Gene genie

[Jo Bowyer]

Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors


http://journals.plos.org/plosone/art...l.pone.0181556


Abstract

Objective


Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.

Methods


To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.

Results


An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of ‘binge-like’ eating.

Conclusions


These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.

[Jo Bowyer]

Human evolution is more a muddy delta than a branching tree


https://aeon.co/ideas/human-evolutio...6e0dc-69418129

Until recently, anthropologists drew the human family tree in the same way that my 10-year-old son solves a maze. He finds it much easier to work from the end to the beginning, because blind alleys lead with depressing sameness away from the start. In just this way, scientists once traced our own lineage from the present into the past, moving backward through a thicket of fossil relatives, each perched upon its own special branch to extinction.

This approach yielded the now-ubiquitous image of the human family tree, with Homo sapiens – the one and only living hominid – sitting alone, seemingly inevitable, at the top. It’s a powerful metaphor, but it also turns out to be a deeply mistaken one. Where once we saw each branch in isolation, DNA evidence now reveals a network of connections. From an African origin more than 1.8 million years ago, human ancestors flowed into different populations, following separate paths for hundreds of thousands of years, yet still coming together to mix their genes.

The recovery of ancient DNA from ancient hominins, first by Svante Pääbo’s research group at the Max Planck Institute in Leipzig and later by others, has started to bring unknown populations into view. Neanderthals provided a proof of principle, showing the recovery of whole-genome evidence from small fragments.

Once geneticists knew what to look for, they began documenting more such lineages from the scattered traces of their genes in living people, even without DNA from ancient bones. Geneticists began to call these ‘ghost populations’, and quickly showed that many Africans, too, carry a legacy of unknown populations.

Even ancient genomes have ghosts within them. The Denisovan genome bears the traces of ancient mixture, not only from Neanderthals but with another even more divergent group – some speculate it might have been Homo erectus. Everywhere geneticists look, they see populations more different than any living people, mixing with each other in small fractions. It is no evolutionary tree. Our evolutionary history is like a braided stream.

Human spit contains ancestral surprises

http://science.sciencemag.org/conten...��

Update 19/08/2017

[Jo Bowyer]

FROM SKIN TO BRAIN: STEM CELLS WITHOUT GENETIC MODIFICATION

http://neurosciencenews.com/stem-cel...fication-6248/

Stem cells have been derived from adult cells before, but not without adding genes to alter the cells. The new process yields neural crest cells without addition of foreign genetic material. The reprogrammed neural crest cells can become smooth muscle cells, melanocytes, Schwann cells or neurons.

[Jo Bowyer]

Yeurch!!!!!!..........but at the same time amazing!

[marcel]

Have you seen this:
intrauterine cannibalism
(of sharks)

[Jo Bowyer]

Pain in the Neck: Using CRISPR to Prevent Tissue Damage and Neck Pain

http://neurosciencenews.com/crispr-neck-pain-6241/

Summary:

Researchers use CRISPR to modulate genes in order to reduce tissue damage and inflammation for people with neck and back pain.

[Jo Bowyer]

War in the womb

https://aeon.co/essays/why-pregnancy...cd029-69418129

A ferocious biological struggle between mother and baby belies any sentimental ideas we might have about pregnancy

[Jo Bowyer]

Gene found to cause sudden death in young people

https://www.sciencedaily.com/release...0309150637.htm

A new gene that can lead to sudden death among young people and athletes has now been identified by an international team of researchers. The gene, called CDH2, causes arrhythmogenic right ventricle cardiomyopathy (ARVC), which is a genetic disorder that predisposes patients to cardiac arrest and is a major cause of unexpected death in seemingly healthy young people.

[Jo Bowyer]

Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position

https://bmcgenet.biomedcentral.com/a...ource=Teradata

Abstract

Background
FTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes.

Methods
In 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump.

Results
In NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10-6).

Conclusion
Collectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia.

Keywords

RugbyGene project IRX3 Lean mass

Environmental lifestyle factors (diet and physical activity) have also been investigated for FTO gene-environment interactions. Risk allele carriers are more likely to choose a high fat diet than protective allele carriers [11, 14, 15]. However, with administration of a high protein diet (25% energy intake) risk allele carriers demonstrated a greater reduction in body mass, fat mass and percentage body fat [16], due to greater appetite suppression than in protective allele carriers [17]. Additionally, physically active risk allele carriers have a 30% reduction in likelihood of becoming obese and have 36% less body fat compared to inactive risk allele carrying individuals [18]. In contrast, data from the HERITAGE Family Study showed that following 20 weeks of endurance training, protective allele carriers exhibited reductions in fat mass three times greater than risk allele homozygotes [19]. Interestingly, when comparing normal weight and obese individuals who participate in sport, no differences in FTO genotype were observed (P = 0.97), which was contrasted by those not participating P = 0.02; [20]. Considering the attenuation of FTO-associated obesity with environmental factors and the greater FTO-associated LM reported in obese populations [9, 12], investigating LM and associated phenotypes in healthy, non-obese, non-resistance trained individuals and habitually trained elite athletes would be worthwhile.

These data suggest the relevance of the FTO rs9939609 T allele to muscle-related phenotypes and subsequently, athletic success. When considering the possible molecular mechanism from FTO via IRX3 to OLIG2 resulting in greater lifelong motor neuron availability, this may have implications for muscle size-related disorders such as sarcopenia and cachexia.

[Jo Bowyer]

Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression

http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9

Highlights

•We devised a flexible method to quantify allele-specific expression across samples

One-quarter of Neanderthal-introgressed haplotypes show cis-regulatory effects

•Introgressed regulatory variants add to genomic complexity and phenotypic diversity

•Neanderthal alleles are downregulated in genes expressed in the brain and testes

Summary

Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.

Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain

https://www.nature.com/articles/s41598-017-06587-0 Abstract

Before their disappearance from the fossil record approximately 40,000 years ago, Neanderthals, the ancient hominin lineage most closely related to modern humans, interbred with ancestors of present-day humans. The legacy of this gene flow persists through Neanderthal-derived variants that survive in modern human DNA; however, the neural implications of this inheritance are uncertain. Here, using MRI in a large cohort of healthy individuals of European-descent, we show that the amount of Neanderthal-originating polymorphism carried in living humans is related to cranial and brain morphology. First, as a validation of our approach, we demonstrate that a greater load of Neanderthal-derived genetic variants (higher “NeanderScore”) is associated with skull shapes resembling those of known Neanderthal cranial remains, particularly in occipital and parietal bones. Next, we demonstrate convergent NeanderScore-related findings in the brain (measured by gray- and white-matter volume, sulcal depth, and gyrification index) that localize to the visual cortex and intraparietal sulcus. This work provides insights into ancestral human neurobiology and suggests that Neanderthal-derived genetic variation is neurologically functional in the contemporary population.

Update 27/07/2017

[Jo Bowyer]

Chronic pain, depression and cardiovascular disease linked through a shared genetic predisposition: Analysis of a family-based cohort and twin study

http://journals.plos.org/plosone/art...l.pone.0170653

Abstract

Background

Depression and chronic pain are the two most important causes of disability (Global Burden of Disease Study 2013). They occur together more frequently than expected and both conditions have been shown to be co-morbid with cardiovascular disease. Although shared socio-demographic risk factors (e.g. gender, deprivation) might explain the co-morbidity of these three conditions, we hypothesised that these three long-term, highly prevalent conditions co-occur and may be due to shared familial risk, and/or genetic factors.

Methods and findings

We employed three different study designs in two independent cohorts, namely Generation Scotland and TwinsUK, having standardised, validated questionnaire data on the three traits of interest. First, we estimated the prevalence and co-occurrence of chronic pain, depression and angina among 24,024 participants of a population-based cohort of extended families (Generation Scotland: Scottish Family Health Study), adjusting for age, gender, education, smoking status, and deprivation. Secondly, we compared the odds of co-morbidity in sibling-pairs with the odds in unrelated individuals for the three conditions in the same cohort. Lastly, examination of similar traits in a sample of female twins (TwinsUK, n = 2,902), adjusting for age and BMI, allowed independent replication of the findings and exploration of the influence of additive genetic (A) factors and shared (C) and non-shared (E) environmental factors predisposing to co-occurring chronic widespread pain (CWP) and cardiovascular disease (hypertension, angina, stroke, heart attack, elevated cholesterol, angioplasty or bypass surgery). In the Generation Scotland cohort, individuals with depression were more than twice as likely to have chronic pain as those without depression (adjusted OR 2·64 [95% CI 2·34–2·97]); those with angina were four times more likely to have chronic pain (OR 4·19 [3·64–4·82]); those with depression were twice as likely to have angina (OR 2·20 [1·90–2·54]). Similar odds were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05–1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63–2·95]), and depression, angina (OR 1·98 [1·49–2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99–4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05–9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85–12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, p<0.01). Considering the CWP-cardiovascular relationship, the most suitable model to describe the observed data was a combination of A, C and E, with a small but significant genetic predisposition, shared between the two traits (2·2% [95% CI 0·06–0·23]).

Conclusion

We found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.

[Jo Bowyer]

Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries

https://elifesciences.org/content/6/e22784

Abstract

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.

The Evolution of Lateralized Brain Circuits

http://journal.frontiersin.org/artic...017.01021/full

In the vast clade of animals known as the bilateria, cerebral and behavioral asymmetries emerge against the backdrop of bilateral symmetry, with a functional trade-off between the two. Asymmetries can lead to more efficient processing and packaging of internal structures, but at the expense of efficient adaptation to a natural world without systematic left-right bias. Asymmetries may arise through the fissioning of ancestral structures that are largely symmetrical, creating new circuits. In humans these may include asymmetrical adaptations to language and manufacture, and as one or other hemisphere gains dominance for functions that were previously represented bilaterally. This is best illustrated in the evolution of such functions as language and tool manufacture in humans, which may derive from the mirror-neuron system in primates, but similar principles probably apply to the many other asymmetries now evident in a wide range of animals. Asymmetries arise in largely independent manner with multi-genetic sources, rather than as a single over-riding principle.

Introduction

Part of the reason for the fascination with handedness and cerebral asymmetry is that they seem to arise from a system that is for the most part structurally symmetrical, suggesting the operation of some non-material force—and perhaps even encouraging a Cartesian notion of mind over matter (Corballis, 1980). Nevertheless lateral asymmetries can scarcely be understood or even defined except in relation to symmetry. Humans belong to the vast clade of animals known as the bilateria, going back some 550 million years, and characterized by near symmetry about the midsagittal plane. This bilateral symmetry makes us almost indistinguishable from our reflection in the mirror, and may be an adaptation to the fact that for freely moving animals, the natural world is essentially indifferent with respect to left and right. So it is that we have limbs and sense organs arranged in bilateral pairs, and even the brain is more obviously symmetrical than it is asymmetrical. You would be hard-pressed to decide whether a picture of the brain is normal or mirror-reversed, although there are a few small give-away signs.

It is against this fundamentally symmetrical plan that asymmetries sometimes arise, and are of interest. Structural asymmetries are especially evident in the way internal organs are located, with the heart, stomach, and spleen displaced to the left, the liver and gall bladder to the right. Some asymmetries, such as the asymmetrical gallop of a horse, or human preference for one or other hand, are more apparent from function than from structure. This also seems to be true of the human brain, which functions in well-documented asymmetrical ways that are all the more remarkable given its apparent anatomical symmetry.

The pressure toward asymmetry may have to do, at least in part, with packaging and efficiency, especially in internal structures that are largely independent of external constraints. It would simply be inefficient to pack a suitcase while retaining perfect symmetry of its contents; rather, you fit the contents in to make optimal use of the space. Similarly, an automobile retains external symmetry for efficient movement and maneuverability, while its internal parts are asymmetrically organized. Sheer efficiency may therefore have guided the placement of internal bodily organs such as the stomach, which processes food regardless of the manner of its arrival—or its departure. The heart, too, functions internally and is asymmetrical, but retains a degree of symmetry because it must pump blood to both sides of the body.

There is greater pressure for the retention of symmetry in the brain than in the internal organs of the body, because it is involved in coordination of symmetrical actions such as walking or swimming, and the processing of input from symmetrical sense organs. As the brain increases in size and complexity, though, there would be increased demand for asymmetrical packaging, and this pressure would be enhanced by constraints on the size of the skull. This is especially true of bipedal animals, since the demands of upright walking constrains the size of the birth canal, which in turn restricts the size of the head. These constraints conflict with heightened demands for cognitive processing, especially in animals such as humans where survival depends on complex social interactions and the manufacture of tools and habitable environments. In humans, these competing pressures create what has been termed the “obstetrical dilemma,” a hypothesis to explain why childbirth is so difficult, and leads to dangerously early birth normally requiring assistance (Washburn, 1960)—yet we need large brains to cope with the complexities of our lives on the planet. The pressure for larger brains in a constrained skull can also explain why the human brain is exceptionally wrinkled and folded, like an old automobile crushed for infill. The same conflict might also explain why asymmetry seems especially pronounced in the human brain, since reducing redundancy and duplication makes better use of the restricted brain space.

Update 17/06/2017

[Jo Bowyer]

Prevalence and associated comorbidities of restless legs syndrome (RLS): Data from a large population-based door-to-door survey on 19176 adults in Tehran, Iran

http://journals.plos.org/plosone/art...l.pone.0172593

Abstract

Background

Discrepancies have been reported in the prevalence rate of restless legs syndrome (RLS) among different ethnic groups and geographic populations. Furthermore, there are disagreements on determinant factors and associated comorbidities of RLS. We aimed to estimate prevalence of RLS and investigate its associated comorbid conditions and risk factors in a large population-based door-to-door survey.

Methods

Following a multistage random sampling from the households lived in 22 urban districts of Tehran, Iran, 19176 participants with ≥30 years of age were recruited. Trained surveyors filled study checklist consisting of baseline characteristics, risk factors and comorbidity profile and the International RLS Study Group (IRLSSG) diagnostic criteria through face-to-face interviews.

Results

In total, 1580 individuals were positively screened for RLS resulting in a standardized prevalence rate of 60.0/1000. There was a gradual increase in RLS prevalence by advancing age, however, sex difference disappeared after adjustment. Parkinsonism [adjusted odds’ ratio (adj-OR) = 7.4 (95% CI: 5.3–10.4)], peripheral neuropathy [adj-OR = 3.7 (95% CI: 3.3–4.1)], subjective cognitive impairment (SCI) [adj-OR = 3.1 (95% CI: 2.7–3.4)], acting out dreams [adj-OR = 2.8 (95% CI: 2.5–3.2)], hyposmia [adj-OR = 2.5 (95% CI: 2.2–2.9)], active smoking [adj-OR = 1.5 (95% CI: 1.3–1.9)] and additional number of cardiometabolic diseases associated with higher risk of RLS [adj-OR = 1.6 (95% CI: 1.2–2.3)].

Conclusion

Our findings showed that neuro-cognitive co-morbidities such as parkinsonism, peripheral neuropathy, SCI, acting out dreams and hyposmia as well as cardio-metabolic risk factors and diseases were independent determinants of RLS. It is recommended to screen individuals with either these comorbid conditions for RLS or the ones with RLS for the accompanying diseases.

Restless legs syndrome and cardiovascular diseases: A case-control study

http://journals.plos.org/plosone/art...l.pone.0176552

Abstract

Objective

The association between restless legs syndrome (RLS), cardiovascular diseases (CVD) and hypertension is inconsistent. This case-control study examined i) the association between primary RLS, CVD and hypertension by taking into account many potential confounders and ii) the influence of RLS duration, severity and treatment, sleep and depressive symptoms on CVD and hypertension in primary RLS.

Methods

A standardized questionnaire to assess the RLS phenotype, history of CVD and hypertension, sleep and depressive symptoms, drug intake and demographic/clinical features was sent to the France-Ekbom Patients Association members. A CVD event was defined as a self-reported history of coronary heart disease, heart failure, arrhythmia or stroke. Hypertension was also self-assessed. Current treatment for hypertension and arrhythmia also defined underlying hypertension and arrhythmia. Controls without RLS and without consanguinity were chosen by the patients.

Results

487 patients with primary RLS (median age 71 years; 67.4% women) and 354 controls (68 years, 47.7% women) were included. Most of the patients (91.7%) were treated for RLS, especially with dopaminergic agonists. The median age of RLS onset was 45 years. CVD and hypertension were associated with RLS in unadjusted association, but not after adjustment for age, sex and body mass index. Patients with RLS and with CVD and/or hypertension were significantly older, with hypercholesterolemia, sleep apnea and older age at RLS and at daily RLS onset compared with patients without CVD and/or hypertension. No significant difference was found for other RLS features, ferritin levels, daytime sleepiness, insomnia and depressive symptoms.

Conclusion

Despite some limitations in the design of this study, we found that most of the treated patients for primary RLS had no association with CVD and hypertension after controlling for key potential confounders. Comorbid CVD or hypertension was associated with cardiovascular risk factors, but not with RLS features except for older age at onset.

Update 27/04/2017




Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

http://journal.frontiersin.org/artic...017.00171/full

Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

Background
The symptoms of the RLS were first described by Willis (1685) and then published by Ekbom (1960). Despite being introduced hundreds of years ago, it’s still a poorly recognized disorder because of the unclear pathophysiology and relatively low morbidity, resulting in limited recognition by primary care physicians and common misdiagnosis and under-diagnosis. RLS is considered as a common neurological sensorimotor disorder that manifests as an irresistible urge to move the body to relieve the uncomfortable sensations. There’s a significant circadian rhythm of the RLS, as it commonly worsens at night.

Update 05/06/2017




Nerve decompression and Restless Legs Syndrome: A retrospective analysis

http://journal.frontiersin.org/artic...00287/abstract

Restless Legs Syndrome (RLS) is a prevalent sleep disorder affecting quality of life, and is often comorbid with other neurological diseases, including peripheral neuropathy. The mechanisms related to RLS symptoms remain unclear, and treatment options are often aimed at symptom relief rather than etiology. RLS may present in distinct phenotypes often described as “primary” vs. “secondary” RLS. Secondary RLS is often associated with peripheral neuropathy.

Nerve decompression surgery of the common and superficial fibular nerves is used to treat peripheral neuropathy. Anecdotally, surgeons sometimes report improved RLS symptoms following nerve decompression for peripheral neuropathy. The purpose of this retrospective analysis was to quantify the change in symptoms commonly associated with RLS using visual analog scales (VAS).

Methods: Forty-two patients completed VAS scales (0-10) for pain, burning, numbness, tingling, weakness, balance, tightness, aching, pulling, cramping, twitchy/jumpy, uneasy, creepy/crawly, and throbbing, both before and 15 weeks after surgical decompression.

Results: Subjects reported significant improvement among all VAS categories except for “pulling” (P = 0.14). The change in VAS following surgery was negatively correlated with the pre-surgery VAS for both the summed VAS (r = -0.58, P < 0.001) and the individual VAS scores (all P < 0.01), such that patients who reported the worst symptoms before surgery exhibited relatively greater reductions in symptoms after surgery.

Conclusion: This is the first study to suggest improvement in RLS symptoms following surgical decompression of the common and superficial fibular nerves. Further investigation is needed to quantify improvement using RLS-specific metrics and sleep quality assessments.

Keywords: Common fibular nerve, Common peroneal nerve, peripheral neuropathy, Willis-Ekbom disease, Nerve entrapment, Surgical Decompression

Hmmm, seems a bit drastic

Update 05/06/2017




Restless Legs Syndrome and Sleep-Wake Disturbances in Pregnancy

http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=31045

Study Objectives

To estimate the association of restless legs syndrome (RLS) and its frequency with sleep-wake disturbances in pregnancy.

Methods
A cohort of 1,563 women in their third trimester of pregnancy were recruited from prenatal clinics between March 2007 and December 2010. Demographic, pregnancy, and delivery data were extracted from medical records and sleep information was collected with questionnaires. To diagnose RLS, we used standardized criteria of RLS symptoms and frequency that were developed by the International Restless Legs Study Group. Logistic regression models were constructed to investigate the association of RLS and its frequency with sleep-wake disturbances (poor sleep quality, daytime sleepiness, poor daytime function) and delivery outcomes.

Results
Overall 36% of the pregnant women had RLS, and half had moderate to severe symptoms. Compared to women without RLS, those with RLS were more likely to have poor sleep quality (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.7–2.9), poor daytime function (OR 1.9, 95% CI 1.4–2.4), and excessive daytime sleepiness (OR 1.6, 95% CI 1.3–2.0). A dose-response relationship also was evident between RLS frequency and each of the sleep-wake disturbances. There was no evidence for any association between RLS and delivery outcomes.

Conclusions
RLS is a significant contributor to poor sleep quality, daytime sleepiness, and poor daytime function, all common and often debilitating conditions in pregnancy. Obstetric health care providers should be aware of these associations and screen women for RLS.
Commentary
A commentary on this article appears in this issue on page 857.
Citation

INTRODUCTION

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder composed of an urge to move, with or without associated discomfort that occurs with inactivity and improves with movement. It follows a circadian pattern, with a predilection for the evening and night.1 RLS is a common, underdiagnosed condition that affects up to 5% of the population worldwide,2–4 with up to 15% prevalence in Caucasians.5 The prevalence of RLS is positively correlated with age and body mass index (BMI) among both men and women.6,7 Although RLS has a genetic predisposition, it is also associated with other conditions such as end-stage renal disease, neuropathy, and pregnancy.8
RLS affects up to one-third of pregnant women9,10 peaks in the third trimester,9–11 and usually subsides after delivery.11 Multiparous women are affected up to three times more often than nulliparous women.10 The high prevalence of RLS during pregnancy has been attributed to hemodynamic and hormonal changes, iron and folate metabolism, and psychomotor behaviors.12 Although RLS is related to reduced quality of life and poor sleep in the general population13,14 data on RLS-associated maternal sleep-wake disturbances are lacking. Prior reports have linked sleep-wake disturbances to adverse pregnancy and delivery outcomes (eg, preterm delivery, prolonged labor, cesarean section deliveries, and postpartum depression).15–17 Therefore, the goal of this study was twofold: (1) to examine the frequency of RLS in a large, heterogeneous sample of pregnant women using standardized diagnostic criteria for RLS; and (2) to investigate the role of RLS in sleep-wake disturbances (ie, poor sleep quality, excessive daytime sleepiness, and poor daytime function) in addition to key delivery outcomes.

Update 16/07/2017

[Jo Bowyer]

Genetic contributions to self-reported tiredness

http://www.nature.com/mp/journal/vao.../mp20175a.html

Abstract

Self-reported tiredness and low energy, often called fatigue, are associated with poorer physical and mental health. Twin studies have indicated that this has a heritability between 6 and 50%. In the UK Biobank sample (N=108 976), we carried out a genome-wide association study (GWAS) of responses to the question, ‘Over the last two weeks, how often have you felt tired or had little energy?’ Univariate GCTA-GREML found that the proportion of variance explained by all common single-nucleotide polymorphisms for this tiredness question was 8.4% (s.e.=0.6%). GWAS identified one genome-wide significant hit (Affymetrix id 1:64178756_C_T; P=1.36 × 10−11). Linkage disequilibrium score regression and polygenic profile score analyses were used to test for shared genetic aetiology between tiredness and up to 29 physical and mental health traits from GWAS consortia. Significant genetic correlations were identified between tiredness and body mass index (BMI), C-reactive protein, high-density lipoprotein (HDL) cholesterol, forced expiratory volume, grip strength, HbA1c, longevity, obesity, self-rated health, smoking status, triglycerides, type 2 diabetes, waist–hip ratio, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, neuroticism, schizophrenia and verbal-numerical reasoning (absolute rg effect sizes between 0.02 and 0.78). Significant associations were identified between tiredness phenotypic scores and polygenic profile scores for BMI, HDL cholesterol, low-density lipoprotein cholesterol, coronary artery disease, C-reactive protein, HbA1c, height, obesity, smoking status, triglycerides, type 2 diabetes, waist–hip ratio, childhood cognitive ability, neuroticism, bipolar disorder, major depressive disorder and schizophrenia (standardised β’s had absolute values<0.03). These results suggest that tiredness is a partly heritable, heterogeneous and complex phenomenon that is phenotypically and genetically associated with affective, cognitive, personality and physiological processes.

[Jo Bowyer]

Low back pain and FokI (rs2228570) polymorphism of vitamin D receptor in athletes

http://bmcsportsscimedrehabil.biomed...102-017-0069-x

Abstract

Background
Low back pain (LBP) is common in athletes. LBP can be detrimental to athletic performance and health. Factors predisposing to LBP in athletes remain elusive and require further studies. We investigated whether carriage of a specific genotype and/or allele of vitamin D receptor gene (VDR) FokI polymorphism (rs2228570) was a risk factor for LBP in athletes of different sports disciplines.

Methods
This genotype/phenotype association case-control study included 60 Italian athletes (25 females and 35 males; mean age 33.9 ± 13.3 years; body-mass-index 23.5 ± 3.5 kg/m2) of which 16.7% were swimmers, 11.7% soccer players, 11.7% volleyball players, 10.0% rugby players and other disciplines. VDR-FokI polymorphism was measured by PCR-RFLP in 24 athletes with LBP and 36 athletes without LBP episodes. Absence or presence of the FokI restriction site was denoted “F” and “f”, respectively. Other risk factors were evaluated by a questionnaire.

Results
The homozygous FF genotype was found in 58.3% (14/24) of athletes with LBP versus 27.8% (10/36) of athletes without LBP, adjusted OR = 5.78, 95% CI 1.41–23.8, P = 0.015. The F allele was a 2-fold risk factor to develop LBP, adjusted OR = 2.55, 95% CI 1.02–6.43, P = 0.046, while f allele was protective. Exposure to vehicle vibrations ≥2 h daily, and family history of lumbar spine pathology were significant risk factors for LBP with OR = 3.54, and OR = 9.21, respectively.

Conclusions
This is the first study in which an association between VDR-FokI polymorphism and LBP in athletes was found. Further research is needed to extend our results, and to clarify the biochemical pathways associated with how vitamin D modulates LBP in athletes. The VDR-FokI polymorphism should be considered when developing genetic focused studies of precision medicine on health in athletes.

Keywords

Lumbar pain Exercise Vitamin D receptor Vitamin D receptor gene Vitamin D receptor polymorphism FokI polymorphism Exposure to vibrations Smoking and low back pain Discopathies