cool coffee and caffeine didn't.
Caffeine increases cells' energy efficiency, and by opposing the effects of adenosine (secreted by cells that are stressed and energy-depleted), it can inhibit vasodilation, angioneogenesis (Merighi, et al., 2007 Ryzhov, et al., 2007), and fibrosis (Chan, et al., 2006).

One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin, bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999). That this ubiquitous toxin has a role in rosacea is suggested by the observation that intestinal stimulation, to speed transit through the bowel, immediately relieved symptoms (Kendall, 2002). Increased cortisol (Simon, et al., 1998) and sepsis (Levy, 2007) interfere with mitochondrial energy production.
Simple nervous blushing or flushing is usually considered harmless, and when a person is overheated, the reddening of the skin has the function of facilitating heat loss, to restore a normal temperature. But even nerve-regulated flushing can involve a distinct interference with mitochondrial respiration, and can stimulate the overgrowth of blood vessels.

Cancer's respiratory defect that Warburg identified, fermentation with lactic acid production even in the presence of adequate oxygen, was the result of some kind of injury to the mitochondria. He showed that one of the injuries that could produce aerobic glycolysis was a deficiency of riboflavin. He observed that tumors generally were anoxic, and that cancers typically appeared in the midst of tissue that was atrophying, and suggested that the cancer cells' survival was favored by their ability to live without oxygen. This may be relevant to the observations of many surgeons of a small cancer embedded in the fibrous tissue of large rhinophymas that have been removed.

The relatively high incidence of rosacea among women (some studies indicate that it may be 3 times as common in women as in men) isn't likely to be the result of greater sun exposure, so it's reasonable to look for hormonal causes.

In old age, it's well recognized that men's estrogen level rises. But the estrogen industry has convinced women that their estrogen declines as they get older. It's common knowledge that aging rodents often go into "persistent estrus," and that their estrogen levels generally increase with age (Parkening, et al., 1978 Anisimov and Okulov, 1981). Several studies in women have shown that serum estrogen levels rise from the teens into the 40s (Musey, et al., 1987 Wilshire, et al., 1995 Santoro, et al., 1996).

Other studies show that serum and tissue estrogen concentrations are not concordant, and that some tissues may contain several times as much estrogen as the serum (Jefcoate, et al., 2001). Local irritation increases tissue estrogen content.

The antiestrogens, especially progesterone, begin declining in the 30s, so that the rising estrogen has more effect on the tissues during those years. These are the years in which the incidence of rosacea rises suddenly. Rosacea develops later on average in men, whose estrogen levels rise significantly at later ages.

Estrogen's most immediate effect on cells is to alter their oxidative metabolism. It promotes the formation of lactic acid. In the long run, it increases the nutritional requirements for the B vitamins, as well as for other vitamins. It also increases the formation of aminolevulinic acid, a precursor of porphyrin, and increases the risk of excess porphyrin increasing light sensitivity. Both aminolevulinic acid and excess porphyrins are toxic to mitochondria, apart from their photosensitizing actions. Nitric oxide, glutamate, and cortisol all tend to be increased by estrogen.
Veins and capillaries are highly sensitive to estrogen, and women are more likely than men to have varicose veins, spider veins, leaky capillaries, and other vascular problems besides rosacea.

Estrogen can promote angioneogenesis by a variety of mechanisms, including nitric oxide (Johnson, et al., 2006). "Estrogens potentiate corticosteroid effects on the skin such as striae, telangiectasiae, and rosacea dermatitis" (Zaun, 1981). Early forms of oral contraceptives, high in estrogen, were found to increase acne rosacea more than three-fold (Prenen & Ledoux-Corbusier, 1971).

Lactic acid, produced under the influence of estrogen, nitric oxide, or other problems of energy formation, besides causing vasodilation, also stimulates the growth of fibroblasts. Oxygen deprivation, or damage to mitochondria, will increase lactic acid formation, and so it will immediately cause vasodilation, and if the problem is prolonged, new blood vessels will grow, and fibrous connective tissue will increase. Estrogen stimulates collagen synthesis, and it has been associated with a variety of inflammatory and fibrotic conditions (for example, Cutolo, et al., 2003. Payne, et al., 2006, suggest the use of the anti-estrogen, tamoxifen, to treat rhinophyma.)

The cornea normally contains more riboflavin even than the retina, which has a much higher rate of metabolism. When the cornea isn't able to get enough oxygen from the air for its needs (and if riboflavin is deficient, its need for oxygen is increased), surrounding blood vessels at first dilate in response to the diffusing lactic acid, to increase the blood supply to the edges of the cornea. If the problem is prolonged, the conjuctiva becomes chronically blood-shot, hyperemic, and larger more visible blood vessels grow, surrounding the cornea, or even invading the cornea. Many people, especially women, experienced problems of this sort from wearing contact lenses, especially when the lenses were made of materials very impermeable to oxygen (Dumbleton, et al., 2006).

Sunlight, and mechanical obstruction of the cornea, produce very localized effects, but those local effects are more likely to be harmful when there is a systemic nutritional deficiency or excess of estrogen. When the systemic problem is very severe, the cheeks, nose, and eyes might not be the first tissues to experience a functional disturbance.

The mitochondrial inhibition produced by the action of the parasympathetic nervous system (occurring in simple blushing) can occur wherever those nerves act, and blood vessels in all parts of the body are responsive to the acetylcholine secreted by those nerves. Sleep typically involves a shift of dominance in the autonomic nervous system toward the parasympathetic nerves, with vasodilation. Nosebleeds, especially in children, commonly occur during sleep (Jarjour & Jarjour, 2005: high incidence in sleep, and association with migraine).

A 3 year-old child who had been having an average of 3 nosebleeds every day, during a nap and at night, for several months, also had an extreme behavior problem. He became angry and sometimes violent when he went a little longer than normal between meals. After an oral dose of about ten milligrams of riboflavin, he was able to sleep without having another recurrence of the nosebleeds, and his tantrums became rare. Apparently, the nerve-regulated vasodilation produced by sleep, combined with a riboflavin deficiency, had been enough to produce nosebleeds. The energy deficit resulting from a systemic riboflavin deficiency had probably been causing him to be abnormally sensitive to glycogen depletion, producing sudden anger. In another individual, the energy problem might have taken the form of a memory problem, or of a hemorrhage in the brain or other essential organ.

A 37 year old slightly alcoholic man with a bright red nose and cheeks was an amateur fiction writer, but he was having trouble with his memory for words, and for everyday events. Even conversationally, he had to struggle for relatively familiar words. On the suggestion that riboflavin might help his memory, by allowing his brain cells to use oxygen more efficiently, he had his doctor give him an intravenous injection of B vitamins. When I saw him the next day, his conversation was perfectly fluent, and he obviously had easy access to a good vocabulary. Just as noticeable was the normal color of his nose and cheeks. For a week, he had a daily injection of the B vitamins, and his nose color and vocabulary stayed normal. But on the weekend, after not having the shots for two days, his nose and cheeks were again maraschino cherry red, and his speech was halting, as he struggled for words. He forgot the whole episode, and neglected to return to the doctor for more of the vitamin injections. Ten years later, he had developed a medium-sized potato nose, and had his heart valves replaced.

His vitamin requirements were apparently abnormally high. At first, the problems resulting from damaged mitochondria seem mostly functional (flushing, mood, memory problems, etc.) and variable, but chronically disturbed functions lead to structural, anatomical changes, as prolonged stimulation alters tissue maintenance and growth.

Abram Hoffer, who had been treating schizophrenia and senile dementia with niacin, accidentally discovered that it cured his bleeding gums. That led to its use to treat heart disease.
The "orthomolecular" ideas of Hoffer and Linus Pauling were developed in a context of biochemistry governed by genetics, molecular biology, in which the goal was to provide a chemical that was lacking because of a genetic defect in metabolism. Their idea of using nutrients as drugs has led to many unphysiological practices, in which an isolated nutrient is supposed to have a drug-like action, and if in isolation it doesn't act like a drug, then it should be used only according to the normal genetically determined nutritional requirement.

But in reality, nutritional requirements are strongly influenced by history and present circumstances. For example, when corneal mitochondria have been damaged by riboflavin deficiency, they have been found to subsequently require more than the normal amount of the vitamin to function properly. And the presence of a certain amount of one nutrient often increases or decreases the amount of other nutrients needed.

When the interactions among energy expenditure and energy production, and cellular activation and cellular inhibition, are taken into account, then it's clear that any particular problem is likely to have many causes and many factors that could contribute to a cure.

Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate, porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to excitatory and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis.

Carbon dioxide, glycine, GABA, saturated fatty acids (for example, Nanji, et al., 1997), vitamin K, coenzyme Q10, niacinamide, magnesium, red light, thyroid hormone, progesterone, testosterone, and pregnenolone are factors that can be increased to protect against inappropriate cellular excitation.

All of the nutritional factors that participate in mitochondrial respiration contribute to maintaining a balance between excessive excitation and protective inhibition. Riboflavin, coenzyme Q10, vitamin K, niacinamide, thiamine, and selenium are the nutrients that most directly relate to mitochondrial energy production.

Coffee is often avoided by people with rosacea, but it is a very good source of niacin and magnesium, and caffeine has some of the same cell-protective functions as niacinamide.
People suffering from rosacea have been found to be more likely than average to have suffered from styes in childhood, to have varicose veins and spider veins, and to suffer from migraines and depression.
Hypothyroidism has been identified as a factor in all of those. Good thyroid function is necessary for resistance to bacterial infection, for regulation of blood sugar, neurotransmitters, and hormones related to mood, and for the formation of progesterone. Progesterone regulates smooth muscle tone, including the walls of veins, so that a deficiency allows veins to enlarge. It also prevents overgrowth of fibrotic tissue, and in some contexts may inhibit angioneogenesis.

GABA itself tends to raise body temperature (Ishiwata, et al., 2005), by controlling vasodilation, and the factors such as progesterone which protect mitochondrial energy production are also thermogenic, supporting the GABA system. Flushing, both by directly causing heat loss and by reducing mitochondrial energy production, tends to lower body temperature.

The sun-damaged areas in rosacea can be directly provided with some of the protective factors by applying them topically. In the same way that topical lactate can cause vasodilation and disturbed energy metabolism (Rendl, et al., 2001), topical niacinamide, progesterone, vitamin K, and coenzyme Q10 can improve the metabolism and function of the local tissues. Riboflavin can probably be useful when applied topically, but because of its extreme sensitivity to light, it should usually be used only internally, unless the treated skin is covered to prevent exposure to light. Topically applied caffeine, even after sun exposure, can reduce local tissue damage (Koo, et al., 2007). Aspirin and saturated fats can also be protective when applied topically.

Some of the benefit from antibiotics probably results from the reduced endotoxin stress when intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that produce vitamin K, so it's important to include that in the diet when antibiotics are used.

Some fibers, such as raw carrots, that are effective for lowering endotoxin absorption also contain natural antibiotics, so regular use of carrots should be balanced by occasional supplementation with vitamin K, or by occasionally eating liver or broccoli.

Abram Hoffer's research was instrumental in getting niacin recognized as a heart protective drug, but nearly everyone who prescribes it does so to lower blood lipids. That wasn't Hoffer's understanding of its function. He thought it acted directly on blood vessels to protect their integrity. During his studies of its effects on heart disease, he saw that it also lowered cancer mortality, and so began treating cancer patients with it, with considerable success, but there was no medical cliché that could allow the profession to follow in that direction.

The arguments I have outlined for considering rosacea to be essentially a problem of metabolic energy, and the mechanisms that I mention for restoring mitochondrial functions, might seem more complex than Hoffer's orthomolecular views. However, this approach is actually much simpler conceptually than any of the ideologies of drug treatment. It simply points out that certain excitatory factors can interfere with energy production, and that there are opposing "inhibitory" factors that can restore energy efficiency. Sometimes, using just one or two of the factors can be curative.

Because mitochondrial respiration is very similar in every kind of tissue, a physiological view of rosacea could incline us toward considering the effects of these metabolic factors in other organs during stress and aging--what would the analogous condition of rosacea and rhinophyma be in the brain, heart, liver, or kidney?


What’s the Difference Between Veins and Arteries?

Veins and arteries are major players in the circulatory system of all vertebrates. They work together to transport blood throughout the body, helping to oxygenate and remove waste from every cell with each heartbeat. Arteries carry oxygenated blood from the heart, while veins carry oxygen-depleted blood back to the heart. An easy mnemonic is "A for ‘artery’ and ‘away’ (from the heart)." (The exceptions to this general rule are the pulmonary vessels. The pulmonary veins transport oxygenated blood back to the heart from the lungs, while the pulmonary arteries move deoxygenated blood from the heart to the lungs.)

As the vessels that are closest to the heart, arteries must contend with intense physical pressure from the blood moving forcibly through them. They pulse with each heartbeat (which is why your pulse is taken from an artery) and have thicker walls. Veins experience much less pressure but must contend with the forces of gravity to get blood from the extremities back to the heart. Many veins, especially those in the legs, have valves to prevent the backflow and pooling of blood. Although veins are often depicted as blue in medical diagrams and sometimes appear blue through pale skin, they are not actually blue in color. Light interacts with skin and deoxygenated blood, which is a darker shade of red, to reflect a blue tone. Veins seen during surgery or in cadavers look nearly identical to arteries.


Exam #1

- Generation of cells
- Response to underuse, disuse, decreased blood supply, nutritional changes, nerve loss, child development, aging
- Protein catabolism ^^
- Protein synthesis decreases
- Endoplasmic reticulum, mitochondria, microfilaments decrease
- ^^ autophagy (hydrolysis)

implications at the organ level:
- e.g. physiologic hypertrophy (as in enlargement of the heart in athletes, a normal compensatory mechanism)
- e.g. pathologic hypertrophy (as in aortic valve stenosis you must pump against high pressure system of systemic circulation, the left ventricle enlarges to compensate)

Gunshot wounds: entrance and exit wounds

- unstable molecules with unpaired electron
- form bonds with proteins, lipids, CHO's, etc causing cell injury and death

causes:
- air pollution
- UV light
- smoking
- aging (cumulative stress/exposure)

due to:
- lipases breaking down fat
- trauma with ischemia/hypoxia

due to:
- Compromised circulation (hypoxia/ischemia, thrombosis), chronic disease (diabetes- lost sensation due to neuropathy means they don't notice injury, recovery can be harder thereafter due to disease),
- infection
- trauma
(lower extremities, intestines, other)

Vasodilation
- Increased flow, vascular permeability and leakage
- WBC's accumulate at site

- facilitates phagocytosis
- degranulation
- chemotaxis
- cell lysis
(marks foreign bodies so immune system cells can kill them)

coagulation
- fibrin meshwork for clotting
- framework for repair and healing

1. PRRs (pattern recognition receptors)
- recognize molecules expressed by infectious agents or products of cellular damage (PAMPs)

2. TLRs (toll-like receptors)
- recognize molecular patterns on viral, bacterial surfaces and microbial nucleic acid

Secreted by macrophages in response to pathogens and TLR recognition

pro-inflammatory cytokine that promotes the systemic effects of inflammation (e.g. fever, malaise)

- release histamine and chemotactic factors
- key players in inflammation/allergy

triggers inflammatory response

increases permeability of capillaries to WBC's

- binds to H1 receptors in various parts of the body, causing various changes

- *CNS (neurotransmission)
- blood vessels (vasodilation, capillary permeability)
- lungs (bronchoconstriction)
- skin (itching, pain)*

1. Recognition and adherence
2. Engulfment/ phagosome formation
3. Fusion with lysosomal granules to form phagolysosome
4. Destruction of the target

helper:
release cytokines required for the differentiation and proliferation of B cells and cytotoxic T cells
- "CD4 positive"

1. Inflammation (1-2 days)
- Platelets, neutrophils, macrophages,
- Coagulation, bacterial clearing, growth factors

2. Proliferation (3-14 days)
- Fibroblasts
- Collagen, epithelial/granular tissue with capillaries, contraction
- Growth factors

- excessive contraction: exaggerated shrinkage (usually at joints)

2. Adaptation
- ACTH causes release of cortisol from adrenal gland (along with epinephrine and norepinephrine)
- inflammation (cytokines) vs. anti-inflammatory effects
- other hormones (endorphins, neuropeptide Y, substance P)

Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system*

a1- postsynaptic smooth muscle

a2- presynaptic neurons, postsynaptic tissues (ocular, adipose, intestinal, hepatic, renal, endocrine, and platelets)

b2- bronchial, uterine, vascular, smooth muscle (relaxation)

increases blood flow to muscles, output of the heart, pupil dilation, and blood sugar (does this by its effects on alpha and beta receptors)

2. norepinephrine
- in PNS
- increases vascular smooth muscle tone

increases heart rate, triggers the release of glucose from energy stores, and increases blood flow to skeletal muscle

HPA is the feedback interactions between the hypothalamus, pituitary gland, and adrenal glands. Part of the neuroendocrine system that regulates the body's response to stress and immunity.

3) adrenal cortex
>> glucocorticoids (cortisol) >>

or adrenal medulla
>> catecholamines (epinephrine and norepinephrine) >>

Anti-inflammatory effects (with high doses in drug therapy)

Immunosuppressive effects (in therapy)

- Dependent on particle concentrations on 2 sides of the membrane

- "draws water"
- Created by proteins (albumin) & other particles glucose, salt

- hypothalamus contains thirst center, stimulated by
1. cellular dehydration - ^ ECF osmolality
2. decreased circulating BV
3. production of Angiotensin II in kidneys

- dryness of mucous membranes

Movement of fluid from the capillaries >> interstitial space
1. Capillary hydrostatic pressure (BP)
2. Interstitial fluid osmotic pressure (protein)

high plasma osmolality or low circulating fluid volume causes this system:

1. Synthesized: hypothalamus
2. Released: posterior pituitary
3. Site of action: distal tubules and collecting ducts of the nephron
4. Effect/Mechanism: reabsorption of water ↓ urine volume ↑ urine concentration

Regulation of sodium balance (SNS and RAAS) measured by osmoreceptors

1. Synthesized: adrenal cortex
2. Released: Angiotensin II which is activated by ↓ circulating blood volume ↑ [K] in plasma
3. Site of action: renal tubules
4. Effect/Mechanism: absorb Na and H2O

↑ aldosterone ↓ urine volume
↓ aldosterone ↑ urine volume

stretch receptors in atria detect high degree of stretch

1. Synthesized: ANP atria of heart BNP ventricles
2. Released: response to stretch of vasculature/vessels
3. Site of action: inhibit renin vasodilate
4. Effect/Mechanism: promote diuresis and natriuresis, decrease BP

a) Neurogenic/central DI: defect in synthesis or release of ADH

b) Nephrogenic DI: inability of kidneys to respond to ADH (common in elderly, can be congenital)

Clinical Manifestations:
- Intense thirst/water craving
- Excretion of large volumes of urine (3-20 L/day)

(ADH secretion continues despite decreased serum osmolality- excess of ADH)*

- Results in water retention and dilutional hyponatremia (dec. Na because it's being diluted by so much H2O)

a) Acute/transient: surgery, pain, stress, severe temperature changes. Some drugs (e.g. lithium)

b) Chronic:
- Tumors (bronchial, lymphoid, prostrate, pancreas) produce/release ADH independent of CNS
- Chest lesions, CNS disorders

Clinical Manifestations: s/s dilutional effects of expanded blood volume. Decreased urine output, urine osmolality is high, while serum osmolality is low.

Extracellular Fluid Volume Excess

Extracellular Fluid Volume Deficit

Intracellular Fluid Volume Excess

Intracellular Fluid Volume Deficit

Extracellular (interstitial) Fluid Volume Excess

1. Increased capillary hydrostatic pressure
- Venous obstruction thrombophlebitis, prolonged standing
- Salt, water retention Heart failure, liver cirrhosis, renal failure

2. Decreased plasma oncotic pressure (maintained by protein, namely albumin) protein leakage from chronic kidney disease, wound drainage, burns, liver cirrhosis

3. Increased capillary permeability

Generalized
-more uniform distribution within ISF
- Dependent

- External loss of Na & water (usually isotonic fluid)

- GI excretion: emesis, overuse of laxatives, diarrhea, gastric suctioning
- Alteration in Na excretion & kidney: adrenal insufficiency, kidney disorders

Etiology: Addition/retention of saline (salt water) in same concentration as plasma.
- Excessive aldosterone renal disease, cushing disease, heart failure, or giving too much IV fluid

Plasma levels: 135-145 mEq/L

Roles
- Maintaining plasma osmolality (concentratedness), neuromuscular irritability, acid-base balance, and cellular chemical reactions and membrane transport

Levels maintained by: kidneys (98% reabsorbed), renin-angiotensin-aldosterone system (RAAS), natriuretic peptides

ECF contains too little water for amount of Na+

Gain of salt: concentrated tube feedings without adequate water, water access

Loss of water: DI, osmotic diuresis (water follows sugar in Diabetes), prolonged emesis, diarrhea

Manifestations:
- Hypovolemia (low BV)
(Tachycardia, weak pulses, and postural hypotension)
- Marked water deficit (relative to Na+)
- Headache, thirst, dry skin and mucous membranes, fever, weight loss, concentrated urine

- Non-specific CNS : confusion, lethargy, convulsions

Etiology: results from factors that cause relative water excess in proportion to salt in ECF

Gain of water over salt:
- Excessive ADH: SIADH or tumors
- Physical stressors: pain, nausea

Loss of Salt (dilutional)
- Diuretics, renal disease, emesis, diarrhea w/o salt replacement

Clinical Manifestations:
- Lethargy, confusion, decreased reflexes, seizures, and coma
- Loss of ECF and hypovolemia, hypotension, tachycardia, decreased urine output

Etiology: excessive loss of hypotonic sodium-containing fluids from body. Ex. gastroenteritis
- ECV deficit + hypernatremia.

Measured in serum: chemistry

- Concentration maintained by Na+/K+ ATPase pump
Regulation of ICF osmolality and fluid balance

Aldosterone, insulin, and catecholamines influence serum potassium levels

Causes: reduced intake of potassium, increased entry of potassium into cells, and increased loss of potassium

Manifestations (depend on rate and severity)
- Membrane hyperpolarization causes a decrease in neuromuscular excitability, skeletal muscle weakness, smooth muscle atony, and cardiac dysrhythmias

Hyperkalemia is rare because of efficient renal excretion

Caused by increased intake, shift of K+ from ICF into ECF, decreased renal excretion, insulin deficiency, or cell injury

Mild
- Increased neuromuscular irritability
- Tingling of lips and fingers, restlessness, intestinal cramping, and diarrhea

Inverse logarithm of the H+ concentration
If the H+ are high in number, the pH is low (acidic) If the H+ are low in number, the pH is high (alkaline)

Determined by relative amounts of acids & bases
- Normal range: 7.35-7.45
pH < 6.8 or > 7.8 = high mortality
- Know the normal ranges for pH!

Acids are formed as end products of protein, carbohydrate, and fat metabolism

Produced continuously in large quantities

Plasma
- Bicarbonate buffer system (ECF) (first buffering system, most important)

ICF
- Hemoglobin
- Phosphate & protein

Carbonic Acid (H2CO3)
- Regulated by lungs

HCO-3 + H+ >><< H2CO3 >> carbonic anhydrase >> CO2 + H2O

During periods of excess acid accumulation in the blood, bicarbonate is released into extracellular fluid where it can take up the extra H+ ions released by the acid and becomes carbonic acid. Carbonic acid is a weak acid and easily gives up H+. Thus, through enzymatic conversion by carbonic anhydrase, H2CO3 cans be dissociated into CO2 and H2O, which can be excreted by the lungs during respiration.

Kidneys can also regenerate H2Co3 from Co2 and H2O

Decreased HCO3- reflects an excess of metabolic acids in the blood.

Excretion of H+ as NH4+ (ammonium)

PaCO2: level of CO2 in blood: 35 - 45 mm Hg

This usually happens only when the underlying disease process is corrected

If the pathology includes the lungs, can the lungs compensate for acid-base imbalance?
If the kidneys are involved in the pathology, can they compensate for acid-base imbalance?

Cause: hyperventilation
- Anxiety, excessive sobbing
- Brainstem stimulation-head trauma, meningitis

S/S: diaphoresis, numbness, tingling

Compensatory response: decreased renal excretion of metabolic acids

Pulmonary diseases: COPD, pneumonia, pulmonary edema, Obstructive Sleep Apnea

Impaired neuromuscular function

Compensation: increased renal excretion of metabolic acids

Compensatory response: hypoventilation (attempt to conserve CO2)

Caused by:
- Chronic renal failure
- Loss of bicarbonate during severe diarrhea
- Ketoacidosis (ex: type 1 diabetes lacking insulin- body breaks down free fatty acids to ketoacids, starvation)
- Methanol and certain medication poisoning

Compensatory Response:
- Respiratory: hyperventilation
- Decreases H2CO3 in attempt to normalize pH when HCO3 is low.

Treatment:
- Correct the underlying cause of acidosis
- Alkalinizing salt (sodium bicarbonate) if severe
- Given oral or IV

S/S: headache, abdominal pain, CNS depression

Relative excess of any acid except carbonic or decrease in base, or both. Decrease in normal 20:1 ration of HCO3 to H2CO3.

- Electroneutrality: concentration of anions (-) should equal the concentration of cations (+) not all normal anions are routinely measured
- The "gap" is unmeasured serum anions phosphate, citrate, sulfate, protein

Sodium: primary measured cation

Bicarbonate & Chloride primary measured anions

Plasma anion gap = [Na] - ([HCO3 + Cl])

Metabolic acidosis with increased anion gap= acid increase: organic anions (ketoacids, lactate, formate, salicylate) accumulate. Decreased HCO3 is offset by increased (but unmeasured) anion. Examples: diabetic acidosis, lactic acidosis, chronic renal failure

Three anatomic compartments
1. Platelets
2. Clotting factors
3. Blood vessel walls

2. formation of platelet plug
- adhesion to damaged surface by Von Willebrand factor (forms bridge b/w 1st layer of platelets and endothelial layer
- platelet aggregation: collagen, ADP, TXA2
- platelet degrangulation/secretion to stimulate the process to continue (activates more platelets)
- procoagulant activity with some platelet inhibition

3. fibrin thrombus and clot retraction
- activation of coagulation cascade (to generate fibrin strands to organize platelets)
- thrombin >> fibrinogen to fibrin

extrinsic- in response to tissue damage and factor VII triggers tissue thromboplastin
- takes seconds

1. Antithrombin III
- inhibits thrombin and factor Xa in the presence of heparin
- decreased activity with inhibition conditions, sepsis

in the presence of heparin there is
- a conformational change
- allows AT-III to bind with and inactivate thrombin

2. Tissue Factor Pathway Inhibitor (TFPI)
- initiates negative feedback on TF:Factor VIIa

2. coagulation
- balanced by Anti Thrombin-III, Protein C & S **know these (and also TFPI)

normal bleeding time 3-10 minutes (single best indicator of platelet function)

PT (prothrombin time) common test (International Normalized Range or INR) examine extrinsic and common pathways
- commonly used to monitor warfarin therapy or to look for vit K deficiency

PTT (Activated Partial Thromboplastin Time)
- evaluates intrinsic and common pathways
- used to monitor heparin therapy

- essential thrombocytosis >> myeloproliferation

usually people are asymptomatic until plt count over 1 million

can occur post splenectomy

or transiently as response to stress, exercise, etc

predisposing conditions
- hereditary
- acquired (venous stasis, e.g. post op)

venous stasis- sluggish flow allows clotting factors to hang out, also there's a slow return of activated factors to spleen

Hemophilia A
- Factor VIII deficiency
- 85% of clinical cases of hemophilia
- sex linked recessive
- most severe

Hemophilia B
- Factor IX deficiency
- sex linked recessive
- less severe than A
- aka Christmas disease

Hemophilia C
- Factor XI deficiency
- not sex linked, autosomal recessive,
- least severe type

easy bleeding/bruising
- hemoarthrosis (bleeding into joints, can lead to degeneration of joints early in life)
- intracranial bleeds, bleeding into the neck (can't stop it in the brain, in neck it affects airway and circulation)
- administer the specific factor that's missing or flash frozen plasma or cryoprecipitate

- always secondary to some other disease process (e.g. circulatory crisis with hypotension and stagnated blood flow leading to activation of coagulation system)
- hypoxemia insults vessel walls
- widespread coagulation in microvasculature leading to anoxia and tissue death
- consumes all clotting factors and platelets leading to diffuse bleeding and hemorrhage

conditions associated with DIC:
- obstetrical complications
- malignancies
- sepsis
- autoimmune reactions
- tissue injuries
- there is a chronic form as well

SUMMARY: widespread fibrin deposition in micro-vasculature >>organ and tissue ischemia triggering more clotting which uses up platelets, clotting factors, increases fibrinolysis >> bleeding

disease: occurs when infection results in change from normal state of heath

relationship with host (symbiosis)
- protective, established colonies prevent overgrowth of harmful microorganisms

resident flora are usually bacteria, re-colonize quickly if disturbed

opportunistic infections
- normal flora may become pathogenic when immune system is compromised

disseminated through enivronment

reproduce
- form spores, detach from parent cell, germinate into new fungi elsewhere, colonize especially when normal flora are disturbed

mycoses
- infections caused by fungi

(prokaryocytes) that have no discrete nucleus (not membrane bound) reactions take place in cytoplasm, target treatments to cell wall

Degrade and break down dead tissue for other organisms

Encapsulation
- Prevents microorganism from being phagocytized- prevents opsonization

Enzymes secreted during bacterial growth, usually act at distinct tissue sites remote from bacterial growth. (Neurotoxins, endotoxins, etc.)

lead to:
- decrease in plasma volume
- increased vascular permeability

Caused by
- Individuals treated with antibiotics taking only part of prescribed dose
- Overprescription of antibiotics

Resistant form may be transmitted to other individuals

Cocci
- Round and nonmotile
- May clump together like bunches of grapes, in pairs, or in long strands

Bacilli
- Rod-shaped
- About ½ are motile

Step 1. Staining with crystal violet.

Step 2. Fixation with iodine stabilizes crystal violet staining. All bacteria remain purple or blue.

Step 3. Extraction with alcohol or other solvent. Decolorizes some bacteria (Gram negative) and not others (Gram positive).

Purposes:
- Destruction of infectious microorganisms that are resistant to inflammation
- Long-term highly effective protection against future exposure to the same microorganism

Inducible-must recognize pathogen/antigen as foreign (nonself)

Specific-unique pathogens identified eliminated

Memory-long-term/permanent protection against pathogen

Immunogens
- bind with antibodies and also induce immune response (production of antibodies, T and B cells)
- Must be foreign to the host and in sufficient quantity
- All are antigens

*She's not gonna ask us the difference between e.g. immunogen or antigen (know the disease process pathogens cause, that's the focus)

Entry route (intravenous, intradermal, oral) stimulates different lymphoid tissue

Cellular: T cells mediated
- Subpopulations (effector T cells)
- - Kill target directly
- - Stimulate other leukocytes

Both produce memory cells

*Autoimmunity (mistaken sensitivity)
- Reacts to "self" antigens causing harm to the body*

Basic mechanism
- Specific antigen-antibody reaction or specific antigen-lymphocyte interaction

Allergy
- Deleterious effects of hypersensitivity to environmental (exogenous) antigens

Autoimmunity
- Disturbance in the immunologic tolerance of self-antigens

*Type I
IgE mediated* (only type when you should know the immunoglobulin involved)

*Type II
Tissue-specific* reactions

*Type III
Immune complex* mediated

- IgE mediated
- sensitivity to environmental antigens (allergens)
- IgE binds to Fc receptors on surface of mast cells - mast cells become "sensitized" and release histamine

*Histamine release : most important mediator
- Causes increased vascular permeability, vasodilation, urticaria, smooth muscle constriction, increased mucus secretion, pruritus, can lead to anaphylactic shock

Mild
*- Hives (urticaria)
- Seasonal allergic rhinitis
- Eczema
- Mild asthma symtoms*

Moderate symptoms
*- Throat constriction
- Localized edema
- Wheezing
- Tachycardia*

When stimulated, release histamine and chemotactic factors

next mechanisms by which Type II responses occur:
1.Cell is destroyed by antibodies and complement
Ex: Erythrocyte destruction in autoimmune hemolytic anemia or Transfusion reaction

2. Cell destruction through phagocytosis
Ex: antibodies against RBC antigens of Rh system e.g., Rh negative mother is sensitized to her fetus's Rh-positive red cell group antigens

3. Soluble antigens (meds, infectious agents) enter the circulation and deposit on tissues tissues destroyed by complement and neutrophil granules.

4. Antibody-dependent cell-mediated cytotoxicity (ADCC)

5. Does not destroy cell causes target cell malfunction (e.g., Graves)

Serum sickness: (systemic) immune complexes in blood-deposited in target tissues (vessels, joints, kidneys). Ex: Raynaud phenomenon temperature-dependent deposition of immune complexes in peripheral capillary beds.

Direct cell-mediated cytotoxicity
- Cytotoxic T cells
- Viral reactions

Immune system recognizes its own cells as foreign and mounts an immune response that injures self tissues.

Failure of self tolerance

Thyroid diseases: Graves Disease & Hypothyroidism

Transplant rejection and transfusion reactions:
- Major histocompatibility complex (MHC)
- Human leukocyte antigens (HLC)

Transfusion reactions
- ABO blood groups

Hallmark: defective cell-mediated immunity
- Decrease in CD4+ T-helper lymphocytes/macrophages

Most common cause of disease in humans

Composed of:
- DNA or RNA surrounded by "capsid"

Totally dependent on host cell
- Do not possess any metabolic organelles
- Lack self-replication "machinery"

Classified by:
- Genetic makeup
- Mode of replication
- Structure of viral capsule (capsid)
- Specific host cell that virus invades

Must enter host cell to replicate/invade:
1.Can adhere to cell membrane, cause phagocytosis. Once inside cell, capsule opens to release viral genetic material.

2. Can stick to cell surface and inject genetic material into host cell.

3. Manufacture envelope to surround viral capsid
- Composed of host cell membrane and viral proteins
- Virus then released by budding from cell surface.

Two Major Categories
a. Contain DNA (ex: herpes simplex)

b. Contain RNA (ex: influenza or HIV)
- Retrovirus
- Replicating virus

- Requires specific enzyme: Reverse Transcriptase for transcription of RNA into DNA.
- Retrovirus

CD4 cells help other cells to battle infections

HIV infection causes a steady decline in CD4 cells

Key enzymes facilitate conversion of RNA to DNA:
Reverse transcriptase
- Allows virus to copy RNA into DNA

Protease
- "Molecular scissors": splits long chains of precursor proteins into smaller, active units

Chemokine co-receptors located on host CD4+ cells
- Required for final binding/entry of virus into host

Early infection: the virus tends to bind to CCR5 co-receptor

2. Fusion: Once HIV particle is bound to both CD4 receptor and chemokine receptor, gp41 implants in the cell membrane, causing lipid bilayer envelope to fuse with host cell and release HIV RNA into cytoplasm of the host cell, producing infection

3. Reverse transcription: HIV RNA transcribed into single-stranded DNA by HIV reverse transcriptase

4. Replication: RT converts single strand HIV DNA into double stranded HIV DNA

5. Integration: HIV DNA integrated into host DNA by HIV integrase

6. Transcription: HIV DNA transcribed into RNA
May become part of genome for new virion or
Is messenger RNA that codes for HIV proteins

7. Translation: mRNA translated into HIV glyco or structural proteins and enzymes

8. Migration/assembly: All components migrate to cell surface and create new virus


Scarlet Letters, dealing with vascular rosacea, face flushing, burning and the rest


My friend from Australia sent me some interesting information about a drug called Xolair (Omalizumab) for the treatment of allergy related skin issues such as Morbihan syndrome or articaria. Morbihan syndrome is a rare condition that can be a late-stage complication of rosacea. People who have this syndrome suffer from bad swelling of the eyes and the upper cheeks (oedema), as well as redness (erythema) sometimes. They can also have visible blood vessels (telangiectasias) and occasionally papules, pustules and nodules. This issue is related to substances in the body which also play a role in allergies an abundance of mast cells which make the blood vessels dilate as well as substances which increase inflammation cathelicidins such as Cath-37, which also seem to play a role in rosacea. Scientists found that Omalizumab can not only help patients with allergy-related asthma and urticaria, but also can help suppress the symptoms of this Morbihan syndrome. It binds the circulating IgE antibodies and may stabilise mast cells. There are some similarities between rosacea subtype 1 and Morbihan syndrome and urticaria: the facial flushing which rosacea can give work through the same pathways as the temporary red swellings observed in urticaria and angioedema. Scientists believe that omalizumab helps stabilize mast cells and reduces the temporary swelling, but that it can also help rosacea subtype 1 by reducing blood vessel dilation and potentially also reducing inflammation. Another drug that is linked to suppressing mast cell activity, ketotifen , shows also beneficial outcome in the treatment of rosacea in studies.

CASE REPORT
"A 56-year-old woman, with moderate erythematous rosacea, developed persistent and prominent erythematous (red) oedema of the face, lasting for one year. Firm swelling of the eyelids, impairing vision, accompanied oedema of the cheeks and forehead. Neither itching nor scaling was observed. Pronounced swelling was seen after exposure to hot, cold and windy weather, and to a lesser extent to stress, sunlight and spicy food. The patient could not work or participate in the social events, due to her symptoms. She was diagnosed with Morbihan disease after excluding allergies, various connective tissue diseases such as dermatomyositis and superior vena cava syndrome. The patient was tested with a normal skin prick test, tryptase, antinuclear antibodies, thyroid function test, full blood count and X-ray of the lungs and mediastinum. Skin punch biopsy demonstrated non-specific inflammation consistent with rosacea. - MS was treated with lymecycline 300 mg twice daily for 3 months and later isotretinoin 10󈞀 mg daily for 4 months, but there was no effect on the swelling or erythema. Because of the temporary swelling caused by physical stimuli, in addition to the permanent oedema, we initiated a trial treatment with omalizumab 450 mg subcutaneously. A dramatic reduction in the swelling was seen 1𔃀 weeks post-treatment (Fig. 1B) and the patient subsequently became tolerant to the physical stimuli. The MS cleared completely after 5 months of monthly omalizumab injections, an initial dose of 450 mg and consecutive doses of 300 mg (Fig. 1C). Maintenance treatment was given for a further two months, every 4𔃄 weeks, and was then discontinued successfully without clinical relapse, 6 months later. The quality of life was markedly improved after omalizumab injections and the patient was able to resume working, instead of being on sick leave. Her photos show first a pre-treatment photo of prominent and persistent erythematous edema of the face. Firm swelling of the eyelids impairing vision. Then a photo showing the reduction of the edema as observed two weeks after the first subcutaneous injection with the monoclonal antibody - omalizumab 450 mg. The patient tolerated windy and cold weather and noticed less tenderness. Last photo: the patient is in her normal condition after monthly injections of omalizumab for five months. Her quality of life was substantially improved, and she was able resume normal life, including returning to work. A written permission from the patient to publish these photos was obtained." Source

On The Rosacea Forum, Lookout wrote on February 6th, 2009 about Xolair (=omalizumab): "Xolair. is used for asthma (allgery based).I would want to try Xolair. I think the research for rosacea needs to include these types of meds since steroids make our condition worse or even brings it on! Xolair. from what I understand would be safe for long term use. that's why I picked it as my "drug" of choice! LOL. I figured most of us here do have allergies but this med is only used for allergery induced asthma. but in my mind why not try it on rosacea patients? If it is effective in reducing inflammation then it just may reduce rosacea symptoms. not cure but give us a pill that really address that inflammation! I would have to go back to my ENT. and get tested and try to sell him on my theroy to let me try it and see. I have to do more reading about it. I guess I am feeling fustrated that there is nothing coming out for rosacea and for some reason most still don't recognize that a flare is an inflammatory response IMO. wish they would do clinical trials with this med for rosacea. maybe I should write the company about it. like they would listen to me LOL!"

Thank you to Gunther, who sent me a link to this German program about a woman with rosacea, who gets tips on how diet can help her skin become less red and inflamed. I realize that diet is not a rosacea trigger for everyone. I read often about people who have not identified dietary skin triggers, despite all sorts of elimination diets. This video and info is therefore not necessarily for everybody with rosacea. But I think diet can play a role sometimes in finding improvement. Maybe more so in subtype 2 rosacea, with background redness and skin outbreaks and pimples. But from own experience I can say that even in subtype 1 rosacea, with skin flushing, burning and redness, diet changes can sometimes give some improvement (not a cure for me though, not even close. ). I notice a pretty significant improvement in my skin as well, like the woman in this video - although she sees bigger results than me - when I stay clear of sugar, wheat, dairy and any spices. In my case there is also an issue with histamine rich foods, which does include quite a long list of food items. But, when I eat lots of vegetables (except tomatoes, eggplant and a couple of other vegetables high in histamine), and stick to carbs like potatoes, as well as eating organic beef or chicken and foods like olives, unions and fruit, my skin is really less red and less inflamed. It also takes more for me to flush then. Although I still flush very easily, even then. But my skin has a base colour which is a bit more pale then. It is much easier to stay cool. My weaknesses are chocolate, bread and pastries, as well as some sugary things pr pizza. I rarely give in to such foods, but when I do it's a good amount of sinning. Not just one square of chocolate :)
I watched this very interesting Ted Talk, from scientist and doctor William Li. He explains how certain foods can increase our chances or developing cancer in life, and others can reduce those chances. Now, he emphasizes that cancer can have different causes and some people have a genetic predisposition. But each and everyone of us endures gene mutations throughout our lives and especially once we are over the age of 40. William Li explains that these cell mutations can remain small clumps of cells and then be cleaned up by the body's immune system, or they can continue dividing and turn into cancerous tumors over time. Now scientists have discovered that certain foods can help speed up this process, or help undo this process. Dairy products for instance contain a substance which promotes it, whereas foods like specific mushrooms and soy beans can help reduce these chances. How? Through new blood vessel mechanisms angiogenesis. Cancerous tumors can grow due to the body creating blood vessel systems for them. Without these blood vessels, the tumor cannot grow. And here a link with rosacea emerges. Because for us rosacea patients who have issues with red or flushed cheeks, the angiogenesis mechanisms have gone haywire too. The human body has a certain set of blood vessels, formed in the uterus, and we are set with those vessels through life. But the body can also create extra blood vessels during very specific circumstances, for instance during wound healing of a skin injury, or when a woman is pregnant and has to develop extra vessels in the uterus to form the placenta. After pregnancy, the body reabsorbs those extra blood vessels again and brings things back to the status quo through naturally occurring angiogenesis inhibitors in the body. Regulating the amount of blood vessels through a system of stimulators and inhibitors of blood vessel growth. Or so it should be. And there are other situations where this happens. Dr. Li even shares an image during his Ted Talk where he mentions rosacea as one of the possible medical conditions of which patients suffer due to angiogensis going rife, and the body not cleaning up the excess blood vessels. Dr. Li then focuses on cancer and how trimming down the bodies ability to grow blood vessels for the tumor is a promising treatment mechanism for early stage tumors. He explains the mechanisms and interesting for us people with rosacea he names potent angiogenesis foods and medication. Something we blushers and flushers may also benefit from. I cut the 20 minute long video up a bit to show you specifically what dr Li says about these blood vessels, I recommend it as it is extremely interesting I think. First the trimmed video in 2 parts (due to limited size options on blogger), then the full 20-minute video, also including info about cancerous tumors: So, Dr. Li mentions a number of natural anti-angiogenesis foods, which help the body prune back excess blood vessels.


This is a study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process

This study proves that artemisinin is a potential option to inhibit inflammation and angiogenesis in rosacea

Why women with neuropathic rosacea have a higher risk of developing migraine

Scientific research has confirmed that people with rosacea, and especially neuropathic rosacea with facial flushing and burning, have a higher risk of developing types of headache such as migraine and cluster headaches. Our blood vessels are linked throughout our body and when the blood vessels in the facial skin do not function correctly, dilating too much, then this can also extend to the blood vessels going to our brain. Patients with cluster headaches for instance - which is a very severe type of headache that happens on one side of the head/face - deal with blood vessels in the head which dilate too much and are pressing on the nerve endings in your head, causing severe nerve pain head aches. Often patients of cluster headaches notice some relief by walking in the cold air. Because just like with facial flushing, cold air makes the blood vessel constrict. And rosacea also involves inflammation of the skin and blood vessels and this inflammation in turn is also involved with migraine. So it is a twofold interaction and overlap thing. It is a two way street, science found that having rosacea increases the risk of developing migraines, and having migraines increases the risk of developing rosacea.

In this research, scientists tracked more than 4.3 million individuals in the Danish National Patient Registry, of which roughly 50.000 were diagnosed with rosacea. The study found that rosacea patients were 31 percent more likely to experience migraines than patients who do not suffer from rosacea. Ocular rosacea patients even had a 69 percent increased risk of migraine, while patients with phymatous rosacea (subtype 3 of the nose) showed no increased risk. Female rosacea patients over the age of 50 had the highest increased risk of migraine. These percentages may even be on the low side, as the researchers determined them based on patients who took anti-migraine medication. And therefore all the rosacea patients with headaches who did not take specific medication for this, or who bought over the counter and freely available pain medication, have been overlooked. Which may be a significant amount, theoretically. Dr. Egeberg, who conducted the research, and his team believe that the vascular abnormalities that cause the rosacea symptoms we all know, are also to blame for the migraines. It is also interesting that both vascular rosacea and migraine have comparable triggers, for instance stress and alcohol consumption.

Another study on this topic was done in the United Kingdom and it included more than 100,000 migraine patients. This study found that a smaller percentage of women with rosacea had also developed migraines: 22 percent. No association was found for rosacea and migraine in male patients. The association found between rosacea and migraine for female patients increased directly with age. Women over the age of 60 had a 66 percent increased risk of rosacea. The researchers also stated that it is possible that a specific medication group for migraines, triptans, can theoretically also help people with vascular and neuropathic rosacea, as they are both anti-inflammatory and vasoconstrictive (so they constrict the blood vessels, something we rosacea patients can benefit from). But that more research is needed for this.

This pubmed article also suggests some more treatment options for vascular and neuropathic rosacea: Conclusions and clinical implications: "Based on the findings linking rosacea to diseases involving dysregulation of the immune, vascular, and nervous systems, several new modalities for treating rosacea have been proposed. The success of neurologically focused drugs including gabapentin, duloxetine, pregabalin, and tricyclic antidepressants in a subset of rosacea patients suggests a neurological component of the disease. [..] The link between rosacea and autoimmune disease has prompted suggestion of probiotics as a potential therapy for both conditions, which may limit overactive innate immune responses to lipopolysaccharide (LPS). Specific targeting of both innate and adaptive immune responses is justified based on the above correlations, although finding the particular drug targets that will impart benefit in rosacea patients remains a challenge."

Another treatment that can help both migraines and rosacea are botox treatments. They are administered differently here than for anti-wrinkle treatment (not in the nerves but in the skin). Some of the most common symptoms of a migraine include throbbing pain, sensitivity to light and sound, nausea and changes in vision. Migraine triggers include:
▪ Hormonal fluctuations.
▪ Certain foods and drinks, including alcohol and caffeine.
▪ Emotional stress.
▪ Changes in the weather.
▪ Some medications.

Triptans are a class of medications that bind to serotonin receptors in the brain and diminish the swelling of blood vessels. They therefore constrict blood vessels and are also anti-inflammatory. Triptans are primarily used in the acute treatment of moderate to severe migraine and are fast acting, generally reducing head pain in about 2 hours. Some subtypes are called sumatriptan, naratriptan, rizatriptan, almotriptan and zolmitriptan. Because these drugs narrow the blood vessels, rosaceams who are also heart patients are not a good candidate. Also, from what I understand this class of medication is not meant to be taken long term.. And there is even mentioning of rebound flushing. After all, like Mirvaso, any medication that chemically constricts the blood vessels, comes with the risk of overcompensation by the body and rebound flaring once the medication is stopped. Yeh, not sounding all too great this, does it.

G. Nase wrote on 12th October 2005: "Do Migraine Medicines "Triptans" help rosacea? - Over the years, many have reported significant temporary clearance of rosacea redness and flushing when taking anti-migraine medications like Sumitriptan and the newer "triptans". Injection seems to be the most potent, followed by oral pills. These medications are meant to work on two parts of the migraine:
1. Stop vasomotion -- dilation and constriction . and place them into a semi-constricted state
2. An unidentified effect on vasodilator nerves up in the cerebral blood vessels (brain blood vessels).
Often times this has a positive action on facial blood vessels too. My general guesstimate is that 80% find relief while the others do not. This would give physicians working knowledge with a known medication."

Bethanne wrote on October 12th 2005: "I have suffered from migraines for over 20 years and have had Rosacea for more than ten years. I just took some Zomig ( Zolmitriptan ) this morning. In my case with this medication and those in its class (I took Imitrex years ago) my Rosacea flushing and redness either stays the same or, more frequently, ramps up. Part of this is often influenced by when I get the migraine and whether I am able to sleep it off after taking the meds. If I cannot continue to sleep after taking the medication, I am more likely to become flushy. I don't know if that is truly a mitigating factor or just stress-related. These meds are also known to have a rebound affect on migraines if used too frequently. I wonder if that means that they would also cause a rebound in Rosacea symptoms for those who are helped by them? Interesting post--thank you. Beth"

Irishgenes wrote on October 13th 2005: "I don't see how the triptan drugs could be used for rosacea. They are not supposed to be used over twice a week. Any effect on rosacea would be quite temporary."

G. Nase replied on 14th October 2005: "This would never be a long term treatment option for rosacea as you pointed out. It has significant constrictor actions and that is why some experience a rebound. The information that could be pulled out of this medication is how it affects vasodilatory nerves and not the second effect on blood vessels. One potential use down the road, is to use it after unusually bad flares that happen to rosacea sufferers. Sometimes, the one major flare can cause significant progression of the disorder -- so in very select cases, this may be an option for those that are caught in a horrific flare. Just anecdotal, but quite a few do notice transient improvement in rosacea symptoms with one or two shots. Of course there are many things that must be discussed with your doctor about these meds. Sometimes you can learn quite a lot about a disorder by how a medication affects its symptoms.

Bethanne replied on October 14th 2005: "Zomig now comes in a nasal spray dispenser. One dispenser administers 5 mg of the drug."

Laser_cat wrote on September 28th 2017: "Triptans for severe flushing - Hi, Just wanted to mention that if I ever take an imitrex ( sumatriptan ) when I feel a migraine coming on, it greatly helps with my flushing problems as well. You can read about the mechanism of action here. But basically it can help constriction of blood vessels and inhibit CGRP and substance P (which are implicated in sub 1 rosacea). A forum member (probably not here anymore) "Meg" I know used to take Maxalt ( Rizatriptan ) sometimes for her flushing/burning, but I am not sure how often she took it. My sense is your body will get used to it if you take it too often. For me any rebound isn't noticeable when the effects wore off. Just in case this helps someone! Lizzy"

Scroll down in this post to one of the earliest updates, which details this link between flushing and CGRP and Substance P.




Immune suppressing anti-inflammatories

I am always on the lookout for ways to reduce inflammation, without wanting to take steroids of any type. I took diclofenac (NSAID) for several years but at some point developed heart cramps whenever I exercised and didn't want to keep taking them therefore. I also felt they stopped working and paradoxically might have made me more red eventually. I now heard about IVIG (Intravenous immunoglobin) , which means that you get intravenously (IV) provided with extra antibodies, which stay in your body for several weeks and help your body fight off a large variety of infections. Unlike steroids, you can do this treatment long term. IVIG has proven to be effective in the treatment of various autoimmune and inflammatory disorders, lowering inflammation in the body. So, considering that rosacea is also an inflammatory disease (and some forms of rosacea quite possibly being an auto-immune related issue), you would think that it could improve rosacea in theory as well. However, apart from being anti-inflammatory, IVIG also boosts your immune system. Which paradoxically can worsen auto-immune related inflammation again. Anyway, the person who tried it for rosacea flushing found IVIG had absolutely no effect on the rosacea. Bummer.. I also read this account from a pregnant woman with rosacea who had a doctor suggest IVIG for her rosacea, and wrote:

However, there are more anti-inflammatory options.

I was suggesting a couple of other anti-inflammatories in addition to NSAID's and steroids (not suitable for rosacea, can make it worse). Methotrexate is one, which lowers the immune system. I have talked with Professor Tony Chu about this in the past. He recalled several patients with rosacea who had very severe cases and responded well to methotrexate. However, he warned, it is a very serious medication which lowers your immune defenses not only in favour of auto-immune diseases and immune related inflammation, but also makes you much more prone to complications from a simple flu or infection. Flu can turn easily into dangerous pneumonia for instance, infections might not heal properly and the immune system in the long term also helps us clear up cancerous cells, if all goes well. So there you have a heap of potentially very serious side-effects, and thus.. he wouldn't prescribe methotrexate to me. I understood. Some other meds that might be interesting for rosacea inflammation are CellCept , and azathioprine . These are non-steroidal medications that are broadly immune suppressive and anti-inflammatory, BUT have the same downsides as methotrexate by suppressing the immune system they also increase potential risks of infection and even certain cancers in the long run. But, they are definitely safer for rosacea itself than prednisone (a steroid), which can cause vasodilation, permanent blood vessel damage, flushing, thinning of the skin and worsening of symptoms.

The problem with steroids is that they can be super effective for certain other conditions, that can overlap in symptoms with rosacea, or can be misdiagnosed as rosacea. Think for instance of lupus, dermatitis, erythromelalgia and even seb derm and quite a few other conditions that can cause flushing. Some doctors can determine through the use of steroids that someone in fact has an auto-immune disease, as corticosteroids will lower the immune response and improve your symptoms, as well as inflammation. Doctors are often easily swayed to throw some steroids your way when your symptoms are inflammatory and vague. But one always needs to be cautious with them when it comes to rosacea. Even short term use of a steroid cream can trigger rosacea (as it did in my case). And existing rosacea can worsen due to steroid creams or pills. But some dermatologists prescribe steroids regardless, as they will help initially to make the skin less red and inflamed. I am of the opinions that steroids, both topical or in pill form, should never ever be used as a rosacea treatment.


"Never, never, never, ever prescribe steroids for rosacea" Dr.Kligman (Dermatology-University of Philadelphia) & Dr. Pleig (Dermatologische Klinik Und Poliklinik der Universitat Munchen, Germany) state in their 1973 book, entitled Acne & Rosacea, First edition. Likewise, their second edition in 1993 harshly criticizes dermatologists that prescribe steroids for rosacea.

P almitoylethanolamide (PEA)

I was also tipped on the supplement palmitoylethanolamide (PEA) for the treatment of pain, inflammation and even of mast cell instability. I ordered it this week and will give it a try as soon as it comes in. So far I have had bad reports with mostly all supplements however. Only Alpha Lipoic Acid seemed to help slightly, the rest either did nothing (a few) or made my flushing worse (most). But will try it anyway. So what is palmitoylethanolamide (PEA)? It is a fatty acid, produced in the body to combat pain and inflammation, by boosting your natural cannabinoids and protecting the nerves throughout your body. My rosacea is both vascular and neuropathic, meaning it shows itself through constant dilating of the blood vessels - flushing, redness - as well as giving me a lot of nerve pain in the face my skin always feels tight, burned up and uncomfortable. And when I get massively flushed or more red than usual, it feels on fire, literally like someone threw something hot or acid-like on it. So the nerves in my facial skin have become hypersensitive after twenty years of rosacea flushing, inflammation and swelling. hence, this supplement sounds good so far :)

What else? Palmitoylethanolamide (PEA) can also be found in soy lecithin, soybeans, egg yolk, peanuts, and alfalfa. However, most of these might not be a suitable option for people with food sensitivities (soy can be a trigger for rosacea as well as the high-histamine peanuts. Eggs can also be a trigger for some). As a supplement, PEA is available in tablet, capsule, and powder form and is considered a strong and safe natural painkiller and anti-inflammatory. More than 30 clinical trials so far have confirmed it can relieve complex pain (but also stated that more large-scale scientific research is needed). This scientific article concluded:

It is also claimed that PEA can activate the cannabinoid receptors, protect the brain and heart, improve mood, reduce allergies, and may help fight the common cold. PEA also activates the energy-boosting, fat-burning, and anti-inflammatory PPAR alpha. This research paper states: "Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through an as-yet-uncharacterized mechanism. Here, we identify the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) as the molecular target responsible for the anti-inflammatory properties of PEA."

In an analysis of 12 human studies, PEA supplements reduced chronic and neuropathic pain intensity without any serious adverse effects. It has to be used for at least 2 weeks to achieve pain relief. PEA was typically given over 3-8 weeks at dosages between 300 and 1200 mg/day. Taking it over a longer period of time strengthens its effects without causing tolerance. Normal dose is 300 or 600 mg/day, however: "At least 600 mg/day may be needed to relieve nerve pain, while doses of 1,2 g/day were used for diabetic nerve pain." You can read more favorable research outcomes in this article. One important benefit of it I like to name here is that PEA is said to reduce gut inflammation. I have a chronic low grade inflammatory condition of the gut (microscopic colitis) and it appears that many people with rosacea have in fact some issue or another with their gut and bowels (you can read my blog post about the link here). AND also depression! For what it's worth, I am truly not sure if this is really the wonder supplement that article makes it out to be :)

PEA Reduces Gut Inflammation
"PEA was successfully used to relieve symptoms of inflammatory bowel disease (IBS) in animals. Mice with chronic gut inflammation have low PEA levels, while PEA supplements normalized bowel movement and prevented damage to the gut lining. In tissues taken by biopsy from people with ulcerative colitis, PEA lowered inflammatory cytokines and the buildup of neutrophils, immune cells that worsen symptoms and contribute to gut damage."

PEA Reduces Depression
"In a recent study of 58 people with depression, PEA (1,2 g/day) given over 6 weeks greatly and rapidly improved mood and overall symptoms. PEA was added to antidepressant treatment (citalopram) and lowered symptoms by an impressive 50%. This clinical study was a follow-up on numerous studies in which PEA improved symptoms of depression in animals."

PEA Reduces Histamine and Allergies
"PEA is a safe histamine-release blocker. People with allergies, histamine issues, and Th2-dominance will likely benefit from it. In animal and cell-based studies, PEA improved eczema and skin allergies by lowering mast cell activation and blocking the release of histamine. [..] In dogs with eczema, PEA helped soothe symptoms by reducing skin inflammation and itching. PEA reduced inflammatory substances (TNF alpha) and increased endocannabinoids in the skin (2-AG), which altogether strongly diminishes the allergic response."

And there is more scientific info for now. Boring boring! But I want to share it anyway:

I was also told about research about a possible link between rosacea inflammation and the peptide LL-37. There is quite a bit of research online available on it, so I will write a bit more about it now. Know and realize here, that the true cause of rosacea has not been discovered yet. Doctors and scientists do not know what causes the different subtypes of rosacea (subtype 1: flushing and redness, Subtype 2: skin outbreaks and inflammation, Subtype 3: rosacea of the nose rhinophyma, Subtype 4: occular rosacea of the eyes and the recently added Subtype 5: neuropathic rosacea with nerve pain and burning). It is likely that these different subtypes may have some different underlying mechanisms. For instance subtype 2 is often improving from topical ivermectin or Soolantra applications (see entire blog post about this here). Indicating that demodex mites can play a role in this subtype. However, for subtype 1 with flushing and burning these creams rarely work well. The flushing is also not improving when using textbook rosacea treatments, such as antibiotic pills or creams. In fact, flushing is one of the most difficult to treat symptoms of all, in rosacea patients. Topicals like Mirvaso (brimonidine) and Rhofade (oxymetazoline) have proven mostly disastrous for rosacea flushers. Large groups of people had their rosacea skin burned or deteriorated, had bad rebound flushing episodes that were often called "hellish" and long lasting. They chemically constrict the blood vessels, only for the body to compensate with abnormal blood vessel dilation rebound flushing) afterwards. It destabilizes the blood vessels in the long run and patients have mentioned their rosacea progressing to areas and severity they never had it before. of course another group states to have success with it, but it's a Russian Roulette drug, just like steroids. Better to reduce the flushing in my opinion are anti-flushing medication, or IPL or laser. (Read all about this here and here). And facial flushing goes by different pathways than the spots and outbreaks that subtype 2 patients tend to get. So, one big discovery, of one single cause, might be unlikely. Nevertheless, a (faulty) peptide called LL-37 may play a role in rosacea inflammation according to some research.

In this scientific research, it is stated that:


So the research article suggests that the skin of people with rosacea has a disturbed functioning of the LL-37 cathelicidin peptide. Does that mean that there are more of these peptides in rosacea skin? or less than normal? Or that there are normal numbers but that the peptides do not work as they should do in rosacea skin? And what is this LL-37 peptide exactly?

Cathelicidins in the human body play a crucial role in the bodies immune defenses against bacterial infections trying to infect from the outside. Wikipedia states that "Patients with rosacea have elevated levels of cathelicidin." And when wiki states that "Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea", it cites this research paper, which is the same as the earlier quoted research. Its authors, M. Reinholz, T. Ruzicka and J. Schauber published in 2012 their research, stating that normal skin has three ways to protect itself from bacteria's from the outside world, trying to get in. First you have the top layer of the skin, which forms a shield (if the skin barrier functions as it should do!). This outer layer of skin has special cells that work as part of the bodies immune system, signalling when substances enter the skin that do not belong to the body itself, for instance a bacteria. They signal to the other cells of the danger once a bacteria does try to invade the skin. If this happens, the bodies immune system sends specific cells to the surface that are causing inflammation, trying to work out or kill the invading bacteria. One of these specific cells are antimicrobial peptides (AMP's), of which there are to date several hundred different types found. They can kill bacteria by messing with their cell membranes (for instance in case of a skin injury), but also fungi and viruses. So they are part of our skins little army, so to say. Cathelicidins are part of this AMP system. The precise cathelicidin involved in AMP is called Cathelicidin antimicrobial peptide (CAMP). And Cathelicidin LL-37 belongs to the CAMP family. It can break up bacteria, fungi and viruses that land on the skin. But they can also give off an "alarm", which brings the skins army into action, causing inflammation to work out or kill the invading substances. They mainly get active and detectable in the skin once there is a skin injury. When all is normal and the skin functions as normal, they are hardly to be found in the upper skin.

But Cathelicidin LL-37 can also trigger the immune system. Thus, it plays an important, dual, role in the immune function of the skin. And when this LL-37 peptide does not function as it should, it can in fact have the reverse effect on the skin, and cause skin inflammation . And also allow bacteria to infect the skin. The scientists found that in rosacea skin, cathelicidin LL-37 often does not function as it should, and what is worse, they found that rosacea skin has much higher levels of this LL-37:

The scientists got confirmation about all this, when they injected these specific cathelicidins in the normal skin of mice. They all developed rosacea-like skin symptoms then. The problem is now, that scientists do not understand yet WHY rosacea skin has these higher numbers of cathelicidins,a lthough they found 3 different 'portals' so to speak, through which the extra peptides were produced. They were retinoid-, vitamin D- and cytokine-activated. The vitamin D -pathway, for instance, could explain why rosacea is only present on the face normally, and not on the rest of the body: the body is usually covered up and it is the face that gets the most sun-exposure and therefore the most vitamin D. And therefore, the more vitamin D is made in the skin, the more Cathelicidin LL-37 (and thus the more disrupting inflammation and vasodilation). But this is only a small part of the puzzle, as many people with rosacea shun the sun and protect their faces from sunlight at all times. Also, many with rosacea have low levels of vitamin D (read more about that in this post).

But scientists also found that cathelicidins could be triggered by keratinocytes (outer layers of skin cells), which have nothing to do with vitamin D. They found that the outer skin cells themselves can signal the making of more Cathelicidin LL-37 when they are injured, get exposed to UV radiation, or when the outer layer of the skin gets disrupted in any way. Skin Stress, one could call it. Ánd, interestingly: skin stress includes heat . "This again could explain why rosacea patients often report on unspecific triggers (e.g. heat) which would mediate their pro-inflammatory activities through ER stress and cathelicidin induction." So when our rosacea skin gets triggered by heat, for instance you enter a very warm room, then this heat touching the skin will cause stress in the outer layer of the skin, sending of "alarm signals", which stimulate the LL-37 and other peptides to come into action and create. inflammation. Physical stress can trigger the same response by the way, as well as alcohol consumption: Inflammation.. Just like we see happening in our rosacea faces when dealing with triggers like heat. Demodex mite infection can also trigger the skin to make these inflammation alarm reactions, as demodex mites can cause increased protease activity in rosacea skin, which does the alarm bells of Cathelicidin LL-37 go off again. Which in turn trigger inflammation, redness and blood vessel dilation in the skin. This is probably why oral and topical antibiotics (tetracyclines for instance), azeleic acid and retinoids can work for rosacea: they directly interfere with this pro-inflammatory system and reduce the inflammation or stop it from being formed altogether. So antibiotics can work for rosacea not because of their ability to kill off bacteria, but instead of how they reduce inflammation. And the same goes for anti-demodex treatment. which can take away the prime trigger for LL-37-related skin inflammation IF you have a demodex mite infection.

And avoid sunlight on your face. Vitamin D from sun is a direct trigger for LL-37-mediated inflammation and blood vessel dilation of rosacea skin. You can bronze on the rest of your body, just not your face, if you want to calm down rosacea-inflammation. (And now that I am at it, could this perhaps explain why so many people flare up from vitamin D supplements?? I get beyond beet red from them and never understood why. Maybe here we have it, the explanation). Certain supplements and herbs can also act as anti-inflammatories. Check my (still not fully finished, sigh) blog post about them here. Think of supplements like turmeric/curcumin or boswellia for instance. If you want to know even more detailed, microscopic information about how exactly this mechanism works on cellular level, I advise you to go to this science article and scroll down to the section Rosacea. You can also read more in this scientific article.

H.pylori infection and rosacea

I have been tested for Helicobacter pylori IgG antistoffen. Seen my general practitioner about it some weeks ago and she sent me for a blood test. This because some people on rosacea forums and groups claimed to have "cured" their rosacea after getting treatment for H.Pylori. Now, that is often an antibiotic, and antibiotics are known to help some case of rosacea, regardless of H. Pylori. Also, the symptoms of H. Pylori in rosacea skin are often said to be skin outbreaks and p&p's, which I don't suffer from. (Only severe flushing, redness and burning for me). Research like this one concluded on this topic:

It is suggested that rosacea patients should be tested for H. pylori infection, the H. pylori-positive rosacea patients should be treated with eradication of H. pylori, so as to enhance the therapeutic effect of rosacea." And this research paper states: "Many studies have been performed in order to evaluate the connection between H. pylori infection and rosacea, however there is still controversy around the matter. There is a lack of information regarding the genetic features and the biology of H. pylori. It is proposed that the bacterium produces specific cytotoxins which lead to the release of histamine, prostaglandins, leukotrienes, and cytokines. Inflammatory mediators from an altered innate immune response lead to higher levels of ROS, whereas in treated rosacea the aforementioned level is lower. However, there are no distinct histological features in rosacea patients positive for H. pylori infection." And it goes on to cite different research done on this matter, with different test outcomes. Some researchers did find a link between rosacea and active H.pylori infection, others failed to find such a link. Researchers agreed that H.pylori is more related to subtype 2 rosacea with skin outbreaks (papulopustular rosacea), than it is with subtype 1 rosacea with flushing and redness:

This summary of various research papers came to a more ambiguous outcome. Some researchers found that anti-H. pylori antibody levels were higher in rosacea patients. Other research found that 67% of rosacea patients tested positive for H. Pylori, and that there was a higher prevalence of H. pylori in patients with rosacea. And some (but not all!) patients who have both rosacea and H. pylori infection can to see their rosacea calm down as well when they treat the H.pylori. Other researchers failed to establish a role of H. pylori in rosacea patients, and some researchers downright concluded that the relationship between rosacea and H. pylori may be a myth.

The authors concluded: "Rosacea is a skin disease with an obscure and complicated pathogenesis. Many mechanisms have been described but its etiology remains an enigma. There is not sufficient evidence regarding how determinant the role of H. pylori is. According to some authors, rosacea is correlated with gastrointestinal disorders which justifies further clinical and laboratory examination. Based on the fact that the studies were not extensive, controlled studies are required. Additional research is mandatory in the field of the microbiology of H. pylori as there are subtypes with different levels of virulence. Further studies are warranted to delve into the multifactorial nature of rosacea in order to elucidate the role of each factor in the pathogenesis of the disease."

But. no harm in testing it or myself! Well I got the results back today and they are negative. No H.Pylori infection.My blood level was 5. The doctor's assistant said that anything under value 50 is considered negative. I looked up the exact values:

From To Unit Comment
0 35 U/mL negatief
35 50 U/mL grenswaarde
50 U/mL positief

Neurovascular System involved in neurogenic and subtype 1 rosacea


The National Rosacea Society reports that NRS-funded researcher (Dr. Martin Steinhoff, director of the Charles Institute of Dermatology at the University College Dublin School of Medicine, and colleagues at the University of California-San Francisco) have found that the nervous system is intimately linked with the vascular system in producing some typical signs and symptoms of rosacea flushing of the face and inflammation of rosacea. Our bodies nervous system coordinates its actions by transmitting signals to and from different parts of its body. The article names several typical rosacea triggers for subtype 1 and neurogenic rosacea: exposure to ultraviolet radiation, changes in temperature, exposure to skin irritants, strong emotions, alcoholic beverages and spicy food. All of these triggers are linked to the sensory nervous system, the researchers said. (The sensory nervous system a part of the nervous system and responsible for processing information we get through our senses, for instance what we see, hear, smell, taste, touch etc. It sends this information from our senses to our brain, which interprets the information).

They also highlighted that there is another nervous system disorder, which is called neurogenic inflammation , that shows some similar symptoms to those of rosacea redness and swelling, as well as activity of cells such as leukocytes at the site of inflammation. Dr. Steinhoff's team found that certain sensory nerves around blood vessels, which may be linked to the stinging and burning sensations that many of us suffer from, actually increase in numbers when rosacea develops and continues to cause trouble. They also discovered that there is an imbalance and a communication problem in rosacea skin between several neuropeptides — small protein-like molecules used by nerve cells to communicate with each other — and their corresponding receptors. Further research is under way to determine whether this imbalance contributes to the development of the flushing and inflammation of rosacea.

The group observed that the lymphatic vessels also may be involved in the initial process of rosacea, which can result in swelling, of the skin of the face (that puffy look so many of us get, especially during a flare up) and noted that neuropeptides affect the function of lymph vessels as well. Dr. Steinhoff thinks that the face is a particularly complex region, with an interaction of both the sympathetic, the parasympathetic and the sensory nervous systems all playing a role and interacting and influencing each other. It is possible that these 3 systems together create a complex cycle of inflammation, which may explain why some cases of rosacea can be resistant to treatment.


Researchers have also discovered something else that is interesting. Adenosine triphosphate (ATP) , — a neurotransmitter and carrier of chemical energy throughout the body — and one of the most common and hard-working substances in the body, may be contributing to rosacea in a variety of ways, according to NRS-funded researchers Dr. Richard Granstein and colleagues at Weill Cornell Medical College. When ATP is released into the skin by the nerves, lots of complex biochemical processes may occur in rosacea sufferers that ultimately leads to the bumps and pimples of subtype 2 (papulopustular) rosacea. ATP has many functions in the body, but its role in the development of rosacea may involve its job as a messenger from the nerves. The nervous system regulates blood flow to the skin, using ATP to start the dilation of blood vessels following exposure to rosacea triggers such as sunlight, emotional stress or alcohol. This process may then result in the flushing and redness of subtype 1 (erythematotelangiectatic) rosacea. In addition, endothelial cells — cells that line the blood vessels — respond to ATP with changes in the expression of inflammatory cytokines, which are proteins that act to recruit the inflammatory cells of subtype 1 rosacea. Dr. Granstein’s group is also investigating whether production of Th17 cells, a newly discovered class of cells that appears to be involved in a number of inflammatory and immune disorders, may lead to inflammation during this process.

Heat triggers greater nerve, blood flow and sweating responses in rosacea patients than in those without rosacea.

A study funded by the National Rrosacea Society (by Dr. Thad Wilson and colleagues at Ohio University), found that heat , a well known rosacea trigger, produces greater nerve, blood flow and sweating responses in people with rosacea than in people without the disorder when exposed to increased heat or stress. This response takes place in the sympathetic nervous system, which for instance controls the “fight or flight” response and other key involuntary functions such as heart rate, digestion, breathing and perspiration.

“Heat and stress have long been recognized as rosacea triggers, but it has not been clear what happens in the body to cause these flare-ups to occur, said Dr. Thad Wilson, associate professor of physiology at Ohio University. “That’s why we devised innovative ways to replicate these triggers in a controlled manner while studying their effects on facial nerves, skin blood flow and sweating.” "To increase body temperature, the researchers had 10 rosacea patients and 10 healthy control individuals wear a tight-fitting suit lined with tubes carrying water heated to 115°F until their body temperature increased by approximately 2°F. Each person was then precisely measured for supra-orbital nerve activity (a nerve just above the eyebrow that serves the forehead skin), forehead skin blood flow and forehead sweat rate.”

The researchers found that rosacea patients had higher skin blood flow and sweating rates compared to normal subjects, both before and after the heating began, and their skin blood flow and sweating also began to increase more rapidly during heating." 12 rosacea patients and 12 healthy control subjects were also tested during mental and physical tasks, involving fast-paced mental subtraction exercises for two minutes, using hand gestures to indicate answers, and tightly squeezing a handgrip for two minutes. While heart rate and blood pressure were the same between the groups during the hand exercises, skin blood flow was higher during mental arithmetic in the rosacea patients. The rosacea patients also experienced heightened sympathetic nerve activity compared to those without rosacea during both the mental and physical portions of the test.

When my skin burns and flares and feels on fire, the most natural urge is to open all the windows and let in cold air. Or to put my head in a bucket of cold water. Or to sit right in front of a powerful air conditioning machine. The colder the better! But according to the Warm Room Theory, this is actually not the best thing to do when you have rosacea. Making your rosacea skin very cold, might cause rebound worsening in the long run. It is normal for anyone with rosacea to get a rush of warmth up the cheeks when entering a warm room. Every person that gets too hot, can rely on their body to deal with the overheating, usually by stimulating the body to sweat (a way to release excess heat from the body) but also by widening the blood vessels in the skin. The wider the vessels are, the more warm blood will be closely exposed to the skin and be able to lose some of its heat that way. When the body signals the blood vessels in our skin that the body is overheating, then the body activates nerves in the skin to dilate the blood vessels in the skin (vasodilation). The way in which the nerves do this, is by releasing certain chemicals, that message to the blood vessels to widen. And to make the effect even stronger the more blood flows through the blood vessels, the more these blood vessels themselves release chemicals to keep this vasodilation going. This is a normal process everyone alive experiences this, or else we humans wouldn't be able to regulate our temperature or fight off infections or have proper wound healing, for instance.


Chemicals involved in facial flushing
There are hundreds of known chemicals involved with nerves and blood vessels. But there are very specific chemicals released by our nerves and blood vessels, when we have rosacea and suffer from facial flushing, such as neurotransmitters, neuropeptides and growth factors . Neurotransmitters are chemicals that transmit a nerve signal to other nerves as well as other tissues, such as blood vessels. Neuropeptidesdo the same, but are stronger and act longer. Both can signal blood vessels to dilate or constrict, and nerves to feel pain or to go numb again. There is something special going on with these neuropeptides research showed. More on this soon. Growth factors, released by skin cells, help to maintain existing blood vessels and nerve structures, and also make it possible for both to grow. They also play a role in the process of our nerves becoming more sensitive and easily triggered to feel burning and pain. When the nerves in our skin are activated (for instance during a flush), this in turn stimulates more growth factor release, like a waterfall-construction. They are all in place to help the body deal with overheating, but with rosacea patients this system of blood vessels and nerves and chemicals are going in overdrive, causing our increasing facial flushing and red faces.

In this article from march 2018, specialists warn that people with rosacea are statistically at a higher risk to develop other health conditions. For instance, rosacea patients have 4 times more chance to develop cardiovascular disease than the average population. Rosacea patients also have a 4 times higher risk to develop g astroesophageal reflux disease (GERD), are 3 times more likely to develop Crohn's disease. Although it is not always clear how exactly rosacea is linked to a higher risk factor, the overlapping theme is inflammation. Rosacea is an inflammatory disease and inflammation is also thought to play a role in cardiovascular, gastrointestinal, neurological and autoimmune diseases. In their cases the inflammation is hidden inside the body, whereas with rosacea the inflammation is visible in and on the skin. Some scientists now say that this visible (rosacea) inflammation is a warning signal for more hidden inflammation inside the body.

*Cardiovascular disease – 4 times higher risk
*Gastroesophageal reflux disease (GERD) - 4 times higher
*Crohn's disease - almost 3 times
*Inflammatory bowel disease (IBD) - 2 times
*Celiac disease - 2 times
*Type 2 diabetes - 2.5 times
*Food allergies - 10 times higher risk
*Urogenital diseases (affecting the urinary tract or reproductive organs) - 7.5 times higher
*Respiratory diseases - 4 times higher risk

The article mentions the following conditions:

Depression is among the most common comorbidities (means an additional health issue that goes with the original disease in our case rosacea) identified in the research, followed closely by anxiety. Multiple studies have found a higher than average prevalence of depression and anxiety in patients with rosacea. Unfortunately, doctors tend to underestimate the psychological impact of having rosacea, and ignore the level of despair and mental suffering it can bring. Reversing this trend, at least one study found no greater risk for rosacea among those who already had clinical depression, but the association may be bidirectional given that stress can trigger rosacea flare-ups. A National Rosacea Society survey of more than 400 rosacea patients found that 75% of them feel low self-esteem, 70% feel embarrassed, and 69% feel frustrated. In those with severe symptoms, 88% cited the disorder as adversely affecting their professional interactions and 51% had missed work because of their condition. Prevalence of anxiety about the condition was present in 41%, and 25% reported having depression related to their disease.


Cardiovascular Disease

Patients with rosacea have a higher incidence of hypertension and dyslipidemia (an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood), which increases with severity of rosacea symptoms, than the general population. Rosacea patients also have higher rates of peripheral artery disease, heart failure, diabetes mellitus, and coronary artery disease — the latter even after controlling for hypertension and dyslipidemia. Recent data have suggested the risk for vascular events increases with tetracycline treatment. People with rosacea were found in research to have four times the risk for cardiovascular disease and reflux. Although several cardiovascular-related conditions have been very clearly associated with rosacea, existing evidence does not suggest an increased risk for heart attack, stroke, or other cardiovascular events in patients with rosacea. It is a good idea to check if your family has a general history of heart disease and if so, to mention this to your doctor and have extra screening if suffering from any symptoms related to cardiovascular disease. Having a higher Body Mass Index (BMI - so a high weight) can increase the risk of such conditions. It is also wise to have your blood pressure checked routinely, and doctors also recommend for rosacea patients of 45 years and older to have their blood work done now and then to check fasting lipid panel, fasting glucose, or hemoglobin A1c levels. If you have 2 or more risk factors, doctors recommend taking 81 mg. of aspirin a day, at the least.


Neurological Disorders

Researchers have identified an increased risk for rosacea patients to develop Parkinson Disease, dementia (particularly Alzheimer disease), and migraine, although risk levels vary. Two Danish cohort studies, for example, revealed a 71% greater risk for Parkinson disease and a 36% greater risk for dementia. Migraine is more often seen in female patients and involves vascular abnormality, just as rosacea does. Both conditions can also be triggered by stress or alcohol.

The only cancers linked with rosacea are a weak association with thyroid cancer in women and glioma (brain cancer) in men, plus a stronger association with basal cell carcinoma (skin cancer). Skin cancer is the least surprising of the three, given that UV radiation from the sun not only can cause skin cancer, but also worsens rosacea for most patients.


Gastrointestinal and Auto-immune Disease

The gastrointestinal disorder with the highest prevalence among patients with rosacea is inflammatory bowel disease, which some researchers have suggested may be related to a shared pathogenesis from Helicobacter pylori or small intentional bacterial overgrowth (SIBO), both also more prevalent in rosacea. One small study found that 21.6% of patients with rosacea had H. pylori and 25% had small intentional bacterial overgrowth.

Evidence also supports an association between rosacea and celiac disease, ulcerative colitis, rheumatoid arthritis, and allergies. For example, a small case-control study published in 20159 found higher odds of airborne and food allergies, plus other systemic diseases, in patients with rosacea. Although male patients show higher risk for glioma (brain cancer), the associations linking rosacea with rheumatoid arthritis, celiac disease, type 1 diabetes, migraines, multiple sclerosis, and hormone imbalances are stronger in females. Environmental risk factors that are under investigation currently for shared pathogenesis with rosacea and other comorbidities, are H pylori infections, small intentional bacterial overgrowth, and differences in gut microbiomes, which are also implicated in celiac disease, diabetes, depression, and cardiovascular disease. Other research into possible shared mechanisms compares rosacea with other autoimmune diseases, other genetic biomarkers, and similar inflammatory elements or pathways. The exact connections are complex, remain mostly unclear at this point, and probably involve mechanisms that underlie chronic inflammatory conditions in addition to metabolic, immune and endocrine changes.

The cause of rosacea is still not well understood, and since there are different subtypes and symptoms of rosacea, the cause will most likely prove to be 'the causes', ranging from an auto-immune response to central nervous system disruption to demodex mites overpopulation to actual skin disease. Rosacea patients have shown an increased level of C-reactive protein in their blood upon testing, which is a marker of systematic inflammation in the body. Researchers also found unbalanced oxidative stress mediators, implying that people with rosacea might have unchecked and higher oxidative stress levels in their blood at times. This oxidative modification of proteins and lipids turned out to be another possible trigger of skin inflammation. Because like most autoimmune diseases, rosacea involves dysregulation of the inflammatory response and may share symptoms with other diseases when it comes to the development of the illness. As stated above, scientists found that there is a higher chance for someone with rosacea to also develop other diseases, including cardiovascular, psychiatric, gastrointestinal, autoimmune, and neurological conditions. But just how much higher that risk is, and how big a group of patients is involved, has not been made specifically clear. I myself have been diagnosed with rosacea, inflammatory bowel disease (colitis), Raynaud's Syndrome, allergies and arthritis.

For people who flush, doctors are looking for proof that there is an interaction taking place between

the nervous and immune systems during neuroinflammation (flushing, erythema), the immune response (erythema, papules and pustules), and through fibrosis, as well as adaptive immunity taking place at a cellular level. Because of different subtypes and their overlapping symptoms, no single treatment exists for all patients with rosacea. However, in addition to avoiding triggers and maintaining a consistent skin care routine with sun protection, several topical and systematic therapies have shown benefits. Read more about rosacea treatments in these blog posts of mine:
Do I have rosacea? What to look for
How to treat rosacea redness, flushing and burning with medication - (The science behind my current medication)

Scientists found an 'override switch' in mouse B cells that messed up this behaviour and caused autoimmune attacks. "Once your body's tolerance for its own tissues is lost, the chain reaction is like a runaway train," said one of the team, Michael Carroll from Boston Children's Hospital and Harvard Medical School. "The immune response against your own body's proteins, or antigens, looks exactly like it's responding to a foreign pathogen." These B-cells-gone-awry could in turn explain the biological phenomenon known as epitope spreading , where our bodies start to hunt down different antigens that shouldn't be on the immune system's 'kill list'. Epitope spreading has long been observed in the lab but scientists have been in the dark about how it happens, and why autoimmune diseases evolve over time to target more and more healthy organs and tissues. In this case the research looked at a mouse model of the lupus autoimmune disease, considered an archetypal or 'classic' type of autoimmune disease that many others are based on. Lupus is known as 'the great imitator' because the disease can have so many symptoms resembling other common conditions and because it affects many organs. When B cells sense a foreign body – or something healthy that appears to be a foreign body – they swing into action in clusters called germinal centres. Those centres are why your lymph nodes become swollen when you've got a cold coming on, for example. B cell clones actually battle each other inside these centres so the body can determine which antibody is best suited to fight the threat, and in the case of this study that meant one colour of protein winning out against the others. The problem comes when the body incorrectly identifies a normal protein as a threat. When that happens, the B cell selection process produces what are known as auto-antibodies that prove very effective at harming our own bodies. Over time, the B cells that initially produce the 'winning' autoantibodies begin to recruit other B cells to produce additional damaging autoantibodies – just as ripples spreading out when a single pebble is dropped into water. This has only been examined in mice so far, but the researchers now want to use this confetti model to look at how B cell production of autoantibodies is regulated and gets sped up. Autoreactive B cells are competing inside germinal centres to design an autoantibody, but the immune response then broadens to attack other tissues in the body, leading to epitope spreading at the speed of wildfire. Hence, why people with one auto immune disease so often develop more and different ones over time. Eventually, blocking the germinal centers in some way could put a break on the vicious cycle that autoimmune diseases create. It would effectively block the immune system's short term memory. Unfortunately, as always, that kind of treatment is still a long way off.

Emmanuella Charpentier came up with a similar system to cut and paste DNA from organisms (CRISPR cas9) . DNA consists of 4 substances, given the letters C, G, A and T. The order of these substances dictates the genetic code of a cell. CRISPR can accurately read this info and change it. It allows DNA reprogramming through cutting and pasting in any cell, not just in virus DNA. She and her colleague Jennifer Doudna are up for a Nobel prize apparently, and won a lot of other prizes already for this discovery. They studied evolution, to change evolution. Rewriting our own genetical make-up. Reprogramming viruses, like an app would do viruses are software anyway, like a memory stick, loaded with specific information, and once it attaches to a physical structure, that allows the virus to load its program onto the cell. That program is nowadays: print more viruses. But viruses could also be loaded with a different message, one that we as humans find interesting to program into the cell. For instance make this protein, because it is a good drug for us, or load the program into a cancer cell and program it to die. Viruses can be reprogrammed and are like software like an app. And viruses today are designed, from scratch, in order to make biological programs with new applications possible. All cancers have different DNA, but some people are already working on viruses that are adjusted to very specific tumour genetics. Special DNA printers can then print that DNA and put it in viruses. Every cancer patient can this way get a personalized cancer drug. Digital synthetic virus designs and it's already tested on dogs with cancer. An epi-pen for all of us, uploaded by the doctor and auto-inject. Personalized medicine. It's going to happen eventually. A medical netflix subscription with which you keep your body healthy. Soon we can print medication and change ourselves genetically (I can't wait for that, hopefully before my old age they can cut out my genetic illnesses, ruthlessly!). People are trying to write programs now that eradicate cancer cells. Science students could soon have opportunities that today only pharmaceutical companies have.

Researchers under guidance of Richard Gallo from the University of California, San Diego, might have figured out why bacteria only causes acne in some people , and how to stop it. Pretty much all of our skin is covered in bacteria always, as a skin defense system against germs. Usually there is a balance and symbioses going on, and we don't get acne from it, but some people are more prone to such infections. Gallo and his colleagues showed that a usually harmless bacterium that lives on our skin starts triggering inflammation and breakouts when it finds itself trapped in airless, oily conditions, such as hair follicles. Everyone has hair follicles in their skin, but not all hair follicles are the same and created equal. Dr. Gallo and researchers now suspect that some people might have hair follicles that are more "suffocating" than others. The researchers specifically looked at a type of bacterium known as Propionibacterium acnes, which can cause acne breakouts.
"Most of us have P. acnes on our face all the time, but it doesn't always cause breakouts. So the team tested the bacteria under a range of conditions on the skin of mice to try and figure out what was going on. They showed that when trapped in airless environments alongside hair and skin cells, P. acnes turned sebum - the oil found on our skin - into fatty acids that activate inflammation in nearby skin cells. Usually this inflammation is switched off by enzymes called histone deacetylases, but the fatty acids produced by the bacteria deactivated that brake, so inflammation continued unchecked - going on to cause red, itchy breakouts. So far, the research has only been done on mice, but the team is now looking to replicate their results in humans, and they're hopeful that the inflammation pathway involved will be the same."

"For the first time, it shows how fatty acids derived from P. acnes act on skin cells to induce inflammation," Holger Brüggemann, an expert on skin bacterium from Aarhus University in Denmark, explained. New findings could also explain why teenagers are so prone to breakouts, because their sex hormones during puberty put their sebum production into overdrive, giving P. acnes more fuel. The bad news is that cleaning your face regularly isn't the answer, because the team showed that the bacteria clump together to form structures called biofilms, which effectively locks them onto your skin. And, when this type of bacterium isn't causing havoc inside suffocating hair follicles, P. acnes is actually beneficial to skin health, which explains why antibiotic treatments don't work for many people - and in some cases, can actually make things worse. But now that the team understands the root cause of the inflammation, they're confident they'll be able to come up with new treatments for acne. "We can either inhibit these fatty acids, or block their impact on the skin," Gallo told New Scientist. "We're working on how to do this . If we get lucky, it could lead to new medications in two to five years."

The researchers now want to investigate what it is specifically that makes some people's faces more susceptible to acne. In addition to having particularly suffocating hair follicles, they might also be genetically disposed to being more vulnerable to the inflammation triggered by P. acnes fatty acids. Or maybe the strains of bacteria they have on their skin make excessive amounts of fatty acids compared to other people's strains. "I think all of these aspects probably play a role," said Gallo. Once they've figured this out, they'll be a step closer to not only treating, but potentially preventing acne in the first place. Right now, doctors treat severe acne with either antibiotics, hormone regulators (such as the contraceptive pill), or isotretinoin - better known as Roaccutane. All of these come with side effects (some more severe than others), and worst of all, most of them don't offer long-term relief, or in some cases, they don't work at all.

New class of menopause drugs reduces severity of hot flushes in three days

A new class of experimental drugs reduces hot flushes in menopausal women by almost three-quarters in just three days. The treatment, tested by scientists at Imperial College London, also reduces the severity of hot flushes by over a third within three days of taking it. The research, funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR), is a new in-depth analysis of data collected from a clinical trial initially published last year. This class of new drugs may provide women with a much-needed alternative to HRT, but it could also be an interesting new treatment on the horizon for people with vascular rosacea and facial flushing. Other medication aimed at reducing the severity of hot flashes (for instance clonidine, mirtazapine, other SSRI-antidepressants and certain beta blockers) all are prescribed by various dermatologists to try to curb facial flushing, a difficult to treat rosacea symptom. The original drug trial, which was a randomised, double-blind, placebo-controlled trial, involved 37 menopausal women aged between 40 and 62 years old – and who experienced seven or more hot flashes a day. Participants were randomly chosen to first receive either an 80mg daily dose of the drug, called MLE4901 (which was previously developed as a drug for schizophrenia) or a placebo over the course of a four-week period. They then switched to receive the other tablet for an additional four weeks. This ensured the women acted as their own controls during the study, and the effects of the drug were clear. The researchers found that the compound MLE4901 significantly reduced the average total number of flushes during the four-week treatment period, as well as their severity, compared to when the patients received the placebo for four weeks.

The new experimental compounds are thought to work by blocking the action of a brain chemical called neurokinin B (NKB). Previous animal and human trials have shown increased levels of NKB may trigger hot flushes. The drug compound is thought to prevent NKB activating temperature control areas within the brain – which appears to halt hot flushes. The new data also revealed that the drug was as effective at improving daytime flush symptoms as it was at improving night time symptoms. Furthermore, the women reported a 82 percent decrease in the amount their hot flushes interrupted their sleep, and a 77 percent reduction in interruption to their concentration. Dr Julia Prague, first author of the study, explained: “As NKB has many targets of action within the brain the potential for this drug class to really improve many of the symptoms of the menopause, such as hot flushes, difficulty sleeping, weight gain, and poor concentration, is huge. To see the lives of our participants change so dramatically and so quickly was so exciting, and suggests great promise for the future of this new type of treatment.” The new analysis shows the compound has a significant effect within just three days explains Professor Waljit Dhillo, an NIHR Research Professor from the Department of Medicine at Imperial: “We already knew this compound could be a game-changer for menopausal women, and get rid of three-quarters of their hot flushes in four weeks. But this new analysis confirms the beneficial effect is obtained very quickly – within just three days.” Professor Dhillo explains this specific compound will not be taken further in trials, due to side effects that may affect liver function. However, two very similar drugs, which also block NKB but do not appear to carry these side effects have entered larger patient trials, with one such trial launched in the US last year. The research was funded by the Medical Research Council and the National Institute for Health Research. The study was supported by the Imperial NIHR/Wellcome Trust Clinical Research Facility. ( source )

In this good research paper, scientists summarized the treatment options for neurogenic rosacea rosacea subtype 1 with skin redness (erythema), skin burning and flushing.

It states that this rosacea subtype requires a unique approach of management. In the paper, typical symptoms and triggers are mentioned for people with this type of rosacea, based on 14 test persons:

Facial erythema is seen in most patients at baseline and uniformly during flares. Inflammatory papules and pustules and rhinophymatous change are unusual in this subset of patients.

*Topical metronidazole (0 of 12 were helped)
*Topical steroids (1 of 8)
*Oral antibiotics, usually tetracyclines (4 of 8).
Most patients benefited from treatments that tried to calm the burning pain down, for instance gabapentin (5 out of 11), duloxetine (4 of 6), pregabalin (1 of 4), tricyclic antidepressants (2 of 3), and memantine (2 of 2). Topically creams were only occasionally effective, for instance doxepin, glycopyrrolate, amitriptyline, capsaicin, and ketamine.

Effective were:
*Hydroxychloroquine (Plaquenil) (3 of 5)
*Beta blockers
*Clonidine

The researchers also added that this group of patients with strikingly prominent neurologic (nerve pain) symptoms, are an underrecognized subgroup of rosacea. By highlighting and formally naming this subgroup, they hope to increase awareness and recognition of these patients and aid the practicing dermatologist in their therapeutic management. The cause of rosacea is complex, poorly understood, and likely multiple causes and factors, including bad functioning blood vessels in the facial skin and with most likely an auto-immune aspect to it. Also the nerves in the skin are no longer functioning as they should with this rosacea type. There is an element of abnormal response to heat and an increase of inflammation in the skin. And the injury of the nerves in the skin of rosacea patients with this subtype 1, also leads to dysesthesias : an abnormal sensation in the skin, of pain, skin burning, wetness, itching, electric shock, and pins and needles. It is sometimes described as feeling like acid under the skin .

Stanford University has started clinical trials for Secukinumab , used to treat rosacea. It is an open label study to assess the effect of Secukinumab in moderate to severe papulopustular rosacea. However hopes are that it will also address rosacea redness and inflammation. Test participants receive injections of secukinumab. First impressions from one rosacea patient who is undergoing these tests were: "Redness was almost completely gone by Saturday afternoon. [one day post injection]. The doctor says full results are shown anywhere from 12 to 16 weeks."


Update from this rosacea patient, September 29th 2017:
"Secukinumab update:

Secukinumab is a "human IgG1κ monoclonal antibody" that binds to the protein interleukin (IL)-17A. It is injected once weekly for four weeks (or around 5 booster shots) and then once a month for 5 months. It works a bit like methotrexate suppressing the immune response and inflammation. Secukinumab lowers the bodies immune response and is used to treat auto immune diseases like psoriasis and related inflammation in the joints (artritis psoriatica). In psoriasis the bodies immune system goes in overdrive, and multiplies the skin cells too quickly, causing plaques of skin, inflammation and scaling and ultimately a lot of skin cell shedding. By lowering the immune system response, the skin symptoms can be calmed down too.

Rosacea does not have an issue usually with increased skin cell formation, but some scientists do think that rosacea can be an auto immune disease as well, having the bodies own immune system attacking normal tissue and as such creating inflammation and redness. I know of some severe rosacea sufferers who were given methotrexate and who had their skin issues (redness, flushing) calm down significantly. Side effects can be significant however, increased risk of infections (viral infections, nose and throat infections, sinus infections and other infections) and it even raises the risk of certain cancers. That is generally the downside of methotrexate. Luckily Secukinumab does not seem to come with an increased risk of cancer. Several studies show that secukinumab demonstrates "a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer."

So despite of secukinumab being somewhat comparable to methotrexate, a drug that lowers (auto)immune response and inflammation as well, it comes with far less severe side effect risks. On January 21, 2015, the FDA announced that it had approved secukinumab to treat adults with moderate-to-severe plaque psoriasis, followed later with the approval for the treatment of ankylosing spondylitis, and psoriatic arthritis. A 2016 study also showed that secukinumab seems to be effective in the treatment of multiple sclerosis. I am a bit hopeful for this new trial! I know that my dermatologist treated some very severe rosacea patients with methotrexate for a little while, and their skin really cleared up (also through suppressed immune response and inflammation), but that the increased risk of infections was too tricky. Since secukinumab does not have that side effect profile as much, it seems a great alternative.

Open Label Study to Assess the Effect of Secukinumab in Moderate to Severe
Papulopustular Rosacea

Study Type:Interventional
Study Design:Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title:An Open Label Phase 1b Study of Secukinumab in Patients With Moderate to Severe Papulopustular Rosacea
    reduction in the number of papules and/or pustules in moderate to severe papulopustular rosacea at week 12 vs 0 [ Time Frame: 12 weeks ]


Estimated Enrollment: 24
Anticipated Study Start Date: July 14, 2017
Estimated Study Completion Date: January 1, 2019
Estimated Primary Completion Date: July 1, 2018 (Final data collection date for primary outcome measure)
Ages Eligible for Study: 18 Years and older (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
  • 1) moderate to severe papulopustular rosacea defined clinically using the grading system of Wilkin et al. (2004) as having at least ten lesions (either papules or pustules) on face at time of enrollment 2) age 18 years or greater willing and able to understand and sign informed consent form
  • 1) known hypersensitivity to secukinumab 2) topical or oral anti-rosacea medication usage for 28 days prior to enrollment 3) active Crohn's disease, as secukinumab may exacerbate this disease 4) active infection including tuberculosis, hepatitis B or C, human immunodeficiency virus 5) participants with latent tuberculosis will need to have treatment initiated prior to starting study drug 6) pregnant or lactating 7) active and/or uncontrolled medical conditions that may interfere with study procedures or obscure rosacea assessment such as cutaneous lupus 8) use of retinoids within past 3 months of enrollment 9) use of antibiotics within 4 weeks of enrollment 10) use of light based or laser treatment to face within 8 weeks of enrollment 11) use of topical or systemic steroids within 4 weeks of enrollment 12) acne conglobate, acne fulminans, chloracne, severe acne requiring systemic treatment
United States, California
Stanford Dermatology Recruiting
Redwood City, California , United States , 94603
Contact: Anne Chang, MD 650-721-7151 [email protected]
Contact: Michaella Montana, BS 650 721 7159 [email protected]

I've read recently that several companies are busy with clinical trials for a new migraine treatment with anti CGRP drugs, with positive results. These drugs are geared for migraine, but the way in which they work (their aim is to constrict blood vessels), makes them also exciting and possible future treatment options for rosacea.

CGRP is a 37–amino acid (neuro)peptide that is released by the nervous system and is a very potent blood vessel dilator. When released from the trigeminovascular nerves, CGRP is a powerful vasodilator of the blood vessels of the brain. Medication that was designed to block CGRP’s receptor turned out to have too many side effects. Then researchers focused on antibodies to block CGRP, because they can last a long time in the body and can be exceptionally specific, reducing the frequency with which people need injections. many colleagues didn't think it was worth a shot, because antibodies are generally too large to pass through the blood-brain barrier, and it was thought to be necessary for migraine meds to target migraines actually in the brain. However, to their surprise, the CGRP peptide-blocking antibody "TEV-48125" managed to just do this treating migraines from outside the brain, by blocking CGRP only in the peripheral nervous system. Trials show significant reductions in number of headache days over placebo, even for the most severe cases. This type of drug also lowers the risk of the side effects often provoked by drugs that act in the brain. Although there are still worries too, because of CGRP’s natural role in dilating arteries and maintaining blood supply to the heart and brain. “Theoretically, if you block CGRP you could translate a minor stroke or cardiac ischemia … into a full blown stroke or heart attack.” So far, the companies say they haven’t seen that or other significant side effects in the several thousand people who have completed phase I and II trials, but the drugs have only been administered for up to 6 months—not long enough to judge long-term effects. CGRP-blocking drugs are also tested now for fibromyalgia, a condition that is
somewhat overlapping in some symptoms with rosacea. And scientists have also discovered that CGRP plays a role in rosacea flushing and skin redness. Interestingly, migraine medication has so far been helping some people with rosacea. Drugs like propranolol, imitrex/sumatriptan and even botox have all been helpful for rosacea. Someone on the Rosacea Forum is successfully using the migraine med Maxalt/Rizatriptan for her severe type 1 rosacea/erythromelalgia.


Stress, rosacea flares and CGRP
CGRP is also part of the puzzle as to why stress can make rosacea flare so badly. Apart from stress raising blood pressure and inflammatory substances, experiments in rats now showed that corticotropin-releasing hormone, which the body releases in response to stress, also increases neuronal production of CGRP. More CGRP means much more blood vessel dilation, which causes our rosacea flares (for those with burning, flushing and redness). Strikingly, many migraine medications also boost CGRP in animal models, possibly explaining why people who use drugs like triptans too frequently end up with more severe migraines.


CGRP antagonistic treatment options for Rosacea

I hope that we can soon benefit from injections of this CGRP peptide-blocking antibody "TEV-48125". Those medications are in the making now, from what I read, so it might take a bit more time before they come on the market. In the meantime, scientists are also working on a topical cream that works in a similar way, blocking CGRP. A patent is created for a special cream for rosacea patients to do just that. 'Therapeutic/cosmetic compositions comprising CGRP antagonists for treating skin redness/rosacea/discreet erythema.' But they are not just focusing on a CGRP blocker: "Skin redness, rosacea and/or discreet erythema afflicting a mammalian, notably human patient, are therapeutically treated by administrating to such patient a therapeutically/cosmetically effective amount of at least one CGRP antagonist , advantageously in combinatory immixture with at least one antagonist of a neuropeptide other than CGRP, e.g., a substance P antagonist , and/or at least one inflammation mediator antagonist . "



So this patent for a new cream will focus on three different things
*blocking CGRP (and thus blocking one factor that leads to blood vessel dilation in our faces)
*blocking P antagonist
*blocking an inflammation mediator in the skin

CGRP is a polypeptide chemical species that is produced and released by nerve endings. CGRP dilates blood vessels and is involved in lung issues and inflammatory diseases, in allergic diseases and in certain skin diseases such as eczema and prurigo. It is a new concept to treat skin redness with a CGRP antagonist. But developers now think that CGRP blocking substances can not only treat skin redness, but also prevent it from occurring. Blocking CGRP in the skin of our faces, through a cream, should help combat skin redness and flushing. This will be tested on test persons with rosacea, by first inducing a flush (with a substance called capsaicin), and then applying the cream and seeing if the redness can be toned down by it. They will test if the levels of CGRP that is released (and that cause blood vessel dilation), will be reduced upon measuring. Secondly, P antagonist will have to be another type of antagonist of a neuropeptide used, reinforcing the CGRP antagonist. A third ingredient will have to reduce inflammation in the skin (and they will select it from a group consisting of histamine antagonists, interleukin 1 antagonists, and tumor necrosis factor alpha antagonists, and the inflammation mediator antagonist is supposed to be a diethylenediamine, aminopropane or phenothiazine compound, selected from a group consisting of cinnarizine, cyclizine, dexchlorpheniramine, triprolidine, alimemazine, promethazine, auranofin, lisophyline, A802715, sulfasalazine, cetirizine hydrochloride, loratidine, esbatine, and setastine hydrochloride).


The patent described rosacea as follows:
"Rosacea is a skin affliction characterized by erythema (redness) of the face, predominantly on the cheeks, the forehead and the nose, hyperseborrhoea (thickened skin) of the face on the forehead, the nose and the cheeks, and an infectious component manifesting acneiform pustules (skin outbreaks and bumps). Moreover, these indications are associated with a neurogenic component, namely, a cutaneous hyperreactivity of the skin of the face and of the neck (nerve burning), characterized by the appearance of redness and subjective sensations of the itching or pruritus type (skin itching), sensations of burning or of heating, sensations of stinging, tingling, discomfort, tightness, etc.
These signs of hyperreactivity may be triggered by very varied factors such as the intake of food or of hot or alcoholic drinks, by rapid temperature variations, by heat and in particular exposure to ultraviolet or to infrared irradiation, by a low relative humidity (dry air), by exposure of the skin to strong winds or to currents of air (conditioned air, fans and blowing machines), by the application of surfactants (soaps, washing detergents), irritant dermatological topical agents (retinoids, benzoyl peroxide, alpha-hydroxy acids, etc.), or the use of certain cosmetics, even when these are themselves not recognized as being particularly irritating.

Hitherto, the mechanism for triggering these indications was very poorly understood and rosacea was treated with active agents such as anti-seborrhoeic agents and anti-infection agents, for example benzoyl peroxide, retinoic acid, metronidazole or cyclins, which act on infection and hyperseborrhoea but do not permit the neurogenic component of this affliction, and in particular hyperreactivity of the skin and redness, to be treated. Similarly, hitherto no treatment existed for the redness which develops in discreet erythema. This latter affliction occurs at times of emotion and is characterized by redness of the face and neckline, which possibly may be accompanied by pruritus (itching). This condition is very irritating for individuals suffering therefrom, and to date it could only be treated by beta-blockers, powerful drugs used for treating hypertension and exhibiting many contraindications.
Thus, serious need continues to exist in this art for an effective treatment of skin redness and of the state of hyperreactivity of skin affected by rosacea or discreet erythema." The patent acknowledges that their invention does not necessarily have to be applied through a cream on top of the skin: it is also possible to inject the CGRP antagonist into the skin, or even to take pills to achieve the same effect. They aim for a acceptable cream carrier, but the problem with most creams is that they contain alcohols (they help the active ingredient to penetrate deeper into the skin) and preservatives (parabens for instance, which are skin irritants). And some companies even put propylene glycol and plastic elements into their creams, which make them pretty much unusable for those with hyper reactive, intolerant rosacea skin. In the examples for cream ingredients that are mentioned in the patent itself, the list seems fairly OK to be honest, the only ingredients I wouldn't tolerate myself (but my skin is sickly reactive) are sunflower oil (12%), stearic acid, fragrance (if they are smart they leave that one out!) and preservatives.

Rosacea is a common skin disorder that is not yet fully understood. It has been suggested that it is linked to interactions between nerves and blood vessels, which release inflammatory substances, but also specific neuropeptides, which cause the blood vessels in our skin to dilate. This is probably especially the case in rosacea subtype 1, with flushing, redness of the skin and burning (and less in subtype 2 with pimples and skin outbreaks). These specific neurotransmitters are easily triggered to be released, for instance by stress, ultra-violet light or microbial antigens. And when they are released, they trigger flushing and redness for us. When you flush from heat or temperature changes, it are primary sensory neurons that stimulate the blood vessels to dilate and to release inflammatory neuropeptides. These neuropeptides play a very important role in rosacea. For example, flushing has been suggested to be controlled by two vasodilatory mechanisms including humoral substances and neuronal stimuli (Wilkin, 1988), but the exact mechanism of action is unknown. Although scientists learn increasingly more over time about how sensory nerve endings are activated to release vasoactive neuropeptides during flushing, which also triggers the inflammatory process in different stages of rosacea. Specific TRP Channels are involved in this.

Capsaicin receptor
This newly discovered TRP channel receptor family is currently composed of 28 channels with seven subfamilies. They sit on neuronal and non-neuronal tissues all over the body. One in particular is interesting for rosacea, as it is singe handedly capable to cause a lot of blood vessel dilation. It is called vanilloid 1 (TRPV1), also known as the “capsaicin receptor”. It has many functions, including as a censor in cells, signalling pain sensations and inflammation. This receptor responds to a lot of triggers, including heat, cold temperatures, touch and changes in the cell membrane.

The image left shows the structure and activators "capsaicin receptor" (TRPV1), as well as ankyrin 1 (TRPA1) receptors in primary sensory neurons with a link to rosacea. Both receptors have a similar structure and can be activated by temperature increases or for instance by spicy food. TRPA1 can be activated by reactive oxygen species (ROS they are chemically reactive chemical species containing oxygen. They are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cells. But during times of environmental stress, for instance when exposed to UV radiation or heat, ROS levels can increase dramatically). And when activated, TRPA1 will signal for signal blood vessel widening. When this happens, mediators, such as proteases, are released, and they create inflammation. It is thought that these two, TRPV1 and TRPA1, have an interaction with each other, that regulates their activity.


TRP Channels as Thermosensors in Rosacea?
Both TRPA1 and TRPV1 channels are triggered by heat and temperature increase. It is no surprise probably that 53% of rosacea patients stated in polls that hot and cold weather are triggers for their rosacea. Very cold temperatures can also directly activate TRPA1 channels. Perhaps TRPA1 is a “cold sensor” channel. Another TRP channel (melastin) TRPM8 is also activated at temperatures below 󕾇 °C. So when you are hypersensitive for the cold, it is most likely this TRPA1 channel deep in your body cells, that is responsible! (Just so you know how to blame haha). Anyway, the cold can also cause inflammation in rosacea skin.

But heat is just as much a trigger for rosacea. Heat, sun, hot baths they all dilate out blood vessels as our body temperature rises. And rosacea skin already is a little bit warmer than 'normal' skin temperature. When the temperature rises quickly, even in healthy people, our cells produce TRPV1. Therefore TRPV1 channels have an essential role in temperature hypersensitivity when it comes to inflammation. And on top of all this, rosacea facial skin has shown to have a significantly lower heat pain threshold compared to the rest of our skin. Our faces notice heat quicker and develop painful skin much quicker (tingling, burning, prickling, blushing, pain) when we are in a warm surrounding than the rest of our bodies skin. I think everyone had detected that for him or herself already anyway :) And again, our little friend TRPV1 seems to be involved in this. The same goes for flushing after eating spices TRPV1 is dubbed the "capsaicin receptor", because it is directly activated when someone eats capsaicin, which is the chemical that makes chilli peppers so hot. The same happened in trials with mice capsaicin also stimulates an increase in mouse skin blood flow, which shows that this blood flow increase is triggered ultimately by TRPA1 stimulation. TRPA1 is triggered by cinnamaldehyde, the main ingredient of cinnamon, which also leads to intense and acute painful burning sensation. This is even the case by those who do not have rosacea, and the burning they can feel from this is probably similar to that observed in rosacea. These findings highlight that TRPA1 and TRPV1 may be activated by the triggers of rosacea, such as cold or hot temperatures and spices, to mediate flushing or burning sensation episodes of rosacea.

Another aspect that makes rosacea skin burn and flush, is blood flow . Flushing longer than 10 minutes is indicative for rosacea (and therefore 'not normal' for normal skin). The smallest systems of blood vessels in our body are dilated in rosacea patients. TRPA1 is also here a factor. It sits in the basal layer of the epidermis, in the dermis, and in the epithelium of the hair follicle, so basically all throughout our skin. And when this TRPA1 is activated (for instance through heat, cold, stress, spices), a substance called "proinflammatory cytokine IL-1" is released, which is a key contributor to skin inflammation. Our skin actually recovers from such a TRPA1 triggered rosacea attack, by exposing our skin to cold air. Apart from more blood flow in the skin, rosacea patients in studies also showed heightened sympathetic nerve activity compared to those without rosacea. The sympathetic nervous system is a part of the body’s autonomic nervous system that controls involuntary functions such as heart rate, digestion, breathing and perspiration. This portion of the autonomic nervous system functions largely below the level of consciousness and has been shown to respond to emotion.


Substance P and CGRP in Rosacea
So, studies have shown that activation of TRPV1 (by capsaicin) and TRPA1 (by mustard oil) caused the release of neuropeptides. Normal human skin that was rubbed in with a cream containing capsaicin, showed a big red flare. But, this flare could then controlled again by a specific TRPV1 antagonist , SB705498. And there is also a new oral CGRP antagonist, telcagepant , which also managed to bring down a capsaicin-induced flushed skin reaction. Ultimately, what makes our skin flare, is not TRPV1, but another chemical, that is triggered by TRPV1: called CGRP . CGRP is one of the strongest blood vessel dilators in the skin. And to make matters worse, it makes sure that your skin also has increased inflammatory substances as a result of all this extra blood flow going around. The neuropeptide SP is elevated in rosacea skin. They linger around the dilated blood vessels. Research showed that laser treatment reduced facial sensitivity, sensory nerve marker, and SP-positive nerve fibers in the skin of 31 rosacea patients. And there is also evidence that SP can also induce skin redness. When rosacea patients have an inflammatory flare, and biopsies are taken from their skin, scientists tend to find widely dilated blood vessels in the skin. SP might play a role in all this, as SP can stimulate mast cells to release histamine and 5-hydroxytryptamine . These mediators bind to histamine H1 receptors and serotonin 5-hydroxytryptamine-1 receptors, and as such they cause blood vessel dilation through the nerves of the skin. CGRP can make matters worse then, by forming skin redness. It is therefore a whole cluster of substances that work together to fire up a flare for us: CGRP creates blood vessel dilation and SP triggers skin redness, histamine release and inflammation, and they even strengthen each others powers by blocking degradation of each other by the body.

Proteases in Rosacea
It is also known that protease activity is higher in the facial skin of rosacea patients, and that antibiotics such as tetracyclines can indirectly inhibit (control) these proteases. Proteases also degrade elastin and collagen, which means your skin becomes less firm and strong and is not beneficial for the lymphatic system in your skin. They also indirectly increase inflammation in the skin, by stimulating the release of SP and CGRP. And in the last place, there is Reactive Oxygen Species (ROS) , which also seems to play a role in rosacea. Substance P can cause their release. There is evidence in the literature suggesting that inflammation in the early stage of rosacea may be linked with ROS such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, which are released by inflammatory cells such as neutrophils. The level of ROS was significantly higher in the facial skin of patients with rosacea compared with healthy control subjects, OR of the same rosacea patients after being treated with the antibiotic azithromycin. ROS is involved in microbicidal activity.

Cathelicidin can stimulate ROS, which plays a role in inflammation. And ROS is in turn again linked to TRPV1 receptor activation, which dilates our blood vessels and increases blood flow in the skin. It is a rosacea avalanche, in other words, when all working and activating each other together. And this is another reason why rosacea should be treated as soon as possible and controlled.

So in summary , TRPV1 and TRPA1 may contribute to the development of rosacea. The high skin reactivity of rosacea skin can be blamed on TRPA1 and TRPV1 receptors. When they are activated, they create blood vessel dilating substances such as CGRP and SP, as well as inflammation, which may further aggravate the symptoms of rosacea. They work together and strengthen each others actions. All the more reason to be very excited about this new treatment option blocking of the neuropeptide-driven inflammatory processes resulting from activation of TRPV1 and TRPA1 receptors. This could become a completely new therapeutic approach to treating rosacea.