Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study.

The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin (Cgn) and claudin 12 (Cldn12) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin (Ocln) and Rho/Rac guanine nucleotide exchange factor 2 (Arhgf2) and cellular structures and interfaces, protein-protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

[Migraine prevalence, migraine incidence and migraine drug prescriptions in primary care in the capital region of Iceland].

INTRODUCTION: The study aim was to describe migraine incidence over the ten-year periods, 2000-2009 and 2010-2019, in individuals aged 10-79 years in primary healthcare centre (PHCC) Sólvangur and Fjörður, Hafnarfirði. Another aim was to estimate migraine prevalence in primary care clinics in the capital area of Iceland over the period 2010-2019 and describe prescriptions for migraine specific drugs and other drugs used for migraine. MATERIAL AND METHODS: This is a retrospective study based on data from medical records from the primary care clinics of the capital region of Iceland. The cohort consisted of individuals aged 10-79 years who were diagnosed with migraine, G43 according to the ICD-10 classification system. RESULTS: Migraine incidence at age 10-79 years over the ten-year period 2000-2009 at the primary care clinic Sólvangur was estimated 3.4 cases per 1000 person-years, during the period 2010-2019 in both Sólvangur and Fjörður clinics migraine incidence was estimated 2.9 cases per 1000 person-years. Increase was shown between the two periods in prescriptions of triptan drugs, opioids, and beta-blockers, where two-thirds of the migraineurs got prescription over the two periods. Women were three times more likely to be diagnosed with migraine than men, but men were diagnosed at younger age than women. Migraine prevalence at age 10-79 years in PHCCs in the capital area of Iceland was 4.4% over the period 2010-2019. CONCLUSION: Migraine prevalence in the PHCCs of the capital area of Iceland was only one third of migraine prevalence in the population-based cohort pilot study Heilsusaga Íslendinga. Increase in opioid drug prescriptions for individuals diagnosed with migraine is of concern and needs further study.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

The prevalence of hypnic headache in Iceland.

OBJECTIVE: To determine the prevalence of hypnic headache. BACKGROUND: The exact prevalence of hypnic headache is unknown since there are no published population-based prevalence studies. METHODS: This study was a pilot for the SAGA cohort study, a population-based study on life stressors and various indices of health. Of 1398 invited adults, 921 (66%) participated; 402 men (average age 45.6 years, SD 13.2) and 519 women (52.6 years, SD 11.1). Subjects answered a headache questionnaire including a screening question for hypnic headache. "Do you have a headache that occurs only during sleep and causes wakening?". Diagnosis of hypnic headache was made by clinical interview using ICHD-3 criteria. RESULTS: Among 921 participants, six screened positive for hypnic headache, of those two 0.22% (95% CI 0.06-0.79%) had probable hypnic headache and none had definite hypnic headache. CONCLUSION: Confirming that hypnic headache is rare, these data suggest a 0.22% prevalence of probable hypnic headache.

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Multimorbidity and use of hypnotic and anxiolytic drugs: cross-sectional and follow-up study in primary healthcare in Iceland.

BACKGROUND: The prevalence of multimorbidity is increasing worldwide, presumably leading to an increased use of medicines. During the last decades the use of hypnotic and anxiolytic benzodiazepine derivatives and related drugs has increased dramatically. These drugs are frequently prescribed for people with a sleep disorder often merely designated as "insomnia" in the medical records and lacking a clear connection with the roots of the patients' problems. Our aim was to analyse the prevalence of multimorbidity in primary healthcare in Iceland, while concurrently investigating a possible association with the prevalence and incidence of hypnotic/anxiolytic prescriptions, short-term versus chronic use. METHODS: Data were retrieved from a comprehensive database of medical records from primary healthcare in Iceland to find multimorbid patients and prescriptions for hypnotics and anxiolytics, linking diagnoses (ICD-10) and prescriptions (2009-2012) to examine a possible association. Nearly 222,000 patients, 83 % being local residents in the capital area, who contacted 16 healthcare centres served in total by 140 general practitioners, were set as a reference to find the prevalence of multimorbidity as well as the prevalence and incidence of hypnotic/anxiolytic prescriptions. RESULTS: The prevalence of multimorbidity in the primary care population was 35 %, lowest in the young, increasing with age up to the 80+ group where it dropped somewhat. The prevalence of hypnotic/anxiolytic prescriptions was 13.9 %. The incidence rate was 19.4 per 1000 persons per year in 2011, and 85 % of the patients prescribed hypnotics/anxiolytics were multimorbid. Compared to patients without multimorbidity, multimorbid patients were far more likely to be prescribed a hypnotic and/or an anxiolytic, OR = 14.9 (95 % CI = 14.4-15.4). CONCLUSIONS: Patients with multiple chronic conditions are common in the primary care setting, and prevalence and incidence of hypnotic/anxiolytic prescriptions are high. Solely explaining use of these drugs by linear thinking, i.e. that "insomnia" leads to their prescription is probably simplistic, since the majority of patients prescribed these drugs are multimorbid having several chronic conditions which could lead to sleeping problems. However, multimorbidity as such is not an indication for hypnotics, and doctors should be urged to greater caution in their prescribing, bearing in mind non-pharmacological therapy options.

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

Movement Termination of Slow-Wave Sleep-A Potential Biomarker?

The duration of slow-wave sleep (SWS) is related to the reported sleep quality and to the important variables of mental and physical health. The internal cues to end an episode of SWS are poorly understood. One such internal cue is the initiation of a body movement, which is detectable as electromyographic (EMG) activity in sleep-electroencephalography (EEG). In the present study, we characterized the termination of SWS episodes by movement to explore its potential as a biomarker. To this end, we characterized the relation between the occurrence of SWS termination by movement and individual characteristics (age, sex), SWS duration and spectral content, chronotype, depression, medication, overnight memory performance, and, as a potential neurological application, epilepsy. We analyzed 94 full-night EEG-EMG recordings (75/94 had confirmed epilepsy) in the video-EEG monitoring unit of the EpiCARE Centre Salzburg, Austria. Segments of SWS were counted and rated for their termination by movement or not through the visual inspection of continuous EEG and EMG recordings. Multiple linear regression was used to predict the number of SWS episodes that ended with movement by depression, chronotype, type of epilepsy (focal, generalized, no epilepsy, unclear), medication, gender, total duration of SWS, occurrence of seizures during the night, occurrence of tonic-clonic seizures during the night, and SWS frequency spectra. Furthermore, we assessed whether SWS movement termination was related to overnight memory retention. According to multiple linear regression, patients with overall longer SWS experienced more SWS episodes that ended with movement (t = 5.64; p = 0.001). No other variable was related to the proportion of SWS that ended with movement, including no epilepsy-related variable. A small sample (n = 4) of patients taking Sertraline experienced no SWS that ended with movement, which was significant compared to all other patients (t = 8.00; p < 0.001) and to n = 35 patients who did not take any medication (t = 4.22; p < 0.001). While this result was based on a small subsample and must be interpreted with caution, it warrants replication in a larger sample with and without seizures to further elucidate the role of the movement termination of SWS and its potential to serve as a biomarker for sleep continuity and for medication effects on sleep.

Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role?

BACKGROUND: Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort). METHODS: Participants are a sub-sample ( N = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association. RESULTS: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.3-1.0), P = 0.07), significantly for women (ORTT 0.45 (0.2-0.9), P = 0.03). Assuming the 'true' (e.g. mid-life) effect of the TT genotype is ORTT 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e.g. ORTT 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers. CONCLUSION: The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Use of benzodiazepines and benzodiazepine-related drugs in the Nordic countries between 2000 and 2020.

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at <1-5%, and clonazepam at <1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population.

Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality-A population-based longitudinal study in primary care with weak opioids most commonly prescribed.

Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent. Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol). Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10-69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years' use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314). Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25-3.09) and in Group 4 where it was 5.12 (95% CI 4.25-6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54-6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08-9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs. Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.

Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study): A protocol for an observational longitudinal case-control study.

Recent studies indicate that the interplay between diet, intestinal microbiota composition, and intestinal permeability can impact mental health. More than 10% of children and adolescents in Iceland suffer from mental disorders, and rates of psychotropics use are very high. The aim of this novel observational longitudinal case-control study, "Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study)" is to contribute to the promotion of treatment options for children and adolescents diagnosed with mental disorders through identification of patterns that may affect the symptoms. All children and adolescents, 5-15 years referred to the outpatient clinic of the Child and Adolescent Psychiatry Department at The National University Hospital in Reykjavik, Iceland, for one year (n≈150) will be invited to participate. There are two control groups, i.e., sex-matched children from the same postal area (n≈150) and same parent siblings (full siblings) in the same household close in age +/- 3 years (n<150). A three-day food diary, rating scales for mental health, and multiple questionnaires will be completed. Biosamples (fecal-, urine-, saliva-, blood samples, and buccal swab) will be collected and used for 16S rRNA gene amplicon sequencing of the oral and gut microbiome, measurements of serum factors, quantification of urine metabolites and host genotype, respectively. For longitudinal follow-up, data collection will be repeated after three years in the same groups. Integrative analysis of diet, gut microbiota, intestinal permeability, serum metabolites, and mental health will be conducted applying bioinformatics and systems biology approaches. Extensive population-based data of this quality has not been collected before, with collection repeated in three years' time, contributing to the high scientific value. The MMM-study follows the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) guidelines. Approval has been obtained from the Icelandic National Bioethics Committee, and the study is registered with Clinicaltrials.gov. The study will contribute to an improved understanding of the links between diet, gut microbiota and mental health in children through good quality study design by collecting information on multiple components, and a longitudinal approach. Furthermore, the study creates knowledge on possibilities for targeted and more personalized dietary and lifestyle interventions in subgroups. Trial registration numbers: VSN-19-225 & NCT04330703.

Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice.

The microbiota-gut-brain axis (MGBA) involves bidirectional communication between intestinal microbiota and the gastrointestinal (GI) tract, central nervous system (CNS), neuroendocrine/neuroimmune systems, hypothalamic-pituitary-adrenal (HPA) axis, and enteric nervous system (ENS). The intestinal microbiota can influence host physiology and pathology. Dysbiosis involves the loss of beneficial microbial input or signal, diversity, and expansion of pathobionts, which can lead to loss of barrier function and increased intestinal permeability (IP). Colostrum, the first milk from mammals after birth, is a natural source of nutrients and is rich in oligosaccharides, immunoglobulins, growth factors, and anti-microbial components. The aim of this study was to investigate if bovine colostrum (BC) administration might modulate intestinal microbiota and, in turn, behavior in two mouse models, wild-type (WT) and Zonulin transgenic (Ztm)-the latter of which is characterized by dysbiotic microbiota, increased intestinal permeability, and mild hyperactivity-and to compare with control mice. Bioinformatics analysis of the microbiome showed that consumption of BC was associated with increased taxonomy abundance (p = 0.001) and diversity (p = 0.004) of potentially beneficial species in WT mice and shifted dysbiotic microbial community towards eubiosis in Ztm mice (p = 0.001). BC induced an anxiolytic effect in WT female mice compared with WT female control mice (p = 0.0003), and it reduced anxiogenic behavior in Ztm female mice compared with WT female control mice (p = 0.001), as well as in Ztm male mice compared with WT BC male mice (p = 0.03). As evidenced in MGBA interactions, BC supplementation may well be applied for prophylactic approaches in the future. Further research is needed to explore human interdependencies between intestinal microbiota, including eubiosis and pathobionts, and neuroinflammation, and the potential value of BC for human use. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Body weight changes and longitudinal associations with cognitive decline among community-dwelling older adults.

INTRODUCTION: We aim to investigate the longitudinal associations between changes in body weight (BW) and declines in cognitive function and risk of mild cognitive impairment (MCI)/dementia among cognitively normal individuals 65 years or older. METHODS: Data from the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) including 2620 participants, were examined using multiple logistic regression models. Cognitive function included speed of processing (SP), executive function (EF), and memory function (MF). Changes in BW were classified as; weight loss (WL), weight gain (WG), and stable weight (SW). RESULTS: Mean follow-up time was 5.2 years and 61.3% were stable weight. Participants who experienced WL (13.4%) were significantly more likely to have declines in MF and SP compared to the SW group. Weight changes were not associated with EF. WL was associated with a higher risk of MCI, while WG (25.3%) was associated with a higher dementia risk, when compared to SW. DISCUSSION: Significant BW changes in older adulthood may indicate impending changes in cognitive function.

A genetic risk factor for periodic limb movements in sleep.

BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.