Earthing – scientific concepts

Transfer those electrons!
Transfer those electrons!

Humans have always been in contact with the earth’s electrical field since the beginning of time. That has changed with the advent of shoes, which have separated us from a direct connection with the earth. The earth is full of electrons that freely travel to things in contact with it. The build up of electrical charges in our bodies as our systems function in their usual way is impacted by direct grounding connection to the earth, which can restore neutrality of our body’s electrical potential. Mounting evidence suggests that the Earth’s negative potential can create a stable internal bioelectrical environment for the normal functioning of all body systems. Moreover, oscillations of the intensity of the Earth’s potential may be important for setting the biological clocks regulating diurnal body rhythms, such as cortisol secretion.

There is evidence that electrons from antioxidant molecules neutralize reactive oxygen species (ROS- free radicals) involved in the body’s immune and inflammatory responses. Electrons are absorbed into the body through direct contact with the Earth and likely neutralize ROS  and reduces acute and  chronic inflammation. Because the body is electrically conductive,   free electrons are able to enter the body.

During recent decades, chronic illness, immune disorders, and inflammatory diseases have increased dramatically, and some researchers have cited environmental factors as the cause. However, the possibility of modern disconnection with the Earth’s surface as a cause has not been considered.

Earthing (also known as grounding) refers to contact with the Earth’s surface electrons by walking barefoot outside or sitting, working, or sleeping indoors connected to conductive systems, some of them patented, that transfer the energy from the ground into the body.  The Earth’s electrons induce multiple physiological changes of clinical significance, including reduced pain, better sleep, a shift from sympathetic to parasympathetic tone in the autonomic nervous system (ANS), and a blood-thinning effect.

Patients who practice grounding reportsignificant relief from asthmatic and respiratory conditions, rheumatoid arthritis, PMS, sleep apnea, and hypertension while sleeping grounded.

The majority of subjects with high- to out-of-range nighttime secretion levels of cortisol experienced improvements by sleeping grounded. This is demonstrated by the restoration of normal day-night cortisol secretion profiles in individuals that sleep while grounded. Patients sleep more and fall asleep quicker by being grounded, with less daytime fatigue and sleepiness and less nighttime pain.

One study showed that when the body is grounded, its electrical potential becomes equalized with the Earth’s electrical potential through a transfer of electrons from the Earth to the body. Feynman said that when the body potential is the same as the Earth’s electric potential (and thus grounded), it becomes an extension of the Earth’s gigantic electric system. The body of the grounded person is not subject to the perturbation of electrons and electrical systems. There is no question that the body reacts to the presence of environmental electric fields, which induce changes in our own bodies and grounding, just like a house’s electrical system, is equilibrated by this process.

Earthing the human body showed significant effects on electrophysiological properties of the brain and musculature,  and on the noise and stability of electrophysiological recordings. Taken together, the changes in EEG, EMG, and BVP suggest reductions in overall stress levels and tensions and a shift in ANS (Autonomic nervous system) balance upon earthing. An immediate decrease (within a few seconds) in skin conductance (SC) at grounding and an immediate increase at ungrounding blood oxygenation (BO) variance decreased during grounding  The immediate decrease in SC indicates a rapid activation of the parasympathetic nervous system and corresponding deactivation of the sympathetic nervous system. This is good for human health. Pain reduction from sleeping grounded has also been documented.

Muscle injury in humans causes inflammation, and studies of grounding demonstrate more rapid recovery. Grounded men had only a slight decrease in white blood cells, indicating scant inflammation and a shorter recovery time in muscle injury.

Grounding may also improve heart rate variability (HRV), a measurement of the heart’s response to ANS regulation. During the grounded sessions, participants had statistically significant improvements in HRV.

Grounding during a single night of sleep resulted in statistically significant changes in concentrations of minerals and electrolytes in the blood serum: iron, ionized calcium, inorganic phosphorus, sodium, potassium, and magnesium. Renal excretion of both calcium and phosphorus was reduced significantly. This may impact bone loss.

Earthing accelerated the immune response, as demonstrated by increases in gamma globulin concentration.

In the absence of Earth contact, internal charge distribution will not be uniform, but instead will be subject to a variety of electrical perturbations in the environment. Absence of a common reference point, or “ground,” electrical gradients, due to uneven charge distribution, can build up along tissue surfaces and cell membranes. Charge differentials will influence biochemical and physiological processes   Local alterations in the charge profiles around these channels can lead to electrical instability of the cell membrane and to the inappropriate spontaneous activity observed during certain pathological states (i.e pain and inflammation)

Reduction in inflammation as a result of earthing has been documented with infrared medical imaging  and with measurements of blood chemistry and white blood cell counts. The logical explanation for the antiinflammatory effects is that grounding the body allows negatively charged antioxidant electrons from the Earth to enter the body and neutralize positively charged free radicals at sites of inflammation.

Earthing  also significantly reduces blood viscosity.

Rapid shifts in the ANS from sympathetic to parasympathetic dominance, improvement in heart rate variability, and normalization of muscle tension has been seen in studies of people who were grounded.

Going barefoot as little as 30 or 40 minutes daily can significantly reduce pain and stress in some studies.

www.earthinginstitute.net  < Link to earthing institute

So the bottom line is there a benefit to barefoot walking in nature. The earth, with it’s negative ionic charges, conducts into our bodies in  a positive manner. Walking, sitting, laying all allow electrons to flow into the body and there is a belief that his promotes health. Earthing improves blood viscosity, heart rate variability, inflammation, cortisol dynamics, autonomic nervous system functioning, and decreases stress levels.

Standing in sand at the beach, for example, drains the positive ions causing stress and inflammation. The body-spirit complex is helped in the process, allowing us to feel renewed.

The effects of grounding (earthing) on inflammation, the immune response, wound healing, and prevention and treatment of chronic inflammatory and autoimmune diseases

Bioenergetics of the aging heart and skeletal muscles modern concepts and controversies

Charge transfer in the living matrix

Can Electrons Act as Antioxidants A Review and Commentary – Links

Can Electrons Act as Antioxidants A Review and Commentary

An Overview of Biofield Devices

Assessment of the redox status in patients with metabolic syndrome and type 2 diabetes reveals great variations.

Variations in oxidative stress markers in elite basketball players at the beginning and end of a season

Assessment of eccentric exercise-induced oxidative stress using oxidation-reduction potential markers.

Effects of Post-Race Nutritional Intervention on delayed -onset muscle soreness and return to activity in triathletes

A review of nutritional intervention on delayed onset muscle soreness

Vibration Therapy in Management of Delayed Onset Muscle Soreness (DOMS)

Whole-Body Vibration and the Prevention and Treatment of Delayed-Onset Muscle Soreness

Pilot Study on the Effect of Grounding on Delayed-Onset Muscle Soreness

Grounding after moderate eccentric contractions reduces muscle damage

Earthing (Grounding) the Human Body Reduces Blood viscosity – a major factor in cardiovascular disease

Can Electrons Act as Antioxidants – A Review and Commentary

Emotional Stress, Heart Rate Variability, Grounding, and improved autonomic tone

Earthing Health Implications of Reconnecting the Human Body to the earths surface electrons

Is modern life ravaging our immune systems_ _ The San Diego Union-Tribune

 

 

Eat your greens – chlorophyll metabolites in our blood may be maintaining our blood anti-oxidants.

  • Eat your greens!
    Eat your greens!

    Everyone knows about CoQ10, with many people frequently taking it for ‘vascular health’ . It is true that ubiquinol in the blood stream is an anti-oxidant that helps maintain vascular integrity. Ubiquinol–10  is an endogenously synthesized lipid antioxidant that scavenges free radicals and is involved in a-tocopherol homeostasis. It prevents lipid peroxidation and in the process is oxidized to ubiquinone.

  • 95 % of the quinone is maintained as ubiquinol, which must be regenerated from ubiquinone after it prevents lipid oxidation.
  • The study below demonstrated derivatives of chlorophyll can catalyze the reduction of ubiquinone to generate ubiquinol in plasma. The chlorophyll in our system is obtained from green leafy vegetables, and it is derivatives of the chlorophyll that may be catalyzing the reforming of ubiquinol, rather than ascorbic acid, carotenoid, tocopherol and flavonoid antioxidants that are usually given the credit for this process.
  • In the blood stream, metabolites of chlorophyll , such as chlorophyllide a, pheophytin-a, pheophorbide-a, methyl pheophorbide-a, 10-OH-pheophorbide-a, 10- OH-methyl pheophorbide-a, pyro pheophorbide-a and methyl pyropheophorbide are formed and may catalyze the photoreduction of ubiquinone to ubiquinol.
  •  Both light and light-absorbing chlorophyll metabolites can be present in capillaries, arteries and veins of several animals including humans. If chlorophyll metabolites catalyze the photoreduction of plasma ubiquinol in vivo, it would be a novel mechanism to maintain high levels of plasma ubiquinol – and this is what the paper listed in it’s research proposes, is that light through our skin drives chlorophyl metabolites to regenerate the phytonutrient ubiquinol.
  • Dietary Chlorophyll Metabolites Catalyze the Photoreduction of Plasma ubiquinone
  • Bottom line: Eat your greens and get sunshine!

Consumption of fruits and vegetables was inversely associated with stroke incidence, stroke mortality, ischemic heart disease mortality, and CVD mortality.

Known modifiable risk factors for CVD include smoking, sedentary lifestyle, diet, dyslipidemia, hypertension, obesity, and type 2 diabetes.

The observed protective effect of consuming plant foods on chronic diseases is likely due to their bioactive components.

Plant Bioactives:

  1. Phytosterols are naturally-occurring plant sterols found in the non-saponifiable fraction of plant oils. Plants synthesize several types of phytosterols (e.g., sterols and stanols) that are structurally similar to cholesterol, except for the functional group substitutions on the sterol side chain at the C24 position. Beta-sitosterol (most abundant), campesterol, and stigmasterol comprise almost our entire intake of phytosterols. Since humans do not synthesize phytosterols, they must be obtained from the diet. The main dietary sources of naturally-occurring phytosterols are vegetable oils, nuts, grains and, to a lesser extent, fruits and vegetables. Commonly consumed products that are fortified with phytosterols, such as Benecol™ and Take Control™ are found in many foods. . Benecol spread contains stanol esters derived from tall oil (pine tree wood pulp) and Take Control margarine contains sterol esters from soybeans. Consuming 2–3 g/d of phytosterols from these products resulted in approximately 14% reduction in LDL  with no change in HDL. Thus, both sterols and stanols are equally effective in lowering LDL concentration. NCEP ATP 111 guuidelines: two grams of plant sterol or stanol esters daily for optimal dietary therapy for elevated LDL.
  2. Flavonoids: The most common flavonoids are flavones, flavanols, catechins, and anthocyanins, along with anthoxanthins. There is an inverse relationship between flavonoid intake and chronic diseases including CVD. Red wines contain an abundance of polyphenols including phenolic acids (for example, gallic acid, and caffeic acid), stilbenes (resveratrol), and flavonoids (for example, catechin, epicatechin, quercetin, rutin) . Gallic acid has more antioxidant activity than caffeic acid. Wine polyphenols can induce vasorelaxation via nitric oxide synthesis , decrease platlet aggregation, and decrease inflammatory mediators. Resveratrol is a polyphenol found principally in the skin of grapes and, in lesser amounts, in peanuts. It inhibits both LDL oxidation and platelet aggregation and scavanges free radicals.
  3. Lignans: Lignans are polyphenols found in plants, especially in flaxseed (secoisolariciresinol diglucoside), sesame seeds (sesamin, sesamolin), and soy, followed by whole-grains cereals (syringaresinol), and legumes, including nuts. Fruits and vegetables contain a wide variety of lignans (e.g., matairesinol (MAT), pinoresinol (PINO) and lariciresinol (LARI)) but in minute quantities. The proposed mechanisms by which dietary lignans could reduce the risk of CVD include the phytoestrogenic, and antioxidant activity of these compounds and their metabolites. Some plant lignans such as matairesinol (MAT), secoisolariciresinol (SECO), pinoresinol (PINO), and lariciresinol (LARI) are metabolized by intestinal bacteria to enterolignans (enterodiol and enterolactone) in various proportions.
  4. Resistant starches: Complex carbohydrates derived from starch contribute over half of humans’ daily energy requirements. Starch is a homopolysaccharide made in plants and stored in granules. Amylose and amylopectin are two polymers found in starch and are identified based on the glycosidic bond linking the α-D-glucose monomers. Amylose is a linear polymer with α-(1,4) linkages while amylopectin has linear α-(1,4) linkages and α-(1,6) branch points. There are four types of resistant starches – types one to four. Dietary sources of RS 1 include partially milled grains and seeds. RS 2 can be found in raw potatoes, legumes, just-ripe bananas, and high-amylose maize (HAM). RS 3 results from retrograded foods, such as potatoes, cereals, and breads. Chemically- or physically-modified starch and resistant maltodextrins are known as RS 4 and 5, respectively.  Due to lack of enzymatic hydrolysis, the direct contribution of glucose to blood from RS is minimal and allows for an attenuated post-prandial glycemic response.  Peripheral insulin sensitivity (Si) also improved by approximately 20% in individuals with metabolic syndrome consuming the same amount or RS.  There is  production of short chain fatty acids (SCFA) from RS fermentation by gut microbiota in the large intestine which tereby makes RS bioactive. The SCFA are capable of influencing risk, and even treatment, of NCDs such as diabetes and cancer through several mechanisms: decreasing luminal pH, enhancing mineral absorption, and stimulating the release of two satiety peptides known as glucagon-like peptide -1 (GLP-1) and peptide tyrosine tyrosine (PYY) to the periphery . RS can act as a prebiotic to selectively increase the concentration and viability of certain bacteria, such as Ruminococcus bromii .Intra-individual variation in gut microbiota may influence RS fermentation, the production of SCFA, and upregulation of GLP-1.
  5. Cyclic Dipeptides: Cyclic dipeptides (also known as 2,5dioxopiperazines; 2,5-diketopiperazines; cyclo (dipeptides); or dipeptide anhydrides) are relatively simple compounds and, therefore, are among the most common peptide derivatives found in nature. Consistent with a role for fermentation process in synthesis of cyclic dipeptides is the observation of high levels of cyclo (His-Pro) in foods that undergo fermentation and/or high heat treatment of protein-rich foods. Such examples are nutritional supplements (e.g., TwoCal HN and Jevity), milk, yogurt, sauces, and fermented fish . Active cyclic dipeptides include cyclo (His-Pro), cyclo (Leu-Gly), cyclo (Tyr-Arg), and cyclo (Asp-Pro). Of these only cyclo (his-Pro)[CHP] has been shown to be endogenous to animal kingdom. CHP may act as an appetite suppressant and satiety-inducer.  There is a possible role of CHP in insulin secretion and glucose metabolism.  CHP  causes higher insulin excursions without any change in C-peptide suggesting that CHP may decrease hepatic insulin clearance.    Items with CHP include tuna, fish sauce, Dried Shrimp , Spent Brewer’s Yeast hydrolysate, and others.
  6. Fruit Berries:  Polyphenols found in berries and other plant foods are particularly associated with anti-inflammatory, antioxidant, cardioprotective, and chemopreventive properties. Several compounds contribute to the antioxidant properties of berries and are typically found in the outer parts of the fruit or berry, most often as cinnamic and/or benzoic acid derivatives. Tanins, Anthocyanins,  carotenoids and stilbenes such as resveratrol are present in berries. Some amounts of resveratrol can be found in cranberries, strawberries, and other berries. Chokeberry, bilberry, and blackcurrant berries have the highest antioxidant capacity of the different berry fruits (umol Trolox/g fresh weight), and whole fruit extracts have greater antioxidant activity than many isolated phenolic compounds or vitamins . Strawberries are known to be high in phenolic compounds such as the phenolic acid derivative ellagic acid, and contain a significant amount of vitamin C. Blueberries are noted for a wide variety of anthocyanin compounds, while both cranberries and blueberries also contain significant concentrations of phenolic acids. Anti-oxidants in  Berries provide  anti-inflammatory activity, free radical scavenging and up-regulation of antioxidant enzyme genes, decreased levels and antioxidation of LDL, increases in circulating HDL, inhibition of platelet activation and aggregation, and improvements in endothelial function. Berries have been shown to provide improvements in blood pressure or hypertensive status due to increased NO bioavailability via activation of endothelial NO synthase.

Bioactive Plant Metabolites in the Management of Non-Communicable Metabolic Diseases

Statins’ effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementatio

Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP  <– we show that mammalian mitochondria can also capture light and synthesize ATP when mixed with a light-capturing metabolite of chlorophyll. To demonstrate that dietary chlorophyll metabolites can modulate ATP levels, we examined the effects of the chlorophyll metabolite pyropheophorbide-a (P-a) on ATP synthesis in isolated mouse liver mitochondria in the presence of red light (lmax5670 nm), which chlorin-type molecules such as P-a strongly absorb (Aronoff, 1950), and to which biological tissues are relatively transparent. We used P-a because it is an early metabolite of chlorophyll, however, most known metabolites of chlorophyll can be synthesized from P-a by reactions that normally take place in animal cells The same metabolite fed to the worm Caenorhabditis elegans leads to increase in ATP synthesis upon light exposure, along with an increase in life span.   Results suggest chlorophyll type molecules modulate mitochondrial ATP by catalyzing the reduction of coenzyme Q, a slow step in mitochondrial ATP synthesis. We propose that through consumption of plant chlorophyll pigments, animals, too, are able to derive energy directly from sunlight. We show that dietary metabolites of chlorophyll can enter the circulation, are present in tissues, and can be enriched in the mitochondria. When incubated with a light-capturing metabolite of chlorophyll, isolated mammalian mitochondria and animal-derived tissues, have higher concentrations of ATP when exposed to light, compared with animal tissues not mixed with the metabolite. The hypothesis is that photonic energy capture through dietary-derived metabolites may be an important means of energy regulation in animals.

  • To synthesize ATP, mitochondrial NADH reductase (complex I) and succinate reductase (complex II) extract electrons from NADH and succinate, respectively. These electrons are used to reduce mitochondrial CoQ10, resulting in ubiquinol (the reduced form of CoQ10). Ubiquinol shuttles the electrons to cytochrome c reductase (complex III), which uses the electrons to reduce cytochrome c, which shuttles the electrons to cytochrome c oxidase (complex IV), which ultimately donates the electrons to molecular oxygen. As a result of this electron flow, protons are pumped from the mitochondrial matrix into the inner membrane space, generating a trans-membrane potential used to drive the enzyme ATP-synthase.
  • Photons of red light from sunlight have been present deep inside almost every tissue in the body. Photosensitized electron transfer from excited chlorophyll-type molecules is widely hypothesized to be a primitive form of light-to-energy conversion that evolved into photosynthesis. Electrons would be transferred by a metabolite of chlorophyll to CoQ10, from a chemical oxidant present in the mitochondrial milieu. Many molecules, such as dienols, sulfhydryl compounds, ferrous compounds, NADH, NADPH and ascorbic acid, could all potentially act as electron donors. Intense red light between 600 and 700 nm has been reported to modulate biological processes. . Exposure to red light is thought to stimulate cellular energy metabolism and/or energy production by, as yet, poorly defined mechanisms. On a clear day the amount of light illuminating your brain would allow you to comfortably read a printed book. Photons between 630 and 800 nm can penetrate 25 cm through tissue and muscle of the calf . Adipose tissue is bathed in wavelengths of light that would excite chlorophyll metabolites. Utilization of these facts may have the potential for new therapies. A potential pathway for photonic energy capture is absorption by dietary-derived plant pigments. Dietary metabolites of chlorophyll can be distributed throughout the body where photon absorption may lead to an increase in ATP .

Chlorophyll-related compounds inhibit cell adhesion and inflammation in human aortic cells.

Chlorophyll Revisited Anti-inflammatory Activities of Chlorophyll a and inhibition of expression of TNFa

An Evidence Based Systematic Review of Chlorophyll by the Natural Standard Research Collaboration

An Evidence Based Systematic Review of Goji Lycium spp by the Natural Standard Research Collaboration

Risk of new-onset diabetes associated with statin use

 

 

 

PCSK-9 inhibitors and neuro-cognitive effects – it’s confusing!

 

PCSK9 (proprotein convertase subtilisin kexin type 9) binding to LDL receptors on hepatocytes promotes receptor degradation, prevents LDL-C clearance from blood, and increases serum concentrations of LDL-C. Evolocumab and Alirocumab  are human IgG2 monoclonal antibodies that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C.

The second FDA-approved PCSK9 inhibitor evolocumab (Repatha) appears to be similar in efficacy and safety to alirocumab (Praluent), but no comparative studies are available

  • Concerns are arising that the use of PCSK9  inhibitors are related to cognitive adverse events (CAE).  These events include delirium, cognition and attention disorders, dementia, disturbed thinking and perceptive disorders, and memory impairment.
  • Two trials brought this concern to light: The OSLER study (Evolocumab) and the ODYSSEY LONG TERM study ( Alirocumab). Both trials demonstrates an increased incidence of neurocognitive deficits, but these evnts were SELF-REPORTED events, for which there was no formal neuropsychiatric testing.
  • In the OSLER study for Evolocumab, there were 1104 patients evaluated using Evolocumab (420mg) and standard of care treatment versus standard of care treatment alone, Of all these patients, three reported amnesia and 5 reported memory impairment, whereas none did so in the standard of care group.
  • The treatment patients had visits every 4 weeks versus standard of care (not treated with Evocolumab)  who visited every 12 weeks with physicians, thus creating a potential responder bias by self reporting. Because the treated group was seen three time more frequently, there could be ascertainment bias involved since they had more opportunity to complain.
  • An 11 month follow up showed CAE’s in Evolocumab to be 0.9% versus 0.3% of those in the non-PCSK-9 treated group. There was no association between degree of LDL lowering and the self-reported cognition issues.
  • In the ODYSSEY LONG TERM trial, Alirocumab use was evaluated. The CAE events were 1.2% versus 0.5% in the placebo group similar to the OSLER trial.
  • Again the cognitive effects were all SELF-REPORTED n the above trials.
  • An investigation looking at cognitive issues with PCSK-9 inhibitors is being initiated currently: Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects (EBBINGHAUS) (ClinicalTrials.gov Identifier: NCT02207634). Participants without dementia or mild cognitive impairment at baseline will be randomized in a double-blind, placebo-controlled, multicenter study to evaluate evolocumab + background statin therapy versus statin therapy alone. The primary outcome will be the Spatial Working Memory test, an assessment of executive function. Results are expected in September 2017 with an enrollment of 4,000 subjects.  ( Early Evidence Linking PCSK9 Inhibitors to Neurocognitive Adverse Events: Does Correlation Imply Causation )
  • You may recall that statins have also faced years of controversy regarding cognitive effects, none of which have panned out. The fact remains that in the OSLER and ODYSSETY trials, there is a 50% reduction in cardiovascular events that offers benefits to a huge group of patients in spite of the neurocognitive risk, much of which is undefined. Remember: correlation does not equal causation and subjectively-reported adverse events are potentially fraught with bias. Even coronary heart disease has been associated with impaired cognition.

 

 

 

Links:

Early Evidence Linking PCSK9 Inhibitors to Neurocognitive Adverse Events_ Does Correlation Imply Causation_ – American College of Cardiology Efficacy and Safety of Alirocumab in Reducing Lipids Efficacy and Safety of Evolocumab in reducing lipids and cardiovascular events EfficacySafetyEvolocumabReducingLipids Lowering LDL Cholesterol Is Good, but How and in Whom PCSK9-inhibitors-their-effect-on-Lipoprotein-apheresis-patients-ISFA-May-2015

Safety and efficacy of anti-PCSK9 antibodies

 

 

Fiber intake and Better Lung Function with More Fiber!

There as a new study demonstrating an association between fiber intake and measures of lung function.

The article below, with the abstract at the following link: ArticleLink

The Relationship between Dietary Fiber Intake and Lung Function in NHANES

Corrine Hanson, Elizabeth Lyden, Stephen Rennard, David M Mannino, Erica P.A. Rutten, Raewyn Hopkins, and Robert Young

In this article, 1921 adults (ages 40-79) from NHANES (National Health and Nutrition Examination Surveys) data from 2009 to 2010 were evaluated.

Read More: http://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201509-609OC#.Vq7ZBbIrK70

 

association between fiber intake and measures of lung function

Read More: http://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201509-609OC#.Vq7ZBbIrK70

records of 1,921 adults between the ages of 40 and 79, each of whom participated in the National Health and Nutrition Examination Surveys (NHANES) during the years 2009 and 2010

In the study, the 1921 participants had FEV1 and FVC measured along with the percent FEV1 and FVC to look at airflow restirciton and obstruciton and apllying GOLD and Spirometry Grade classifications to determine airflow issues. Patients were categorized by grams of fiber consumed to asses change in airway parameters. Subjects in the highest quartile intake of fiber had mean FEV1 and FVC measurements that were 82 mL and 129 mL higher that the lowest quartile of intake (p=0.05 and 0.01, respectively), and mean percent predicted FEV1 and FVC values that were 2.4 and 2.8 percentage points higher (p=0.07 and 0.02, respectively)

Higher fiber intake was associated with a higher percentage of those with normal lung function (p=0.001) and resulted in a significant decline in the proportion of participants with airflow restriction (p=0.001)

Participants consuming more than 17.5 grams of fiber daily comprised the top quartile (and, at 571, the largest number of participants), while those whose diets included less than 10.75 grams each day (360 participants) were in the lower and smallest group

Bottom Line: 17 grams of fiber per day from fruits, vegetables, and legumes had better lung health, compared with those who consumed the least.  Fiber decreases inflammation!

Links for Fiber sources:

Foods with Fiber

Foods with Fiber Help Guide

Web MD Fiber Chart

High Fiber Foods Medline

Fiber-Famished Gut Microbes Linked to Poor Health <<- SciAM article  :: Short-chain fatty acids obtained from fiber are of particular interest, as they have been linked to improved immune function, decreased inflammation and protection against obesity

In a small study of 21 healthy adults with average U.S. fiber intake, one daily fiber snack bar (containing 21 grams of fiber) for three weeks significantly increased the number of Bacteroidetes bacteria and decreased the number of Firmicutes compared with levels before the study or after three weeks of eating fiber-free bars. Such a ratio—of more Bacteroidetes to fewer Firmicutesis correlated with lower BMI.  Fiber supplementation influences phylogenetic structure and functional capacity of the human intestinal micobiome  <<  The study link is here.

As gut microbes are starved of fermentable fiber, some do die off. Others, however, are able to switch to another food source in the gut: the mucus lining. As fiber consumption increased, the activity of genes associated with protein metabolism declined.  that this fuel switch had striking consequences in rodents. A group of mice fed a high-fiber diet had healthy gut lining, but for mice on a fiber-free diet, “the mucus layer becomes dramatically diminished

Notes: Yogurt, which is fermented milk, the main bacteria are Streptococcus thermophilus and lactobacillus.

Yogurt bacteria generally last two weeks in our gut. They help break down complex polysacharrides (sugars):

  • Xylans: polysaccharides in fruits, vegetables, milk, wheat
  • Pectins: found in apples, plums, orange, carrots – pectins are the jelling agents in jams and jellies
  • Fructans: found in barley, wheat, garlic, onion, and asparagus
  • Bottom line: Get more Fiber!

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Bacteria penetrate the normally impenetrable inner mucus layer

Mucin glycan foraging in the human gut microbiome

Saccharomyces boulardii CNCM I-745 in different clinical condition

Saccharomyces boulardii CNCM I-745 supports regenration of intestinal microbiota after diarrhea dysbiosis

Ulcerative colitis as a polymicrobial infection characterized by sustained broken mucus barrier

Saccharomyces boulardii Administration Changes Gut Microbiota and reduces hepatic steatosis, low grade inflammation, and fat mass on obese

Effects of Oral Saccharomyces boulardii on bacterial overgrowth, translocation in small bowel resection in rats

A new study finds that populations of bacteria in the gut are highly sensitive to the food we digest  these changes can happen incredibly fast in the human gut—within three or four days of a big shift in what you eat – and changes gene expression in the gut ability to rapidly change the microbiome would ensure maximum nutrient absorption from even the most unfamiliar foods. In the subjects eating animal products the researchers saw a significant uptick in Bilophila wadsworthia, a bacteria known to contribute to colitis, a variety of inflammatory bowel disease, in mice

The Effect of Diet on the Human Gut Microbiome

Dietary-fat-induced taurocholic acid promotes pathohbiont expansion and colitis  <<–Summary : we show that consumption of a diet high in saturated (milkderived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia2 . This was associated with a pro-inflammatory T helper type 1 (TH1) immune response and increased incidence of colitis in genetically susceptible Il102/2, but not wild-type mice. These effects are mediated bymilk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il102/2 mice. Together these data show that dietary fats, by promoting changesin host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. e low-fat purified mouse diet  LF promoted Firmicutes, but also resulted in a lower abundance of most other phyla, whereas polyunsaturated (safflower oil) fat (PUFA) and saturated (milk-derived) fat diets (MF) resulted in a higher abundance of Bacteroidetes and a lower abundance of Firmicutes. Whereas MF (Monounsaturated Fat)  and PUFA had similar effects on Bacteroidetes and Firmicutes, a significant bloom of a member of the Deltaproteobacteria, B. wadsworthia, was consistently observed only with MF. B. wadsworthia is a sulphite-reducing, immunogenic microbe that is difficult to detect in healthy individuals, but emerges under pathological conditions such as appendicitis and other intestinal inflammatory disorders  We find the dependence of B. wadsworthia on diet-induced taurocholic acid intriguing and possibly representative of how certain gut microbes use bile to their advantage. Bile formation is unique to vertebrates, providing the host with the ability to digest and utilize a far greater variety of dietary substrates. Bile also has potent antimicrobial properties that can contribute to the selection or exclusion of many potential gut microbiota. However, several intestinal pathogens, including protozoa such as Giardia, Microsporidia and Cryptosporidia, and bacteria such as B. wadsworthia, H. hepaticus and Listeria monocytogenes, are not only bile-resistant, but highly favoured in the presence of bile21,22, possibly through suppression of symbiotic, commensal microorganisms, allowing pathobionts and pathogens an opportunity to establish a niche.  Once established, the by-products of these bacteria, whether H2S or secondary bile acids, can serve as gut mucosal ‘barrier breakers’, allowing for increased immune-cell infiltration and thus acting synergistically with the bacterial antigenspecific immune response to induce tissue damage. 

Chowing Down On Meat, Dairy Alters Gut Bacteria A Lot, And Quickly

Ulcerative Colitis – Topic Overview

Diet rapidly and reproducibly alters the human gut microbiome <<– . Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes,Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals , reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease.

Gut Bacteria Might Guide The Workings Of Our Minds  <<–found that the connections between brain regions differed depending on which species of bacteria dominated a person’s gut. That suggests that the specific mix of microbes in our guts might help determine what kinds of brains we have — how our brain circuits develop and how they’re wired.

The adoptive transfer of behavioral phenotype via the intestinal microbiota  < Review of Evidence of microbiome– brain interactions in mice and focus on the ability to transfer behavioral traits between mouse strains using fecal microbiota transplantation.

Gut Microbiome and Weight  << Obese people appear to have less diverse microbes in their guts than  lean people.

Gut Microbiota from Twins Discordant for obesity modulate metabolism in mice   In this paper, scientists removed bacteria from the guts of four pairs of human twins in which one was obese and the other was lean. The researchers then transplanted those microbes into the guts of lab mice who didn’t have any of their own microbes. It was found that the mice that got microbes from the obese twins gained more weight and accumulated more fat than those who got microbes from the lean twin, even when the mice ate identical diets. Differences in body composition were correlated with differences in fermentation of short-chain fatty acids (increased in Lean), metabolism of branched-chain amino acids (increased in Obese), and microbial transformation of bile acid species (increased in Lean and correlated with down-regulation of host farnesoid X receptor signaling). Cohousing Lean and Obese mice prevented development of increased adiposity and body mass in Obese cage mates and transformed their microbiota’s metabolic profile to a leanlike state. Transformation correlated with invasion of members of Bacteroidales from Lean (Ln) into Obese (Ob) microbiota. Invasion and phenotypic rescue were diet-dependent and occurred with the diet representing the lower tertile of U.S. consumption of saturated fats and upper tertile of fruits and vegetables but not with the diet representing the upper tertile of saturated fats and lower tertile of fruit and vegetable consumption.  Collections generated from human microbiota samples can transmit donor phenotypes of interest (body composition and metabotypes) has a number of implications. Bottom line: Ridaura et al. ( 2) demonstrate that the microbiota from lean or obese humans induces similar phenotypes in mice and, more remarkably, that the microbiota from lean donors can invade and reduce adiposity gain in the obese-recipient mice if the mice are fed an appropriate diet. Analysis showed that members of the Bacteroidetes phylum, particularly Bacteroides spp., could pass from the Lean mice and colonize the Obese mice, suggesting that these bacteria were largely responsible for protection against increased adiposity. Lean twin–derived bacterial strains effectively colonized and ameliorated excess adiposity in Obch mice when the recipients were fed a low-fat, high-fi ber diet. This was not the case when the mice were fed a diet that was high in saturated fat but low in fiber. One of the main activities of the intestinal microbiota is to break down and ferment dietary fibers into short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. The host absorbs these acids, and humans obtain perhaps 5 to 10% of daily energy requirements from them. Ridaura et al. show that the microbiota in Lean mice produces greater amounts of SCFAs, particularly propionate and butyrate, and digests more of the plant fiber present in the mouse’s diet than the microbiota of Ob mice. Thus, increased weight gain in Ob mice does not result from increased energy harvest. Rather, the finding supports previous studies showing that although SCFAs are a source of energy, they promote leanness by inhibiting fat accumulation in adipose tissue, raising energy expenditure, and enhancing production of hormones associated with feelings of satiety.  Other putative mechanisms include a role for the microbiota in metabolizing bile acids, branched-chain amino acids, and acylcarnitines, which have all been linked to either insulin resistance or obesity in humans and mice.  Notably, a recent study showed that fecal transplants from lean individuals into obese counterparts improved insulin sensitivity in some obese recipients .

Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.   << . We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients’ microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 mol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota.  Gut bacteria in samples for fecal transfer

 

Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders

 

 

Fighting Obesity with Bacteria

American Gut Project

An introduction to the analysis of shotgun metagenomic data

Automated and Accurate Estimation of Gene family abundance from shotgun metagenomes

Intestinal Permeability Regulation by Tight Junction Implication on IBD

Encyclopedia of life – Actinobacteria

Effect of garlic powder on the growth of commensal bacteria from the gastrointestinal tract.   << Lactic acid bacteria were found to be more resistant to Garlic powder (GP)  compared to the clostridial members of the gut microbiota. While for most bacteria the antimicrobial effect was transient, the lactobacilli showed a degree of resistance to garlic, indicating that its consumption may favour the growth of these beneficial bacterial species in the gut.

Edible plants and their defences

Article on things to eat for your microbiome

Dietary fiber is food for your gut bacteria. Too little fiber in your diet results in the bacteria eating your gut mucins that line your gut. When fed, the bacteria give us nutrients. Certain foods have positive effects. Garlic/Leeks have a lot of INULIN, which feeds actinobacter bacteria that are beneficial to us. Inulin is a prebiotic that feeds good bacteria. Garlic has antimicrobial properties taht help us out by diminishing harmful bacteria. Whole grain sources of fiber, however, are questionable in that they result in elevated levels of  Prevotella spp. (Prevotella) that are associated with inflammation and increased incidence of Rheumatoid Arthritis. As for fermented foods, Kimchi, Sauerkraut, and yogurt, the jury is out, but they may be helpful.

PLOS ONE_ A Taxonomic Signature of Obesity in the Microbiome_ Getting to the Guts of the Matter

Anxiety and gut microbiome

Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity  – yogurt helps anxiety in some

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression  << Abstract: There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

It has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic–pituitary–adrenal (HPA) axis response to stress , and anxiety behavior, which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression. Evidence suggests that probiotics can modulate the stress response and improve mood and anxiety symptoms in patients with chronic fatigue and irritable bowel syndrome. One such organism is Lactobacillus rhamnosus (JB-1), which has been demonstrated to modulate the immune system because it prevents the induction of IL-8 by TNF-α in human colon epithelial cell lines (T84 and HT- 29). This event was found to be mediated by connections of the gut and brain through the vagus nerve, which if cut, prevented the bacteria from causing emotional changes. 

Probiotics as delivery vehicles or neurological compounds

That Gut Feeling – APA association

Postnatal microbial colonization programs HPA system for stress response in mice  Absatract: Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic–pituitary–adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution withBifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.

Gut microbiota in autism and mood disorders

Bygiene The New Paradigm of Bidirectional hygiene Abstract: The pervasive dogma surrounding the evolution of virulence – namely, that a pathogen’s virulence decreases over time to prevent threatening its host – is an archaic assertion that is more appropriately cast as an optimization of virulence cost and benefit. However, the prevailing attitudes underlying practices of medical hygiene and sanitization remain entrenched in these passé ideas. This is true despite the emergence of evidence linking those practices to mounting virulence and antimicrobial resistance in the hospital. It is, therefore, our position that just as the microbe has sought an optimized balance in virulence, so should we seek such an optimized balance in vigilance, complementing warfare with restoration. We call this approach “bygiene,” or bidirectional hygiene.

Gut Dysbiosis in Patients with Anorexia  Abstract: Anorexia nervosa (AN) is a psychological illness with devastating physical consequences; however, its pathophysiological mechanism remains unclear. Because numerous reports have indicated the importance of gut microbiota in the regulation of weight gain, it is reasonable to speculate that AN patients might have a microbial imbalance, i.e. dysbiosis, in their gut. In this study, we compared the fecal microbiota of female patients with AN (n = 25), including restrictive (ANR, n = 14) and binge-eating (ANBP, n = 11) subtypes, with those of age-matched healthy female controls (n = 21) using the Yakult Intestinal Flora-SCAN based on 16S or 23S rRNA–targeted RT–quantitative PCR technology. AN patients had significantly lower amounts of total bacteria and obligate anaerobes including those from the Clostridium coccoides group, Clostridium leptum subgroup, and Bacteroides fragilis group than the age-matched healthy women. Lower numbers of Streptococcus were also found in the AN group than in the control group. In the analysis based on AN subtypes, the counts of the Bacteroides fragilis group in the ANR and ANBP groups and the counts of the Clostridium coccoides group in the ANR group were significantly lower than those in the control group. The detection rate of the Lactobacillus plantarum subgroup was significantly lower in the AN group than in the control group. The AN group had significantly lower acetic and propionic acid concentrations in the feces than the control group. Moreover, the subtype analysis showed that the fecal concentrations of acetic acid were lower in the ANR group than in the control group. Principal component analysis confirmed a clear difference in the bacterial components between the AN patients and healthy women. Collectively, these results clearly indicate the existence of dysbiosis in the gut of AN patients.

Dietary Agents and Phytochemicals in the Prevention and Treatment of Experimental Ulcerative Colitis

Normal Gut Microbiota modulates brain development and behavior <<– found that germ-free, unstressed mice were more active and more willing to explore exposed areas of a maze than mice that had normal gut microbiota. Like Sudo’s group, Heijtz and her colleagues were able to erase those behavioral differences by transplanting normal gut bacteria into the germ-free mice, but only if they did so while the mice were babies—again suggesting that there is a critical window for gut bacteria to establish normal patterns of behavior in its host animal.

Exposure to a Social Stressor Alters the Structure of the intestinal microbiota Abstract: Stressor exposure significantly changed the community structure of the microbiota, particularly when the microbiota were assessed immediately after stressor exposure. Most notably, stressor exposure decreased the relative abundance of bacteria in the genus Bacteroides, while increasing the relative abundance of bacteria in the genus Clostridium. The stressor also increased circulating levels of IL-6 and MCP-1, which were significantly correlated with stressor-induced changes to three bacterial genera (i.e., Coprococcus, Pseudobutyrivibrio, and Dorea). In follow up experiments, mice were treated with an antibiotic cocktail to determine whether reducing the microbiota would abrogate the stressor-induced increases in circulating cytokines. Exposure to SDR failed to increase IL-6 and MCP-1 in the antibiotic treated mice. These data show that exposure to SDR significantly affects bacterial populations in the intestines, and remarkably also suggest that the microbiota are necessary for stressor-induced increases in circulating cytokines.

Psychobiotics and the gut–brain axis in the pursuit of happyness

GIT flora and psychological behaviour – clinical correlation

prebiotics, probiotics, and synbiotics

Regulation of intestinal barrier function by host peptides

Resistant Starch Alters the Microbiota-Gut brain axis – dietary modulation of behavior

Host-microbiome interaction in Crohn’s disease

Intestinal permeability – a new target for disease prevention and therapy

Nutritional Keys for intestinal Barrier modulationAdvances in nutritional therapy in inflammatory bowel diseases review

Resistant starch and protein intake enhances fat oxidation and feelings of fullness in lean and overweight women

Combination of Lactobacillus helveticus R0052 and Bifidobacterium longum reduces post MI depression

Dairy constituents and neurocognitive health in ageing

Assessment of psychotropic-like properties of a probiotic formulation Lactobacillius helveticus and bifidobacterium longum in humans

APA gut related psychiatric issues

 

 

 

 

 

 

 

 

 

Microbiome

Rubella and zika

 

 

 

 

 

 

Hanson C, Lyden E, et al. The Relationship between Dietary Fiber Intake and Lung Function in NHANES. Annals ATS. 2016

The relationship between Dietary Fiber Intake and Lung Function

 

 

Punicalagin and Pomegranate juice for Alzheimer’s disease and inflammatory conditions!

Save your brain! Drink Pomegranate juice!
Save your brain! Drink Pomegranate juice!

Polyphenols have been shown to exhibit neuroprotective effects suppress neuroinflammation and activate antioxidant mechanisms.

A polyphenol found in pomegranate fruit, punicalagin, inhibits neuroinflammation in LPS-activated rat primary microglia by suppressing the production of pro-inflammatory cytokines (TNF- and IL-6), and PGE2 after 24 h of stimulation with LPS.

Punicalagin, which is a polyphenol – a form of chemical compound found in pomegranate fruit, can inhibit inflammation in specialised brain cells known as microglia. This inflammation leads to the destruction of more and more brain cells, making the condition of Alzheimer’s sufferers progressively worse . Recent results suggest that punicalagin inhibits neuroinflammation in microglia through interference with NF-[kappa]B signalling.

It is recommended to consume juice products that are 100 per cent pomegranate, meaning that approximately 3.4 per cent will be punicalagin. Unfortunately, most of the anti-oxidant compounds are found in the outer skin of the pomegranate, not in the soft part of the fruit. Pomegranate may be useful in neuroinflammatory conditions other than Alzheimer’s disease, including cancer and Parkinson’s disease.

Bottom Line: EAT YOU pomegranates! Punicalagin is good for your brain. The juice is the best was to get the most of the phytonutrient. It’s role in reducing the risk of Alzheimer’s disease and other inflammatory conditions is still being evaluated, but seems very promising.

 

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Below is Nonsense relating to neuroinflammation, studies involving Punicalagin, and cytokines in the CNS:

Cytokines are polypeptides (proteins) that cause inflammation, immune activation, cellular differentiation, and death. They include interferons (INF) , tumor necrosis factor (TNF) , interleukins(IL) , chemokines, and growth factors. None of these are present to any degree in healthy tissues, but rather are induced by cell damage and tissue injury.

In the CNS, Tumor necrosis factor alpha (TNFa), Interleukin-1 (IL-1), and Transforming Growth Factor Beta (TGFb) are primarily the main cytokines. Each of these cytokines binds a specific receptor, which activates a process or signaling pathway, which include the NfkB and MAPK (mitogen activated protein kinase) pathways.

In the CNS, other cytokines include:

  1. IL-2
  2. IL-3
  3. IL-10
  4. Chemokines (fractalkine, IL-8, RANTES)
  5. Neuropoietic cytokines (IL-6, IL-11)

In a  very basic categorization, the pro-inflammatory cytokines are : IL-1, TNF-a, IL-6, and the anti-inflammatory cytokines are IL-1ra (IL-1 receptor antagonist), IL-10, and TGFb

It has been noted that TNFa and IL-1 increase in the brain prior to neuronal death, and there are increased cytokines in stroke. The presence of IL-6 and TNFa are found to be increased in areas of tissue injury and in tissues in which there were poor clinical outcomes.

Some cytokines are synergistic – i.e. IL1 and TNFa or INFg (gamma) cause neurotoxicity when they are around together. TNFa may have a dose-dependent neurotoxicity.

TNFa/IL-1 increase ischemic injury in the brain.

TGFb/IL-10/IL-1ra reduce neurological injury.

Chronic IL-6 expression is neurotoxic in mice.

Endogenous IL-1 expression induces neurodegeneration

IL-1ra inhibits brain damage caused by injury or excitotoxins.

If you inhibit IL-1ra, it has been found that ischemic damage occurs more frequently, hence IL-1ra is protective in the brain. If you block it, then you lose protection.

TGFB2 receptor (which binds protective TGFB), will induce damage in the brain by removing the protective TGFB, but having too much TGFb causes autoimmune encephalitis. Thus too much of a good thing can cause problems as well!

SO again :

IL-1 = neurodegenerative

TGF-b= neuroprotective

IL-10 = protective against injury

TNFa/IL-6 cause damage, but sometimes inhibit damage. It’s not always just they cytokines presence but WHEN they are present that counts. Il-1 and TNFa protect neurons if they are present BEFORE an injury, but if delivered at the time of injury, they cause destruction.

Different cells in the brain secrete cytokines. Glia, endothelial cells (lining of blood vessels),  microglia, and neurons express TNFa, which in turn induces IL-10 that feeds back to decrease TNFa production (negative feedback). There is a TNF alpha binding protein that influences and decreases TNFa and also fractalkins that cause microglia to secrete less TNFa as well.  All of these create feedbacks to limit cytokine production in complicated ways.

When damage occurs, the microglia (structural cells in the brain) first produce IL-1b(beta). The damage to cells causes extracelular ATP to be released and that activates P2X7 receptors that cause decreased intracellular potassium. This results in caspase 1 activation that causes the production of IL-1B, which in turn KILLS microglia and macrophages in the brain.

Also, during injury, TNFa release causes TGFb/IL6 expression.

Injury causes IL-1 to induce TNFa, IL-6, TGFb expression as well!

Infection and inflammation in the brain or periphery cause increased CNS cytokines and further inflammation. Hence peripheral inflammation affects CNS inflammation as well.

Excitotoxic amino acids also regulate cytokines after CNS injury as below:

Postsynaptic Density Protein 95 binds NMDA receptor subunit NR2 and Kainate recptor GLUR6 – which then phosphorylates C-JUn-N terminal kinase (JNK) and activates JUN. JUN promotes IL-1, IL-6, TNFa, INFa/g production.

Of note Cannabomids INHIBIT TNFa and IL-1 release from glial cells and are anti-inflammatory.

Neurons depend on glial cells for survival. Glial cells (astrocytes) produce neurotropins and growth factors (nerve growth factor (NGF), BDNF, GDNF)

Cytokines affect blood flow in the CNS as well indirectly. IL-1 induces neovasculariztion. IL-1 and TNFa damage the blood brain barrier and allow migration of molecules in and out of the CNS. They also cause NO (Nitric oxide) to be released, which is neurotoxic. They also upregulate adhesion molecules for leukocytes, that then enter the brain. What follows in vasogenic edema (swelling).

IL-1, IL-6, and TNFa also mediate fevers, endocrine reactions, and cardiovascular changes. This causes increased neuronal loss by alterations in blood flow and inflammation.

 

The COX-2 enzyme pathway and subsequent generation of prostaglandins play a significant role in neuroinflammation. mPGES-1 is the terminal enzyme for the biosynthesis of PGE2 (prostoglandin) during inflammation, and is functionally coupled with COX-2. This enzyme is markedly induced by pro-inflammatory stimuli and is down-regulated by antiinflammatory glucocorticoids  –   mPGES-1 inhibitors produced inhibition of PGE2 production

The transcription factor NF-B plays a crucial role in neuro-inflammation.

In resting cells, NF-B is sequestered in the cytoplasm by the inhibitory IB protein. When activated by a variety of stimuli that includes LPS (lipopolysacharride), IB is phosphorylated by IKK. Phosphorylated IB then undergoes ubiquitinisation and degradation . Dissociation and degradation of IB activates the translocation of NF-B subunit from the cytosol to the nucleus. The translocated subunit thereafter facilitates the transcription of several pro-inflammatory genes, including those encoding pro-inflammatory cytokines, and COX-2. Furthermore, microglial NF-B activation has been linked to brain damage

Punicalagin significantly inhibited LPS-induced NF-B signalling in microglia by suppressing the phosphorylation of IKK, IB and nuclear p65

Punicalagin produced a modest suppressive action on the phosphorylation of p38 and JNK MAPKs following LPS activation

Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways. Of particular interest is the role of p38, which has been shown to be a critical mediator of LPS-induced inflammation  .

It appears that the effects of punicalagin on neuroinflammation are mediated mainly through targeting NF-B signalling, while MAPKmediated actions are minimal. Studies have shown that the TLR-4-mediated TRAF- 6/IKK/NF-B pathway has been well established as a signalling pathway responsible for inflammatory responses.

In addition to NF-B activation, TLR-4 can also initiate MAPK signalling

Punicalagin inhibited TRAF-6 protein expression, suggesting that this compound may inhibit the IKK/IB/NF-B signalling pathway, as well as p38 and JNK MAPK via selective inhibition of TRAF-6

Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways.

 

Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia (1)  <–   punicalagin inhibited COX- 2 and mPGES-1 after 24 h of LPS stimulation, suggesting that punicalagin acts to reduce PGE2 production by interfering with both COX-2 and mPGES-1 enzymatic activities in LPS-activated microglia.

Graphics from NATURE –

Signal transduction through IL-1RI and TNFR1

MAP kinases and innate immunity - call

 

 

Xu, X., Yin, P., Wan, C., Chong, X. et al., Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation. Inflammation 2014, 37, 956–965.  Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation

Punicalagin Inhibits Inflammation in LPS-Induced RAW264 7 macrophages   <– punicalagin (25–100 M) suppressed NO, PGE2, TNF-, IL-6 and IL-1 production from LPS stimulated RAW 264.7 cells.

Winand, J., Schneider, Y. J., The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophages. Food Funct. 2014, 5, 310–318.  The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophage  <–Demonstrated the  inhibitory effects of punicalagin on TNF- and NO production in LPS-stimulated RAW 264.7 cells, as well as IL-6 production in LPS-stimulated 3T3-L1 adipocytes.

Nature and consequences of non-covalent interactions between flavonoids and macronutrients in food

The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer  <<–  The p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion. The p38 MAPK, originally referred as cytokine-suppressive anti-inflammatory drug binding protein (CSBP). p38 MAPK is activated by pro-inflammatory cytokines such as interleukins and TNF-α. Stimulation of receptors that initiate this cascade  include GPCR, cytokine receptors, Toll-like receptors, growth factor receptors, and receptors associated with environmental stress such as heat shock, radiation and ultraviolet light. p38 MAPK is activated by upstream MAPK kinases (MKK) p38 MAPK pathway plays a central role in the expression and activity of pro-inflammatory cytokines such as TNF-α, IL-1, IL-2, IL-6, IL-7, and IL-8 and plays a regulatory role in cell proliferation and differentiation in the immune system.   It also regulates the expression of several MMPs involved in inflammation such as MMP-2, MMP-9, and MMP-13.

 

p38 MAPK inhibitors have been shown to reduce LPS-induced TNF-α production (Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function.)

(CYTOKINES AND ACUTE neurodegenration)   <<- Brain inflammation has been implicated in the pathogenesis of neurodegeneration in common neurological diseases such as stroke and Alzheimer’s disease

 

b-Amyloid Fibrils Activate Parallel Mitogen-Activated Protein kinase pathways in microglia  < – Noted  that p38 MAPK was upregulated in the brains of a transgenic mouse model of Alzheimer’s disease.  Fibrillar forms of b-amyloid (Ab), which are the primary constituents of senile plaques, have been shown to activate tyrosine kinase-dependent signal transduction cascades, resulting in inflammatory responses in microglia.

There is involvement of p38 MAPK in cancer cell invasion. Of note,  p38α and p38β were found to play important roles in cell differentiation and invasion of several different cancer cells such as breast cancer, squamous carcinoma cell, colon cancer, and ovarian cancer

 

The Evolving Biology of Microglia in Alzheimer’s Disease

Cannabinoids and Neuroprotection in Global and Focal Cerebral ischemia  <–CANNABINOIDS inhibit IL-1 and TNFα expression and release from glia, and have anti-inflammatory and neuroprotective actions in vitro and in vivo

Common pathways of neuronal cell death have been identified in response to diverse insults, such as ischaemia, trauma or excitotoxicity. These include early disruption of ion homeostasis, excessive neuronal activation, seizures and spreading depression, massive release and impaired uptake of neurotransmitters such as glutamate, intracellular entry of Ca2+, and release of nitric oxide and free radicals. More recently, further factors have been identified, including activation of genes that initiate or execute apoptosis, and the influence of glial and endothelial cells, extracellular matrix and invading immune cells. There is evidence that specific cytokines can act at most, if not all, of these steps, and probably have multiple actions on several cells or systems involved in neurodegeneration.

Increased expression of p38 MAPK and extracellular-signal-regulated kinase (ERK) has been found in ischaemic brain tissue after MCAo. Selective inhibitors of these pathways markedly reduce the ischemic injury in rodents. TNFR1 and TNFR2 (Tumor necrosis factor receptors) belong to the low-affinity neurotrophin receptor gene superfamily. TNFα elicits its biological effects on multiple cell types in the CNS through these receptors.

TGFβ- mediated signalling is also regulated through crosstalk with other signal transduction pathways, including MAPK.

So, IL-1ra, or a small molecule antagonist of IL-1 receptors, might be beneficial in acute neurodegenerative conditions. Studies are currently evaluating this.

 

 

 

 

 

Relton, J. K. & Rothwell, N. J. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res. Bull. 29, 243–246 (1992). The first study to report that inhibition of endogenous IL-1 limits neuronal death induced by cerebral ischaemia or excitotoxicity in vivo.

Prehn, J. H., Backhauss, C. & Krieglstein, J. Transforming growth factor-β 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 13, 521–525 (1993). An early study showing neuroprotective effects of TGFβ in vivo against cerebral ischaemia, and in vitro against glu

Chao, C. C., Hu, S., Ehrlich, L. & Peterson, P. K. Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methylD-aspartate receptors. Brain. Behav. Immun. 9, 355–365 (1995). An early study showing interactions between cytokines to influence neuronal death in vitro, using human fetal brain cell cultures composed of neurons and glia.

Nawashiro, H., Martin, D. & Hallenbeck, J. M. Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J. Cereb. Blood Flow Metab. 17, 229–232 (1996). An early study indicating that endogenous TNFα mediates ischaemic brain damage in vivo. TNFbinding protein — a naturally occurring inhibitor of TNF — reduced damage caused by focal cerebral ischaemia in mice.

Scherbel, U. et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc. Natl Acad. Sci. USA 96, 8721–8726 (1999). This study might provide an explanation for seemingly conflicting reports indicating that endogenous TNFα is either neurotoxic (based largely on acute interventions) or neuroprotective (based largely on stadies on genetically modified animals). It reports that functional outcomes in TNFα-null mice were improved early after brain injury compared with wild type mice, but TNFα-null mice showed permanent deficits and reduced recovery.

Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S. & Di Virgilio, F. Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185, 579–582 (1997). An early study showing that IL-1β is released from microglia by activation of purinergic, P2X7 receptors. Bacterial LPS is required for activation of microglial IL-1β expression, whereas ATP induced cleavage and release.

Ohtsuki, T., Ruetzler, C. A., Tasaki, K. & Hallenbeck, J. M. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J. Cereb. Blood Flow Metab. 16, 1137–1142 (1996). The first demonstration that endogenous IL-1 can mediate ischaemic tolerance. Pre-treatment of gerbils three days before global ischaemia reduced brain injury. IL-1 was induced by a brief period of ‘preconditionary’ ischaemia.

Carrié, A. et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genet. 23, 25–31 (1999). A direct link between one of the recently identified members of the IL-1/Toll receptor family in brain function. Cognitive function in patients with X-linked mental retardation is strongly associated with a nonsense mutation in a gene identified as IL-1-receptor-like protein (IL-1R AcPL).

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[1] van Marum, R. J., Current and future therapy in Alzheimer’s disease. Fundam. Clin. Pharmacol. 2008, 22, 265–274. [2] Morales, I., Guzman-Mart ´ ´ınez, L., Cerda-Troncoso, C., Far´ıas, G. A. et al., Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014, 8, 112. [3] Hu, N., Yu, J. T., Tan, L., Wang, Y. L. et al., Nutrition and the risk of Alzheimer’s disease. Biomed. Res. Int. 2013, 2013, 524820. [4] Lin, C. C., Hsu, Y. F., Lin, T. C., Effects of punicalagin and punicalin on carrageenan-induced inflammation in rats. Am. J. Chin. Med. 1999, 27, 371–376. [5] Adams, L. S., Seeram, N. P., Aggarwal, B. B., Takada, Y. et al., Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J. Agric. Food. Chem. 2006, 54, 980–985. [6] Xu, X., Yin, P., Wan, C., Chong, X. et al., Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation. Inflammation 2014, 37, 956–965. [7] Bhatia, H. S., Candelario-Jalil, E., de Oliveira, A. C., Olajide, O. A. et al., Mangiferin inhibits cyclooxygenase-2 expression and prostaglandin E2 production in activated rat microglial cells. Arch. Biochem. Biophys. 2008, 477, 253–258. [8] Olajide, O. A., Bhatia, H. S., de Oliveira, A. C., Wright, C. W. et al., Inhibition of neuroinflammation in LPS-activated microglia by cryptolepine. Evid. Based Complement Alternat. Med. 2013, 2013, 459723.[9] Vinet, J., Weering, H. R., Heinrich, A., Kalin, R. E. et al., Neu- ¨ roprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation 2012, 9, 27. [10] Olajide, O. A., Velagapudi, R., Okorji, U. P., Sarker, S. D. et al., Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1-stimulated SKN-SH neuronal cells. J. Ethnopharmacol. 2014, 152, 377–383. [11] Fiebich, B. L., Lieb, K., Engels, S., Heinrich, M., Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J. Neuroimmunol. 2002, 132, 18–24. [12] Munoz, L., Ammit, A. J., Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 2010, 58, 561–568. [13] Winand, J., Schneider, Y. J., The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophages. Food Funct. 2014, 5, 310–318. [14] Kudo, I., Murakami, M., Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J. Biochem. Mol. Biol. 2005, 38, 633–638. [15] Wang, J., Limburg, D., Carter, J., Mbalaviele, G. et al., Selective inducible microsomal prostaglandin E(2) synthase- 1 (mPGES-1) inhibitors derived from an oxicam template. Bioorg. Med. Chem. Lett. 2010, 20, 1604–1609. [16] Baeuerle, P. A., Baltimore, D., NF-kappa B: ten years after. Cell. 1996, 87, 13–20. [17] Huang, C. Y., Fujimura, M., Noshita, N., Chang, Y. Y. et al., SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21, 163–173. [18] Zhang, W., Potrovita, I., Tarabin, V., Herrmann, O. et al., Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 2005, 25, 30– 40. [19] Gu, J. H., Ge, J. B., Li, M, Wu, F. et al., Inhibition of NF- B activation is associated with anti-inflammatory and antiapoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury. Eur. J. Pharm. Sci. 2012, 47, 652–660. [20] Sastre, M., Walter, J., Gentleman, S. M., Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation 2008, 5, 25. [21] Gong, P., Xu, X., Shi, J., Ni, L. et al., Phosphorylation of mitogen- and stress-activated protein kinase-1 in astrocytic inflammation: a possible role in inhibiting production of in- flammatory cytokines. PLoS One 2013, 8, e81747. [22] Yong, H. Y., Koh, M. S., Moon, A., The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin. Investig. Drugs 2009, 18, 1893. [23] Liu, S. L., Kielian, T., Microglial activation by Citrobacter koseri is mediated by TLR4-and MyD88-dependent pathways. J. Immunol. 2009, 183, 5537–5547. [24] Butler, M. P., Hanly, J. A., Moynagh, P. N., Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-de

Pelvic congestion syndrome as a frequent cause of chronic pelvic pain!

Pelvic congestion syndrome (PCS) is characterized by chronic pelvic discomfort exacerbated by prolonged standing and coitus in women who have periovarian varicosities on imaging studies. The etiology of PCS is unclear and the optimum treatment is uncertain. It primarily affects multiparous women in the reproductive age group and no cases have occurred in menopausal women.

The most commonly made diagnosis in chronic pelvic pain is endometriosis (31%). The majority are undiagnosed or improperly diagnosed.  In the majority of women with no obvious pathological cause for their pain, they may be suffering from pelvic congestion syndrome (PCS) instead. PCS accounts for up to 30% of patients presenting with chronic pelvic pain and is characterized by symptoms of dysmenorrhea, dysuria, and dyspareunia. PCS also carries a psychological burden and is often found in conjunction with increased levels of anxiety, stress, and depression.  It can often be found in conjunction with vulvar and pelvic varices in women and with varicoceles in men. Many patients will present with chronic, dull, lower abdominal pain often accompanied by dyspareunia and bladder irritability and urgency. The pain is typically relieved by lying down and exacerbated by standing up or increased intra-abdominal pressure, such as during pregnancy and the premenstrual period. Pain during intercourse or during the postcoital period is not uncommon.

Differential diagnosis in chronic pelvic pain is lengthy and includes pelvic inflammatory disease, endometriosis, pelvic tumors, interstitial cystitis, and inflammatory bowel disease

It has been found that there is gross dilatation, incompetence, and reflux of the ovarian veins in women with PCS.  Anatomic and hormonal factors lead to venous insufficiency of the ovarian veins and/or internal iliac veins, resulting in periovarian pelvic varicosities, thus producing pelvic venous congestion. Ovarian vein dilatation, stasis, and/or reflux on pelvic venography are common findings in multiparous premenopausal women but only some have symptoms. The use of venoconstrictors or ovarian vein ligation has produced relief of pain in some patients. Studies using Dihydroergotamine during an acute attack demonstrated relief of pain when the veins in the pelvis constrict.  (Lancet. 1987;2(8555):351) Multiparous women (who have had multiple pregnancies) have a higher prevelance of PCS due to the 50% increase in vascular congestion that occurs in pregnancy, leading to venous incompetence and reflux in the non-pregnant state and thus pain.

Extrinsic compression of the left renal vein between the aorta and superior mesenteric artery leads to an increase incidence of PCS on the left side of the pelvis. This results in left flank pain, hematuria, and pelvic congestion. It has been noted that the left ovarian veins have no valves, increasing congestion on the left side as well.

Menopause decreases the incidence of PCS because estrogen acts as a venodilator and of course is no longer present after menopause.

Examination will show tenderness on abdominal examination over the adnexa and history of postcoital aching pain.  Ultrasound may show incompetent and dilated ovarian veins which  are common but nonspecific findings. Also,  dilatation of the left ovarian vein with reversed caudal flow, presence of tortuous and dilated pelvic venous plexuses, and dilated arcuate veins crossing the uterine myometrium are found in PCS with increased diameters of the left ovarian vein at 7.9 mm (usual is 5.4 mm).

Selective ovarian and internal iliac venography through catheterization of the right and left ovarian veins via a percutaneous femoral or jugular approach demonstrate abnormally dilated ovarian veins (>10 mm in diameter), sluggish blood flow, reflux causing retrograde fill and congestion of the ovarian venous plexus in PCS. Up to 80 % of premenopausal women  are found to have pelvic varicosities and venous stasis.

 Computed tomography (CT) and magnetic resonance (MR) imaging identify tortuous, dilated pelvic and ovarian veins, broad ligament vascular congestion, and ovarian varicoceles better than ultrasound imaging. A growing body of data suggests that magnetic resonance venography (MRV) and CT scan are just as useful as pelvic Ultrasound.

Treatment :

Treatment of PCS consists of hormone therapy, embolotherapy, sclerotherapy, and endovascular and open surgery

First options are medical treatment using Goserelin, Medroxyprogesterone acetate, or etongestrel implants to hormonally treat the vascular congestion.

Invasive therapies that are successful include procedures such as embolization or sclerotherapy of the ovarian veins with or without the internal iliac veins. This involves interventional radiology:

Pelvic congestion link

http://www.thedoctorschannel.com/view/pelvic-congestion-syndrome-is-under-diagnosed/

Success rates of ovarian vein embolization range from 89 to 100 percent.  Surgical ligation of the ovarian vein has been associated with improvement in pain in approximately 75 percent.

DIagnosis and treatment of pevic congestion syndrome (1)

Current Concepts of Pelvic Congestion and chronic pelvic pain

Pelvic Congestion Syndrome Diagnosis and treatment

Mast Cell-Mediated Mechanisms of Nociception

Pelvic congestion syndrome
Pelvic congestion syndrome

pelvic congestion 220px-9cmFibroidUS PelvicCongestion-Ex1

 

Edwards RD, Robertson IR, MacLean AB, Hemingway AP. Case report: pelvic pain syndrome – successful treatment by ovarian vein embolization. Clin Radiol. 1993;47:429-431.

14. Kindgen-Milles D, Arndt JO. Nitric oxide as a chemical link in the generation of pain from veins in humans. Pain. 1996;64:139-142.

13. Stones RW, Thomas DC, Beard RW. Suprasensitivity to calcitonin gene-related peptide but not vasoactive intestinal peptide in women with chronic pelvic pain. Clin Auton Res. 1992;2:343- 348.

12. Stones RW, Vials A, Milner P, Beard RW, Burnstock G. Release of vasoactive agents from the isolated perfused human ovary. Eur J Obstet Gynecol Reprod Biol. 1996;67:191-196.

Beard RW, Reginald PW, Pearce S. Psychological and somatic factors in women with pain due to pelvic congestion. Adv Exp Biol Med. 1988;245:413-421.

Allen WA. Chronic pelvic congestion and pelvic pain. Am J Obstet Gynecol. 1971:109:198-202.

Capasso P, Simons C, Trotteur g, Dondelinger RF, Henroteaux D, Gaspard U. Treatment of symptomatic pelvic varices by ovarian vein embolization. Cardiovasc Intervent Radiol. 1997:20:107-111.

Kim HS, Malhotra AD, Rowe PC, Lee JM, Venbrux AC. Embolotherapy for pelvic congestion syndrome: long-term results. J Vasc Interv Radiol 2006;17(Pt 1):289-97.

Soysal ME, Soysal S, Vicdan K, Ozer S. A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion. Hum Reprod 2001;16:931-9.

Kim KW, Cho JY, Kim SH, Yoon JH, Kim DS, Chung JW, et al. Diagnostic value of computed tomographic findings of nutcracker syndrome: correlation with renal venography and renocaval pressure gradients. Eur J Radiol 2011;80:648-54.

Malgor RD, Labropoulos N. Diagnosis of venous disease with duplex ultrasound. Phlebology 2013;28(Suppl 1):158-61.

Asciutto G, Asciutto KC, Mumme A, Geier B. Pelvic venous incompetence: reflux patterns and treatment results. Eur J Vasc Endovasc Surg 2009;38:381-6.

Kurklinsky AK, Rooke TW. Nutcracker phenomenon and nutcracker syndrome. Mayo Clin Proc 2010;85:552-9.

Asciutto G, Mumme A, Marpe B, Koster O, Asciutto KC, Geier B. MR venography in the detection of pelvic venous congestion. Eur J Vasc Endovasc Surg 2008;36:491-6.

 

 

Zika Virus Infection – Global Threat for 2016 – Microcephaly and Guillian Barre Syndrome

Zika virus (ZIKV) is a flavivirus related to yellow fever, dengue, West Nile, and Japanese encephalitis viruses.

CDC site for Zika alerts

ZIKV has been isolated from Ae. africanus, Ae. apicoargenteus, Ae. luteocephalus, Ae. aegypti, Ae vitattus, and Ae. furcifer mosquitoes

Zika virus was first discovered in 1947 in the Zika Forest, Uganda, when a Rhesus monkey, placed in a cage to study Yellow Fever developed a febrile illness that was transmitted by innoculation into mice. The Zika Virus was discovered.

In 1948, Zika virus was found in the Aedes Africanus mosquito in the Zika Forest.

In 1968, the virus was found in humans in Nigeria causing a febrile illness. Also in 1971-1975 as well.

Later the virus was found to cause illness in various other parts of Africa and asia, including India, Malaysia, Philippines, and Vietnam.

Then the virus was found to exist in the Aedes aegyptii mosquito.

The Yap island infection in 2007 was the first time infection had spread outside of Asia and Africa.

The disease went on to French Polynesia in 2013  and the Cook islands and new Caledonia in 2014

Clusters of infection started to appear in Brazil in 2014 and 2015. This is because of the mosquito vectors that spread the disease can travel to these areas.

Zirka (ZIKV) virsu causes a self-limited infection in the form of an exanthematous- type rash, low grade fevers, conjunctivitis, and arthralgias. Guillain-Barre syndrome has been associated with this infection (an ascending paralysis). there is much confusion between ZikV and Dengue infection .

(Zika Virus) ZrkV now joins Chikungunya (CIKV) and Dengue Virus (DENV) as global health threats!

 

Zika virus is believed to be transmitted to humans by infected mosquitoes and has been isolated from Aedes africanus, Aedes luteocephalus, and Aedes aegypti

Until the YAP island/Micronesia outbreak, no transmission of Zika virus had been reported outside of Africa and Asia (2007) in which an outbreak of illness characterized by rash, conjunctivitis, subjective fever, arthralgia, and arthritis occurred on YAP island. Reverse-transcriptase–polymerase-chain-reaction assay determined the source to be Zika virus.  Dengue, chikungunya, o’nyongnyong, Ross River, Barmah Forest, and Sindbis viruses were all NEGATIVE in this study.

The Federated States of Micronesia is an archipelago nation located northeast of Papua New Guinea. Yap State is the westernmost of the four states of the country. In Yap cases were defined by fhaving generalized macular or papular rash, arthritis or arthralgia, or nonpurulent conjunctivitis. Acute phase studies were taken 10 days after symptoms and convalescent titers were taken at Day 14. In this Zika virus outbreak, approximately three quarters of Yap residents were infected with Zika virus, and we estimated that more than 900 people had illness attributable to Zika virus infection. It was a mild illness. It appeared that  Aedes hensilli was a vector of Zika virus transmission in Yap. More than 73% of Yap islanders were found to have had infection after the age of 3.

The attack rates of Zika virus disease detected by surveillance were higher among females than males and among older persons than younger persons.  These discrepancies may be because of differences in health care–seeking behavior for this relatively mild illness.

In the NEJM article regarding the Zika infection on Yap: “The accessibility of air travel and the abundance of mosquito vectors of flavivirus in the Pacific region raise concern for the spread of Zika virus to other islands in Oceania and even to the Americas.” This was in 2007. Also they ended the article with : “The emergence of Zika virus as an important human pathogen on Yap in 2007 underscores the ease with which exotic pathogens are transported between continents and the need for clinical vigilance and strong epidemiologic and laboratory surveillance systems to detect the spread of infectious diseases”

So as a summary, ZikV, ChickV, and DenV cause an exanthemotous illness with a generalized rash and fever and all three spread by the same Aedes mosquito species. It is hard to distinguish between the illnesses. The effect of the concurrent outbreaks caused by these three different arboviruses is unknown.

Fever and arthralgias are more common in Dengue and ChikV infections whereas Guillan Barre episodes are more associated with Zika infection.

The first well-documented report of human ZIKV disease was in 1964 when Simpson described his own occupationally acquired ZIKV illness at age 28 (27). It began with mild headache. The next day, a maculopapular rash covered his face, neck, trunk, and upper arms, and spread to his palms and soles. Transient fever, malaise, and back pain developed. By the evening of the second day of illness he was afebrile, the rash was fading, and he felt better. By day three, he felt well and had only the rash, which disappeared over the next 2 days. ZIKV was isolated from serum collected while he was febrile.  . Other manifestations included anorexia, diarrhea, constipation, abdominal pain, and dizziness.  Yap Island infection was characterized by rash, conjunctivitis, and arthralgia.

Diagnostic tests for ZIKV infection include PCR tests on acute-phase serum samples, which detect viral RNA, and other tests to detect specific antibody against ZIKV in serum. An ELISA has been developed at the Arboviral Diagnostic and Reference Laboratory of the Centers for Disease Control and Prevention (Atlanta, GA, USA) to detect immunoglobulin (Ig) M to ZIKV. IgM was detectable as early as 3 days after onset of illness.  In the samples from Yap Island, cross-reactive results in sera from convalescent-phase patients occurred more frequently among patients with evidence of previous flavivirus infections than among those with apparent primary ZIKV infections . Cross-reactivity was more frequently noted with dengue virus than with yellow fever, Japanese encephalitis, Murray Valley encephalitis, or West Nile viruses.  Zika Virus Outside Africa <Link

ZIKV illness to date has been mild and self-limited, but before West Nile virus caused large outbreaks of neuro-invasive disease in Romania and in North America, it was also considered to be a relatively innocuous pathogen.

In the early 2015, records of patients presenting a “dengue-like syndrome” appeared in the public health service in the city of Natal (05°47’42”S 35°12’32”O), state of Rio Grande do Norte, Brazil. A physician specialist in infectious disease evaluated the patients and the clinical signs and symptoms and laboratory findings indicated a non-DENV and non-Chikungunya virus (CHIKV) infection. Symptoms included arthralgia, oedema of extremities, mild fever, maculopapular rashes frequently pruritic, headaches, retroorbital pain, no purulent conjunctivitis, vertigo, myalgia and digestive disorder. http://www.ncbi.nlm.nih.gov/pmc/articles/PFirst report of autochthonous transmission of Zika virus in Brazil

Zika Rash from "First report of autochthonous transmission of Zika virus in Brazil" article
Zika Rash from “First report of autochthonous transmission of Zika virus in Brazil” article.

In Brazil’s caese:  The most commonly reported symptoms were maculopapular rash (100%)  and pain, with pain lasting 2-15 days. Headaches, myalgias, and retro-orbital pain was common, and joint pains included the hands , ankle, elbow , knee, wrist, and foot.  Periarticular swelling occurred, fever (around 39ºC),  and submandibular or cervical lymphadenopathy in some. Most had normal levels of leukocytes and neutrophils and platelets were normal in all of them.

As of January 23 – the CDC recommends that pregnant women not travel to  Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela and Puerto Rico. Zika has been found in Bolivia, Brazil., COlombia, Ecuador, French Guiana, Guyana, Suriname, Venezuela, and Paraguay. In the Caribbean, Barbados, Guadeloupe, Haiti, Martinique, and Saint Martin have Zika Virus present. Also Mexico, Puerto Rico, Honduras, Panama, and Guatemala have Zika virus present as well.

Microcephaly has been linked to this infection as a result of infection during pregnancy. Obviously microcephaly results in developmental delay (Mental Retardation.)

In this Dec. 23, 2015 photo, Solange Ferreira bathes her son Jose Wesley in a bucket at their house in Poco Fundo, Pernambuco state, Brazil. Ferreira says her son enjoys being in the water, she places him in the bucket several times a day to calm him. (AP Photo/Felipe Dana)
In this Dec. 23, 2015 photo, Solange Ferreira bathes her son Jose Wesley in a bucket at their house in Poco Fundo, Pernambuco state, Brazil. Ferreira says her son enjoys being in the water, she places him in the bucket several times a day to calm him. (AP Photo/Felipe Dana)

In El Salvador, cases of a demyelinating condition called Guillian Barre syndrome has occurred in association with the Zika infection.

El Salvador has recommended a Two year halt on pregnancies and Jamaica recommends a 6-12 month wait for women to become pregnant. Obviously, these recommendations will be challenging to follow.

For those who get pregnant in high risk areas, ultrasound and amniocentesis ( a needle is used to collect amniotic fluid for analysis) is performed and tested for Zika virus. If positive, options are discussed.

Prevention of the disease if travel is a necessity includes wearing long sleeved shirts and pants, using insect repellents that have DEET, Picardin, oil of lemon eucalyptus (OLE), or IR3535. DEET can be used on infants 2 months or older and pregnant women can safely use EPA-registered insect repellents.

 

 

CDC Zika website

Possible link between Zika virus and birth defects

Zika virus: a new global threat for 2016

Outbreak of Exanthematous Illness Associated with Zika, Chikungunya, and Dengue Viruses, Salvador, Brazil

Zika Virus Outbreak on Yap Island, Federated States of Micronesia NEJM

Zika virus outside Africa.

Comparing dengue and chikungunya emergence and endemic transmission in A. aegypti and A. albopictus

Zika virus – following the path of dengue and chikungunya

First report of autochthonous transmission of Zika virus in Brazil.

First report of autochthonous transmission of Zika virus in Brazil

Factors responsible for the emergence of arboviruses; strategies, challenges and limitations for their control.

Factors responsible for the emergence of arboviruses – strategies, challenges and limitations for their control.

Emerging arboviruses in the Pacific

Zika Virus in an American Recreational Traveler

Zika Virus in an American Recreational Traveler

zika rash back
zika rash – back

Symptomatic management with supportive care is indicated for acute cases. Prevention is achieved by vector control and insect bite precautions. Aedes spp. is adapted for indoor and daytime biting in urban areas. They are known to breed in aquatic environments such as small puddles, open water storage containers, and plants that hold water between the leaves and stems. Insect bite precautions (during early morning and late afternoon peak biting times) and vector control should be tailored to known epidemiology.

Outbreak of Exanthematous Illness Associated with Zika, Chikungunya, and Dengue Viruses, Salvador, Brazil

Zika Virus Outbreak in Bahia Brazil

This report illustrates the potential for explosive simultaneous outbreaks of ZIKV, CHIKV, and DENV in the Western Hemisphere and the increasing public health effects of Aedes spp. mosquitoes as vectors. The apparent increase in reports of Guillain-Barré syndrome during the outbreak deserves further investigation to elucidate whether this syndrome is associated with ZIKV infection.

Identification of ZIKV, CHIKV and DENV as etiologic agents of acute exanthematous illness suggests that these 3 Aedes spp. mosquito-transmitted viruses were co-circulating in Salvador and highlights the challenge in clinically differentiating these infections during outbreaks.  In Brazil,  that ZIKV sequences obtained belonged to the Asian lineage and showed 99% identity with a sequence from a ZIKV isolate from French Polynesia (KJ776791) .

Reported cases of indeterminate acute exanthematous illness and suspected dengue fever in Salvador, Brazil, by date of medical care, February 15−June 25, 2015
Reported cases of indeterminate acute exanthematous
illness and suspected dengue fever in Salvador, Brazil, by date of
medical care, February 15−June 25, 2015

Immunological Surveys of Arbovirus Infections in Southeast Asia

The Global Ecology and Epidemiology of West Nile Virus

Potential Sexual Transmission of Zika Virus

Potential for Zika virus transmission through blood tranfusion in French Polynesia

Evidence of perinatal transmission of Zika virus

Two cases of Zika fever imported from French Polynesia to Japan

Detection of Zika Virus in Urine

Complete Coding Sequence of Zika Virus from a French Polynesia outbreak 2013

A diagnostic polymerase chain reaction assay for Zika virus

Zika virus infection complicated by Guillain-Barré syndrome

Zika virus a previously slow pandemic spreads rapidly through the Americas

Zika and transfusion medicien

Zika virus in Brazil and the danger of infestation by Aedes mosquitoes

Febrile Illness with Skin Rashes

Viral exanthems

 

Update: January 20, 2016

Hawaii baby born with small head had prior Zika infection   A child born in the past few weeks in Hawaii had microcephaly ( a small head) and the mother had lived in Brazil in 2015. Both were positive for prior Zika infection. Currently,  cases in Brazil increased to 3,500, and 46 babies have died. The CDC gave recommendations not to travel to Brazil if pregnant or if wishing to get pregnant due to concerns over Zika Virus:

CDC issues interim travel guidance related to Zika virus for 14 Countries and Territories in Central and South America and the Caribbean

CDC has issued a travel alert (Level 2-Practice Enhanced Precautions) for people traveling to regions and certain countries where Zika virus transmission is ongoing: Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela, and the Commonwealth of Puerto Rico.  

This alert follows reports in Brazil of microcephaly and other poor pregnancy outcomes in babies of mothers who were infected with Zika virus while pregnant. However, additional studies are needed to further characterize this relationship. More studies are planned to learn more about the risks of Zika virus infection during pregnancy.

Until more is known, and out of an abundance of caution, CDC recommends special precautions for pregnant women and women trying to become pregnant:

As a reiteration, Zika virus is a flavivirus that is related to Japanese encephalitis virus, West Nile, Dengue, and yellow fever. It originated in the Zika Forest in Uganda and was first found in 1947 in a rhesus monkey.

As of February 1, 2016 the virus has spread in Africa, Southeast Asia, the pacific Islands, and the Americas.

Zika is likely to spread to the United States since the mosquito vector, Aedes, an aggressive daytime biter, is present in the US as well. Obviously international travelers will promulgate the spread of the disease.

The symptoms of infection are fever, rash, muscle and joint pains with conjunctivitis (pink eye) primarily, but there is associations with microcephaly and Guillian Barre syndrome (GBS) as well.  GBS is a neurological syndrome of weakness and paralysis.

Brazil has had 4000 cases of microcephaly in 2015 which i 20 times higher than the year before with evidence of viral infection in the mother’s of these patients.

Infections have been found in travelers in Hawaii, Florida, Illinois, and Texas. All were international travelers.

The primary goal to thwart continued spread and infection is vector control. Physical removal of standing water and adding fish to areas with water so as to eat larvae are part of a solution, Insecticides are beneficial as well. Also being tried is the release of sterile male mosquitoes.

The Pan American Health Organization (PAHO) has been issuing updates for increased surveillance for Zika, including immunological effects of the virus as well as congenital effects from infection.

Travel advisories are in effect from the CDC primarily for pregnant women in which they suggest postponing travel if  pregnant if one is travelling to Zika-affected areas.

There are licensed vaccines for yellow fever, Japanese encephalitis, and dengue fever currently, but non e for Zika. NIH and Brazilian agencies are currently working on this.

80 % of Zika infections are asymptomatic and most are self-limited. It is hard to test for the virus due to cross-reactivity with other flaviviruses. The CDC is able to test amniotic fluid and serum  for the virus currently.

NEJM Zika in the US NEJM article re: zika in the US

microcephaly alert in Brazil

Interim Guidelines for Pregnant Women During a Zika Virus Outbreak — United States, 2016 _ MMWR  – Guidelines from CDC for pregnant women 2016

CDC Guidelines for ZIKA 2016

Ebola epidemic – JAMA 2014  Ebola epidemic in 2014

WHO Ebola final report July 2015

Clinical resources Ebola

Zika Virus: An Emerging Health Threat

<Blog from NIH – video

Zika Virus: An Emerging Health Threat

Notes from NIH blog:

According to the researchers’ calculations, about 200 million Americans—more than 60 percent of the population—reside in areas of the United States that might be conducive to the spread of Zika virus during warmer months through biting mosquitoes, including areas along the East and West Coasts and much of the Midwest. In addition, another 22.7 million people live in humid, subtropical parts of the country that might support the spread of Zika virus all year round, including southern Texas and Florida. Already, there are reports of local spread of the virus within Puerto Rico and of travelers returning to the U.S. with the Zika infection.

In November, health authorities in French Polynesia also reported an unusual increase of central nervous system malformations in fetuses and infants that seemed to coincide with the Zika outbreak there. And, last week, came news reports of the first child born in the U.S. with microcephaly possibly linked to Zika. The child’s mother had lived in Brazil during her pregnancy before moving to Oahu, Hawaii [5]. As an additional concern, there are reports in French Polynesia and Brazil of a possible connection between Zika infection and Guillain-Barré syndrome, a mysterious condition in which the immune system attacks part of the peripheral nervous system [1]

Zika virus infection can be spread by yellow fever mosquitoes (Aedes aegypti), and experimental evidence suggests the virus also can be transmitted by Asian tiger mosquitoes (Aedes albopictus).Aedes mosquitoes—already known for transmitting other viral illnesses, such as dengue and chikungunya—have a wide and expanding global distribution, including in the United States.

zika-virus-americas-association-with-microcephaly-rapid-risk-assessment

The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus

Zika and blood transfusions

The global compendium of Aedes aegypti and Ae. albopictus occurrence

Zika Virus in the Americas — Yet Another Arbovirus Threat

CDC teleconference Januray 2016 re ZIKA

 

 

 

 

 

 

 

 

 

Hymenolepis nana as a cause of cancer

Malignant Transformation of Hymenolepis nana in a Human Host from NEJM November 5, 2015
Malignant Transformation of Hymenolepis nana in a Human Host from NEJM November 5, 2015

Hymenolepis nana   is the most common tapeworm infection in humans and is unique in it’s ability to fully reproduce in the human host without intermediate hosts.

The tapeworm stays in the small intestine, where it deposits eggs that hatch into oncopshpere embryos that invade the intestinal villi and become cystecercoid larva. These reattach to the intestine and the cycle continues. There is rarely extraintestinal infection, but in the New England Journal of Medicine, a case of an HIV positive man was documented in which the tapeworm itself produced malignant proliferation that spread throughout the body of the patient. In other words, the tapeworm itself became cancerous and spread throughout the victim’s body. The patient was immunosuppressed with HIV and had a high viral load of HIV since he was non-compliant with his medications. This most likely resulted in the accumulation of somatic mutations in H. nana stem-cells leading to malignancy. The cells of the malignancy in this patient were not of human origin!

Per the report: The proliferative cells had overt features of a malignant process — they invaded adjacent tissue, had a crowded and disordered growth pattern, and were monomorphic, with morphologic features that are characteristic of stem cells (a high nucleus-to-cytoplasm ratio) — but the small cell size (<10 μm in diameter) suggested infection with an unfamiliar, possibly unicellular, eukaryotic organism…Although many cestode tissues are syncytial — notably, their tegument — a tapeworm infection was initially considered less likely because of the primitive appearance of the atypical cells, the complete absence of architecture that was identifiable as tapeworm tissue, and the rarity of previously reported cases of invasive cestodiasis…We performed Myxogastria and panfungal PCR assays in an attempt to target an unknown eukaryote, but these assays unexpectedly identified H. nana with 99% sequence identity….Normal tapeworm development probably requires signals from immune responses of normal hosts, as is further suggested by in vitro cultures of hydatid tapeworms. Atypical proliferative infections with other tapeworm species have also been reported in humans and in other animals, including orangutans and cats. In contrast to the current case, all previously reported cases of invasive cestodiasis showed recognizable metazoan tissue architecture.

The H. nana DNA was identified by DNA analysis and compared with Wormbase Parasite sequences.

There are examples of transmissible clones of cancer cells in other animals, such as Tasmanian devils, which can spread cancers from one animal to another. There is also an association of human cancer with certain infections such as Human papilomaviruses (cervical and anal cancer) and Schistosoma haematobium (bladder cancers). Helicobacter Pylori infection in the GI tract is also associated with MALT lymphoma in humans. Cancers in humans have also been spread via organ transplantation and from mother to fetus. This New England Journal article demonstrates that parasite derived cancer can cause tissue invasion in humans.

This article is interesting in that some cancers may be the result of clonal proliferations of cells that originate from another invading organism. One organism’s cancer becomes ours! Thus there is clearly a relationship between infections and cancers in some situations. In this case, it was found that treatment of the original tapeworm infection with Albendazole did not cure the cancer because the invading malignancy was not an entire tapeworm malignancy, but rather a mutation from it.

 

 

 

 

Malignant Transformation of Hymenolepis nana in a Human Host

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Zika Virus, Aging, nutrition, diseases and discussions regarding healthy life choices and physical activity. Alternative medicine and mainstream medicine included!