Research Forum


Enhanced Cognition with Vitamin D

Vitamin D has proven to be a champion of cognitive health in a recent study assessing healthy adults who possessed a baseline vitamin D of ≤ 100nmol/L, and located in British Colombia, Canada (54˚ North Latitude).  82 adults were randomized and blinded to receive either high dose vitamin D3 (4000 IU/day) or low dose vitamin D3 (400 IU/day) for 18 weeks. The serum levels of 25(OH)D were observed to increase significantly in the high dose vitamin D group, from 67.2 ± 20 to 130.6 ± 26, compared to the low dose group, which increased from 60.5 ± 22 to 85.9 ± 16 nmol/L (p=0.0001).  The high dose group also experienced performance improvement on nonverbal (visual) memory, assessed by the Pattern Recognition Memory task (PRM), (84.1 ± 14.9 to 88.3 ± 13.2) (d = 0.3), as well as the Paired Associates Learning Task, (PAL) number of stages completed, from 4.86 ± 0.35 to 4.95 ± 0.22 (p=0.044) (d=0.5).  These improvements were not exhibited in the low dose group.  It was also noted that the “degree of improvement was comparatively greater in the high dose group for these tasks.” For those possessing insufficient 25(OH)D at baseline (<75nmol/L), a significant improvement (p=0.005, d=0.7) was demonstrated in the high dose group (n=23) (p=0.005, d=0.7). “Nonverbal (visual) memory seems to benefit from higher doses of vitamin D supplementation, particularly among those who are insufficient at baseline (<75nmol/L).” Thus, they suggested that “higher 25(OH)D is particularly important for higher level cognitive functioning, specifically nonverbal (visual) memory.”

Ref: Petterson JA. Does high dose Vitamin d supplementation enhance coginition? A randomized trial in healthy adults. Exp. Gerontol. 2017 Apr; 90:90-97.  Doi: 10.1016/j.exger.2017.01.019. Epub 2017 Feb 4.  

Ginkgo Biloba Extract Improves Both Cognitive and Neurological Functions Following Stroke

Ginkgo biloba has a long history of use in China "as a traditional herb for memory, depression, tinnitus and confusion." In this randomized, controlled trial, Ginkgo biloba was demonstrated to improve both cognitive and neurological functions following acute ischemic stroke. Within seven days of the onset of acute ischemic stroke, patients from five hospitals in China were enrolled in this study. Study participants were assigned to either a Ginkgo biloba extract (GBE) group (450mg GBE, along with 100mg aspirin daily), or a control group (100mg aspirin daily), for a duration of 6 months. The ingredients of GBE are complex, "and vary by age, cultivation source, and gender of the Ginkgo biloba tree." The extract GBE EGb761 was utilized as it is a well-defined GBE extract, that "contains approximately 24% flavone glycosides (primarily quercetin, kaempferol and isorhamnetin), 6% terpene lactones (ginkgolides A, B and C, and bilobalide), 0.8% Ginkgolide B and <5 ppm [of the] harmful ginkgolic acid."The primary consequences were defined as a "decline in the Montreal Cognitive Assessment score at 6 months, [with] secondary outcomes [defined from] other neuropsychological tests of cognitive and neurological function." In the GBE group a "marked slowdown in the decline in the Montreal Cognitive Assessment scores" was observed, as compared to controls. Other neuropsychological tests of cognitive function were also performed, including National Institutes of Health Stroke Scale (NIHSS), the Modified Rankin Scale (mRS) independent rate, and the Mini-Metal State Examination (MMSE). These examinations also demonstrated favorable improvements in neurological function with GBE treatment. The study concluded in affirming that patients having a stroke and receiving GBE "manifested better memory function, executive functions, neurological function and daily life." There was no increases the incidence of adverse events. It was also noted that "compared to donepezil (5 mg daily) in the treatment of Alzheimer’s dementia, GBE (160 mg daily) showed comparable efficacy."

Li S, Zhang X, Fang Q, et al. Ginkgo biloba extract improved cognitive and neurological functions of acute ischaemic stroke: a randomized controlled trial. Stroke and Vascular Neurology 2017;2: e000104. doi:10.1136/svn-2017-000104.

Ashwagandha is Beneficial in Alleviating Cognitive Dysfunction

In the obese individual, cognitive disturbances, including problem solving, working memory, and neuro-muscular coordination, have been demonstrated to affect both social and mental abilities. Ashwagandha (ASH), recognized for its memory boosting and restorative functions “is traditionally used as a rasayana (tonic) that works in a holistic manner to promote overall health and vitality”, and has also been reported to support memory. Cognitive shortfalls across the lifespan have been associated with “obesity (without any comorbid medical condition)”. In fact, both genetics and dietinduced obesity (DIO) are recognized to seriously impair both Hippocampal synaptic plasticity and spatial memory. Applying an animal model of Alzheimer’s disease, animals were administered a standardized dose of ASH dry leaf powder in an effort to investigate AHS’s potential benefits on the recovery of “cognitive skills and neuromuscular functions impaired by DIO.” It was determined that in rats fed a high fat diet “ASH treatment improved the memory and learning-based functions by promoting the activity dependent hippocampal plasticity and cell survival,” as well as by decreasing the cellular stress. ASH supplementation also enhanced the expression of total and phosphorylated Akt-1 in rats fed both the low-fat diet extract (LFDE) and the high fat diet extract (HFDE) in both the brain regions, and in neuronal cells, thereby promoting survival conditions. AKT is defined as a “critical mediator of growth factor-induced neuronal survival, and Akt1 is critical for transmitting growth-promoting signals.”(1) ASH intake in HFDE group was noted to normalize the upregulated levels of corticosterone to basal levels. It was thus concluded that “ASH treatment improved memory and learning based functions by promoting activity dependent hippocampal plasticity and cell survival, and by reducing cellular stress.”

Manchanda S, Kaur Gurcharan. Withania somnifera leaf alleviates cognitive dysfunction by enhancing hippocampal plasticity in high fat diet induced obesity model. BMC Complementary and
Alternative Medicine. 2017 17:136. DOI 10.1186/s12906-017-1652-0

Medicinal Properties of Curcumin

Curcumin has demonstrated several medicinal properties, including possessing an inhibitory effect on the virulence, quorum sensing (QS), and biofilm initiation.(1) Curcumin has also exhibited an inhibitory effect on the QS system of numerous pathogens, including E. coli and P. aeruginosa. This study examined the liposomes of curcumin as an inhibitory mechanism on QS system of Aeromonas sobria (AS), which “is a Gram-negative, rod-shaped, facultative anaerobic, motile, and flagellated bacterium,” that typically flourishes in various types of waters, as well as in soil and food. It is also “an opportunistic pathogen for animals and humans, [as] it can cause extra-intestinal infections and gastrointestinal diseases.”(2) In bacteria, a cell to cell communication mechanism called “Quorum sensing” allows the bacteria to monitor their population density by secreting signaling molecules or autoinducers.(3) These chemical signals are released from bacteria and accumulate in the environment. Once a threshold concentration is reached, the bacteria can bind to receptor proteins and trigger the expression of a series of QS targeting genes.(4) “Blocking the bacterial QS system has been considered as an alternative of traditional antibiotics.” Indeed, “many natural products and synthetic materials have been [demonstrated] to be quorum sensing inhibitors (QSIs). In this study the QS-controlled swimming and swarming motility of A. sobria was significantly inhibited by curcumin, as both liposome and free curcumin forms. Additionally, curcumin liposomes were demonstrated to be more effective than free curcumin in inhibiting swimming and swarming motility of A. sobria. Inhibition of biofilm formation was demonstrated up to 93.35% when compared to control (p < 0.05). The results also suggested that curcumin, “although having an effect on the on the biofilm formation, did not interfere with normal growth of bacteria.”

Ting Ding T, Li T, Zhi Wang Z, Jianrong Li J. Curcumin liposomes interfere with quorum sensing system of Aeromonas sobria and in silico analysis. Scientific Reports. Published online: 17 August 2017.
1. Rudrappa T, Bais HP. Curcumin, a known phenolic from Curcuma longa, attenuates the virulence of Pseudomonas aeruginosa PAO1 in whole plant and animal pathogenicity models. J. Agric. Food
Chem. 2008 Mar 26;56(6):1955-62.
2. Chang, H., Hung, Y. S., Shie, S. S. & Lin, T. L. Fulminant necrotizing fasciitis caused by Aeromonas sobria in neutropenic patients. Intern Med. 2012 51,3287–3290.
3. Bucio-Cano, A. et al. Targeting quorum sensing by designing azoline derivatives to inhibit the N-hexanoyl homoserine lactonereceptor CviR: Synthesis as well as biological and theoretical evaluations.
Bioorg Med Chem. 2015 23:7565–7577.
4. Boyle KE, Monaco H, van Ditmarsch D, Deforet M, Xavier JB. Integration of Metabolic and Quorum Sensing Signals Governing the Decision to Cooperate in a Bacterial Social Trait. PLoS Computational
Biol. 2015 11, e1004279.

Eating Nuts Strengthens Brainwave Frequencies

In a study by researchers from Loma Linda University Health, it was determined that “eating nuts on a regular basis strengthens brainwave frequencies associated with cognition, healing, learning, memory and other key brain functions.” The researchers tested six nut varieties, including almonds, cashews, peanuts, pecans, pistachios and walnuts, and determined that “some nuts stimulated [particular] brain frequencies more than others.” Pistachios, for example were determined to “produced the greatest gamma wave response”, a critical component for “enhancing cognitive processing, information retention, learning, perception and rapid eye movement during sleep.” Peanuts, also included in the study, were determined to produce “the highest delta response.” Delta responses are “associated with healthy immunity, natural healing, and deep sleep.” The study concluded by affirming, “this study provides significant beneficial findings by demonstrating that nuts are as good for your brain as they are for the rest of your body."

Loma Linda University Adventist Health Sciences Center. "Consuming nuts strengthens brainwave function: Researchers find that nuts benefit the brain by enhancing cognition,
memory, recall and rest." ScienceDaily. ScienceDaily, 15 November 2017.

Low Muscle Insulin Sensitivity in Poorly Controlled T2D is Associated with Incomplete Skeletal Muscle Fatty Acid

The mechanisms responsible for progressively worsening glycemic control are poorly understood. In a study by Gavin TP, et al. it was observed that “lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D.” The insulin sensitivity in skeletal muscle was investigated, and the difference between well (WCD) and poorly (PCD) controlled T2D was determined. They also determined if the “skeletal muscle insulin sensitivity was different between well (WCD) and poorly (PCD) controlled T2D, and if the difference was associated with differences due to mitochondrial respiratory function.” It was determined that both insulin sensitivity (SI) and acute response to glucose (AIRg) were lower in PCD as compared to WCD. The study concluded that the “current results suggest that greater skeletal muscle incomplete FAO [fatty acid oxidation] in poorly controlled T2D is due to elevated β oxidation and is associated with worsening muscle insulin sensitivity.”

Gavin TP, Ernst JM, Kwak H-B, Caudill SE, Reed MA, Garner RT, Nie Y, Weiss JA, Pories WJ, Dar M, Lin C-T, Hubal MJ, Neufer PD, Kuang S, Dohm GL. High incomplete skeletal
muscle fatty acid oxidation explains low muscle insulin sensitivity in poorly controlled T2D. J Clinical Endocrinology & Metabolism. 2017 15 November.

The Slow Down of Brain Cells with Fatigue

In a study published in Nature Medicine, it was reported “that individual neurons slow down when we are sleep deprived, leading to delayed behavioral responses to actions around us.” With sleep deprivation, the neural lapse, or slowdown that occurs “affects the brain’s visual perception and memory associations.” They determined that certain tasks are difficult when one is tired, and especially difficult after pulling an all-nighter. They observed “that sleepiness slows down the responses of individual neurons, leading to behavioral lapses,” and that “sleep deprivation affected the area associated with visual perception and memory,” resulting in “neuronal lapses — slow, weak and sluggish responses.” They also found “that neuronal lapses co-occurred
with slow brain waves in the same regions. As the pressure for sleep mounted, specific regions ‘caught some sleep’ locally. Most of the brain was up and running, but temporal lobe neurons happened to be in slumber, and lapses subsequently followed.” This research demonstrated that sleep deprivation disrupts and slows normal neural activity in specific regions of the brain. Accordingly, sleep deprivation is a major source of morbidity and induces widespread health effects.

Nir Y, Andrillon T, Marmelshtein A, Suthana N, Cirelli C, Tononi G, Fried I. Selective neuronal lapses precede human cognitive lapses following sleep deprivation. Nature Medicine.
2017 October. doi:10.1038/nm.4433

High Fiber Intake Associated with Improved Survival Rate in Colorectal Cancer

Colorectal cancer (CRC) is recognized as “the third most common cancer and the third leading cause of cancer death in the United States.” According to a recent JAMA Oncology study, a high fiber intake following a diagnosis of CRC is associated with an improved rate of survival. In this study, researchers evaluated 1575 healthcare professionals with stage I to III in 2 prospective cohorts, the Nurses’ Health Study and the Health Professionals Follow-up Study. The patient population consisted of 61.1% women with a mean (SD) age of 68.6 (8.9) years. As noted above, a lower mortality rate was observed in “patients who increased their fiber intake after diagnosis from levels before diagnosis.” Specifically, for “each 5-g/d increase in intake [there] was [an] associated 18% lower CRC-specific mortality (95% CI, 7%-28%; P = .002) and 14% lower all-cause mortality (95% CI, 8%-19%; P < .001).” It was thus concluded that a higher intake of total fiber following diagnosis of nonmetastatic CRC was associated with a lower mortality rate.

Song M, Wu K, Meyerhardt JA, Ogino S, Wang M, Fuchs CS, Giovannucci EL, Chan AT. Fiber Intake and Survival After Colorectal Cancer Diagnosis. JAMA Oncol. 2017 Published
online November 2, 2017. doi:10.1001/jamaoncol.2017.3684.

Elderly Chromosomes Trigger Genes Differently Than in the Young

The chromosomes are our instruction manuals. They facilitate instructs on making every protein in the body, many of which are needed for life. Physically the chromosomes appear as “long necklaces of DNA, coiled and curled in the center of every cell in the body.” When it’s time to encode a gene, parts of the “necklace” open up and are loose, other parts “are coiled tightly or obscured by other sections of the chain.” When the chain is tightly coiled, it is more difficult “for the cell’s machinery to access the DNA in that section and [in turn to] activate the genes that DNA describes.” “New research by a team from UConn Health and the Jackson Laboratory for Genomic Medicine (JAX-GM) shows that our chromosomes age along with us, with some
sections of the chromosome curling and closing up, and making it harder to access DNA,” which may be critical in our defense against disease. What the authors observed is that “in young people, thousands of sites are open, seemingly ready to activate genes and make protein.” In “younger people there are genes and pathways that are very active, but these genes “appear to lose their activity in older adults.” Additionally, in younger people “the portions that are open and the portions that are closed look very different.” This study “determine[d] the regions of chromosomes and genes that lose their activity with aging.” In a “combined analyses of chromatin accessibility and the transcriptome [they] uncovered immune molecules activated/inactivated with aging.” They also “identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers.” “This signature is borne by memory CD8+ T cells.” It was observed that these cells “exhibited an aging-related loss in binding of NF-κB and STAT factors.” Thus, they “provide[d] a unique and comprehensive approach to identifying candidate biomarkers” as well as providing “mechanistic insights into aging-associated immunodeficiency.”

Ucar D, Márquez EJ, Chung C-H, Marches R, Rossi RJ, Uyar A, Wu T-C, George J, Stitzel ML, Palucka AK, Kuchel GA, Banchereau J. The chromatin accessibility signature of human
immune aging stems from CD8+ T cells. J of Exp Medicine. Sep 2017, jem.20170416; DOI: 10.1084/jem.20170416.

Berberine’s Benefits with Methicilln Resistant Staphyloccus Aureus

Berberine has numerous beneficial health promoting attributes, and one of these is its antibacterial properties. In fact it has been widely used in the management of bacterial diarrhea and gastroenteritis. Recently, however, berberine was demonstrated to “enhance the inhibitory efficacy of antibiotics against clinical multi-drug resistant isolates of methicillin-resistant Staphylococcus aureus (MRSA).” Its action was also described to act synergistically along with antibiotic therapy. In fact, it was stated that “the combined use of Berberine improved the bactericidal activity of antiobiotics against MRSA, lowered the minimum inhibitory concentrations (MICs) of antibiotics, and notably decreased adhesion and intracellular invasion of MRSA.” Berberine was demonstrated to be very beneficial against MRSA, which is commonly referred to as an “antibiotic-resistant bacteria.”

Chu M, Zhang M, Liu Y, Kang J, Chu Z, Yin K, Ding L, Ding R, Xiao R, Yin Y, Liu X, Wang Y. Role of Berberine in the Treatment of Methicillin-Resistant Staphylococcus
aureus Infections. Scientific Reports. 2016 6:24748. doi:10.1038/srep24748.

More Bad News on PPI Use and Chronic Kidney Disease

In a population-based Taiwanese study of those taking proton pump inhibitors (PPIs), the long-term safety of PPI-associated chronic kidney disease (CKD) and kidney injury was evaluated, as it is viewed as a significant concern in these patients. The use of PPIs predisposed these individuals to a 1.4-fold higher odds of CKD, as compared to those who never used PPIs. The study also recognized that “almost all major types of PPIs present a weak association with increased odds of CKD in cumulative duration and dosage regression analysis.” Thus, according to this evaluation, the use of proton pumpinhibitors correlated with an increased risk of chronic kidney disease, as an elevated risk of acute kidney injury was demonstrated in these individuals. [“The OR for CKD was 1.41 for subjects using PPIs [95% confidence interval (CI) 1.34, 1.48] compared with subjects who had never used PPIs. The OR in relation to cumulative duration (per month) of PPIs use was 1.02 (95% CI 1.01, 1.02) and the OR in relation to cumulative dosage (per microgram) of PPIs use was 1.23 (95% CI 1.18, 1.28).”]

Hung S-C, Liao K-F, Hung H-C, Lin C-L, Lai S-W, Lee P-C, Hung S-R. Using proton pump inhibitors correlates with an increased risk of chronic kidney disease: a
nationwide database-derived case-controlled study. Family Practice. 14 October 2017 cmx102,

DHA, EPA, and GLA for RA

Researchers evaluated the effects of supplemented marine polyunsaturated fatty acids (PUFA) supplying DHA and EPA, with and without GLA, on patients with rheumatoid arthritis (RA). Sixty patients with active RA participated in this prospective randomized 12 week trial. Patients were randomly allocated to three groups of 20. Group 1 received 1500 mg of DHA and 1000 mg of EPA daily. Group 2 received 600 mg of DHA, 400 mg of EPA, and 234 mg of GLA daily. Group 3 received no supplementation. Clinical and laboratory evaluations were conducted at the beginning and end of the study. Results showed the Disease Activity Score 28 (DAS 28 score), and number of tender joints and visual analogue scale (VAS) score decreased notably after supplementation in groups 1 and 2. The combination of n-3 PUFAs and GLA increased GLA, which was undetectable in all groups before the treatments. In this study, supplementation with both fish oil and GLA resulted in significantly improved clinical variables, and the consumption of fish oil combined with GLA had positive effects in RA patients which were similar or even better than the fish oil supplementation alone, suggesting the combination has a great potential for patients with RA and other chronic inflammatory diseases.

Veselinovic M, et al. Clinical Benefits of omega-3 PUFA and gamma Linolenic Acid in patients with Rheumatoid Arthritis. Nutrients 2017, 9, 325; doi:10.3390/nu9040325

The Chronic Obesity Epidemic in America

In the United States, the prevalence of obesity has steadily increased over the last 50 years, and presently greater than two-thirds of adults and one-third of children, including adolescents, are overweight or obese. According to a recent review of more than 1000 studies, there is “sufficient evidence to link weight gain, overweight, and obesity with 13 cancers”. These cancers include “adenocarcinoma of the esophagus; cancers of the gastric cardia, colon and rectum, liver, gallbladder, pancreas, corpus uteri, ovary, kidney, and thyroid; postmenopausal female breast cancer; meningioma; and multiple myeloma.”(1) In the Nurses’ Health Study, “an 18-year follow-up of almost 93 000 women, a dose-response association of weight gain and obesity with several cancers” was revealed.(2) “Youths who are obese are more likely to be obese as adults, compounding their risk for health consequences such as cardiovascular disease, diabetes, and cancer.” Comprehensive weight loss strategies are required to achieve sustainable weight loss, and includes “significant lifestyle changes.” However, as noted by this study, “it is possible that many cancers related to overweight and obesity could be prevented, and physicians have an important responsibility in educating patients and supporting patients’ efforts to lead healthy lifestyles.” Tailored nutritional supplementation can be a part of supporting these efforts.

Massetti GM, Dietz WH, Richardson LC. Excessive Weight Gain, Obesity, and Cancer Opportunities for Clinical Intervention. JAMA. Published online October
03, 2017. doi:10.1001/jama.2017.15519
1. Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K; International Agency for Research on Cancer Handbook Working Group. Body
fatness and cancer—viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-798.
2. Zheng Y, Manson JE, Yuan C, et al. Associations of weight gain from early to middle adulthood with major health outcomes later in life. JAMA.

More Bad News for Commonly Used Surfactants (detergents) as Emulsifying Agents

An altered microbiota (dysbiosis) can play a central role in the pathogenesis of numerous intestinal disorders including inflammatory bowel disease (IBD) and are associated with colorectal cancer. An altered microbiota can play a role in promoting colitis-associated cancer through the induction of inflammation, and also through the production of toxins that create a favorable niche for tumor cells. Commensal organisms can have an enormous impact on tumorigenesis through the production of tumor-promoting genotoxins that can induce chromosomal instability. Common emulsifies such as carboxymethylcellulose (CMC) and polysorbate-80 (P80) are detergent-like molecules that are incorporated into many processes foods. It has been demonstrated that both CMC and P80 promoted microbiota encroachment and increased levels of proinflammatory flagellin and lipopolysaccharide (LPS), which correlated with a change in microbiota composition and intestinal inflammation. In this study researchers subjected mice to chronic exposure of CMC and P80. They reported that these agents created and maintained a proinflammatory environment in the colon, associated with alteration of the proliferation/apoptosis balance that resulted in exacerbated carcinogenesis. These changes were associated with, and dependent upon, alterations in microbiota composition and diversity that created a favorable niche for tumorigenesis, supporting the concept that a perturbed host-microbiota interaction resulting in alteration of the intestinal homeostasis can promote colonic carcinogenesis.

Veinnois E, Merlin D, Gewirtz A, Chassaing B. Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Cancer Research; 77(1)
Jan 1, 2017. doi: 10.1158/0008-5472./CAN-16-1359

Common Emulsifiers (surfactants) Impact the Gut Microbiota

It is now understood that the disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and metabolic syndrome. It has been hypothesized that detergent-like molecules that are a ubiquitous component of processed foods, and that can increase bacterial translocation across epithelia, may be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Researchers reported that in mice, relatively low concentrations of two commonly used emulsifiers (carboxymethylcellulose and polysorbate-80), induced low grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. This chemically induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Researchers’ results support the emerging concept that perturbed host-microbiota interaction resulting in low-grade inflammation can promote adiposity and its associated metabolic effects, and they suggest that the broad use of chemical emulsifying agents (surfactants) might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

Chassaing B, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. Vol 519. 5 March 2015.

Metformin may not be as safe as previously believed

A recent Taiwanese study suggests that long-term use of the popular diabetes medication Metformin may actually increase the risk of neurodegenerative disease in patients with type 2 diabetes mellitus. Their research contradicts the results of a recent large-scale study that suggested Metformin exerts a protective effect against the same diseases. Both studies were large scale longitudinal research projects. The Taiwan study followed 9,300 patients for up to 12 years and found the risk for Parkinson’s or Alzheimer’s more than doubled for those taking Metformin compared with those who did not. Medscape reported that researchers found that outcome risks increased progressively with higher dosage and longer duration of treatment, especially with use for more than 300 days. The US study consisted of 6,046 patients (>90% male) and were followed for a median of 5.25 years. In contrast to the Taiwan study, the US study showed that Metformin exposure for longer than two years resulted in a significant reduction in neurodegenerative disease. Interestingly, recent evidence suggests metformin may cause B12 deficiency, particularly in those who take it long-term.

Yi-Chun Kuan, et al. The 13th International Conference on Alzheimer’s and Parkinson’s Diseases. Vienna Austria March 29, 2017

More Bad News for PPI Users

Proton pump inhibitors are widely prescribed and are also available for sale over the counter without prescription in the US. Use of proton pump inhibitors (PPIs) are associated with increased risk of a number of adverse health outcomes including acute interstitial nephritis, chronic kidney disease and end-stage renal disease, incident dementia, increased risk of incident and recurrent Clostridium difficile infections, and increased risk of osteoporotic fractures, including hip and spine fractures. There is even in vitro evidence that suggests that PPI results in inhibition of lysosomal acidification and impairment of proteostasis, leading to increased oxidative stress, endothelial dysfunction, telomere shortening and accelerated senescence in human endothelial cells. A longitudinal observational cohort study of new PPI or histamine H2 receptor antagonists, and additional cohorts including PPI versus no PPI and PPI versus no PPI and no H2 blockers was conducted using administrative data from the US Department of Veterans Affairs, with a median follow-up of 5.71 years. Study results suggest excess risk of death among PPI users. Risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Among new PPI users, there was a graded association between the duration of exposure and the risk of death. Clearly, limiting PPI use and duration of PPI use is warranted.

Yan Xie, Benjamin Bowe, et al. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. http://dx.doi.

Zinc for Depression

Unsatisfactory clinical efficacy and a variety of adverse effects of current antidepressant drugs have incited search for better therapy. Zinc is an antagonist of the glutamate/N-methyl-D-aspartate (NMDA) receptor, and exhibits antidepressant‑like activity in animal models of depression. Zinc induces brain derived neurotrophic factor (BDNF) gene expression and increases level of synaptic pool of zinc in the hippocampus. Clinical observations demonstrated serum hypozincemia in depression, which was normalized by effective antidepressant treatment. Moreover, preliminary clinical research by researchers in Poland and the USA demonstrated the benefit of zinc supplementation in antidepressant therapy. All the data indicate the important role of zinc homeostasis in psychopathology and therapy of depression and potential clinical antidepressant activity of this ion.

G Nowak, B Szewczyk, A Pilc. Zinc and depression. An Update. Pharmacological Reports, 2005, 57, 713-718.

Multi-Vitamin/Mineral Supplementation (MVMS) Prevents Nutrient Deficiencies

Based on nationally representative data in 10,698 adults from the National Health and Nutrition Examination Surveys (NHANES), assessments were made of intakes of 17 nutrients with an estimated average requirement (EAR) and tolerable upper intake level (UL), and of the status of five nutrients with recognized biomarkers of deficiency. Compared to food alone, the use of MVMS was associated with a lower prevalence of inadequacy for 15 or the 17 nutrients examined. With the exception of calcium, magnesium and vitamin D, most frequent MVMS use (≥21 days/30 days) virtually eliminated inadequacies of the nutrients examined, and was associated with significantly lower odds ratios of deficiency for the examined nutrient  biomarkers except for iron. The bottom line is that MVMS use is associated with decreased micronutrient inadequacies, intakes slightly exceeding the UL for a few  nutrients, and a lower risk of nutrient deficiencies. Who knew?

Blumberg JB, Frei BB, Fulgoni VL, Weaver CM, Zeisel SH. Impact of Frequency of Multi-Vitamin/Multi-Mineral Supplement Intake on Nutritional Adequacy and Nutrient Deficiencies in  U.S. Adults. Nutrients. 2017 Aug 9;9(8). Pii: E849. doi: 10.3390/nu9080849.

Lower Levels of DHA and EPA Observed with ADHD

In a meta-analysis review of both randomized controlled trials (RCT) and case-control studies, the effects of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on both clinical symptoms and cognition in children and adolescent with ADHD was assessed. The RCT reviewed 534 youths with ADHD, supplemented with omega-3 polyunsaturated fatty acids. Improved clinical symptoms of ADHD (p<0.0001) was demonstrated in this group. In the three RCTs (n=214) ADHD diagnosed youths, supplemented with omega-3 polyunsaturated fatty acids were also demonstrated to “improve cognitive measures associated with attention (g=1.09, p=0.001)”. It was also observed that both children and adults diagnosed with ADHD had lower levels of n-3 PUFAs, “DHA (seven studies, n=412, g=−0.76, p=0.0002), EPA (seven studies, n=468, g=−0.38, p=0.0008), and total n-3 PUFAs (six studies, n=396, g=−0.58, p=0.0001).” It was concluded that n-3 PUFA supplementation “improve(d) clinical symptoms and cognitive performances in children and adolescents with ADHD,” and thus substantiates the use of omega-3 fatty acid in both of these groups with ADHD.

Chang J-C, Su K-P, Mondelli V, Pariante CM. Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder (ADHD): A Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies. Neuropsychopharmacology. (25 July 2017) | doi:10.1038/npp.2017.160.\r\nPublished online ahead of print.

Berberine Determined to be Beneficial Against Candida Albicans

Berberine is recognized as having antibacterial activity, and has demonstrated such activity against “staphylococcal, streptococcal, and enterococcal species, including multi drug resistant strains of Mycobacterium tuberculosis and MRSA” (methicillin-resistant Staphylococcus aureus). In in vitro studies berberine was demonstrated to have “activity against clinical isolates of MRSA, with minimal inhibitory concentration (MICs) ranging from 32 to 128 μg/mL.” Additionally, berberine demonstrated synergism with antifungal medications (amphotericin, fluconazole, and miconazole) thus may be beneficial for opportunistic infections resistant to antibiotics. Previous studies also observed that berberine did not instill bacterial resistance, “since [the] MIC of berberine within same bacterial cultures (E. coli, S. aureus, Bacillus subtilis, Proteus vulgaris, S. typhimurium and P. aeruginosa) did not increase over 200 generations.” Thus, berberine may be viewed as a potential alternative or adjunctive therapy for the treatment and/or prevention of candidiasis.

Ref: Zorić N, Kosalec I, Tomić S, Bobnjarić I, Jug M, Vlainić T, Vlainić J. Membrane of Candida albicans as a target of berberine. BMC Complementary and Alternative Medicine. (2017) 17:268. DOI 10.1186/s12906-017-1773-5.

Vitamin D Supplementation Reduces Glycosylated Hemoglobin A1c

A recent study summarized evidence from randomized controlled trials (RCTs) in an effort to “assess the efficacy of vitamin D supplementation” on decreasing glycosylated haemoglobinA1c (HbA1c) and fasting blood glucose (FBG) levels. Included in the evaluation were 24 studies that assessed HbA1c levels, along with 18 studies that assessed fasting blood glucose. Utilizing a systematic method of statistical analysis to integrate data from a number of independent studies, it was observed that “vitamin D supplementation was associated with reduced HbA1c levels (standardized mean difference (SMD) -0.25 [-0.45 to -0.05])”. No association was observed in the meta-analysis between vitamin D and FBG. However, when subgroup analysis was performed, vitamin D supplementation was associated with both reduced HbA1c levels (SMD -0.39 [-0.67 to -0.10]) and reduced FBG (SMD -0.27 [-0.46 to -0.07]) in patients initially having deficiency levels of vitamin D. Vitamin D supplementation was also correlated to “significantly reduced HbA1c levels, which included type 2 diabetes patients.+

Chunhua Wu, Shanhu Qiu, Xiangyun Zhu, Ling Li. Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. Metabolism Clinical and Experimental. August 2017 73: 67–76.

Is Magnesium’s Performance Comparable a Statin?

“Statins” are documented as “the most prescribed pharmaceuticals in history”, and according to Dr. Timothy Marshall “are also one of the most controversial classes of drugs in use today.” A paper published in 2004 Mildred Seeling, M.D., provided evidence that magnesium functions in lowering cholesterol “by the same mechanisms as statin drugs”. In the body, enzymes are required for all metabolic activity, including the production of cholesterol. For cholesterol, the specific enzyme required is HMG-CoA reductase, which functions as the rate-controlling enzyme for the mevalonate pathway, the pathway that produces cholesterol and other isoprenoids. This is the enzyme targeted by the statin drugs. However, Magnesium, when present in sufficient quantities, also functions to slow down this enzymatic reaction. Thus, according to Dr. Marshall, “magnesium is the natural way that the body has evolved to control cholesterol when it reaches a certain level, whereas statin drugs are used to destroy the whole process.” The adverse events of statin use “include hepatotoxicity, diabetes, myopathies, insomnia, memory loss, confusion, peripheral neuropathy, impaired myocardial contractility, autoimmune diseases, rhabdomyolysis, erectile dysfunction, and mitochondrial dysfunction,” all likely associated with CoQ10 depletion. There are close to 900 published studies documented the adverse effects of statin medications, thus magnesium as an alternative to statin use is a valid, safe choice, that is void of negative consequences.

Marshall TM. J Am Physicians and Surgeons. Summer 2014 19(2)

Policosanol Supplementation for Enhanced HDL Functionality

Researchers at Yeungnam University in South Korea investigated functional and structural changes in lipoproteins after consumption of policosanol. They analyzed serum parameters in young non-smokers (YN), young smokers (YS), and middle-aged subjects (MN) who consumed policosanol daily (10 mg/day) for 8 weeks. After 8 weeks, systolic blood pressure was significantly lowered from initial levels in the YS and MN groups. Moisture content of facial skin increased from initial levels in the YS and MN groups. Serum triglyceride (TG) levels decreased in the YN and MN groups. The percentage of high-density lipoproteins-cholesterol (HDL-C) in total cholesterol was elevated in all subjects after 8 weeks of policosanol supplementation. All groups showed a reduction in serum glucose and uric acid levels. Serum cholesteryl ester transfer protein (CETP) activity was significantly diminished from initial levels in the YN and MN groups. Oxidation of the low-density lipoprotein fraction was markedly reduced accompanied by decreased apolipoprotein B (apoB) fragmentation. In the HDL fraction, paraoxonase activity was elevated along with elevation of apoA-I and cholesterol contents. The size and number of HDL particle increased, and the YS group showed a 2-fold increase in particle size. Daily consumption of policosanol for 8 weeks resulted in lowered blood pressure, reduced serum TG level and CETP activity, and elevated HDL-C contents. Researchers concluded that these functional enhancements of HDL can prevent and/or attenuate aging-related diseases, hypertension, diabetes and coronary heart disease.

Jae-Yong Kim, et al. Consumption of policosanol enhances HDL functionality via CETP inhibition and reduces blood pressure and visceral fat in young and middle-aged subjects. Int J of Mol Med 39: 889-899, 2017. DOI: 10.3892/ijmm.2017.2907

Magnesium Supplementation for Systemic Inflammation?

Researchers conducted a review and meta‑analysis of 11 randomized controlled trials (RTCs) to evaluate the effect of oral magnesium supplementation on plasma C-reactive protein (CRP) concentrations. The analysis was stratified to compare subgroups of populations; those with a baseline plasma CRP values of ≤ 3 and those having CRP values > 3. The difference between the subgroups was statistically significant. There was no significant reduction in the first (≤ 3) subgroup. However, there was a significant reduction in CRP for the latter subgroup (> 3). The results of this meta-analysis indicate that magnesium supplementation reduces CRP levels among individuals with inflammation (as indicated by CRP levels > 3 mg/dL). Researchers concluded that their finding suggests that magnesium supplements may have a beneficial role as an adjuvant for the management of low-grade chronic systemic inflammation.

Simental-Mendia LE, Sahebkar A, Rodriguez-Moran M, Zambrano-Galvan G, Guerroro-Romero F. Effect of magnesium supplementation of plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. Curr Pharm Des. 2017 May 25. doi: 10.2174/1381612823666170525153605. [Epub ahead of print]

Proton Pump Inhibitor Use and Increased Risk of Death

Proton Pump Inhibitor (PPI) are widely used by millions of people for indications and durations that were never tested or approved, and are available via prescription or as over the counter (OTC) in several countries including the United States. They are often overprescribed, rarely deprescribed, and frequently started inappropriately during a hospital stay. Their use is often extended for log-term duration without appropriate medical indications. Studies estimate between 53% and 69% of PPI prescriptions are for inappropriate indications. While PPIs are generally perceived as a safe class of therapeutics, PPI use is associated with a number of adverse health outcomes. They include acute interstitial nephritis, chronic kidney disease and progression to end stage renal disease, a rare but potentially fatal risk of hypomagnesemia, increased risk of incident and recurrent Clostridium difficile infections, and even a higher risk of incident dementia. In this large primary cohort of new users of acid suppression therapy followed for a median of 5.71 years, researchers show a significant association between PPI use and risk of all-cause mortality. Risk was increased among those with no documented indication for PPI use and with prolonged duration of use.

Xie Y, Bowe B, Li T, et al. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open 2017; e015735. Doi:10.1136/bmjopen-2016-015735

Chondroitin Sulfate (CS) for the Management of Symptomatic Knee Osteoarthritis

In a prospective, randomized, 6-month, 3-arm, double-blind, crossover trial, placebo was compared to Chondroitin Sulfate (800mg/day) and celecoxib (200mg/day). The changes in pain on a Visual Analogue Scale (VAS), and in the Lequesne Index (LI) were assessed as co-primary endpoints. Secondary endpoints of Minimal-Clinically Important Improvement (MCII) and Patient-Acceptable Symptoms State (PASS) were used. 604 patients diagnosed with knee osteoarthritis, according to American College of Rheumalogy (ACR) criteria, were recruited in five European countries, and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. Pain reduction in VAS at day 182 in the CS group (−42.6mm) and in celecoxib group (−39.5mm) was significantly greater than the placebo group. [(−33.3mm) (p=0.001 for CS and p=0.009 for celecoxib)]. The LI demonstrated a similar trend. No difference was observed between CS and celecoxib. At the 182 day mark, “both secondary endpoints (MCII and PASS) improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles. The study concluded in stating, “800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.”

Reginster J, Dudler J, Blicharski T, Pavelka P. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the Chondroitin versus Celecoxib versus Placebo Trial (CONCEPT) Annals of the Rheumatic Diseases Published Online First: 22 May 2017. doi: 10.1136/annrheumdis-2016-210860.

Probiotics and Reduced Upper Respiratory Tract Infection in Trained Athletes

Prolonged intense exercise has been associated with transient suppression of immune function and an increased risk of infections. The catabolism of tryptophan via kynurenine may play an important role. Researchers examined the effect of probiotic supplementation on the incidence of upper respiratory tract infections (URTI) and the metabolism of aromatic amino acids after exhaustive aerobic exercise in trained athletes during three months of winter training. Thirty-three highly trained participants were randomly assigned to either the probiotic group, receiving 1 X 1010 colony forming units (CFU) of a multi-species probiotic or the placebo group using double blind procedures, once daily for 12 weeks. Serum concentrations of tryptophan, phenylalanine and their primary catabolites kynurenine and tyrosine, as well as the concentration of the immune activation marker neopterin were determine at baseline and after 12 weeks, both at rest and immediately after exercise. After 12 weeks, post-exercise tryptophan levels were lowered by a significant 11% in the placebo group compared to baseline, but remained unchanged in the probiotic group. The ratio of subjects taking the placebo who experienced one or more URTI symptoms was increased 2.2- fold compared to those on probiotics. The data indicates reduced exercise-induced tryptophan degradation rates in the probiotic group, and that daily supplementation with probiotics limited exercise-induced drops in tryptophan levels and reduced the incidence of URTI.

Strasser B., et al. Probiotic Supplements Beneficially Affect Tryptophan-Kynurenine Metabolism and Reduce the Incidence of Upper Respiratory Tract Infections in Trained Athletes: A Randomized, Double-Blinded, Placebo-Controlled Trial. Nutrients 2016, 8, 752; doi:10.3390/nu8110752

B6 and Autism – What Do We Know?

Researchers have reported elevated and unusually broad vitamin B6 (RBC and plasma) concentrations in autistic children. Autistic children from the US had vitamin B6 concentrations [measured as RBC pyridoxal 5-phosphate (P5P) and total vitamin B6 in plasma] >2 times SDs of their non-sibling neurotypical controls, and neither group was taking vitamin/mineral supplements. These findings indicate that children with autism may have a low activity of pyridoxal kinase that converts pyridoxal and pyridoxine into the active form P5P. This would ultimately result in high amounts of pyridoxal and, therefore, total vitamin B6, as well as low amounts of P5P, which is the active cofactor for several enzymatic reactions, including the formation of many key neurotransmitters. Broad distribution of RBC P5P also suggests that there is a subset of children who need more vitamin B6 and a subset who have high concentrations of B6. This explains the benefits of high-dose B6 supplementation in individuals with autism with low RBC P5P. Inadequate intake of B6 by autistic children in China was observed, and researchers suggested that supplementation with B6 can have positive benefits for behavior because it is required for brain development and function.

Sabhana Ranjan and Jennifer Nasser. Nutritional Status of Individuals with Autism Spectrum Disorders; Do We Know Enough? Advances in Nutrition. July 2015 vol. 6: 397-407, 2015

Curcumin for Prostate Cancer

The natural product curcumin has been demonstrated to inhibit numerous targets in prostate epithelial cells with an importance in cancer formation and progression, including transcription factors, receptors, intracellular kinases, cytokines and growth factors. The effect on androgen receptor (AR) and on its target PSA has been demonstrated by several independent investigators using both endogenously expressed AR in in LNCaP cells and ectopically expressed AR in PC-3 cells. AR has a critical role in prostate cancer development and progression. Several curcumin analogues with different linker groups were investigated for their effects in human prostate cancer cell lines. The activities of compounds with a heteroatom linker [E10 and F10] demonstrated improved effects compared with those without a heteroatom linker, which suggests that flexibility of curcumin-like compounds may enhance their antitumor activities by having interactions with the DNA of cancer cells and disrupting the activity of transcription factors, such as AR. The results indicate that one of the potential mechanisms for the anticancer effect of curcumin analogues was inhibition of AR pathways in human prostate cancer cells.

Zhou, Dai-Ying, et al. Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation. Molecular Medicine Reports published online July 14, 2014. pages 1315-1322.

The Health Benefits of Intermittent Fasting

Intermittent fasting appears to calm inflammation and rescue cognitive function in animals’ brains. The action is associated with “knocking down the quantity of proinflammatory cytokines, elevating levels of brain-derived neurotrophic factor (BDNF), and activating the transcription factor known as NF-κB, which is involved in adaptive stress responses. In addition, BDNF activates PGC-1α, which functions in the regulation of the production of new mitochondria, dendritic spines, and synapses in the hippocampus. Fasting that involves longer periods of food deprivation has been demonstrated to result in changes to the immune system and the hematopoietic stem cells that support it. The director of USC’s Longevity Institute, Longo has studied periodic fasting, less frequent but longer bouts of severe calorie restriction. He has found that the routine can reshape immune cell populations in the body. Most studies utilize the fasting-mimicking diet (FMD). Using a periodic three-day FMD regimen for 30 days in a mouse model of multiple sclerosis, Longo and colleagues showed that the fast-and-feed cycles pruned away populations of autoimmune T cells, replacing them with immune cells that were no longer set on attacking neural tissue. Much of the basic biological work on fasting diets has been performed in animal models of disease. These models demonstrated improvements in or protection against symptoms of diseases such as Alzheimer’s, multiple sclerosis, cardiovascular disease, diabetes, and other metabolic disorders.

Grant B. Running on Empty. The Scientist June 1, 2017.

Vitamin D for Perinatal Depression

Researchers wishing to study the effect of vitamin D3 supplementation on prenatal depression scores conducted a randomized clinical trial on pregnant women under prenatal care. Participants were 18 years of age or older with a gestational age of 26-28 weeks, no history of mental illness and no pregnancy complications. Participants had a depression score of 0-13 using the Edinburg Postnatal Depression scale for evaluation of depression scores. 169 participants were randomized to the placebo group or the supplemented group receiving 2,000 IU of vitamin D3 daily from 26-28 weeks of gestation until child birth. Maternal serum 25-hydroxyvitamin D concentrations were measured at baseline and childbirth. Additionally, depression scores were evaluated at weeks 26-28 and 38-40 weeks of gestation, as well as at 4 and 8 weeks after birth. There was no significant difference between the two study groups at baseline. However, there was significant reduction in depression scores in the supplemented group compared to placebo at 38-40 weeks of gestation, and at 4 and 8 weeks after birth. Researchers concluded that 2,000 IU of vitamin D3 per day for at least 8 weeks during late pregnancy, can be effective in decreasing perinatal depression levels.

Vaziri et al. BMC Pregnancy and Childbirth (2016) 16:239 doi 10.1186/s12884-016-1024-7

Folate and Hemoglobin – Biomarkers for Alzheimer’s Disease

Researchers investigated the association between serum folate levels and amyloid imaging to clarify whether serum folate could be a biomarker for Alzheimer’s disease (AD). They examined the usefulness of a combined assessment of serum folate levels and red blood cell hemoglobin content. Apolipoprotein E (APOE) gene polymorphisms were also assessed. “Serum folate levels and hemoglobin content were evaluated by receiver operation characteristic analysis for their diagnostic capability as AD biomarkers relating to brain amyloid β accumulation.” A high probability of also testing positive for amyloid was correlated to folate deficiency with low folate levels or non-anemia with high hemoglobin content. Of the 17 patients tested, eight were found to be folate deficient and non-anemia. Of these eight, seven were determined to be amyloid positive (87.5%), with only one amyloid negative (12.5%). Results suggest that a deficiency of serum folate and high hemoglobin levels may reflect an increased risk of amyloid β accumulation in the brain, and that the combination of serum folate levels and hemoglobin content is a more specific and sensitive blood biomarker for AD than APOE or folate alone. Consequently, these findings may be used to support clinical diagnosis of AD using a simple blood test.

Yoshinaga T, Nishimata H, Kajiya Y, Yokoyama S. Combined assessment of serum folate and hemoglobin as biomarkers of brain amyloid β accumulation. PLoS ONE. 12(4): e0175854. Pub April 13, 2017.

EGCG Improves Maternal and Neonatal Gestational Diabetes Outcomes

Gestational diabetes mellitus (GDM) is an increasing health risk for pregnant women, and Epigallocatechin 3-gallate (EGCG), an extract from Green Tea, is known to benefit the insulin secretory process. Researcher investigated the effect of daily EGCG supplementation on both maternal and neonatal treatment outcomes in GDM-affected pregnancies in a double-blind, randomized controlled trial. 404 pregnant women in their third trimester of pregnancy were diagnosed with GDM and participated in the study. They were randomly assigned into EGCE and placebo groups, and administered either 500 mg of EGCG or placebo on a daily basis until full term. Maternal diabetic parameters at baseline and full term, including metabolism of glucose and insulin, as well as neonatal symptoms at birth, including birth weight, macrosomia, hypoglycaemia, respiratory distress and Apgar scores were analysed. 326 patients completed the trail. Research found that the patients from the EGCE group displayed significantly improved maternal diabetic parameters, and fewer cases of neonatal complication, compared to the placebo group. They concluded that EGCG supplementation improves both maternal and neonatal treatment outcomes of GDM.

Ahang H, et al. Dietary epigallocatechin 3-gallate supplement improves maternal and neonatal treatment outcome of gestational diabetes mellitus: a double-blind randomized controlled trial. J Hum Nutr Diet. 2017 March 6. doi: 10.1111/jhn.12470 [Epub ahead of print]

Crohn’s Disease - A Microbial Signature?

Existing profiles of gut microbiome dysbiosis in adult IBD patients are inconsistent among published studied and have not provided identification of microbial signatures for Crohn’s disease (CD) and Ulcerative colitis (UC). Researchers conducted a longitudinal study to compare the fecal microbiome of CD with patients having UC and with non-IBD subjects. A cohort of 2045 non-IBD and IBD fecal samples from four countries (Spain, Belgium, the UK and Germany was analyzed, applying a 16S rRNA sequencing approach, and analyzed a total dataset of 115 million sequences. Researcher found that in the Spanish cohort, dysbiosis was found significantly greater in patients with CD than with UC, as shown by a more reduced diversity, a less stable microbial community, and eight microbial groups were proposed as a specific microbial signature for CD. Tested against the whole cohort, the signature achieved an overall sensitivity of 80% and a specificity of 94%, 94%, 89% and 91% for the detection of CD versus healthy controls, patients with anorexia, IBS and UC, respectively. Researchers concluded that although UC and CD share many epidemiologic, immunologic, therapeutic and clinical features, the data showed that they are two distinct subtypes of IBD at the microbiome level, and are therefore proposing micro-biomarkers to discriminate between CD and non-CD, independently of geographical regions.

Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn’s disease. Gut Online First Published Feb 7, 2017: doi: 101136/gutjnl-2016-313235

Potential Management for Depression and Suicidal Behavior

Unmanageable depression poses significant morbidity and mortality, as well as a substantial societal price. In this study young adults (n=33) who were non-responsive to traditional therapy were assessed for abnormalities in their cerebral spinal fluid (CFS) metabolites, plasma and urine. Cerebral folate deficiency was observed to be the most common deficiency (n=12), with these patients exhibiting low levels of 5-MTHF. These subjects were treated with folinic acid, which improved their depression score. This study concluded by stating that an unexpectedly large proportion of the patients had “potentially treatable abnormalities”, which was improved with the folinic acid therapy. It was also noted that none of the healthy controls had a metabolite deviation.

Pan LA, Martin P, Zimmer T, et al. Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients with Treatment-Refractory Depression and Suicidal Behavior. Am J Psychiatry. 2017 174(1):42-50.

Better Cognitive Function with Lutein and Zeaxanthin

Lutein is a carotenoid vitamin related to beta-carotene and vitamin A. Many foods are rich in lutein and these include broccoli, spinach, kale, corn, orange, pepper, kiwi fruit, grapes, orange juice, zucchini, and squash. Lutein is often thought of as “the eye vitamin,” as it is most often utilized in the prevention of eye diseases, including age-related macular degeneration (AMD), cataracts, and retinitis pigmentosa. In this study an association between plasma levels of lutein and zeaxanthin and “domain-specific cognitive performance” was observed in community-dwelling adults aged 50 years or older derived from The Irish Longitudinal Study on Ageing (n=4,076). Specifically, higher plasma levels of lutein and zeaxanthin were observed to be independently associated with global cognition, memory, and executive function. Also there was evidence that “higher plasma zeaxanthin, but not lutein, was associated with better processing speed,” which was consistent across the differing domains, consisting of demographic, socioeconomic factors, health conditions and health behaviors.

Feeney J, O’Leary N, Moran R, O’Halloran AM, Nolan JM, Beatty S, Young IS, Kenny RA. Plasma Lutein and Zeaxanthin Are Associated With Better Cognitive Function Across Multiple Domains in a Large Population-Based Sample of Older Adults: Findings from The Irish Longitudinal Study on Aging. J Gerontol A Biol Sci Med Sci glw330. 20 January 2017.

Rubidium as an Aide for Depression?

Rubidium (Rb) belongs to the elemental group 1A of the periodic table, the same group as lithium, sodium, potassium and hydrogen. It is a naturally occurring mineral in the human body, estimated to contain 400–900 mg Rb. It is projected that on a weekly basis from dietary consumption 15–25 mg of Rb is absorption, while 20 mg is excreted, with a half-life of 30–60 days. Rb also has a history of reverting noted melancholy actions, including loss of pleasure of daily activities, lack of reactivity to positive news and events, deep feelings of hopelessness and worthlessness, sleep disruptions, or persistent feeling of excessive or untimely guilt. In uremic patients (excess levels of amino acid and protein metabolism end products) undergoing dialysis treatment, a deficiency in Rb was discovered. The subjects in this study were determined to have a low dietary rubidium intake, and the extent of the deficiency was inversely correlated to the duration of the dialysis. Rb treatment lead to at least a partial correction of the defect. The primary dietary source of Rb is red meat. In this study group it was noted that those patients who consumed processed and cured meats, such as salami, bresaola (aged salted beef), sausages and cured meats on a fairly regular basis had a higher serum levels of rubidium. These processed meats contain a high concentration of rubidium. Thus it was determined that Rb may be beneficial for patients who are undergoing dialysis, and have amino acid and protein imbalances, as a deficiency in Rb was observed in these patients.

Canavesea C, DeCostanzi E, Bergamo D, Sabbioni E, Stratta P. Rubidium, Salami and Depression. You Cannot Have Everything in Life. Blood Purif. 2008; 26:311–314. DOI: 10.1159/000129657.

Resveratrol for Ocular Health?

Resveratrol (3, 4, 5-trihydroxystilbene), a natural polyphenolic phytoalexin found in grapes, as well as other botanicals such as knotweed. Interest has arisen due to its cardioprotective action on the vasculature, particularly its ability to inhibit formation of new blood vessels, and to facilitate vasorelaxation. However, recent evidence has noted that it may also be beneficial for eye support. In this study resveratrol and its three metabolites was detected in the ocular tissues following oral administration. Although detected at low concentrations, there is some speculation that resveratrol and its metabolites could play a role in the treatment of ocular diseases. Additionally, along with quercetin, and catechins, resveratrol was demonstrated to significantly reduce cell proliferation and to block cell cycle progression in vitro. The main quantitative substances in the aqueous and vitreous humor were noted to be the hydrophilic substances of resveratrol metabolites. Resveratrol and its metabolites were noted to be higher in the conjunctiva. Other studies have demonstrated that resveratrol is beneficial to the human eyes.

Wang S, Wang Z, Yang S, Yin T, Zhang Y, Qin Y, Weinreb RN, Sun X. Tissue Distribution of trans-Resveratrol and Its Metabolites after Oral Administration in Human Eyes. J of Ophthalmology, 2017, Article ID 4052094, 12 pages, 2017. doi:10.1155/2017/4052094.

Periodontitis and RA Often Go Hand-in-Hand

Researchers suspect that oral bacteria could be involved in rheumatoid arthritis (RA). In patients with RA, hypercitrullination, an abnormal buildup of citrullinated proteins, triggers the immune system to generate autoantibodies that attack these modified self-proteins, inducing joint-destroying inflammation. Citrullination is a normal, function altering process that changes the structure of proteins. In patients with RA, hypercitrullination, an abnormal buildup of citrullinated proteins, triggers the immune system to generate autoantibodies that attack these modified self-proteins, inducing joint-destroying inflammation. Andrade Konig, et al. found a mouth bug, Aggregatibacter actinomycetenocomitans, can cause these runaway protein changes, and drive RA-specific autoantibody production, key steps in the path to RA. Nineteen of the modified proteins induced by the toxin are known autoantigens targeted by autoantibodies in RA. There are data suggesting that treating periodontitis can decrease RA disease severity, and it was noted that several large prospective trials are currently under way to further investigate this possibility. Cigarette smoking is also strongly associated with RA, and bacteria with pore-forming toxins in the lungs of smokers could explain the link.

Abbasi J. To Prevent Rheumatoid Arthritis, Look Past the Joints to the Gums. JAMA. Published online March 08, 2017. doi:10.1001/jama.2017.0764.

Vitamin D Supplementation for Chronic Low Back Pain

In a study performed by Ghana B., et al. the value of vitamin D supplementation was assessed in patients with chronic low back pain (CLBP). A high prevalence of hypovitaminosis D (50-90%) was observed in the study group, attributed to low dietary intake, skin color, and “changing lifestyle”, despite ample sunlight. The patients (18-75 year olds) had CLBP for <-3 months, and were not responding to medical or physical therapies. Their pain score was >- 50 on a 0 – 100 visual analog scale, and the mean baseline of vitamin D was 12.8 ng/mL. This study involved two phases; an induction phase and a maintenance phase. In the induction patients received a dose of 60,000 IU of vitamin D3 orally each week for 8 weeks. In those patients with vitamin D levels <5mg/mL, 60,000IU/day of vitamin D3 was administered once daily for the initial 5 days, then they received supplementation as noted above for eight weeks. After the initial 8-week induction phase, if the vitamin D remained below 29 ng/mL, the regimen was repeated. In the maintenance phase patients were given 60,000IU/month for six months. Following six months of therapy two-thirds of the group achieved normalization of vitamin D. A significant reduction in pain scores were also observed, as well as improved disability, which increased over the six months. Serum vitamin D levels increased significantly, to 36.07 post supplementation (p<0.01). Of the group 45 (66%) attained normal vitamin D levels (>29ng/mL), while 18 (27%) remained insufficient and 5 (7%) remained deficient. Although a single-arm, open-label study, without concomitant assessment of medication use, this study demonstrated an improvement in pain and disability with vitamin D supplementation in patients with CLBP.

Ghai B, Bansal D, Kanukula R, Gudala K, Sachdeva N, Dhatt SS, Kumar V. Vitamin D Supplementation in Patients with Chronic Low Back Pain: An Open Label, Single Arm Clinical Trial. Pain Physician. 2017; 20:E99-E105 • ISSN 2150-1149

Butyrate Corrects Gut Microbiota Imbalance

In an animal study, sodium butyrate (NaB) was demonstrated to correct gut microbiota imbalance induced by a high fat diet (HFD), while considerably elevating the magnitude of the beneficial bacteria Christensenellaceae, Blautia and Lactobacillus. These bacteria characteristically produce high amounts of butyric acid. Butyrate in turn served to restore the intestinal mucosa damage induced by the high fat diet, increase the expression of the gastrointestinal barrier indicator zonula occluden-1 (ZO-1) in the small intestine, and decreased the level of gut endotoxin in both the serum and liver, as compared to the high fat group. NaB also served to downregulate multiple genes, including endotoxin-associated genes such as Toll-like receptor 4 (TLR4) and Myd88, and numerous pro- inflammatory genes such as MCP-1, TNF-α, IL-1, IL-2, IL-6 and IFN-γ in liver or epididymal fat. Other benefits of NaB administration were also observed, including the amelioration of liver inflammation and fat accumulation, decreased levels of triglycerides and cholesterol in liver, and a significantly decreased nonalcoholic fatty liver activity (NAS) score. Metabolic indices (FBG and HOMA-IR) and liver function indicators (ALT and AST) were also improved compared to the high fat group. It was concluded that NaB may restore the dysbiosis of gut microbiota to attenuate steatohepatitis, which may be therapeutic for non-alcoholic fatty liver disease (NAFLD). “NaB was able to correct the HFD-induced gut microbiota imbalance in mice, while it considerably elevated the abundance of beneficial bacteria. These bacteria can produce butyric acid in what seems like a virtuous circle, and butyrate restored HFD induced symptoms.”

Zhou D, Pan Q, Xin F-Z, Zhang, R.-N., He, C.-X., Chen, G.-Y, Liu C, Chen Y-W, Fanet J-G. Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. World Journal of Gastroenterology. 2017;23(1):60-75. doi:10.3748/wjg.v23.i1.60.

Vitamin E Supplementation for Improved Liver Histology

Vitamin E supplementation was previously reported to improve liver histology in patients with nonalcoholic steatohepatitis, which is a manifestation of the metabolic syndrome (MetS). α-tocopherol bioavailability in healthy adults is higher than in those with MetS, thereby suggesting that the latter group has increased requirements. In populations with MetS-associated hepatic dysfunction, impaired α-tocopherol trafficking is likely. The α-tocopherol catabolites α-carboxyethyl hydroxychromanol (α-CEHC) and α-carboxymethylbutyl hydroxychromanol (α-CMBHC) are useful biomarkers of α-tocopherol status. During the first 24 h, participants with MetS excreted 41% less α-CEHC, 63% less hexadeuterium-labeled (d6)-α-CEHC, and 58% less d6‑α‑CMBHC, and had 52% lower plasma d6-α-CEHC areas under the concentration curves compared with healthy adults. It was concluded that in populations with MetS-associated hepatic dysfunction impaired α-tocopherol trafficking is likely, thus making these patients prime candidates for supplementation.

Traber MG, Mah E, Leonard SW, Bobe G, Bruno RS. Metabolic syndrome increases dietary α-tocopherol requirements as assessed using urinary and plasma vitamin E catabolites: a double-blind, crossover clinical trial. Am J Clin Nutr. 2017 Jan 11. pii: ajcn138495. doi: 10.3945/ajcn.116.138495. [Epub ahead of print] This trial was registered at as NCT01787591.

Probiotics Provide General Health Benefits on Various Systemic and Gastrointestinal Disorders

Gastric ulcer is one of the most common chronic gastrointestinal [ailments] characterized by a significant defect in the mucosal barrier. Helicobacter pylori (H. pylori) infection and the frequent long term use of non steroidal anti inflammatory drugs are major factors involved in gastric ulcer development. Acid inhibitors and antibiotics are commonly used to treat gastric ulcer. However, in the last few decades, the accumulating evidence for resistance to antibiotics and the side effects of antibiotics and acid inhibitors have drawn attention to the possible use of probiotics in the prevention and treatment of gastric ulcer. Probiotics are live microorganisms that when administered in adequate amounts confer health benefits on the host. The experimental and clinical studies currently available indicate that probiotics are promising for future applications in the management of gastric ulcers. This review aims to provide an overview of the general health benefits of probiotics on various systemic and gastrointestinal disorders with a special focus on gastric ulcer and the involved cellular and molecular mechanisms: i) Protection of gastric mucosal barrier; ii) upregulation of prostaglandins, mucus, growth factors and anti inflammatory cytokines; iii) increased cell proliferation to apoptosis ratio; and iv) induction of angiogenesis. Notably, administration of the exogenous probiotic strain Lactobacillus accelerated ulcer healing. Finally, some of the available data on the possible use of probiotics in H. pylori eradication are discussed.

Khoder G, Al-menhali AA, Al-Yassir F, Karam SM. Potential role of probiotics in the management of gastric ulcer. Experimental and Therapeutic Medicine. 2016; 12(1):3-17. doi:10.3892/etm.2016.3293.

PPI Use – More Bad News

Proton pump inhibitors (PPIs) are among the most commonly prescribed and used drugs worldwide, and have been linked to acute interstitial nephritis. It has been estimated that between 25% and 70% of these prescriptions have no appropriate indication, and the duration of use extends well beyond recommended guidelines. The object of this study was to quantify the association between PPI use and incident kidney disease (CKD) in the general population, and as a secondary outcome, to evaluate the link between PPI use and acute kidney injury (AKI). Using data collected from the Atherosclerosis Risk In Communities (ARIC) study, there were 56 incident CKD events among the 322 baseline PPI users (14.2 per thousand person-years), and 1382 events among the 10,160 baseline nonusers (10.7 per 1000 person-years). An even stronger association was seen between PPI use and AKI.  In the replication cohort, PPI use was significantly associated with incident CKD in unadjusted analyses, in adjusted analyses, and when estimated using a time-varying ever-use model. Similar associations were seen with incident AKI, with PPI use resulting in a higher risk. Researchers concluded that PPI use is an independent risk factor for CKD and AKI.

Lazarus B, et al. Proton Pump Inhibitor use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016;176(2):238-246.

Vitamin D Supplementation Positively Impacts GI Diseases

It is well known that vitamin D positively influences human health, but data on its impact on the human gut microbiome are lacking. Researchers conducted a pilot study on sixteen healthy volunteers. They were endoscopically examined to access a total of 7 sites to investigate the effects of oral vitamin D3 supplementation on the human mucosa-associated and stool microbiome, as well as CD8(+) T cells. Supplementation decreased relative abundance of Gammaproteobacteria including Pseudomonas spp. and Escherichia/Shigella spp. and increased bacterial richness. While no major changes occurred in the terminal ileum, appendiceal orifice, ascending colon, and sigmoid colon or in stools, the CD8(+) T cell fraction was significantly increased in the terminal ileum. Researchers concluded vitamin D3 modulates the gut microbiome of the upper GI tract, which might explain its positive influence on GI diseases such as inflammatory bowel disease or bacterial infections, and local effects of vitamin D demonstrate pronounced regional differences in the response of the GI microbiome to external factors.

Bashir M, et al. Effects of high djoses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract. Eur J Nutr. 2016;55(4): 1479-89. doi: 10.1007/s00394-015-0966-2. Epub 2015 Jul 1.

Chondroitin and Glucosamine Reduced Colon Cancer Risk

Epidemiologic evidence suggest that the use of chondroitin and glucosamine supplements are associated with reduced risk of colorectal cancer (CRC). Researchers evaluated the association between the use of these supplements and the CRC risk in two prospective cohorts: The Nurses’ Health Study and Health Professionals Follow-up Study. Cox proportional hazards regression was used to estimate relative risk (RRs) within each cohort, and results were pooled using a random effects meta-analysis. Associations were comparable across cohorts. The use of glucosamine in the absence of chondroitin was not associated with CRC risk. However, the association between the use of chondroitin and glucosamine was significantly associated with risk, with a 23% reduction in RR of CRC. The association between the use of chondroitin and glucosamine did not change when accounting for change in exposure status over follow-up, nor did the association significantly vary by sex, aspirin use, body mass index, or physical activity. Researchers concluded that there is a protective association between the use of chondroitin and glucosamine supplementation and the risk of CRC. These findings are supportive of earlier research on chondroitin and glucosamine intake and CRC risk. 

Kantor ED, et al. Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses’ Health Study and Health Professionals follow-up study. Int J Cancer. 2016 Nov 1; 139(9): 1949-57.

Vitamin D supplementation for Autism Symptoms

Researchers from 8 institutions in five countries (Egypt, Saudi Arabia, Norway, China and England) participated in a double-blinded, randomized clinical trial of 109 children (ages 3-10) to determine the efficacy of vitamin D3 supplementation in Autism Spectrum Disorder (ASD) patients. Of those participating, 57% had vitamin D deficiency, and 30% had vitamin D insufficiency. These levels were linked with the severity of autism. During the 4 month trial, patients received either 300 IU of vitamin D3 per kg of body weight (never exceeding 5,000 IU/day) or placebo. Autism severity and social maturity of the participants were assessed using the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and the Autism Treatment Evaluation Checklist (ATEC). Scores tracked symptoms such as irritability, hyperactivity, social withdrawal and inappropriate speech. In the treated group, CARS scores improved in 94.6%, while only 5.4% showed no improvement. This research follows previous findings suggesting an association between the risk of ASD and low vitamin D levels.

Khaled Saad, et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. Journal of Child Psychology and Psychiatry, 2016. Published online ahead of print, doi: 10.1111/jcpp.12652

Coenzyme Q10 for Metabolic Syndrome

Researchers wishing to determine the effects of CoQ10 supplementation on glucose homeostasis parameters, designed a study to assess the effect of CoQ10 supplementation on patients with metabolic syndrome (MetS). They conducted a randomized, double-blind, placebo-controlled trial with 60 overweight or obese and type 2 diabetes mellitus (T2DM) patients with coronary heart disease (40-85 yrs old). They were randomized into group A (receiving 100 mg CoQ10 daily) or group B (receiving placebo) for 8 weeks. Fasting blood samples were taken at the beginning and after the 8 week intervention to quantify glucose homeostasis parameters, lipid profiles and biomarkers of inflammation and oxidative stress. Compared with the placebo group, CoQ10 supplementation resulted in a significant reduction in serum insulin levels, and homeostasis model of assessment-insulin resistance (HOMA-IR) and homeostatic model assessment-beta (HOMA-B) cell function. The group supplemented with CoQ10 also had a significant positive trend in plasma glutathione and a significant reduction in malondialdehyde. Researchers concluded that overall, daily supplementation of 100 mg of CoQ10 among patients with MetS for 8 weeks had beneficial effects on serum insulin levels, HOMA-IR, HOMA-A and plasma TAC concentrations. 

Raygan R, et al. The effects of coenzyme Q10 administration on glucose homeostasis parameters, lipid profiles, biomarkers of inflammation and oxidative stress in patients with metabolic syndrome. Eur J Nutr. 2016 Dec;55(8):2357-2364. Epub 2015 Sep 18.

Saccharomyces boulardii for Obesity and Type 2 Diabetes

Evidence shows that gut microbes are key factors involved in regulating energy homeostasis, metabolic inflammation, lipid metabolism, and glucose metabolism. Researchers conducted a study to evaluate the impact of S boulardii on obesity and associated metabolic features including fat mass development, hepatic steatosis, and low-grade inflammation in obese mice. S. boulardii was administer orally each day to leptin-resistance obese and type 2 diabetic (T2D) mice for 4 weeks. S. boulardii treated mice exhibited reduced body weight, fat mass, hepatic steatosis and inflammatory tone. These effects on host metabolism were associated with local effects in the intestine. S. boulardii increased cecum weight and cecum tissue weight but also induced dramatic changes in the gut microbial composition at the phylum, family, and genus levels. These changes may also be correlated with the host metabolism response. Researchers concluded that their study demonstrated for the first time that S. boulardii may act as a beneficial treatment in the context of obesity and T2D.

Everard A, et al. 2014. Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice. mBio 5(3):e01011-14. doi:10.1128/mBio.010011-14. Published 10 June 2014.

Vitamin D for Statin Induced Myalgia

Research has demonstrated that low serum vitamin D can cause myalgia, myositis, myopathy, and myonecrosis. Statin-induced myalgia is a major and common cause of statin intolerance. In a study of 146 adults with myalgia related statin intolerance found to have low (<32 ng/mL) serum vitamin D, researchers prospectively assessed whether vitamin D supplementation  to normalize serum vitamin D would allow successful re-challenge therapy with statins. Median serum vitamin D levels at entry in the 24 month study was 22-23 ng/mL, and rose at 6, 12, and 24  months to 53-55 ng/mL, normalizing in 95% of patients after 24 months following vitamin D therapy. On the 6, 12 and 24 month follow-up on re-challenged patients on statins and vitamin D, 88%, 91% and 95% of the previously statin-intolerant patients, respectively, were free of myalgia, myositis, myopathy, and/or myonecrosis! Before beginning the study, all the patients had experience myalgia, myositis, myopathy, or myonecrosis on statins (predominantly simvastatin, atorvastatin or lovastatin). This current study supports the findings of three previous studies associating statin related myalgias with low serum vitamin D status. By providing supplemental vitamin D to statin-intolerant patients with low serum vitamin D at entry, 88% were subsequently able to tolerate re-challenge with stains with excellent tolerability, and the LDLC lowering to targeted levels. Researchers concluded that statin intolerance because of myalgia, myositis, myopathy, or myonecrosis in vitamin D deficient patients can, in most cases (88%-95%)be safely resolved by vitamin D supplementation!

Khayznikov M, et al. Statin Intolerance Because of Myalgia, Myositis, Myopathy, or Myonecrosis Can in Most Cases be Safely Resolved by Vitamin D supplementation. N Am J Med Sci. 2015 Mar; 7(3): 86-93.

Potassium for Reduced Risk of Stroke

Researchers from Italy, Sweden and the USA reviewed the observational cohort studies addressing the relation between potassium intake and the incidence or mortality of total stoke or stroke subtypes published through August 6, 2016.Researchers carried out a meta-analysis of 16 cohort studies based on the relative risk (RR) of stroke, comparing the highest versus lowest intake categories. They also plotted for blood pressure. Relative to the lowest category of potassium intake, the highest category of potassium intake was associated with a 13% reduced risk of stroke in the blood pressure-adjusted analysis. Summary RRs tended to decrease when original estimates were unadjusted for blood pressure. Analysis for stroke subtypes yielded comparable results. Researchers concluded that their meta-analysis shows an inverse associating between potassium intake and risk of total, hemorrhagic, and ischemic stroke, with the lowest risk occurring at a potassium intake of around 90 mmol (≈3,500 mg) per day. They also suggest that the mechanisms by which potassium intake may affect stroke risk can only partially be explained by an effect on blood pressure, particularly for ischemic stroke and in females. Interestingly, the new Recommended Daily Intake (RDI) for potassium has been increased to 4,700 mg!

Vinceti M, et al. Meta-Analysis of Potassium Intake and the Risk of Stroke. J of the Am Heart Assoc. 2016;5:e004210 doi:10.1161/JAHA.116.004210

CoQ10 for Metabolic Syndrome?

Most cells are sensitive to a deficiency of co-enzyme Q10 (CoQ10), an essential component of the mitochondrial electron transport chain. Deficiency has been implicated in clinical disorders such as heart failure, hypertension, Parkinson’s disease and obesity. While lipid lowering statin drugs inhibit the conversion of HMG-CoA to mevalonate and lowers plasma CoQ10 concentrations, CoQ10 supplementation improves the pathophysiological condition of statin therapy. Evidence suggests that CoQ10 supplementation may be useful for the treatment of obesity, oxidative stress, and the inflammatory process in metabolic syndrome. The anti-inflammatory response and lipid metabolizing effect of CoQ10 is probably mediated by transcriptional regulation of inflammation and lipid metabolism. CoQ10 has proven potential as an antioxidant molecule with anti-inflammatory properties. Recent evidence also suggests that CoQ10 may serve as adenosine monophosphate activated protein kinase (AMPK) and peroxisome proliferator activated receptors (PPARs) activators and increases the fat burning capacity of cells.

Alam A, Rahman M. Mitochondrial dysfunction in obesity: potential benefit and mechanism of C0-enzyme Q10 supplementation in metabolic syndrome. J. of Diabetes & Metabolic Disorders 2014, 13:60 

Chondroitin and Glucosamine Protect Against Colorectal Cancer

Researchers, led by the Harvard T.H. Chan School of Public Health, evaluated the association between the use of chondroitin and glucosamine supplementation and the risk of colorectal cancer (CRC) in two prospective cohorts: the Nurses’ Health Study and Health Professionals follow-up Study, consisting of over 96,000 participants. Regular use of the supplements was first assessed in 2002 and participants were followed until 2010. Cox proportional hazards regression was used to estimate relative risks (RRs) within each cohort and results were pooled using a random effects meta-analysis. Associations were comparable across cohorts, with a RR observed for any use of glucosamine and any use of chondroitin. Use of glucosamine in the absence of chondroitin was not associated with risk of CRC. However, use of chondroitin and glucosamine was significantly associated with risk of CRC, with supplement uses having a 23% lower risk of developing colon cancer compared with those not taking the supplements. The association was comparable for cancers of the colon and rectum. The results support a protective association between the use of chondroitin and glucosamine and risk of CRC.

Kantor ED, et al. Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses’ Health Study and Health Professionals follow-up study. Int J Cancer. 2016 Nov 1;139(9): 1949-57. doi: 10.1002/ijc.30250. Epub 2016 Jul 18.

Gluten Allergy Causes Bone Disease

Researchers investigated the association between celiac disease (CD), a chronic immune mediated disorder, and bone mass density (BMD)(1). CD is characterized by inflammation of the small intestine, and has an increasing prevalence in the population and is often undiagnosed. If unrecognized or untreated it can lead to numerous health complications including malabsorption micronutrient deficiencies. Additionally, without strict adherence to a gluten-free diet, extra-intestinal manifestations, including osteopenia, anemia, neurologic symptoms, growth retardation and others may result(2). Data from the National Health and Nutrition Examination Survey was used, with CD being defined by positive tissue transglutaminase IgA antibody test. In children (8-17 yrs) CD was associated with decreased Z-scores by 0.85 for hip and 0.46 for spine. In men (≥ 18 yrs) CD was associated with 0.06 g/cm2 decrease in BMD in hip and with 0.11 g/cm2 decrease in BMD in spine. In women, there were no statistically significant differences in the multiple-adjusted model. In men aged ≥ 40 years, CD predicted FRAX scores, resulting in increased scores by 2.25% for hip fracture and by 2.43% for major osteoporotic fracture. CD did not predict FRAX scores in women aged ≥ 40 years. Researchers concluded that CD is independently associated with reduced BMD in children and adults aged ≥ 18 years and is an independent risk factor of osteoporotic fractures in men aged ≥ 40 years.

1. Kamycheva E, et al. Celiac disease is associated with reduced bone mineral density and increased FRAX scores in the US National Health and Nutrition Examination Survey. Osteopor Int. 2016 Oct 6. [Epub ahead of print]
2. Pantaleoni S, et al. Bone Mineral Density at Diagnosis of Celiac Disease and after 1 Year of Gluten-Free Diet. Scientific World Journal. Published online 2014 Oct 14. doi: 10.1155/2014/173082

Vitamin D for Autism?

Researchers performed a case-controlled cross-sectional analysis on 122 autism spectrum disorder (ASD) children, to assess their vitamin D status compared to controls and the relationship between vitamin D deficiency and the severity of autism. They also conducted an open trial of vitamin D supplementation in ASD children. Results showed 57% of the patients in the study had vitamin D deficiency and 30% had vitamin D insufficiency. Mean 25(OH)D levels in patients with severe autism were significantly lower than those in patients with mild/moderate autism. 25(OH)D levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores. Of the ASD group, 83 patients with low serum 25(OH)D levels (<30 ng/ml) completed the open label trial. They received 300 IU/Kg/day of vitamin D3, not to exceed 5000 IU/day, for 3 months. 67 (80.72%) had significantly improved outcome, which was mainly in the sections of the CARS and aberrant behavior checklist subscales that measure behavior, stereotypy, eye contact, and attention span. 

Khaled Saad, et al. Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutritional Neuroscience. 2015

Probiotics Supplementation for RA

Researchers conducted a study to determine the effects of probiotic supplementation on clinical and metabolic status of patients with rheumatoid arthritis (RA). In this randomized, double-blind, placebo controlled trial of patients with RA (aged 25-70) 30 were assigned to the probiotic group and 30 were assigned to the placebo group. The probiotics group received a capsule each day containing 2 Lactobacillus species and Bifidobacterium bifidum for 8 weeks. After the 8 weeks of intervention, compared with the placebo, probiotic supplementation resulted in improved Disease Activity Score of 28 (DAS-28) joints.  They also had a significant decrease in serum insulin levels, homeostatic model assessment-B cell function and serum hs-CRP compared to placebo. Overall, the results of this study indicated that taking probiotic supplements for 8 weeks among patients with RA had beneficial effects on DAS-28, insulin levels, HOMA-B and hs-CRP levels.

Zamini B, et al. Clinical and metabolic response to probiotic supplementation in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. Int J Rheum Dis. 2016 Sept; 19(9):869-79. doi: 10.1111/1756-185X.1288. Epub 2016 May 2.

Vitamin D Receptor, Dysbiosis and Intestinal Microbiome Function

The microbiome modulates numerous aspects of human physiology and is a crucial factor in the development of various human diseases. Vitamin D deficiency and downregulation of the vitamin D receptor (VDR) are also associated with the pathogenesis of diseases such as inflammatory bowel disease, cancers, obesity, diabetes and asthma(1). VDR is a nuclear receptor that regulates the expression of antimicrobial peptides and autophagy regulator ATG16L1. The Paneth cell is a unique intestinal epithelial cell that can sense the gut microbiome and secrete anti-microbial peptides, thereby playing critical roles in the maintenance of homeostasis at the intestinal microbial interface(2). These roles in regulating innate immunity and intestinal microbial ecology are dependent on a functional autophagy pathway through ATG16L1, a regulator for autophagy and a risk gene for inflammatory bowel disease (IBD)(1,2). Researchers demonstrated that a low VDR level in the intestine is associated with abnormal Paneth cells, impaired autophagy function, and imbalance bacterial profile (dysbiosis), accompanied by a reduction of ATG16L1. They determined that VDR transcriptionally regulates ATG16L1 as a VDR target gene. Interestingly, administration of butyrate increases intestinal VDR expression and suppresses inflammation in a colitis model(2). Research indicates that VDR may be a determinant of IBD risk through its actions on ATG16L1, and these findings and insights can be leveraged to define therapeutic targets for restoring Paneth cells and autophagy through VDR in chronic inflammation, and may have applicability for infectious disease and autoimmune diseases where the host is in contact with bacteria.

1. Jin D, et al. Lack of Vitamin D Receptor Causes Dysbiosis and Changes the Functions of the Murine Intestinal Microbiome. Clin Ther. 2015 May 1;37(5):996-1009.e7. doi: 10.1016/j.clinthera.2015.04.004
2. Sun J. VDR/vitamin D receptor regulates autophagic activity trough ATG16L1. Autophagy. 2015 July 28: 1057-1058

Child and Adolescent Obesity Linked to Inflammasome Activity and Gut Permeability

Immune activation contributes to the systemic inflammation associated with metabolic dysfunction in obesity. Researchers looked at forty children and adolescents: 22 obese subjects and 18 age-matched normal weight controls. Obese subjects participated in an 18-month therapeutic protocol based on intensive lifestyle modification including dietary regimen, physical activity and behavior interventions. Gene expression involved in the inflammasome pathway, plasma concentration of the inflammasome-associated pro-inflammatory cytokines, and indexes of microbial translocation and intestinal fatty acid-binding protein were analyzed at baseline and after therapy. Cross-sectional analysis showed that the LPS-induced expression of genes involved in inflammasome, Nod-like receptors, downstream signaling, and effector molecules were significantly increased in obese subjects at baseline compared to controls. Baseline plasma concentration of inflammasome-related cytokines and of microbial translocation markers was augmented in obese subjects as well. Intensive lifestyle modification resulted in normalization of parameters in subjects with a significant BMI reduction after 18 months of therapy. Researchers concluded the obesity in children and adolescents is characterized by the activation of the inflammasome and by an alteration of gut permeability, and that successful lifestyle modification is effective in reducing inflammation. It would be wise to give significant consideration to the inhibition of the inflammasome as a therapeutic strategy in obesity.

Rainone V, et al. Upregulation of inflammasome activity and increased gut permeability are associated with obesity (15 Feb 2016) doi:10.1038/ijo.2016.26

Microglia Activation, the Core Process in Neuroinflammation?

Neuroinflammation is a brain immune response that is associated with neurodegenerative diseases, and is primarily driven by activation of microglia, the brain’s resident macrophages. Dysregulation in peripheral and central inflammatory cytokine signaling interrupts normal microglial function, leading to neuronal dysfunction, neurotoxicity, neurodegeneration , and attenuated neurogenesis, processes that underlie most CNS diseases and result in deleterious effect on behavior, mood, motivation and cognition. Researchers measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS: endotoxin) in eight healthy male subjects with the PET radiotracer [11C]PBR28 which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. They also measured inflammatory cytokines in serum and sickness behavior profiles before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. LPS administration significantly increased [11C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain, which was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms. This is believed to be the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. 

Sandiego, CM, et al. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. PNAS, October 6, 2015, vol. 112, no. 40

Exercise = Larger Brain Size and Lower Dementia Risk

Although results have been inconsistent, several studies indicate an inverse relationship between physical activity levels and cognitive decline, dementia, and/or Alzheimer’s disease (AD). Therefore, in order to examine the association of physical activity with the risk of incident dementia and subclinical brain MRI markers of dementia, researchers followed an older, community-based cohort for over a decade. Using the Framingham Study Original and Offspring cohorts (aged 60 yrs and older) the physical activity index (PAI) was assess. Researchers examined the link between PAI and risk of incident all-cause dementia and AD in participants of both cohorts who were cognitively intact and had available PAI. They also examined the association between PAI and brain MRI in the Offspring cohort. Over a decade of follow-up, in a multivariable adjusted model, participants in the lowest quintile of PAI had an increased risk of incident dementia compared with those in higher quintiles. Secondary analysis revealed that this relation was limited to participants who were apolipoprotein (APO)E є4 allele non-carriers, and strongest in participants aged 75 years and older. PAI was also linearly related to total brain and hippocampal volumes. The researchers concluded that low physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.

Tan ZS, et al. Physical Activity, Brain Volume, and Dementia Risk: The Framingham Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2016 (First published online: July 15, 2016)

Anabolic Steroid Use and Structural Decline of the Brain

Prolonged anabolic-androgenic steroid (AAS) use has been associated with psychiatric symptoms and cognitive deficits. Researchers investigated the association between long-term AAS exposure and brain morphometry, including subcortical neuroanatomical volumes and regional cortical thickness. Using high-resolution magnetic resonance imaging, they compared 82 weightlifters who had used AASs for longer than one year with 68 weightlifters who had never used AASs or other doping substances. Researchers discovered negative correlations between AAS use and brain volume and cortical thickness, raising concerns about the use of AASs on brain structure. Commenting on the study, Dr. Dubovsky with NEJM Journal Watch Psychiatry commented that steroids readily enter the brain and bind to androgen receptors. The possible mechanisms of steroid-induced neurotoxicity include formation of β-amyloid, oxidative stress, and cardiovascular effects on brain circulation. Consequences include accelerated brain aging, cognitive decline, and dementia, as well as decreased resilience associated with psychiatric syndromes. 

Bjørnebekk A, et al. Structural Brain Imaging of Long Term Anabolic-Androgenic Steroid Users and Non-using Weightlifters. Biol Psychiatry 2016 June 30;

Alzheimer’s Misdiagnoses and Overlapping Pathologies

According to recent research, Alzheimer’s disease (AD) is commonly misdiagnosed. To investigate the frequency and nature of misdiagnoses, researchers used data from the National Alzheimer’s Coordinating Center Database on autopsies of nearly 1,100 patients with confirmed AD, including neuropathological and clinical diagnoses. 10.8 % were false positives, with clinical presentation of AD that was not confirmed on pathology, and an equal number (10.8%) were false negatives, showing AD pathology but not clinically diagnosed with the disease. Interestingly, of the false positives, over 30% had primary vascular pathology. Researchers speculated that multiple overlapping pathologies could have played a role in the variance of diagnoses, but underscored that regardless of the reasons, the potential implications of misdiagnoses are significant, noting that diagnostic errors can have important implications for patient treatment and outcomes.

W. Qian, D Munoz, et al. Misdiagnosis of Alzheimer’s disease: inconsistencies between clinical diagnosis and neuropathological confirmation (Funder(s): University of Toronto; Canadian Institutes of Health Research). Alzheimer’s Asso. International Conf. Toronto 2016 July 22-28.

High Cortisol and Accelerated Cognition Decline

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to cognitive dysfunction, hippocampal atrophy and an increased risk for Alzheimer’s disease (AD). Less is known of the role of cortisol levels in the prediction of cognitive decline or in moderating the effect of beta-amyloid in preclinical AD. Researchers evaluated 401 cognitively normal adults enrolled in the Australian Imaging Biomarker & Lifestyle Flagship Study of Ageing (AIBL) who had undergone beta-amyloid neuroimaging at a single time point. Subjects also underwent comprehensive neuropsychological assessment. After 54 months, results showed that higher plasma cortisol levels at baseline were associated with a 2.2 times greater risk of having beta-amyloid presence. Higher cortisol levels were also associated with increased declines in global cognition in general. Compared with older adults with low cortisol and beta-amyloid deposits, those with high cortisol and beta-amyloid showed faster declines in various measures. Researchers concluded that in cognitively normal older adults, high plasma cortisol levels are associated with greater decline in global cognition, and accelerate the effect of beta-amyloid on decline in global cognition, episodic memory and attention over a 54 month period. The results suggest that therapies targeted toward lowering plasma cortisol and beta-amyloid levels may help mitigate cognitive decline in the preclinical phase of AD.

Pietrzak RH, et al. Plasma Cortisol, Amyloid-BETA, and Cognitive Decline in Preclinical Alzheimer’s Disease. (Abstract A 10218) Alzheimer’s Asso International Conf. Toronto 2016 July 22=-28.

Vitamin D Insufficiency and Cognitive Decline

According to researchers with the UC Davis Alzheimer’s Disease Center and Rutgers University, vitamin D insufficiency among the elderly is highly correlated with accelerated cognitive decline and impaired performance, especially as it relates to memory loss associated with Alzheimer’s disease (AD) and dementia. The large, longitudinal study was conducted on just under 400 diverse men and women in Northern California (mean age 76 yrs) participating in research at the Alzheimer’s Disease Center in Sacramento. Participants were either cognitively normal, had mild cognitive impairment, or dementia. Over 5 years of follow-up, those that were vitamin D deficient experienced cognitive declines that were two to three times faster than those with adequate serum vitamin D levels. According to researchers, “We expected to see declines in individuals with low vitamin D status. What was unexpected was how profoundly and rapidly low vitamin D impacts cognition.” According to Charles DeCarli, director of the Alzheimer’s Disease Center, “This is a vitamin deficiency that could easily be treated and that has other health consequences. Dr. Miller, chair of the Department of Nutritional Sciences at Rutgers University stated that this work and others “suggests that there is enough evidence to recommend that people in their 60s and older discuss taking a daily vitamin D supplement with their physicians.”

Charles DeCarli, et al. Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults. JAMA Neurology, Sept 2015.
U. C. Davis Health System. Low vitamin D among elderly associated with decline in cognition, dementia. ScienceDaily, 14 Sept 2015

Chondroitin and Glucosamine for Colorectal Cancer Prevention?

Recent evidence suggests the long term use of chondroitin and glucosamine supplements may be linked to reduced risk of colorectal cancer (CRC). Researchers evaluated the association between the use of these compounds and the risk of CRC in two prospective cohorts; the Nurses’ Health Study and the Health Professionals Follow-up Study. Regular use of these supplements was first assessed in 2002 and were followed until 2010. 672 CRC cases occurred over that time. Cox proportional hazards regression was used to estimate relative risks (RRs) within each cohort, and results were pooled using a random effects meta analysis. Associations were comparable across cohorts, with a RR of 0.79 observed for any use of glucosamine and a RR of 0.77 observed for any use of chondroitin. Use of glucosamine in the absence of chondroitin was not associated with risk of CRC, whereas use of chondroitin and glucosamine was significantly associated with risk. The association was comparable for cancers of the colon and rectum. Results support a protective association between the use of chondroitin and glucosamine and risk of CRC.

Fuchs C, Giovannucci E; Use of glucosamine and chondroitin supplements in relation to risk of colorectal cancer: Results from the Nurses’ Health Study and Health Professionals Follow-up Study. International Journal of Cancer (June 2016).

Oil of Oregano — More Evidence for Effective Pest Control:

Giardia is a neglected parasite that produces diarrhea and different degrees of malabsorption. The drugs used for treatment (such as 5-nitroimidazoles, benzimidazoles, nitrofuranes, acridine and nitrotiazoles) produce undesirable secondary effects including genetic damage and the selection of resistant strains(1). A fraction of oregano was tested against two strains of Giardia. In-vitro testing demonstrated it to be effective against both strains (G. duodenalis, G lamblia). Another study using a patented, emulsified oil of oregano in a sustained release formula was shown to be effective for intestinal parasites including Blastocystis hominis, Entamoeba hartmanni and Endolimax nana(2). Of the 14 participants who tested positive at the beginning of the trial, 10 tested negative, and 3 showed significant reduction following 6 weeks of oral supplementation. In a separate trial of patients testing positive for H. pylori, 39 participants completed a full 2-week course of treatment of a combination of supplements which included oil of oregano (same patented product as previously mentioned), mastic gum and bismuth(3). Follow-up testing demonstrated eradication of H. pylori in 29 (73.4%) of participants. All successfully treated patients also showed improvement in their presenting symptoms of dyspepsia or irritable-bowel type symptoms. 

1. Rufino-Gonzalez Y, et al. In vitro activity of the F-6 fraction of oregano against Giardia intestinalis. Parasitjology. 2012 Apr; 139(4):434 40.
2. Mark Force, William Sparks and Robert Ronzio. Inhibition of Enteric Parasites by Emulsified Oil of Oregano in vivo. Phytotherapy Research 14, 213-214 (2000).
3. Liponis M, Geyer C, and Hubkova T. Successful Eradication of Helicobacter pylori with over-the-counter Products; An observational study of 39 patients treated with 3 nonprescription remedies. Natural Medicine Journal May 2015 Vol. 7 Issue 5

Oil of Oregano – The Ultimate In Pest Control?

Herbs and culinary spices have been used for centuries to slow the spoilage of food, due to their antimicrobial properties. Recent research has documented the use of oil of oregano against antibiotic resistant Salmonella enterica on leafy greens(1). The use of oil of oregano has been documented for a variety of candida species including Candida albicans(2,3). The evaluation of oil of oregano on Pseudomonas aeruginosa (Ps. aeruginosa) and Staphylococcus aureus indicated that treatment led to reduction of cells viability due to induction of membrane damage resulting in ultrastructural alterations and the loss of cell viability(4). Other research looked at the antibacterial properties of oil of oregano against clinical strains of Escherichia coli (E. coli) and Ps. aeruginosa(5). The oil was shown to be active against all of the clinical strains from both genus of bacteria, and researchers concluded oil of oregano is an alternative antibacterial enhancing healing process in bacterial infections and as an effective means for the prevention of antibiotic-resistant strain development.

1. Moore-Neibel K, et al. Antimicrobial activity of oregano oil against antibiotic-resistant Salmonella enterica on organic leafy greens at varying exposure times and storage temperatures. Food Microbiol. 2013 May;34(1):123-9.
2. Pozzatti P, et al. in vitro activity of essential oils extracted from plants used as spices against fluconazole-resistant and fluconazole-susceptible Candida spp. Can J Microbiol. 2008 Nov;54(11:950-6.
3. Stiles J, Sparks, W, Ronzio R. The Inhibition of Candida Albicans by Oregano. J of Applied Nut. Vol 47, No 4, 1995.  
4. Bouhdid S, et al. Investigation of functional and morphological changes in Pseudomonas aeruginosa and Staphylococcus aureus cells induced by Origanum campactum essential oil. J A;ppl Microbiol. 2009 May;(106(5):1558-68.
5. Seinkiewicz M, et al. The antibacterial activity of oregano essential oil against clinical stains of Escherichia coli and Pseudomonas aeruginosa. Med Dosw Mikrobiol. 2012;64(4):287-307.

Omega-3 Fatty Acids Protect Cognitive Function in Aging Adults!

In neurodegenerative diseases such as Alzheimer’s disease (AD) or mild cognitive impairment (pre-dementia phase of AD) changes in cognitive function and memory decline occur quicker than in normal aging. In this study, researchers looked at the effects of 2,200 mg of Omega-3 (n3) fatty acids (FA) taken daily for six months on memory function. Using LOCATO, a robust and sensitive tool for assessing object-location memory (OLM) in older adults to evaluate the impact of n3-FA on memory and learning formation, they conducted a double-blind placebo-controlled proof-of-concept study. 44 healthy female participants (50-74 yrs) completed before and after OLM-task (testing). As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. They received either n3-FA or placebo for 26 weeks. Omega-3 index increased significantly in the n3-FA group compared to placebo. Recall of object locations was significantly better after n3-FA supplementation compared to placebo, although the AVLT was not significantly affected. This study provides further evidence that n3-FA exert positive effects on memory functions in healthy older adults, and the findings suggest novel strategies to maintain cognitive function into old age.

Külzow N, et al. Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. Journal of Alzheimer’s Disease. Feb 10 2016 doi:10.3233/JAD-150886

Resveratrol, Inflammation, and Osteoarthritis:

Osteoarthritis (OA), a chronic articular disease characterized by cartilage degradation and osteophyte formation, involves mechanical and hereditary factors. French researchers investigated pro inflammatory paracrine interactions between human primary chondrocytes and macrophages following interleukin 1-β (IL-1β) treatment, to evaluate the molecular mechanism responsible for the inhibitory effect of resveratrol. They found that the activation of NF-kB in chondrocytes by IL-1β induced IL-6 secretion, which will then activate STAT3 protein in macrophages. Also, STAT3 was able to positively regulate IL-6 secretion, as confirmed by the doubling level of IL-6 in the coculture compared to macrophage monoculture. Resveratrol showed a strong inhibitory effect on the pro inflammatory marker secretion. The decrease of IL-6 secretion is dependent on the NF-kB inhibition in the chondrocytes, and the reduction of the IL-6 level can limit STAT3 activation in the macrophages, leading to the interruption of the inflammatory amplification loop. Researchers concluded that these results increase our understanding of the anti-inflammatory actions of resveratrol and open new potential approaches to prevent and treat osteoarthritis.

Limagne, E, et al. Resveratrol Interferes with IL1-β-Induced Pro-Inflammatory Paracrine Interaction between Primary Chondrocytes and Macrophages. Nutrients 2016, 8,280; doi: 10.3390/nu8050280

SAMe for Depression?

A review in Naturopathic Currents looked at SAMe and its impact on mental health(1). Selective serotonin reuptake inhibitors (SSRI), the most frequently prescribed antidepressant, are frequently the first line treatment for depression. SSRI often provide inadequate symptom relief for mild-to-moderate depression, or a high relapse rate. Common side effects include fatigue, worsening mood, insomnia, poor concentration, loss of libido and weight gain. A randomized, double blind, placebo controlled study examined the ability of SAMe to augment the effectiveness of SSRI meds(2). Seventy three non-responders to SSRI treatment were enrolled. All continued to receive their SSRI plus 800 mg of oral SAMe BID or placebo. Over 36% of the SAMe group experienced treatment response compared to 17% in the placebo group, and 25% of the SAMe group experienced remission compared to only 11% of the placebo group. Researchers concluded that oral SAMe can be an effective, well-tolerated, and safe adjunctive treatment strategy for SSRI non-responders with major depressive disorder. Secondary analysis was performed on the same patients examining the effect of SAMe on the rate of cognitive-related impairments frequently associated with depression(3). Results showed a greater improvement in the ability to recall information, and a trend toward improved word-finding for the SAMe group vs. placebo. Researchers concluded that SAMe can improve memory-related cognitive symptoms in depressed patients.

1. Rouchotas P. S-Adenosylmethionine (SAMe) – Effects on mental health. Naturopathic Currents. Nov 6, 2014
2. Papakostas GI, et al. Evidence for S-adenosylmethionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant non-responders with major depressive disorder: a double-bling, randomized clinical trial. Amer J. Psychiatry 2010; 167 (8): 942-8.
3. Levkovits Y, et al. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. J. Affect. Disord. 2012; 136(3): 1174-8.

Zinc, Hedgehog Autoprocesssing, and Chronic Disease!

Zinc is an essential trace mineral with a wide range of biological functions. Hedgehog (Hh) pathway is a key regulator of cell growth and development that helps to establish the body plan of all animals with bilateral symmetry. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. In this study, researchers demonstrate that there is a link between zinc and Hh signaling. The Hh ligand, which is the upstream activator of Hh signaling, originates from Hh autoprocessing. In an in vitro Hh autoprocessing assay, researchers showed that zinc inhibits Hh autoprocessing. They then demonstrated that zinc inhibits Hh autoprocessing in a cellular environment. They found that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. According to corresponding author Chunyu Wang, under normal conditions “zinc will inhibit the production of the Hh ligand, and therefore inhibit the Hh pathway, but if there is a zinc deficiency, the pathway can be activated due to enhanced production the Hh ligand.” Their data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand. 

J Xie, et al. Zinc Inhibits Hedgehog Autoprocessing: Liking Zinc Deficiency with Hedgehog Activation. Journal of Biological Chemistry, 2015; jbc.M114.623264 DOI: 10.1074/jbc.M114.623264
ML Martialay. Zinc Deficiency Linked to Activation of Hedgehog Signaling Pathway. RPI News. Apr 16, 2015

Zinc, Prenatal LPS and Autism:

In order to understand the causes of autistic-like behaviors, researchers from the University of Sao Paulo evaluated maternal serum metal concentrations involved in intra uterine development and infection/inflammation. They identified reduced maternal levels of zinc, magnesium, selenium and manganese after lipopolysaccharide (LPS) exposure in prenatal rats. They selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS, as cytokines produced after LPS exposure induce metallothionein, which sequesters zinc and induces maternal and fetal hypozincemia. They then treated the dams with zinc in an attempt to prevent or ease the impairments in the offspring, and evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that trigger the development of autism. LPS exposure impaired play behaviors and induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating their rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. Findings reveal a possible relation between maternal zinc deficiency during gestation and the onset of autism. In this study, prenatal zinc administration demonstrates a beneficial effect on the prevention of autism.

TB Kirsten, et al. Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring. PLOS.ONE DOI:10.1371/journal.pone.0134565 July, 28, 2015

Heavy Metals and Migraines!

According to a study published in 2012, Migraines affect 12% of the US population. While the number of studies related to migraine pathophysiology have increased in recent years, the exact aetioloty is not well understood. Wishing to compare the levels of trace elements and heavy metals in patients with acute migraine and healthy controls, researchers conducted a prospective study comprising migraine patients and an equal number of healthy controls. International Headache Society classification was used for diagnosing migraine. Serum copper (Cu), zinc (Zn), lead (Pb), iron (Fe), cadmium (Cd), cobalt (Co), manganese (Mn) and magnesium (Mg) levels were measured and assessed. Among the case participants were 22 females and 3 males (mean age 36 yrs). Among controls there were 21 females and 4 males (mean age 42 yrs). Results showed serum levels of Cu, Mg and Zn were significantly lower in patients with acute migraines (AMA) compared to controls, while Cd , Fe, Mn and Pb levels were higher in AMA patients compared to controls. No significant difference was seen for Co between the two groups.  Researchers concluded that lower Mg and Zn concentrations may be related to the frequency of migraine attacks, and their administration may reduce the frequency of such attacks. Also, trace elements and heavy metals may have a role in the genesis of considerable oxidative stress in AMA patients. 

Gonullu H, et al. The levels of trace elements and heavy metals in patients with acute migraine headache. J Pak Med Asso 65: 694; 2015

Gluten-Free Diet Impacts the Human Microbiome:

A gluten-free diet (GFD) is commonly adopted as an effective treatment for celiac disease, and is often followed to alleviate GI complaints. While we know there is an important link between diet and the gut microbiome, how a switch to a GFD affect the human gut microbiome is largely unknown. Twenty one healthy human volunteers followed a GFD for four weeks. Researchers collected stool samples from each at baseline, four during the GFD period, and four when they returned to their habitual diet (HD). They determined microbiome profiles using 16S rRNA sequencing, then processed the samples for taxonomic and imputed functional composition. They also measured six gut health related biomarkers in all samples. Inter-individual variation in the gut microbiota remained stable during the short term GFD intervention. A number of taxon-specific differences were seen during the GDF: the most striking shift was seen for the family Veillonellaceae (class Clostridia), which was significantly reduced during the intervention. Seven other taxa also showed significant changes; the majority of them known to play a role in starch metabolism. Stronger differences in pathway activities were seen: 21 predicted pathway activity scores showed significant association to the diet change. Strong relation between the predicted activity of pathways and biomarker measurements were observed. Researchers concluded that GFD changes the gut microbiome composition and alters the activity of microbial pathways.

Bonder MJ, et al. The influence of a short-term gluten-free diet on the human gut microbiome. Genome Med. 2016 Apr 21;8(1):45. doi: 10.1186/s13073-016-0295-y.

Important Info on US Sodium and Potassium Intakes and Their Ratio:

Sodium-to-potassium ratio (Na:K) is shown to be strongly associated with an increased risk of Cardiovascular disease (CVD) and CVD related mortality, more than either Na or K intake alone. Researchers from the NIH Office of Dietary Supplements, Department of Nutrition Science at Purdue University, and the USDA Agricultural Research Service set out to estimate the Na:K in the diet of US adults. Using data from the 2011-2012 NHANES, the National Cancer Institute method was used to estimate  Na and K intakes, Na:K, and the percentage of those with Na:K <1.0. What they found was that only 12.2% of US adults had a Na:K <1.0, a ratio that while not necessarily ideal,  would certainly be considered preferable to the 1.38 average seen for all adults, and is compatible with the WHO guidelines for reduced risk of mortality. On average, 90% consumed more than the 2300 mg/d recommended daily intake (3600 mg/d average intake) of Na, whereas less than 3% had K intakes above the recommended 4700 mg/d (2800 mg/d average intake). Their report illustrates that only about 10% of US adults have a Na:K consistent with preferred guidelines. In order to improve the risk of CVD related mortality, efforts to reduce sodium intake, with novel strategies to increase potassium intakes are warranted. These dietary modifications offer a cost-effective public health intervention strategy.

Bailey RL, et al. Estimating Sodium and Potassium Intakes and Their Ratio in the American Diet: Data from the 2011-2012 NHANES1-4. The Journal of Nutrition Apr 2016; Vol 146, No. 4; 745-750

Long Term Multivitamin Use Linked to Lower Cardiovascular Disease (CVD) in Men!

Researchers from Harvard TH Chan School of Public Health, Karolinska Institute (Stockhilm) and Brinham and Women’s Hospital (Boston) investigated how multivitamin use is associated with the risk of CVD in men who were initially (as baseline) healthy. They studied over 18,500 male physicians (≥40 yrs) from the Physicians’ Health Study 1 cohort who were free of CVD and cancer at baseline. All self-reported lifestyle and clinical factors, plus intake of selected foods and dietary supplements. During a mean follow-up of 12.2 years, there were no significant associations observed among baseline multivitamin uses compared with nonusers for the risk of major CVD events. However, at a duration of 20 years or more, a 44% reduction of risk of major CVD events. There was no evidence of any safety concerns from long-term multivitamin use.

S Rautiainen, et al. Multivitamin Use and the Risk of Cardiovascular Disease in Men. First published April 27, 2016, doi: 10.3945/jn.115.227884 J. Nutr.

Fish Oil for Healthy Community Dwelling Senior Women!

As we age, we typically experience a decrease in muscle mass and metabolic rate and an increase in fat mass, thereby predisposing older adults to chronic disease and functional impairment. The result is an eventual decrease in the quality of life. Researchers from the Department of Human Health and Nutritional Sciences at the University of Guelph in Canada, conducted a study to evaluate the effect of fish oil (FO) supplementation in a cohort of healthy, community-dwelling older females. They evaluated 1) metabolic rate and substrate oxidation at rest and during exercise; 2) resting blood pressure and exercise heart rates; 3) body composition; 4) strength and physical function, and; 5) blood measures of insulin, glucose, CRP and triglycerides. Twenty-four females (66 ± 1 yr) were randomly assigned to receive either 3g/day of EPA and DHA or a placebo for 12 weeks. Exercise measurements were taken before and after 12 weeks and resting metabolic measures were made before and at 6 and 12 weeks. Results showed that FO supplementation significantly increased resting metabolic rate by 14%, energy expenditure during exercise by 10%, and the rate of fat oxidation during rest by 19% and during exercise by 27%. Additionally, FO consumption lowered triglycerides by 29%, increased lean mass by 4%, and functional capacity by 7%. No changes occurred in the placebo group.  

Logan SL, Spriet LL. Omega-3 Fatty Acid Supplementation for 12 Weeks Increases Resting and Exercise Metabolic Rate in Healthy Community-Dwelling Older Females. PLoS ONE 10 (12): e0144828. doi:10.1371/journal.pone.0144828 (Dec 17, 2015)

Omega-3 Fatty Acids, Adiponectin, Leptin and Obesity:

Increased adiposity is linked to altered levels of biologically active proteins, including the hormones adiponectin and leptin. Adiponectin is negatively correlated with obesity, with lower levels associated with increased risk of death or myocardial infarction (MI). Conversely, leptin levels are positively correlated with obesity, with higher levels identified as an independent risk factor for CVD. Researchers reviewed animal and human data relating to the effects of Omega-3 (n-3) fatty acids on adiponectin and leptin. The beneficial effects of n-3 polyunsaturated fatty acids (PUFA) are not just due to the modulation of the amount and types of eicosanoids produced, but also the regulation of intracellular signaling pathways, transcription factor activity, and gene expression, resulting in the regulation of inflammation, platelet adhesion, blood pressure regulation, heart rhythm and triglycerides. The majority of available studies assessing the effect of n-3 fatty acids on adiponectin reported n-3 intake induced statistically significant increases in adiponectin levels in both animal and human models. These include studies with subjects in normal weight range, overweight and obese. Results were consistent between healthy individuals and those investigating hyperlipidemic patients with 2TDM, or recent history of MI. Of the limited studies on n-3 and circulating leptin utilizing stable weight participants, the majority demonstrated either minimal change or a reduction in leptin levels. 

B Gray, F Steyn, PSW Davies and L Vitetta. Omega-3 fatty acids: a review of the effects on adiponectin and leptin and potential implications for obesity management. European Journal of Clinical Nutrition (2013) 67, 1234-1242

Vitamin D3 for Enhanced Cardiac Function!

Vitamin D deficiency is common among older adults.  Researchers from the University of Leeds designed the Vitamin D Treating Patients with Chronic Heart Failure (VINDICATE) study, involving 163 older patients already being treated for heart failure using standard accepted treatment, to learn whether vitamin D supplementation would benefit heart failure patients. They focused on patients with left ventricular systolic dysfunction. Using ejection fraction, they measured how much blood pumps away from the heart with each beat. In healthy people, the ejection fraction is generally between 60 and 70%. Study participants average ejection fraction was 26%. Compared to placebo, patients taking a daily dose of 4,000 IU of vitamin D3 for twelve months experienced up to a 34% improvement in heart function.

Witte K, Gierula J, Paton MF, et al. Vitamin D Supplementation Improves Cardiac Function in Patients with Chronic Heart Failure. American College of Cardiology 65th Annual Scientific Session. 2016.

Vitamin D Status Linked to Significantly Reduced Cancer Risk!

Higher serum vitamin D [25(OH)D] concentrations have been associated with lower risk of multiple cancer types. Researchers investigated whether previously reported inverse association between 25(OH)D and cancer risk could be replicated, and if a 25(OH)D response region could be identified among women 55 and older across a broad range of 25(OH)D concentrations. Data from two cohorts representing different median 25(OH)D concentrations were pooled to afford a broader range of concentrations. The analysis of over 2300 women included all invasive cancers excluding skin cancer. Breast cancer was the most common type of cancer diagnosed during the study (43% of all cancers in the pooled cohort).  Results show that cancer incidence was substantially lower at higher concentrations of 25(OH)D with women with concentrations ≥40 ng/ml having a 67% lower risk of cancer than women with concentrations ≤20 ng/ml.

McDonnell SL, et al. Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLOS ONE doi:10.1372/journal.pone.0152441 April 6, 2016

Pycnogenol® and Grape Seed Extract for Cognitive Function?

In this study, 44 subjects (55-70 yrs) with high oxidative stress were supplemented with Pycnogenol® daily for 12 months. Another group with comparable oxidative stress was followed as a reference group. Cognitive testing, including IQ Code, cognitive function and SBT were conducted using defined scales. Results after 12 months showed significant improvement in the supplemented group vs the reference group for all tests conducted. Researchers concluded that Pycnogenol® supplementation appears to improve cognitive function and oxidative stress in normal subjects between 55 and 70 years old.(1) Researchers at Mount Sinai School of Medicine and the University of Minnesota evaluated the ability of grape-derived polyphenols to prevent the generation of a specific form of β-amyloid (Aβ) peptide, a substance in the brain known to cause neurotoxicity associated with Alzheimer disease (AD). They administered grape seed extracts to mice genetically determined to develop memory deficits and Aβ neurotoxins similar to those found in AD. They found that the brain content of Aβ*56, a specific form of Aβ previously implicated in the promotion of AD memory loss, was substantially reduced after treatment. Their study corroborates other studies suggesting grape polyphenols may protect against cognitive decline in AD.(2, 3)

1. Belcaro G, et al. The COFU3 Study. Improvement in cognitive function, attention mental performance with Pycnogenol® in healthy subjects (55-70) with high oxidative stress. J Neurosurg Sci 2015;59: 437-46.
2. Lie P, et al. Grape Seed Polyphenolic Extract Specifically Decreases Aβ*56 in the Brains of Tg2576 Mice. Journal of Alzheimer’s Disease, Vol 26, No. 4.
3. Natural chemicals found in grapes may protect against Alzheimer’s disease. ScienceDaily, 18 July 2011

EGCG to Treat Rheumatoid Arthritis (RA)?

EGCG, a bioactive phytochemical found in green tea, was found to regulate transforming growth factor β-activated kinase 1 (TAK1) in human rheumatoid arthritis synovial fibroblasts (RASF), indicating that TAK1 regulation may be a therapeutic target in RA. EGCG appears to effectively inhibit TAK1 by blocking its phosphorylation. As a mediator of inflammation, TAK1 is integral to the activation of downstream mitogen-activated protein kinases (MAKPs) in response to receptor stimulation by the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF). A team of researchers led by Associate Professor Salah-uddin Ahmed of Washington State University College of Pharmacy in Spokane, analyzed the mechanism of TAK1 regulation in a pre-clinical mouse model of human RA. After 10 days of treatment with EGCG, the researchers found a significant reduction in ankle circumference, a measurement used as a surrogate for symptomatic inflammation. Authors stated that they have provided a rationale for targeting RASF TAK1 in RA and identified a unique mechanism through which EGCG inhibits the interaction between signaling molecules important in cytokine signaling, ultimately inhibiting inflammation and tissue destruction in RA.

Singh AK, Umar S, Riegsecker S, et al Regulation of transforming growth factor β-activated kinase activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts: suppression of K63-linked autoubiquitination of tumor necrosis factor receptor-associated factor 6. Arthritis Rheum. 2016;68(2):347-358.
CP Sison (Med Editor) Rheumatoid Arthritis Advisor. March 01, 2016

Proton Pump Inhibitors (PPIs) Increase Risk of Dementia!

While PPIs are widely used to treat gastrointestinal illnesses, recent evidence suggests they may be related to cognitive decline. A group of German researchers conducted a prospective cohort study to examine the association between the use of PPIs and the risk of incident dementia in the elderly. They used observational data (from 2004-2011) from the largest German statutory health insurer. Their analysis of 73,679 participants (≥ 75 yrs.) concluded in November 2015. The association between PPI use and dementia was analyzed using time-dependent Cox regression, adjusted for potential confounding factors such as age, sex and polypharmacy. Researchers discovered that patients receiving regular PPI medication had a significantly increased risk of incident dementia compared with patients not receiving PPIs. The researchers concluded that the avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data, and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice.

Comm, W, et al. Association of Proton Pump Inhibitors with Risk of Dementia; A Pharmacoepidemikological Claims Data Analysis. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791 Published online Feb 14, 2015

Gluten Sensitivity and Neurological Disorders – From Gut to Brain!

Gluten sensitivity (GS) may be defined as a state of heightened immunological responsiveness in genetically susceptible people. This definition does not imply bowel involvement. The authors, all affiliated with the Department of Neurology at The Royal Hallamshire Hospital, Sheffield, UK, suggest that regarding GS as principally a disease of the small bowel is a historical misconception. They state that GS can be primarily, and at times exclusively a neurological disease, and that IgG antigliadin antibody should be part of the routine investigation of all patients with neurological dysfunction of obscure aetiology, particularly patients with ataxia and peripheral neuropathy. Statistical evidence showed that patients with neurological disease of unknown aetiology were found to have a much higher prevalence of circulating antigliadin antibodies (57%) in their blood than either healthy controls (12%) or those with neurological disorders of known aetiology (5%). More celiac disease (CD) specific serological markers such as anti-endomysium and transglutaminase antibodies may have helped in diagnosing CD, but their sensitivity as markers of other manifestation of GS (where the bowel is not affected) is low. Early diagnosis and removal of the trigger factor by the introduction of a gluten-free diet may be the most promising therapeutic intervention.

Hadjivassiliou M, et al. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 2002 72:560-563. 
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