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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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Gut microbiota varies by opioid use, circulating leptin and oxytocin in African American men with diabetes and high burden of chronic disease.
Barengolts, E, Green, SJ, Eisenberg, Y, Akbar, A, Reddivari, B, Layden, BT, Dugas, L, Chlipala, G
PloS one. 2018;13(3):e0194171
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Obesity and type 2 diabetes (T2D) can lead to alterations of the composition of the gut microbiota. The gut microbiota, in turn, has been suggested to play a role in the development of psychological conditions, such as anxiety, depression and drug addiction. This cross-sectional study included 99 mostly overweight/obese African American men, with or without T2D, and with or without opioid addiction and other psychiatric disorders. The aim of the study was to determine, whether the gut microbiota composition was linked to T2D and the use of opioids in these patients. Furthermore, the researchers looked at the associations between leptin and oxytocin levels in the blood and the gut microbiota, and whether these hormone biomarkers could be indicative of obesity and psychosocial behaviour, such as opioid addiction. The authors found that some bacterial species in the gut were affected by T2D, diabetes medication and opioid use in the studied subjects. A relationship was also observed between leptin and oxytocin levels and the abundance of certain bacteria in the gut in subjects without T2D. The authors conclude that targeting the gut microbiota could be used for the management of T2D and associated psychiatric disorders. However, more studies are needed to provide further understanding of the connections between the gut microbiota and the brain.
Abstract
OBJECTIVE The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior. RESULTS The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04). CONCLUSIONS The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin.
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Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.
Murtola, TJ, Vihervuori, VJ, Lahtela, J, Talala, K, Taari, K, Tammela, TL, Auvinen, A
British journal of cancer. 2018;118(9):1248-1254
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Studies have shown that people with diabetes mellitus have lower risk of developing prostate cancer compared with non-diabetics. Glucose metabolism (the process by which simple sugars found in food are processed and used to produce energy) may have an independent role in prostate cancer development and progression. The aim of this study was to investigate the associations between fasting blood glucose and glycaemic control and prostate cancer risk. The study recruited 80,144 men who were randomly assigned either to be screened with PSA at four-year intervals (the screening arm, 31,866 men) or to control arm with no intervention and followed through national registries (48,278 men). Results indicate an association between fasting blood glucose level and elevated prostate cancer risk. This association was more noticeable in the screening arm, and concerned both poorly and well-differentiated cancers. Furthermore, compared to the normoglycemic men, overall prostate cancer risk was elevated in diabetic, but not in pre-diabetic men. Authors conclude that diabetic fasting blood glucose level is associated with elevated prostate cancer risk in a population-based cohort of Finnish men.
Abstract
BACKGROUND Diabetic men have lowered overall risk of prostate cancer (PCa), but the role of hyperglycaemia is unclear. In this cohort study, we estimated PCa risk among men with diabetic fasting blood glucose level. METHODS Participants of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to laboratory database for information on glucose measurements since 1978. The data were available for 17,860 men. Based on the average yearly level, the men were categorised as normoglycaemic, prediabetic, or diabetic. Median follow-up was 14.7 years. Multivariable-adjusted Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for prostate cancer overall and separately by Gleason grade and metastatic stage. RESULTS In total 1,663 PCa cases were diagnosed. Compared to normoglycaemic men, those men with diabetic blood glucose level had increased risk of PCa (HR 1.52; 95% CI 1.31-1.75). The risk increase was observed for all tumour grades, and persisted for a decade afterwards. Antidiabetic drug use removed the risk association. Limitations include absence of information on lifestyle factors and limited information on BMI. CONCLUSIONS Untreated diabetic fasting blood glucose level may be a prostate cancer risk factor.
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Improvements in health-related quality of life over 3 years with liraglutide 3.0 mg compared with placebo in participants with overweight or obesity.
Kolotkin, RL, Gabriel Smolarz, B, Meincke, HH, Fujioka, K
Clinical obesity. 2018;8(1):1-10
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Obesity is associated with reduced health-related quality of life affecting physical, psychological and social function and well-being. The aim of the study was to determine the durability of improvement of health-related quality of life in participants taking Liraglutide 3.0mg after 3 years. The study included participants with prediabetes who were overweight or obese and presented weight-related conditions (hypertension or dyslipidaemia). Results indicate that participants taking 3.0mg of liraglutide for 3 years saw improvements in obesity-specific and physical aspects of health-related quality of life, and health utility. However, it showed little effects on the mental components when compared to the placebo. Authors conclude that Liraglutide 3.0mg, together with diet and exercise, lead to weight loss in obesity which is linked with improved health related quality of life.
Abstract
Previously in the SCALE Obesity and Prediabetes trial, at 1 year, participants with obesity (or overweight with comorbidities) and prediabetes receiving liraglutide 3.0 mg experienced greater improvements in health-related quality of life (HRQoL) than those receiving placebo. The current study extends these findings by examining 3-year changes in HRQoL. HRQoL was assessed using the obesity-specific Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, as well as the Short-Form 36 v2 (SF-36) health survey. At 3 years, mean change (±standard deviation) in IWQOL-Lite total score from baseline for liraglutide (n = 1472) was 11.0 ± 14.2, vs. 8.1 ± 14.7 for placebo (n = 738) (estimated treatment difference [ETD] 3.4 [95% confidence interval (CI): 2.0, 4.7], P < 0.0001). Mean change in SF-36 physical component summary (PCS) score from baseline for liraglutide was 3.1 ± 7.3, vs. 2.6 ± 7.6 for placebo (ETD 0.87 [95% CI: 0.17, 1.6], P = 0.0156). Mean change in SF-36 mental component summary score did not significantly differ between groups. Both IWQOL-Lite total score and PCS score demonstrated an association between greater HRQoL improvement with higher weight loss. Liraglutide 3.0 mg was also associated with improved health utility (Short-Form-6D and EuroQol-5D, mapped from IWQOL-Lite and/or SF-36) vs. placebo. Liraglutide 3.0 mg, plus diet and exercise, is associated with long-term improvements in HRQoL with obesity or overweight with comorbidity vs. placebo.
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Prevalence and determinants of physical activity in a mixed sample of psychiatric patients in Saudi Arabia.
Alosaimi, FD, Abalhasan, MF, Alhabbad, AA, Fallata, EO, Haddad, BA, AlQattan, NI, Alassiry, MZ
Saudi medical journal. 2018;39(4):401-411
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Physical activity has been shown to considerably reduce the burden of several non-communicable disorders (are diseases of long duration and generally slow progression), such as heart disease, stroke, diabetes, and breast and colon cancers. The aim of the study is to estimate the prevalence of physical activity among a mixed group of patients with psychiatric illnesses in Saudi Arabia. Furthermore, the study sought to evaluate the associations between physical activity, patients with different psychiatric diagnoses and the use of psychotropic medications. The study is a cross-sectional observational study that recruited 1185 patients seeking psychiatric advice, with an average age of 38.0±13.0 years. Results indicate a low prevalence of physical activity in a large, mixed sample of patients with psychiatric illnesses in both inpatient and outpatient settings in Saudi Arabia. Authors conclude that physical activity levels vary according to the type of psychiatric disease and the medications used. They outline that it is important to assess the physical activity status in patients with psychiatric illnesses and promote physical activity programs among psychiatric patients.
Abstract
OBJECTIVES To estimate prevalence of physical activity and its associations with various psychiatric disorders and the use of psychotropic medications. METHODS A cross-sectional observational study was carried out between July 2012 and June 2014. Patients were enrolled from a number of hospitals located in 5 regions of the Kingdom of Saudi Arabia. RESULTS A total of 1185 patients were included in current analysis: 796 were outpatients, and 389 were inpatients. Out of 1,185 patients, 153 (12.9%) were physically active. Much higher rates of physical activity were reported among males than females (15.9% versus 9.6%, p less than 0.001). According to the univariate analysis, higher rates of physical activity were positively correlated with primary bipolar disorders, the use of antianxiety medications and, to a lesser extent, use of antipsychotic medications, but they were negatively correlated with primary anxiety disorders, use of antidepressant medications, and use of multiple psychotropic medications. The associations between physical activity and primary bipolar disorders (odds ratio [OR]=2.47, p=0.002), use of antianxiety medications (OR=3.58, p=0.003), and use of multiple psychotropic medications (OR=0.33, p less than 0.001) remained significant after adjusting for demographic and clinical characteristics. CONCLUSION We report a variable but generally low prevalence of physical activity among a large, mixed sample of psychiatric patients in Saudi Arabia. These findings may highlight the importance of assessing physical activity status of psychiatric patients and the critical need for physical activity promotion programs among this group of disadvantaged patients.
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Navy Beans Impact the Stool Metabolome and Metabolic Pathways for Colon Health in Cancer Survivors.
Baxter, BA, Oppel, RC, Ryan, EP
Nutrients. 2018;11(1)
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Colorectal cancer (CRC) is one of the leading cause of cancer-related death around the world. Emerging evidence supports that increased consumption of pulses / legumes, such as navy beans, can reduce risk. Consuming navy beans as part of one's diet has been previously shown to positively affect the relationship between a person's gut bacteria and their health status. This study looked at stool samples to assess the impact of navy bean consumption on health based on the by-products of metabolism generated by gut bacteria (metabolites). The study was a 4-week, randomised-controlled trial with overweight and obese CRC survivors and involved consumption of 1 meal and 1 snack daily. People in the intervention group ate 35g of cooked navy bean daily whereas those in the control group had 0g of navy beans. From amongst the hundreds of metabolites identified in both groups, there was a 5-fold increase in ophthalmate for navy bean consumers, which can indicate an increase in glutathione. Glutathione is an antioxidant and detoxifying substance produced in the human liver. It is involved in cancer control mechanisms such as detoxification of xenobiotics (toxins), antioxidant defense, proliferation, and apoptosis. Other interesting results include the metabolism of the amino acid lysine, which supports health immune function, and an increase in plant-based nutrients or phytochemicals in those who consumed navy bean vs the control group. These results are indicative of an acute response to increased navy bean intake, which merit further investigation for improving colonic health after long-term consumption.
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States and emerging evidence supports that increased consumption of legumes, such as navy beans, can reduce risk. Navy bean consumption was previously shown to modulate host and microbiome metabolism, and this investigation was performed to assess the impact on the human stool metabolome, which includes the presence of navy bean metabolites. This 4-week, randomized-controlled trial with overweight and obese CRC survivors involved consumption of 1 meal and 1 snack daily. The intervention contained 35 g of cooked navy bean or macronutrient matched meals and snacks with 0 g of navy beans for the control group (n = 18). There were 30 statistically significant metabolite differences in the stool of participants that consumed navy bean at day 28 compared to the participants' baseline (p ≤ 0.05) and 26 significantly different metabolites when compared to the control group. Of the 560 total metabolites identified from the cooked navy beans, there were 237 possible navy bean-derived metabolites that were identified in the stool of participants consuming navy beans, such as N-methylpipecolate, 2-aminoadipate, piperidine, and vanillate. The microbial metabolism of amino acids and fatty acids were also identified in stool after 4 weeks of navy bean intake including cadaverine, hydantoin-5 propionic acid, 4-hydroxyphenylacetate, and caprylate. The stool relative abundance of ophthalmate increased 5.25-fold for navy bean consumers that can indicate glutathione regulation, and involving cancer control mechanisms such as detoxification of xenobiotics, antioxidant defense, proliferation, and apoptosis. Metabolic pathways involving lysine, and phytochemicals were also modulated by navy bean intake in CRC survivors. These metabolites and metabolic pathways represent an acute response to increased navy bean intake, which merit further investigation for improving colonic health after long-term consumption.
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Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies.
Carrasquilla, GD, Frumento, P, Berglund, A, Borgfeldt, C, Bottai, M, Chiavenna, C, Eliasson, M, Engström, G, Hallmans, G, Jansson, JH, et al
PLoS medicine. 2017;14(11):e1002445
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Postmenopausal hormone therapy (HT) is a recognised treatment for menopausal symptoms, however there is some evidence that it may increase the risk of stroke. HT initiated early in the onset of menopause may have a favourable impact on subclinical atherosclerosis but again, the results are not consistent. There may also be a difference in the risk of the types of stroke; haemorrhagic and ischaemic stroke. This study explored the association between HT and the risk of developing a stroke, focusing on the timing of initiation, how the HT was administered, type of HT, active ingredient and duration. 88,914 postmenopausal women using HT and with no history of cardiovascular disease were included in the study. Strokes were identified from national population registers. Early initiation (HT started less than 5 years after the onset of menopause) was not associated with an increase risk of stroke regardless of type of HT, active ingredient, how it was administered and duration. Generally, this is for both types of stroke. Late initiation (later than 5 years) was associated with an increase risk of stroke when conjugated equine oestrogen was used as single therapy. Late initiation was also associated with increased risk of haemorrhagic stroke.
Abstract
BACKGROUND Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT. METHODS AND FINDINGS Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out. CONCLUSIONS When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.
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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.