Reviewing the epigenetics of schizophrenia.

BACKGROUND: Epigenetic research in mental health has grown exponentially during the last decade and holds what some claim are "revolutionary" potentials for the development of new interdisciplinary models of mental ill health. Schizophrenia is the most appropriate diagnosis against which to assess progress in this regard. METHOD: Papers on epigenetics and schizophrenia identified in a systematic literature search are subject to a conceptually-driven narrative review that assesses the relations between schizophrenia and epigenetics; considers some issues associated with empirical studies; and thereby identifies key assumptions guiding this research. FINDINGS: The revolutionary potentials of epigenetics are thus far not being realised due to various influences, including a preponderance of hypotheses that begin from a primarily biological question; the "condensation" of environmental influences and their effective reduction to their molecular consequences; and a frequent reliance upon animal studies that effectively preclude some important influences already established as relevant to this diagnosis. CONCLUSION: Epigenetic research in schizophrenia (and mental health generally) could benefit from being more thoroughly interdisciplinary, from testing hypotheses that foreground social as well as biological influences, and from reconsidering its reliance upon psychiatric diagnoses.

Stretch imposed on active muscle elicits positive adaptations in strain risk factors and exercise-induced muscle damage.

INTRODUCTION: Stretching highly-contracted plantar flexor muscles (isokinetic eccentric contractions) results in beneficial adaptations in muscle strain risk factors; however its effects in other muscle groups, and on architectural characteristics and exercise-induced muscle damage (EIMD), are unknown. METHODS: The influence of a 6-week knee extensor training program was studied in 26 volunteers (13 control; 13 experimental). Before and after the training program, passive and maximal isometric and eccentric knee extensor moments and range of motion (ROM) were recorded on an isokinetic dynamometer with simultaneous ultrasound imaging of vastus lateralis (VL). On a separate day, EIMD markers (creatine kinase [CK], delayed onset muscle soreness [DOMS]) were measured before and 24 hours after a 20-minute downhill run. The 6-week training program was performed twice-weekly where five sets of 12 stretches (3 seconds per stretch) were imposed on maximally contracted knee extensor muscles. RESULTS: Significant (P < 0.05) increases in eccentric (29.5%) and isometric (17.4%) moments, ROM (5.2°), stretch tolerance (55.4%), elastic energy storage (73.0%), VL thickness (7.8%), pennation angle (9.0%), and tendon stiffness (8.7%) occurred. No change (P > 0.05) in passive muscle-tendon stiffness (-9.4%) or resting fascicle length (-0.7%) occurred. The downhill run resulted in substantial DOMS and significant increase in CK concentration before the training program (107.6%); however, DOMS was eliminated from the knee extensors and a significantly smaller increase in CK (-70.0%) occurred post-training. CONCLUSION: Positive adaptations in functional and physiological variables confirm that imposing stretch on maximally contracted muscle provides beneficial adaptations likely to mitigate EIMD and injury risk and enhance functional performance.

Stretching of Active Muscle Elicits Chronic Changes in Multiple Strain Risk Factors.

INTRODUCTION: The muscle stretch intensity imposed during "flexibility" training influences the magnitude of joint range of motion (ROM) adaptation. Thus, stretching while the muscle is voluntarily activated was hypothesized to provide a greater stimulus than passive stretching. The effect of a 6-wk program of stretch imposed on an isometrically contracting muscle (i.e., qualitatively similar to isokinetic eccentric training) on muscle-tendon mechanics was therefore studied in 13 healthy human volunteers. METHODS: Before and after the training program, dorsiflexion ROM, passive joint moment, and maximal isometric plantarflexor moment were recorded on an isokinetic dynamometer. Simultaneous real-time motion analysis and ultrasound imaging recorded gastrocnemius medialis muscle and Achilles tendon elongation. Training was performed twice weekly and consisted of five sets of 12 maximal isokinetic eccentric contractions at 10°·s. RESULTS: Significant increases (P < 0.01) in ROM (92.7% [14.7°]), peak passive moment (i.e., stretch tolerance; 136.2%), area under the passive moment curve (i.e., energy storage; 302.6%), and maximal isometric plantarflexor moment (51.3%) were observed after training. Although no change in the slope of the passive moment curve (muscle-tendon stiffness) was detected (-1.5%, P > 0.05), a significant increase in tendon stiffness (31.2%, P < 0.01) and a decrease in passive muscle stiffness (-14.6%, P < 0.05) were observed. CONCLUSION: The substantial positive adaptation in multiple functional and physiological variables that are cited within the primary etiology of muscle strain injury, including strength, ROM, muscle stiffness, and maximal energy storage, indicate that the stretching of active muscle might influence injury risk in addition to muscle function. The lack of change in muscle-tendon stiffness simultaneous with significant increases in tendon stiffness and decreases in passive muscle stiffness indicates that tissue-specific effects were elicited.

The effects of acute arm crank ergometry and cycle ergometry on postural sway and attentional demands during quiet bipedal standing.

Current evidence suggests that acute bouts of lower limb exercise elicits a number of adverse effects on both sensory and motor components of postural control. The effects of acute exercise on quiet standing balance while concurrently performing an attentional task remains equivocal. This study aimed to compare the alterations in postural control and attentional demands elicited by upper and lower limb exercise. Twelve healthy young males (mean ± SD age, 22.2 ± 3.2 years) were examined on six separate occasions. The first two visits determined maximal aerobic fitness on an arm crank ergometer (ACE) and cycle ergometer (CYC). Subsequently, participant's postural sway was assessed during single- (ST) and dual-task (DT) conditions before and immediately after moderate- and high-intensity exercise engaging the upper or lower body musculature. The order of the four exercise tests was counterbalanced. The centre of pressure displacement in the anteroposterior (COPAP) and mediolateral (COPML) directions and the COP path length (COPL) were computed using a force platform. A time × mode interaction was observed for COPAP (ST; p = 0.011, DT; p = 0.018) and COPML (ST; p = 0.001). CYC elicited large (ES; 1.6-2.0) increases in COPAP and COPML, but there were no differences between aerobic and anaerobic tests (p > 0.05). The effect of cognitive load appeared to increase sway in the frontal plane following anaerobic CYC (p = 0.001) but not ACE (p < 0.05). Exercise has different effects on frontal and sagittal plane sway following different cognitive loads. In particular, COPML was increased at the cost of maintaining attentional performance following exercise.

Radiogenomics: the search for genetic predictors of radiotherapy response.

'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation.

A comparison of two anaerobic test measurement systems using an upper body Wingate test.

This study aimed to compare performance measures acquired by two different Wingate Anaerobic Test systems; Cranlea and Monark. Twenty participants undertook 58 Wingate tests against a 4% body mass resistive load on a cycle ergometer adapted for arm cranking. Corrected peak power output (PP; W) was recorded using 1 rev min(-1), 0.5, 1 and 5 s averages and mean power output (MP; W). The Cranlea system recorded the greatest PP (589 ± 267 W) compared with the Monark (546 ± 267 W; P < 0.001). The PP using all other methods was also greater for the Cranlea compared with the Monark system (P < 0.001) with mean differences of 55 ± 18 W for 1 s averages and 22 ± 18 W for MP. Correlations between all PPs were strong (r = 0.99 - 0.97; P < 0.001). In conclusion, although the Cranlea system provides a consistently greater corrected PP it may not be enough to substantially differentiate between systems.

A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity.

BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5×10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable.

Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity.

BACKGROUND AND PURPOSE: Reported associations between risk of radiation-induced normal tissue injury and single nucleotide polymorphisms (SNPs) in TGFB1, encoding the pro-fibrotic cytokine transforming growth factor-beta 1 (TGF-ß1), remain controversial. To overcome publication bias, the international Radiogenomics Consortium collected and analysed individual patient level data from both published and unpublished studies. MATERIALS AND METHODS: TGFB1 SNP rs1800469 c.-1347T>C (previously known as C-509T) genotype, treatment-related data, and clinically-assessed fibrosis (measured at least 2years after therapy) were available in 2782 participants from 11 cohorts. All received adjuvant breast radiotherapy. Associations between late fibrosis or overall toxicity, reported by STAT (Standardised Total Average Toxicity) score, and rs1800469 genotype were assessed. RESULTS: No statistically significant associations between either fibrosis or overall toxicity and rs1800469 genotype were observed with univariate or multivariate regression analysis. The multivariate odds ratio (OR), obtained from meta-analysis, for an increase in late fibrosis grade with each additional rare allele of rs1800469 was 0.98 (95% Confidence Interval (CI) 0.85-1.11). This CI is sufficiently narrow to rule out any clinically relevant effect on toxicity risk in carriers vs. non-carriers with a high probability. CONCLUSION: This meta-analysis has not confirmed previous reports of association between fibrosis or overall toxicity and rs1800469 genotype in breast cancer patients. It has demonstrated successful collaboration within the Radiogenomics Consortium.

The Role of FRMD7 in Idiopathic Infantile Nystagmus.

Idiopathic infantile nystagmus (IIN) is an inherited disorder in which the nystagmus arises independently of any other symptoms, leading to the speculation that the disorder represents a primary defect in the area of the brain responsible for ocular motor control. The inheritance patterns are heterogeneous, however the most common form is X-linked. FRMD7 resides at Xq26-27 and approximately 50% of X-linked IIN families map to this region. Currently 45 mutations within FRMD7 have been associated with IIN, confirming the importance of FRMD7 in the pathogenesis of the disease. Although mutations in FRMD7 are known to cause IIN, very little is known about the function of the protein. FRMD7 contains a conserved N-terminal FERM domain suggesting that it may provide a link between the plasma membrane and actin cytoskeleton. Limited studies together with the knowledge of the function of other FERM domain containing proteins, suggest that FRMD7 may play a role in membrane extension during neuronal development through remodeling of the actin cytoskeleton.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.