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Life extension – healthspan – strategies for successful aging

Dietary restriction with and without caloric restriction for healthy aging

“Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates.  However, caloric restriction, which in most cases entails a 20–40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects.”

CAloric restriction (CR)  refers to a dietary intervention with an overall 20–40% reduction of total caloric intake, and dietary restriction to represent a broader scope of dietary interventions that encompass those with specific macronutrient and feeding pattern restrictions. There is mounting evidence that healthspan can be maximized and aging  can be reduced by  methods other than caloric reduction.

In 1935, Crowell and McCay demonstrated that simply reducing caloric intake without causing malnutrition nearly doubled the lifespan of rats.

Walford and Weindruch reported that “adult-initiated” caloric restriction started at 12 months of age not only increased lifespan but also reduced the incidence of spontaneous cancer by more than 50% in rats. Dietary Restriction in Mice Beginning at 1 Year of Age effect on life span and cancer  This same effect has been shown in yeast, worms, flies, and other animals, hence the genes for this are highly conserved.  Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Caloric restriction and lifespan extension involves the down-regulation of insulin and insulin-like signalling (IIS)[ The genetics of ageing ], as well as of the amino signalling target of rapamycin (TOR)-S6 kinase pathway [Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway and Regulation of Longevity and Stress Resistance by Sch9 in Yeast , and the glucose signalling Ras-protein kinase A (PKA) pathway[The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for longevity]

In yeast, down-regulation of (a) the amino acid-sensing TOR and the ribosomal protein S6 kinase (S6K) ortholog Sch9 pathway6 , and (b) the Ras-AC-PKA pathway13 [Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras PKA, Tor, and Sch9 ] are key changes mediating part of the effects of caloric restriction on chronological lifespan, the measurement of cellular survival under non-dividing conditions. In contrast, elevated activity of sirtuin (SIR2) [ Sir2 Blocks Extreme Life-Span Extension] and [Requirement of NAD and SIR2 for Life-Span Extension by Calorie Restriction in Saccharomyces cerevisiae  has been described as a key change in the extension of replicative lifespan, measured by counting the number of buds generated by an individual mother cell In worms, the lifespan extension caused by the inactivation of IIS, or by different forms of caloric restriction, requires Forkhead FoxO transcription factor daf-16 Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans  . In rodents, growth hormone (GH) and IGF-1 levels are reduced following caloric restriction Fasting vs dietary restriction in cellular protection and cancer treatment from model organisms to patients, but the link between dietary restriction, GH and aging is still being investigated, with focus on the genes and pathways regulating longevity in the simple organisms described above.

The ultimate question that lingers is the relevance of these models to human lifespan and healthspan.  Two notable studies performed by independent programs, the National Institute on Aging (NIA) Intramural Research Program and the Wisconsin National Primate Research Center (WNPRC), subjected male and female rhesus monkeys to 30% caloric restriction from levels of baseline caloric intake. The NIA reported no improvement in lifespan but observed a positive trend for the delay of age-related diseases (i.e. healthspan) Impact of caloric restriction on health and survival in rhesus monkes – the NIA study, whereas WNPRC reported significant improvement in both lifespan and healthspan Caloric restriction delays disease onset and mortality in rhesus monkeys

CALERIE (Comprehensive Assessment of the Long term Effects of Reducing Intake of Energy), recently reported that a two year 25% caloric restriction is feasible for humans and provides health benefits, such as reduced inflammatory markers and cardiometabolic risk factors. A 2-Year Randomized Controlled Trial of Human Caloric Restriction Feasibility and Effects on Predictors of Health Span and Longevity  and Energy requirements in nonobese men and women results from CALERIE and Caloric Restriction in Humans

CALERIE was conducted in three independent centers and involved 218 overweight participants, suggesting that caloric restriction can be beneficial even in a very genetically heterogeneous group. Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) Screening and Recruitment Methods and Results

The ability of caloric restriction to prevent the damage caused by exogenous toxins is likely to be associated with the protection, repair and replacement effects that prevent the age-dependent dysfunction caused by endogenous processes and toxic molecules. CALORIE RESTRICTION AND AGING A LIFE-HISTORY ANALYSIS At the cellular level, caloric restriction and longevity mutations allow resistance to stressors, especially oxidative stress.

Likewise, it could be that hormesis occurs, in which repeat stresses allow adaptation and survival.

Dietary options for food restriction include: short-term starvation, periodic fasting, fasting-mimetic diets, intermittent fasting, normocaloric diets with planned deficiencies (in particular macronutrients: proteins, carbohydrates, etc.), and time-restricted feeding.Fasting involves a 60% decrease in food intake. Intermittent fasting refers to practicing this intervention every other day whereas periodic fasting refers to severe restriction for two or more days periodically (every two weeks, month, etc.) Caloric restriction and fasting result in lower glucose levels and insulin levels. Fasting vs dietary restriction in cellular protection and cancer treatment from model organisms to patients  Both intermittent and periodic fasting can increase lifespan, even when there is little or no overall decrease in calorie intake. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake and Brandhorst S, Choi IY, Wei M, et al.: A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015; 22(1): 86–99. 

The restriction of specific macronutrients (or macronutrient restriction) without the restriction of calories is among the most promising interventions that have emerged to promote healthy aging in humans, with  reduced intake of proteins and amino acids is the most effective pro-longevity intervention: Protein and amino acid restriction, aging and disease from yeast to humans [ Protein or Anino Acid (AA)  restriction has been shown to be as potent as calorie restriction in extending healthspan in multiple model organisms. AA restriction affects lifespan partly through modulation of the amino acid sensing pathways TOR and GCN2. Human epidemiological studies highlight the detrimental effects of high protein diets, in particular animal-derived protein sources in contrast to plant-based sources. Epidemiological studies indicate that low protein diets are associated with lower risk of chronic and age-related diseases such as CVDs, diabetes, and cancer.]  Also, Amino acid imbalance explains extension of lifespan by dietary restriction in Drosophila : Adding essential amino acids to a DR diet increased fecundity and decreased lifespan, similar to full feeding, with other nutrients having little or no effect. However, methionine alone increased fecundity as much as full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the DR responses. Lifespan was reduced by amino acids, particularly essential amino acids. Hence an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during DR. Reduced activity of the insulin/Igf signaling pathway extends lifespan in diverse organisms 7, and it protected against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits for lifespan of DR without reduced fecundity, through a suitable balance of nutrients in the diet.

A recent analysis of the National Health and Nutrition Examination Survey (NHANES) showed that low protein intake was associated with reduced overall mortality for those under 65 years of age. Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population : High protein intake is linked to increased cancer, diabetes, and overall mortality. High IGF-1 levels increased the relationship between mortality and high protein. Higher protein consumption may be protective for older adults. Plant-derived proteins are associated with lower mortality than animal-derived proteins. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

A high-carbohydrate, low-protein diet resulted in longer lifespan and improved cardiometabolic health, despite increased food intake and body fat: The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice —  Food intake is regulated primarily by dietary protein and carbohydrate. Low-protein, high-carbohydrate diets are associated with the longest lifespans. Energy reduction from high-protein diets or dietary dilution does not extend life. Diet influences hepatic mTOR via branched-chain amino acids and glucose. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake.Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. 

Also: Dietary Protein to Carbohydrate Ratio and Caloric Restriction Comparing Metabolic Outcomes in Mice Abstract: Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake Ad libitum low-protein, high-carbohydrate diets (LPHC) improve metabolic health. Caloric restriction combined with LPHC diet does not provide added health benefits. Energy intake and energy expenditure are increased on LPHC diets.

The restriction of a single essential amino acid in a normal diet increased lifespan and stress resistance: Zimmerman JA, Malloy V, Krajcik R, et al.: Nutritional control of aging. Exp Gerontol. 2003; 38(1–2): 47–52.  In this paper, reducing specific essential amino acids in rats demonstrated longevity effects. Reduced tryptophan content in the diet extended maximum lifespan. In fact, decreasing sulfhydryl-containing amino acids in the diet by removing cysteine and methionine extended survival. Calorie restriction (CR) delays cancer, reduces the diminution of the immune system in aging, and improves insulin sensitivity.  Essential amino acid restriction in this study, i.e. methionine restriction (MR) , resulted in decreased growth in rats, but produced life extension in the same was as CR would. MR produced 42% increase in longevity. The animals grew less, but they lived longer. As for tryptophan- restricted mice who were fed ad libitum, they too had less growth but lived 10% longer. CR, on the other hand, results in a 65% life extension, but off course the animals had to eat much less. It is felt that oxidation results in age-related physiological defects and that CR attenuates the generation of oxidative end products in aged animals. Glutathions (GSH) is one of the anti-oxidants and detoxifying agents that decreases in aging. This study demonstrated that cysteine-restriction did not decrease levels of GSH, but rather increased GSH levels in mice. Considering that cyteine is a precursor of GSh, this is counter intuitive.

The Abstract:  For more than 60 years the only dietary manipulation known to retard aging was caloric restriction, in which a variety of species respond to a reduction in energy intake by demonstrating extended median and maximum life span. More recently, two alternative dietary manipulations have been reported to also extend survival in rodents. Reducing the tryptophan content of the diet extends maximum life span, while lowering the content of sulfhydryl-containing amino acids in the diet by removing cysteine and restricting the concentration of methionine has been shown to extend all parameters of survival, and to maintain blood levels of the important anti-oxidant glutathione. To control for the possible reduction in energy intake in methionine-restricted rats, animals were offered the control diet in the quantity consumed by rats fed the low methionine diet. Such pair-fed animals experienced life span extension, indicating that methionine restriction-related life span extension is not a consequence of reduced energy intake. By feeding the methionine restricted diet to a variety of rat strains we determined that lowered methionine in the diet prolonged life in strains that have differing pathological profiles in aging, indicating that this intervention acts by altering the rate of aging, not by correcting some single defect in a single strain.

Also: Methionine restriction increases blood glutathione and longevity in F344 rats

Low-protein, high-carbohydrate diet increases glucose uptake and fatty acid synthesis in brown adipose tissue of rats.

De Marte ML, Enesco HE: Influence of low tryptophan diet on survival and organ growth in mice. Mech Ageing Dev. 1986; 36(2): 161–71. Abstract: Greater survival and reduced growth were found to characterize mice on a tryptophan deficient diet as compared to fully fed control mice. The 50% survival point was reached by the tryptophan restricted group at 683 days, and by the control group at 616 days. Measurements of body weight, organ weight, and DNA level were made at 8, 12, 24, 36, 52 and 78 weeks of age. Both whole body weight and organ weight of liver, kidney, heart and spleen were about 30% lower in the tryptophan restricted group as compared to the controls, so that the ratio of organ weight to body weight remained at a constant value for both groups. There was no significant change in cell number as determined by DNA measurements, as a result of the tryptophan restriction.

Ooka H, Segall PE, Timiras PS: Histology and survival in age-delayed low-tryptophan-fed rats. Mech Ageing Dev. 1988; 43(1): 79–98. Abstract:  Diets containing tryptophan in concentrations 30 and 40 percent of those fed to controls from weaning to 24-30 months or more, can delay aging in Long-Evans female rats. Mortality among low-tryptophan-fed rats was greater in the juvenile period, but substantially less than controls at late ages. Histological biomarkers of aging were also delayed after tryptophan restriction in some organs (liver, heart, uterus, ovary, adrenal and spleen) but not in others (kidney, lung, aorta). Brain serotonin levels were low in tryptophan-deficient rats but showed remarkable capacity for rehabilitation. Effects on early and late mortality and brain levels of serotonin were proportional to the severity of the restriction.

Laboratory rodents fed a methionine-restricted diet displayed an extended lifespan with decreased age-dependent diseases and increased resistance to oxidative stress, in part due to increased antioxidant capacity : Methionine restriction increases blood glutathione and longevity in F344 rats. Abstract as follows: Little is known about the biochemical mechanisms responsible for the biological aging process. Our previous results and those of others suggest that one possible mechanism is based on the loss of glutathione (GSH), a multifunctional tripeptide present in high concentrations in nearly all living cells. The recent finding that life-long dietary restriction of the GSH precursor methionine (Met) resulted in increased longevity in rats led us to hypothesize that adaptive changes in Met and GSH metabolism had occurred, leading to enhanced GSH status. To test this, blood and tissue GSH levels were measured at different ages throughout the life span in F344 rats on control or Met-restricted diets. Met restriction resulted in a 42% increase in mean and 44% increase in maximum life span, and in 43% lower body weight compared to controls (P < 0.001). Increases in blood GSH levels of 81% and 164% were observed in mature and old Met-restricted animals, respectively (P < 0.001). Liver was apparently the source for this increase as hepatic GSH levels decreased to 40% of controls. Except for a 25% decrease in kidney, GSH was unchanged in other tissues. All changes in GSH occurred as early as 2 months after the start of the diet. Altogether, these results suggest that dramatic adaptations in sulfur amino acid metabolism occur as a result of chronic Met restriction, leading to increases in blood GSH levels and conservation of tissue GSH during aging.

Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance  : A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/ cJ × C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age  Abstract:   Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the fi rst 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also signifi cantly increases longevity. Furthermore, mice exposed to a CR diet show changes in liver messenger RNA patterns, in phosphorylation of Erk, Jnk2, and p38 kinases, and in phosphorylation of mammalian target of rapamycin and its substrate 4EBP1, HE-binding protein 1 that are not observed in liver from agematched Meth-R mice. These results introduce new protocols that can increase maximal life span and suggest that the spectrum of metabolic changes induced by low-calorie and low-methionine diets may differ in instructive ways.

Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction Abstract: Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals. These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF and CF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction.

A fasting-mimicking diet, consisting of very low calorie and protein that leads to similar physiological response to fasting, including reduced levels of glucose and IGF-1 and increased levels of ketone bodies IGFBP-1, enhanced healthspan and rejuvenated the hematopoietic system while promoting adult neurogenesis :  Brandhorst S, Choi IY, Wei M, et al.: A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015; 22(1): 86–99. 

Feeding schedule has also been shown to have a significant impact on health and survival. In flies, time-restricted feeding (limited to 12 daytime hours every day) had profound effects on neural, peripheral, and cardiovascular physiology and improved sleep, body weight maintenance, and delayed signs of cardiac aging, under unchanged caloric intake and activity.  Time-restricted feeding attenuates age-related cardiac decline in Drosophila  Abstract: Circadian clocks orchestrate periods of rest or activity and feeding or fasting over the course of a 24-hour day and maintain homeostasis. To assess whether a consolidated 24-hour cycle of feeding and fasting can sustain health, we explored the effect of time-restricted feeding (TRF; food access limited to daytime 12 hours every day) on neural, peripheral, and cardiovascular physiology in Drosophila melanogaster. We detected improved sleep, prevention of body weight gain, and deceleration of cardiac aging under TRF, even when caloric intake and activity were unchanged. We used temporal gene expression profiling and validation through classical genetics to identify the TCP-1 ring complex (TRiC) chaperonin, the mitochondrial electron transport chain complexes, and the circadian clock as pathways mediating the benefits of TRF.

When mice were given access to food for only 8–9 hours during the active phase of the day, metabolic diseases induced by a high-fat, high-fructose, and high-sucrose diet, were reduced without lowering caloric intake : Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet  Abstract: While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes’ expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.

Ad lib feeding during the weekend did not interfere with the protective effects of time-restricted feeding: Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges Abstract:  Time-restricted feeding (TRF) confines food access to 9–12 hr during the active phase. TRF is a therapeutic intervention against obesity without calorie restriction.TRF protects against metabolic diseases even when briefly interrupted on weekends. TRF is effective against high-fat, high-fructose, and high-sucrose diets. Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8–9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.

A restricted feeding pattern reversed the progression of pre-existing obesity and type II diabetes, suggesting it has the potential to be a clinically relevant and feasible dietary intervention, useful to prevent and treat obesity and metabolic disorders : Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges

. Considering that key metabolic factors, such as 5’ AMP-activated protein kinase (AMPK), sirtuins, and protein kinase B (AKT), are regulated by an interplay of circadian rhythm and feeding time54,55, dietary schedules should be more carefully studied in the context of dietary restriction. Metabolism and the Circadian Clock Converge : Abstract: Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. 

Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression Abstract: In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system. 








Proton Pump inhibitors Adverse effects – Kidney disease, dialysis, pneumonia, heart disease, increased fracture risk, etc…

It has been known for many years that Proton Pump Inhibitors are associated with adverse events, especially kidney problems. This was brought to light ‘suddenly’ in the following abstract released in April 2016:

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. b

The abstract reads:

The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m2 and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31–90, 91–180, 181–360, and 361–720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

Using the VA database, the study evaluated exposure to PPI’s and CKD (Chronic kidney disease) outcomes over 5 years showing an increased risk of lowering GFR (renal insufficiency) and chronic kidney disease and eventually, end stage renal disease (dialysis). This  type of information has been out there for a long time but now people are taking notice.

Adverse Effects Associated With Proton Pump Inhibitors

All medications are poisons. The goal is to poison the person enough so as to make them feel better I guess.

The evidence for PPI’s adverse effects is all observational in nature and it is possible that patients that use PPI’s are generally more ill than the overall population, hence the findings of many of these studies that PPI’s carry adverse health effects or that it is the other medications that they take are producing the bad side effects. However, evidence has been building to show that the adverse effects are likely causal, meaning that the PPI is causing the adverse effect.

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. b

Chronic Kidney Disease – In the Atherosclerosis Risk in Communities study (ARIC), 10439 patients followed for 13.9 years demonstrated CKD was 50% higher in PPI users relative to non users. The risk was higher in those using higher doses of the PPI and also CKD was higher in those on PPI’s versus  H2 blockers. This was also seen in a study of patients in the Geisinger Health system as well.  The mechanism f this injury to the kidneys is in part due to hypomagnesemia (low magnesium).

Acute Kidney InjuryProton pump inhibitors and the risk of acute kidney injury in older patients a population-based cohort study  290,592 study patients age 66 and above demonstrated AKI (acute kidney injury) in rates of 2.5 to 3 fold higher in PPI users compared with non-users.A 2 – fold increased risk of AKI was also seen in studies that controlled for confounding problems: Proton pump inhibitors and acute kidney injury a nested case-control study.

The FDA has issued warning regarding bad effects from PPI’s. The link is here:

Hypomagnesemia: Low magnesium is damaging to the kidney and PPI’s, when taken for periods of time, are associated with hypomagnesemia. Proton pump inhibitors linked to hypomagnesemia a systematic review and meta-analysis of observational studies . IN this metanalysis, PPI’s resulted in a 40% increase in hypomagnesemia. Also reviewed here: Hypomagnesemia and proton-pump inhibitors, along with a general overview of PPI issues here: Perils and pitfalls of long-term effects of proton pump inhibitors.  And here: The Association between the Use of Proton Pump Inhibitors and the Risk of Hypomagnesemia A Systematic Review and Meta-Analysis

Clostridium difficile Infection: Likewise, PPI increase the risk of  C. dificile infection due to lower stomach acid levels – this is a 74% increase in risk and a 2-fold increase risk based on  a metaanalysis study as follows: Risk of Clostridium difficile Infection With Acid Suppressing Drugs and Antibiotics Meta-Analysis A more generic overview can be found here: Proton pump inhibitors potential adverse effects

Pneumonia:  Pneumonia is also increased in PPI users, some 34% per one meta analysis: Use of acid-suppressive drugs and risk of pneumonia a systematic review and meta-analysis. ALso this is considered in this article as well: Are proton pump inhibitors associated with the development of community-acquired pneumonia A meta-analysis The risk applied to community pneumonia, but not hospital-acquired pneumonia. There was no increase in hospitalization for these pneumonia: Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia replicated cohort studies with meta-analysis

Cardiovascular events: Research had suggested that antiplatlet agents, in particular, clopidogrel, may interact with PPI’s such that CLopidogrel as not activated in a normal fashion due to antagonism by Protonix ( a PPI) The FDA has warned against the use of Protonix and clopidogrel due to decreased efficacy. Concomitant use of clopidogrel and proton pump inhibitors impact on platelet function and clinical outcome- a systematic review. Again the FDA site mars this interaction with a warning as well:  Yet a randomized clinical trial did not demonstrate any increased risk: Concomitant use of clopidogrel and proton pump inhibitors impact on platelet function and clinical outcome- a systematic review. In short, the evidence is not solid in regards to the safety of PPI’s in Cardiovascular disease. Another recent study in PLOS one indicates an increased risk: Proton Pump Inhibitor Usage and the Risk of MI in the general population with results in the abstract as follows: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Fractures: PPI’s are associated with increased fracture risk as well. One metanalysis showed a 26% increease risk of hip and 58% increase of spine fractures even with short term use of PPI :Proton-pump inhibitors and risk of fractures an update meta-analysis . Also noted in the following study: Proton pump inhibitors and risk of fractures a meta-analysis of 11 international studies.

Gut Microbiome: Proton pump inhibitors affect the gut microbiome Those who use PPI’s tend to be heavier and have a less diverse gut microbiome. This may be why they are at risk for enteric infections and URI’s. There are changes towards a less healthy gut microbime. The odds of infection is 1.5 times as much.This was demonstrated in a study of 1815 people in the Netherlands.

B-12 deficiency: Also at risk with use of PPI’s is vitamin B12 deficiency: Proton Pump Inhibitor and Histamine 2 Receptor Antagonist use and vitamin B12 deciciency A discussion od B12 deficiency as follows: Biomarkers of vitamin B-12 status in NHANES a roundtable summary B12 deficiency is 65% more deficient in patients using PPI’s, especially when taking 1.5 pills a day or under age 30.


Long-term proton pump inhibitor therapy and risk of hip fracture.

Systematic review proton pump inhibitor-associated acute interstitial nephritis

Proton pump inhibitors and the risk of acute kidney injury in older patients a population-based cohort study.

Chronic kidney disease after acute kidney injury a systematic review and meta-analysis

Proton pump inhibitor-induced acute interstitial nephritis.

Overview of the Epidemiology Methods and Applications Strengths and Limitations of Observational Study Designs

Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials.

Active-comparator design and new-user design in observational studies

Economic evaluations of gastroesophageal reflux disease medical management.

Proton Pump Inhibitor Prescriptions and Subsequent Use in US Veterans Diagnosed with Gastroesophageal Reflux Disease

Inappropriate prescribing of proton pump inhibitors in primary care.

Bias in observational studies of prevalent users lessons for comparative effectiveness research from a meta-analysis of statins.

Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients  << This study demonstrates that there is over prescription in 73.9% of older patients of PPI’s, with which is associated cardiac diseases (Odds ratio 4.17), metabolic diseases (OR=2.14), and corticosteroids (OR=5.39)  Magnitude and Economic Impact of Inappropriate Use of Stress Ulcer Prophylaxis in Non-ICU Hospitalized Patients < Over-utilization of PPI outside the ICU setting. The over-utilization of PPI’s in association with metabolic disease may be related to events such as Diabetes in which the medications such as Metformin use lead to GI side-effects leading to PPI prescriptions. Likewise, many physicians initiate patients on PPI’s on when corticosteroids are being used, despite no scientific evidence supporting this in the absence of other risk factors.Factors associated with inappropriate inpatient prescribing of acid-suppressive therapy


Bottom- line: The use of PPI’s is associated with a 20-50% increased risk of CKD (adjusting for clinical measurements, socioeconomic status, and concomitant medications), whereas H2 blockers are NOT. PPI’s are also associated with acute interstitial nephritis as well.  Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease 15 mllion Americans use these PPI’s at a cost of $10 billion/year, of which 70% of the prescriptions are without indication Overprescribing proton pump inhibitors ans 25% could dicontinue the medication without symptoms! Proton pump inhibitor-induced acute interstitial nephritis.


Ask your doctor about your PPI!





Mediterranean Diet healthful effects and long term weight loss relative to other diets


The Mediterranean diet is a healthy diet that is not necessarily low-fat. It is low in omega-6 fatty acids and high in omega-3 fatty acids (olive oil). The use of herbs and spices in place of salt for seasoning makes the food more flavorful. Combined with 9 servings of fruits and vegetables every day, one gets plenty of nutrients from the diet.  Red meat is eaten maybe twice a week as is fish, such as mackerel, herring, sardines, and anchovies. Eggs and poultry are eaten frequently but less than in  an American diet. Wine or alcohol is common consumed with food. Mealtimes occur in a social setting with family and friends, which creates an excellent atmosphere. The diet is associated with lower rates of type 2 diabetes, Alzheimer’s disease, and cardiovascular disease.

Systematic Review of the Mediterranean Diet for long term weight loss

A recent Review in The American Journal of Medicine (April 2016) as above evaluated MEDLINE, EMBASE, and the Cochrane libraries for randomized controlled studies of trials showing the effects of a Mediterranean diet with more than 12 months follow-up. Five RCT’s (998=n) were found and evaluated and compared the Mediterranean diet to a low-fat diet, a low carbohydrate diet, and an American Diabetes Association diet.

The Mediterranean diet resulted in a greater weight loss (4 to 10 Kg) when compared to a low-fat diet  (3 to 5 kg loss), but produced similar weight loss at 12 months compared with the other diets.

The Mediterranean diet was found to be similar to the other diets in terms of cardiovascular risk factor levels, including blood pressure and lipid levels as well.

  • The Mediterranean diet has been found to work better than a low-fat diet based on this analysis. It also produced greater improvements in triglyceride levels but similar changes in other lipids and blood pressure. Likewise, the Mediterranean diet was better at improving glycemic (blood-sugar) control in diabetics ( but not non-diabetics).
  • There is no ideal diet for achieving sustained weight loss in overweight or obese individuals.

Long-Term Effects of 4 Popular Diets on Weight Loss and Cardiovascular Risk Factors  << This study reviewed the Atkins, Weight Watchers, and the Zone, and demonstrated that all produced similar weight loss at 12 months and beyond. There is no demonstrable problem with the carbohydrate load in a Mediterranean diet, and the similar weight loss among these diets suggests no optimal macronutrient composition to sustain weight loss.

Mediterranean diet benefits

Weight loss strategies for treatment of obesity. << There needs to be a three step approach to treating obesity and weight loss. First, life-style modification through diet, behavioral therapy, and physical activity need to occur.

Weight loss is increased with the addition of exercise – physical activity and dieting added together give greater increments of weight loss than dieting alone. The references below include links to evidence for this:

Long-term weight loss after diet and exercise a systematic review

Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss a meta-analysis

The role of exercise and physical activity in weight loss and maintenance.

Exercise Effects on White Adipose Tissue Beiging and Metabolic Adaptations

Exercise-Induced Skeletal Muscle Adaptations Alter the Activity of Adipose Progenitor Cells.

Endurance Exercise Training Up-Regulates Lipolytic proteins and reduces triglycerides in skeletal muscle of obese subjects

Bottom line is that physical activity alone is unlikely to yield significant weight loss unless it is added to a calorie-restricted diet.

After these two components of exercise and low-calorie dieting, one then adds pharmacochotherapies. The final component is bariatric surgery for those who do not achieve goals and are of sufficiently high BMI and comorbidities.

Mediterranean diet pyramid today. Science and cultural updates  << The Mediterranean diet is composed of fruits, vegetables, legumes, cereals, fruits, ad olive oil based food. The origins of the diet were Middle Eastern and ‘biblical’ in their origins: >> The Middle Eastern and biblical origins of the Mediterranean diet

Mediterranean Diet – From a Healthy Diet to a Sustainable Dietary Pattern  < the diet is composed of a tasteful selection of foods designed for a sustainable lifestyle.

Sustainable diets the Mediterranean diet as an example

Natural Resources – Food Nexus Food-Related Environmental Footprints in the Mediterranean Countries << – Soon it will be hard to eat a ‘true’ Mediterranean diet due to environmental changes!

Mediterranean Diet – From a Healthy Diet to a Sustainable Dietary Pattern

Importance of functional foods in the Mediterranean diet <<< Numerous food types play an important role in the Mediterranean diet

Does a Mediterranean-Type Diet Reduce Cancer Risk <<

Nutrition and lifestyle in healthy aging the telomerase challenge << Nutrition that is done correctly may improve our life-spans and quality.

The Mediterranean Diet, its Components, and Cardiovascular disease << there is plenty of evidence demonstrating the decreased cardiovascular disease with the Mediterranean diet (The Seven Countries study)

There is also a decreased risk of breast cancer by following a Mediterranean diet: Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial as well as the metabolic syndrome:  Adherence to Mediterranean diet reduces the risk of metabolic syndrome a 6-year prospective study.

Certain dietary patterns are beneficial for the metabolic syndrom- reviewing the evidence.

The Mediterranean Lifestyle as a Non-Pharmacological and Natural Antioxidant for Healthy Aging

Anti-inflammatory Dietary Inflammatory Index scores are associated with healthier scores on other dietary indices.

Sticking to the Mediterranean diet decreases the chances of metabolic syndrome by 50% [Adherence to Mediterranean diet reduces the risk of metabolic syndrome a 6-year prospective study.], decreases mortality over 20 years [ Mediterranean diet and other lifestyle factors in relation to 20-year all-cause mortality a cohort study in an Italian population] , and healthier markers of aging [ Mediterranean diet and telomere length in Nurses’ Health Study_ population based cohort study 1]

The PREDIMED RCT showed, using 7447 individuals, that the Mediterranean diet that is supplemented with nuts or olive oil relative to a low-fat diet will decrease the risk of myocardial infarction, stroke, or cardiovascular death. —> Primary Prevention of Cardiovascular Disease with a Mediterranean diet and Benefits of the Mediterranean Diet Insights From the PREDIMED Study.

Other benefits of the diet include decreased inflammation and coagulation disorders [Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults – ATTICA study] as well as Type 2 diabetes, metabolic syndrome improvement, lower blood pressure, decreased atrial fibrillation rates, and decreased peripheral arterial disease. Benefits of the Mediterranean Diet Insights From the predimed study

Adherence to Mediterranean diet and health status_ meta-analysis

Preventive obesity agent montmorillonite adsorbs dietary lipids and enhances lipid excretion from the digestive tract

Certain dietary patterns are beneficial for the metabolic syndrom- reviewing the evidence.

Obesity as an independent risk factor for cardiovascular disease a 26-year follow-up of participants in the Framingham Heart Study. << The bottom line is adherence is critical to have the benefits of any diet, including the Mediterranean diet!

Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss a meta-analysis

Importance of functional foods in the Mediterranean diet

Indicators for the evaluation of diet quality

Sustainable diets the Mediterranean diet as an example

What current literature tells us about sustainable diets emerging research linking dietary patterns, environmental sustainability, and economics

Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss a meta-analysis

Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors Among Overweight Premenopausal Women

Fruit, vegetable, and fiber intake in relation to cancer risk findings from the European Prospective Investigation into Cancer and Nutrition (EPIC

British Journal of Nutrition – Increased intake of fruits and vegetables in overweight subjects_ effects on body weight, body composition, metabolic risk factors and dietary intake –

New Obesity Guidelines

A Diet by Any Other Name Is Still About Energy

Comparison of Weight Loss Among Named Diet Programs in Overweight and Obese Adults

Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study

Behavioral Counseling to Promote a Healthy Lifestyle for Cardiovascular Disease Prevention in Persons With Cardiovascular Risk Factors An Updated Systematic Evidence Review

Mediterranean diet and cardiodiabesity a review.

Food Processing and the Mediterranean Diet

Dietary patterns, inflammation and the metabolic syndrome.

Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome a randomized trial.

Mediterranean diet and risk for Alzheimer’s disease.














Parkinson’s Disease risk decreased by Nicotine intake; Eat more potatoes, tomatoes, and Peppers!

Peppers, Eggplant, tomatoes, potatoes have nicotine, which seems to decrease the risk of Parkinson's Disease.
Peppers, Eggplant, tomatoes, potatoes have nicotine, which seems to decrease the risk of Parkinson’s Disease.

Nicotine from edible Solanaceae and risk of Parkinson disease

There have been found associations of cigarette smoking with a decrease in the occurrence of Parkinson’s Disease (PD):

Parkinson’s Disease Risks Associated with Cigarette Smoking, Alcohol Consumption, and Caffeine Intake

The abstract of this study is below in which smoking and coffee intake both currently decrease the risk of PD:

A reduced risk for Parkinson’s disease (PD) among cigarette smokers has been observed consistently during the past 30 years. Recent evidence suggests that caffeine may also be protective. Findings are presented regarding associations of PD with smoking, caffeine intake, and alcohol consumption from a case-control study conducted in western Washington State in 1992–2000. Incident PD cases (n = 210) and controls (n = 347), frequency matched on gender and age were identified from enrollees of the Group Health Cooperative health maintenance organization. Exposure data were obtained by in-person questionnaires. Ever having smoked cigarettes was associated with a reduced risk of PD (odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.4, 0.8). A stronger relation was found among current smokers (OR = 0.3, 95% CI: 0.1, 0.7) than among ex-smokers (OR = 0.6, 95% CI: 0.4, 0.9), and there was an inverse gradient with pack-years smoked (trend p < 0.001). No associations were detected for coffee consumption or total caffeine intake or for alcohol consumption. However, reduced risks were observed for consumption of 2 cups/day or more of tea (OR = 0.4, 95% CI: 0.2, 0.9) and two or more cola drinks/day (OR = 0.6, 95% CI: 0.3, 1.4). The associations for tea and cola drinks were not confounded by smoking or coffee consumption. Am J Epidemiol 2002;155:732–8.

But cigarette smoking is bad for your lungs, increasing cancer risks and emphysema among other things, so why would anyone want to smoke just to decrease PD risk? Is there another way to decrease PD risk and why do cigarettes work for PD?

  • The study at the top of the page (ANN NEUROL 2013;74:472–477) helps demonstrate the possibility that nicotine is neuro-protective among all the millions of compounds found in cigarette smoke.
  • Nicotine is derived from nicotiana spp. of solanaceae species which includes capsicum and solanum species whose edible fruits and tubers include peppers, eggplants, potatoes, and tomatoes. All of these have nicotine in them. In peppers, there is approximately 102 micrograms/kg, while tomatoes have 43 mcg/kg of nicotine. A potato has ~19 mcg/kg of nicotine. Since we consume more tomatoes and potatoes than peppers, they make up most of the nicotine consumption in people.
  • It is noted that nicotine stimulates alpha4beta2 (a4B2) receptors in the brain which protect dopaminergic neurons by binding the receptors. This may be how PD is prevented.
  • In the study, 490 people with PD were assessed for vegetable intake, in particular peppers, tomatoes, and potatoes. It  was found that PD frequency was inversely related to solanaceae intake but not other vegetables, in particular peppers. Weighted for those with the most nicotine intake,  those with the highest nicotine consumption had the lowest frequency of PD. There were 644 controls in this study.
  • After calculating risks, pepper consumption 2-4 times a week was associated with a 30% reduction in PD risk in people who did not smoke.
  • The food impact was highest in non-smokers since the nicotine content in food is so much lower than the intake of nicotine in active smokers.
  • There was an inverse association of PD in consumption of tomatoes (Fall PA, Fredrikson M, Axelson O, et al. Nutritional and occupational factors influencing the risk of Parkinson’s disease: a casecontrol study in southeastern Sweden. Mov Disord 1999;14:28–37) , potatoes ( Hellenbrand W, Seidler A, Boeing H, et al. Diet and Parkinson’s disease. I: A possible role for the past intake of specific foods and food groups. Results from a self-administered food-frequency questionnaire in a case-control study. (Neurology 1996;47: 636–643) and a Mediterranean Diet with tomatoes ( The Association between Mediterranean Diet Adherence and Parkinson’s Disease ) [ Abstract: The most consistent data support the association between higher consumption of dairy products and increased PD risk. More recently, a prospective analysis of two large cohorts, the Health Professionals Follow-Up Study (HPFS) and the Nurses’ Health Study (NHS), revealed an association between PD risk and dietary patterns as assessed by the Alternate Healthy Eating Index (AHEI) and the alternate Mediterranean Diet Score. The Mediterranean diet (MeDi) has received attention in recent years because of growing evidence associating MeDi with lower risk for AD, cardiovascular disease, several forms of cancer, and overall mortality.The MeDi is characterized by high intake of vegetables, legumes, fruits, and cereals; high intake of unsaturated fatty acids (mostly in the form of olive oil) compared to saturated fatty acids; a moderately high intake of fish; a low to-moderate intake of dairy products, meat and poultry; and a regular but moderate consumption of ethanol, primarily in the form of wine and generally during meals. This study suggests that lower adherence to MeDi is associated with PD status. The association persisted after adjustment for multiple potential confounders. The fact that among PD participants, lower adherence was associated with earlier PD age-at-onset further suggests a possible dose-response effect. The relation between MeDi adherence and PD status was not driven by any individual category of the diet but rather the whole pattern. Previous studies have indicated that environmental factors play a major role in PD; however, most nutritional studies in PD have shown conflicting results. Possible explanation for the conflicting data is that most studies have focused on single nutrients, e.g. vitamins C or E,7,  rather than on dietary patterns. Indeed, the largest prospective study of dietary patterns identified a Mediterranean-like diet as protective of PD both in males (HPFS) and females (NHS). Assessing dietary patterns may be more informative than assessing specific nutrients separately. First, this approach is more consistent with individuals’ eating habits, and second, it takes into account interactions among nutrients. This approach has been successful in AD and in non-neurological diseases.The mechanism by which MeDi may be protective in neurodegenerative disorders is largely unknown. Mechanisms that have been hypothesized in the AD literature, include oxidative stress and inflammation. Indeed, oxidative stress has been implicated in the pathogenesis of PD.  Complex phenols and other substances including vitamin C, vitamin E, and carotenoid may serve as antioxidants,  and are found in high concentrations in the typical components of the MeDi. Inflammation has also been implicated in the pathogenesis of PD, and anti-inflammatory non-steroidal medications may be associated with a lower risk for PD. Adherence to the MeDi may attenuate inflammation. In addition, MeDi adherence may be protective because of lower consumption of compounds which are associated with higher PD risk. We and others have shown an association between animal fat consumption and PD,  and the association between higher dairy intake and PD was previously reported.]
  • There are still unknowns in this study – i.e relative to smoking, diet is a modest contributor of nicotine. Biological effects of Solanaceae nicotine has not been established but substantial a4B2 nicotine receptors are occupied without active smoking in patients who take in solanaceae products.As compared to smoking, smokers with just a puff get enough nicotine to occupy a third of the receptors for more than three hours. It is also unknown if french fries, salsa, sauces, or fried potatoes give a similar nicotine effect as the original vegetable.
  • There may be other neuroprotective chemicals in these vegetables such as Anatabine, which is antiinflammatory and has less toxicity. Anatabine Ameliorates Experimental Autoimmune thyroiditis << Key components: Tobacco smoking has numerous detrimental effects on human health, but it has also been associated with a few apparent salutary actions, including the amelioration of autoimmune (Hashimoto) thyroiditis and ulcerative colitis. Smokers in the Third National Health and Nutrition Examination Survey were found to have lower prevalence of thyroperoxidase and/or thyroglobulin antibodies than nonsmokers (1). This protective effect of smoking was confirmed in two additional cross-sectional studies, one from the Amsterdam autoimmune thyroid disease cohort (2) and the other from the Danish population (3), as well as in a 5-yr prospective study also based on the Amsterdam autoimmune thyroid disease cohort (4). In the prospective study, cigarette smoking women who had one or more relative with documented thyroid autoimmunity but no thyroid dysfunction or autoantibodies at study entry showed lower odds of developing thyroperoxidase and/or thyroglobulin antibodies (4). Similarly in ulcerative colitis, smoking has been shown to decrease flares (5), hospitalizations (6), and a need for oral glucocorticoids (7) so that low-dose smoking resumption has been successfully used in ex-smokers with refractory disease (8). The mechanisms underlying this influence of tobacco smoking on some autoimmune diseases have been related to the effects of tobacco components on the immune system (9). There are numerous (4000) components in tobacco, including alkaloids (such as nicotine and anatabine), gases (e.g. carbon monoxide), and carcinogens (e.g. polycyclic aromatic hydrocarbons, aldehydes, free radicals, and solvents), and of them nicotine is known to possess antiinflammatory properties (10). Nicotine acts via binding to the nicotinic receptor, a pentameric ion channel (mainly for sodium and calcium) formed by the arrangement of 16 different subunits in hetero- or homomeric conformations (11). The receptor is classically expressed in the peripheral (all preganglionic fibers and neuromuscular synapses) and central nervous system, but more recently it has been described in cells of the immune system, including CD4 T lymphocytes, dendritic cells, and macrophages (12). Indeed, the 7-homopentameric nicotinic receptor has emerged as a novel therapeutic target for diseases with an inflammatory pathogenesis (13). Nicotine has been used successfully in mice with experimental autoimmune encephalomyelitis in which it reduced disease severity, shifting the autoimmune profile from pathogenic Th1 and Th17 responses to protective Th2 responses (14). Nicotine, however, cannot be used in humans because it is addictive and toxic and has a short 3-h plasma half-life. Consequently, we reasoned that other alkaloids of tobacco could share similar antiinflammatory properties but have a more favorable pharmacological profile. The minor tobacco alkaloid anatabine is nonaddictive and nontoxic at therapeutic doses and has a longer 8-hr half-life. Furthermore, anatabine has been recently shown to inhibit nuclear factor-B (NF-B) activation and reduce neuroinflammation in a mouse model of Alzheimer disease (15). In the present study, we therefore tested the antiinflammatory properties of anatabine in a mouse model of experimental autoimmune thyroiditis.  Anatabine is an alkaloid with a structure similar to nicotine, found in tobacco and other solanaceous plantsas tomatoes, potatoes, green pepper, and eggplant. Its lack of addictive potential or any demonstrated toxicity. Given the structure similarity with nicotine, we postulated that anatabine initiates its effects by binding to the nicotine receptor and modulating the cholinergic control of inflammation (10, 24). The nicotinic receptor that has been clearly associated with antiinflammatory responses is the 7-homopentamer, classically found on neural cells but also on immune cells (12). Activation of the 7-nicotinic receptor present in lymphocytes, dendritic cells, and macrophages has been shown to suppress nuclear translocation of NF-B and transcription of high mobility group box 1, ultimately decreasing danger signals that initiate inflammation (25). Consistent with this mechanism, Paris and colleagues demonstrated that anatabine suppresses in a dose-dependent manner the transcription of NF-B induced by tumor necrosis factor- (15). However, anatabine suppressed the thyroidal expression of IL-18 and IL-1R2. IL-18, a member of the IL-1 family, is produced by activated macrophages and stimulates production of interferon- from T cells and natural killer cells (26), overall acting as a proinflammatory stimulus. IL-18 has been shown to increase during thyroid inflammation both in vitro (27) and in vivo (28) ]
  • Capsinoids in peppers and capsaicinoids in spicy peppers may activat TRPV1 (Transient Receptor Potential Cation Channel subfamily vanilloid member 1) in the midbrain dopaminergic neurons. This seems to e protective. Transient Receptor Potential Vanilloid Subtype 1 Mediates Cell Death of Mesencephalic Dopaminergic Neurons In Vivo and In Vitro and Somatostatin prevents lipopolysaccharide‑induced neurodegenration
  • Major nutritional issues in the management of Parkinson’s disease

Summary: To safely decrease your risk of Parkinson’s disease, increase your peppers, tomatoes, potatoes, and eggplant intake. They have nicotine that when consumed, is protective of dopaminergic receptors of your brain and seem to decrease the risk of PD.

Diet and Parkinson’s disease I A possiblerole for intake of specific foods and food groups

Systematic review and meta-analysis of hydrocarbon exposure and the risk of Parkinson’s disease.

Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease.

Outdoor work and risk for Parkinson’s disease

Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson’s disease.

Iron and Oxidative Stress in Parkinson’s Disease An Observational Study of Injury Biomarkers

Can Tea Consumption be a Safe and Effective Therapy Against Diabetes Mellitus-Induced Neurodegeneration

Parkinson’s disease no milk today

Parkinson’s Disease Risks Associated with Cigarette Smoking, Alcohol Consumption, and Caffeine Intake n

Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE

HFE gene variants, iron, and lipids a novel connection in Alzheimer’s disease.

Diet and Parkinson’s disease I A possiblerole for intake of specific foods and food groups

Vitamin D and Sunlight Exposure in Newly-Diagnosed Parkinson’s Disease.

parkinsons and solanaceum

Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease


Eat your Fresh Fruit! – for better cardiovascular health: Latest New England Journal April 11, 2016

A recent study released in the April 10 edition of The New England Journal of Medicine demonstrated that fresh fruit consumption was associated with decreased blood pressure and decreased blood glucose.

Fresh Fruit Consumption and Major Cardiovascular disease in China

Increased fresh fruit consumption was associated with decreased risk of cardiovascular disease, decreased cardiovascular death, decreased coronary events, decreased hemorrhagic stroke, and decreased ischemic strokes.


Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer_ systematic review and dose-response meta-analysis of prospective cohort studies

Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases.

Dietary Nitrate Lowers Blood Pressure

Fruit and vegetable consumption and all-cause, cancer and CVD mortality analysis of Health Survey for England data.

Fruit and Vegetable Consumption and Risk of CAD – a metanalysis of cohort studies

Quantity and variety in fruit and vegetable intake and risk of coronary heart disease

Greater Total Antioxidant Capacity from Diet and Supplements Is Associated with a Less Atherogenic Blood Profile in U.S. Adults

Novel insights of dietary polyphenols and obesity

Cruciferous vegetable consumption is associated with a reduced risk of total and Cardiovascular disease mortality

The NEJM study released in this issue death with Chinese populations, some 450,000 Chinese in fact, with no prior stroke or hypertension to avoid confounding factors. IN Western populations, an inverse association had been seen in patients eating 80 gm of fruit a day, leading to a 5% decrease in cardiovascular death.

A low level of fruit intake is associated with a major increased cardiovascular risk rate. The study above chose China, since vegetable intake is high but fresh-fruit intake is much lower.  Cardiovascular disease causes 17 million deaths a year and is especially high in lower income countries. The effect of adding fruit to the diet of people with low consumption rate can detect larger effects.


The association between the level of fruit consumption and cardiovascular risk in our study (a 40% lower risk of cardiovascular death and a 34% lower risk of major coronary events among participants who consumed fresh fruit daily as compared with those who never or rarely consumed fresh fruit) was much stronger than the associations observed in previous studies. < Current NEJM study April 2016.    This study involved some 512,000 people who had low intake of fruit already, making it easy to detect positive benefits. None of the patients had hypertension or Diabetes, and thus were not on any confounding medications. The study also took into account regression dilution bias (changes in baseline characteristics of a population during a study) that may impact findings. 

Fruit is high in fiber, potassium, folate, phytochemicals, and antioxidants all of which may mediate the positive impact of fruit intake.


In conclusion, our evaluation of the relationship between fresh fruit consumption and cardiovascular disease in China showed that the level of fruit consumption was inversely associated with blood pressure and blood glucose levels.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010 a systematic analysis for the Global Burden of Disease Study 2010.

Up-regulating the Human Intestinal Microbiome Using Whole Plant foods, polyphenols and fiber

Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals

What is Xenohormesis

White Pitaya (Hylocereus undatus) Juice attenuates insulin resistance and hepatic steatosis in obese mice

Greater Total Antioxidant Capacity from Diet and Supplements Is Associated with a Less Atherogenic Blood Profile in U.S. Adults b

Feeding the brain and nurturing the mind linking nutrition and the gut microbiota to brain development

Cultivating healthy growth and nutrition through the gut microbiota.




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.  < 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



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:


association between fiber intake and measures of lung function

Read More:

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











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



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

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


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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.

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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.

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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. 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.


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