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Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary.
Richman, S, Morris, MC, Broderick, G, Craddock, TJA, Klimas, NG, Fletcher, MA
Clinical therapeutics. 2019;41(5):798-805
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Myalgic encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/ CFS), is a disease characterized by an inability to exert oneself physically, often coupled with a combination of other symptoms, including sleep disorders, severe unpredictable pain, and compromised cognitive abilities. The aim of this review was to delineate a number of the more prominent treatments for ME/CFS into different categories and evaluate the methods and results of corresponding drug trials. Results indicate that: • antiviral drugs appear to show limited efficacy in treating ME/CFS over a broad demographic. • there is a lack of clinical research focusing on the use of specific cyclooxygenase-2 inhibitors [analgesic] to treat ME/CFS. • antidepressants may be of use in delivering improvements in the quality of life of patients with ME/CFS. • recalibration of endocrine-immune regulation may be involved in supporting the persistence of ME/CFS and may be responsible at least in part for its resistance to single agent interventions. Authors conclude that there is a great need for larger, longitudinal studies focused on a more clearly defined subset of ME/CFS as well as a greater consideration of potential synergies between interventions and the suitability of combination therapies.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms. Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts to treat ME/CFS have been directed mainly toward symptom management. These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and -executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define. Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies in which a more focused precision-medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.
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Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence.
Zhang, L, Rana, I, Shaffer, RM, Taioli, E, Sheppard, L
Mutation research. Reviews in mutation research. 2019;781:186-206
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Glyphosate is a highly effective broad-spectrum herbicide that is typically applied in mixtures known as glyphosate-based herbicides (GBHs). Glyphosate and its metabolites persist in food, water, and dust, potentially indicating that everyone may be exposed ubiquitously. The objective of this study was to focus on an a priori hypothesis - the highest biologically relevant exposure to GBHs, i.e., higher levels, longer durations and/or with sufficient lag and latency, will lead to increased risk of non-Hodgkin lymphoma (NHL) in humans. This study is a meta-analysis of six studies (one cohort and five case-control control studies) with almost 65,000 participants. Results demonstrated a significantly increased NHL risk in highly GBH-exposed individuals. Authors conclude that the overall evidence from human, animal, and mechanistic studies presented in this study, supports a compelling link between exposures to GBHs and increased risk for NHL.
Abstract
Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.
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Fluoride exposure and kidney and liver function among adolescents in the United States: NHANES, 2013-2016.
Malin, AJ, Lesseur, C, Busgang, SA, Curtin, P, Wright, RO, Sanders, AP
Environment international. 2019;132:105012
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Fluoride is added to the water supply in some parts of the UK, US and Canada to help prevent tooth decay, but there is some concern that long-term exposure to fluoride could be harmful to health. Animal studies have indicated that fluoride may cause kidney and liver damage. This US study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver function in adolescents. This cross-sectional study looked at data collected from the National Health and Nutrition Examination Survey (2013-2016). The average age of adolescents was 15 years. Fluoride levels were measured in blood and in household tap water. Higher levels of fluoride in the blood were associated with a lower estimated glomerular filtration rate, a higher blood uric acid concentration, and a lower blood urea nitrogen concentration. Higher levels of fluoride in tap water were associated with a lower blood urea nitrogen concentration. The researchers concluded that fluoride exposure may contribute to complex changes in kidney and liver function in US adolescents. However, researchers could not rule out the possibility that an altered kidney or liver function may impact the body’s ability to absorb or metabolise fluoride.
Abstract
BACKGROUND Hepato- and nephrotoxicity of fluoride have been demonstrated in animals, but few studies have examined potential effects in humans. This population-based study examines the relationship between chronic low-level fluoride exposure and kidney and liver function among United States (U.S.) adolescents. This study aimed to evaluate whether greater fluoride exposure is associated with altered kidney and liver parameters among U.S. youth. METHODS This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2013-2016). We analyzed data from 1983 and 1742 adolescents who had plasma and water fluoride measures respectively and did not have kidney disease. Fluoride was measured in plasma and household tap water. Kidney parameters included estimated glomerular filtration rate (calculated by the original Schwartz formula), serum uric acid, and the urinary albumin to creatinine ratio. Liver parameters were assessed in serum and included alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, gamma-glutamyl transferase, and albumin. Survey-weighted linear regression examined relationships between fluoride exposure and kidney and liver parameters after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons. RESULTS The average age of adolescents was 15.4 years. Median water and plasma fluoride concentrations were 0.48 mg/L and 0.33 μmol/L respectively. A 1 μmol/L increase in plasma fluoride was associated with a 10.36 mL/min/1.73 m2 lower estimated glomerular filtration rate (95% CI: -17.50, -3.22; p = 0.05), a 0.29 mg/dL higher serum uric acid concentration (95% CI: 0.09, 0.50; p = 0.05), and a 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: -1.87, -0.70; p < 0.001). A 1 mg/L increase in water fluoride was associated with a 0.93 mg/dL lower blood urea nitrogen concentration (95% CI: -1.44, -0.42; p = 0.007). CONCLUSIONS Fluoride exposure may contribute to complex changes in kidney and liver related parameters among U.S. adolescents. As the study is cross-sectional, reverse causality cannot be ruled out; therefore, altered kidney and/or liver function may impact bodily fluoride absorption and metabolic processes.
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A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring.
Alpert, A, Pickman, Y, Leipold, M, Rosenberg-Hasson, Y, Ji, X, Gaujoux, R, Rabani, H, Starosvetsky, E, Kveler, K, Schaffert, S, et al
Nature medicine. 2019;25(3):487-495
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The human immune system changes with age, ultimately leading to a clinically evident, profound deterioration resulting in high morbidity and mortality rates attributed to infectious and chronic diseases. The aim of this study was to assess at high resolution the dynamics of older adults’ immune systems. The study uses multiple ‘omics’ technologies in a cohort of 135 adults (63 young adults and 72 older adults) of different ages who were sampled longitudinally over the course of 9 years to comprehensively capture population- and individual-level changes in the immune system over time. Results indicate that immune-cell frequencies changed at substantially different rates; some cell subsets show no directionality of change yet differ between young and old individuals, whereas other cell subsets continued changing (either increasing or decreasing) throughout the course of the study. Authors postulate that an individual’s immune age is a function of life history, namely environmental exposure coupled with genetic background. Thus, immune modulators may one day be identified that affect the position of an individual’s immune system along the immunological landscape.
Abstract
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
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Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome.
Nagy-Szakal, D, Williams, BL, Mishra, N, Che, X, Lee, B, Bateman, L, Klimas, NG, Komaroff, AL, Levine, S, Montoya, JG, et al
Microbiome. 2017;5(1):44
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, swollen lymph glands and irritable bowel syndrome (IBS). It is associated with gut bacterial dysbiosis, systemic inflammation and both gastro intestinal (GI) and neurological disturbances. The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. This experiment looked at fecal bacterial samples and metabolic pathway markers in 50 ME/CFS patients and 50 healthy controls. In ME/CFS subgroups, measures of symptom severity including pain, fatigue, and reduced motivation were correlated with the amounts and types of gut bacteria and certain metabolic pathways. Future prospective studies should consider more detailed exploration of IBS subtypes, associated GI symptoms, and their relationship to ME/CFS dysbiosis. This may enable more accurate diagnosis and the development of specific therapeutic strategies.
Abstract
BACKGROUND Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. RESULTS Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. CONCLUSIONS Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.
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Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans.
Johnston, JD, Ordovás, JM, Scheer, FA, Turek, FW
Advances in nutrition (Bethesda, Md.). 2016;7(2):399-406
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Chrononutrition is an emerging field that links the body’s metabolism to its endogenous circadian rhythm. It is now recognised that numerous circadian clocks are found within all major tissues and most cells of the body. This complex network of clocks influences a wide range of biological processes including neuronal, endocrine, metabolic and behavioural function. When there is a disruption in a single circadian clock, whole-organism homeostasis can be impacted, potentially resulting in the development of disease. This review explains the potential mechanisms by which circadian clocks influence biological processes through transgenic animal studies, and how they are being translated to human genetics and metabolomics. The principles of chrononutrition are clinically significant factors that should be considered when managing and treating metabolic disease, as well as maintaining health in the general population.
Abstract
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.
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Inhalational Alzheimer's disease: an unrecognized - and treatable - epidemic.
Bredesen, DE
Aging. 2016;8(2):304-13
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Alzheimer’s disease (AD) is the third leading cause of death in the USA, with around 5.2 million Americans diagnosed with AD. Effective treatment with medications has yet to be found. A recent multiple therapy programme (originally known as MEND, now called ReCODE) proposed by Professor Bredesen and team, has shown some promising anecdotal results. Identifying sub-types of AD has been proposed as a means to develop targeted protocols for treatment. Recently, 3 sub-types of AD have been described: Type 1 (inflammatory), Type 2 (non-inflammatory or decreasing brain size) and Type 3 (damage to the outer layer of the cerebrum). This report describes 7 patients with Type 3 AD. Type 3 AD is characterised by exposure to specific toxins (usually inhaled) and is often associated with Chronic Inflammatory Response Syndrome (CIRS). The report provides the symptoms, signs and laboratory values representative of Type 3 AD and could be used by Nutrition Practitioners to help with implementation of appropriate nutrition protocols when working with clients with AD.
Abstract
Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins. The appropriate recognition of IAD as a potentially important pathogenetic condition in patients with cognitive decline offers the opportunity for successful treatment of a large number of patients whose current prognoses, in the absence of accurate diagnosis, are grave.