Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.

PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets

Impact of Hepatitis C Treatment as Prevention for People Who Inject Drugs is sensitive to contact network structure

Treatment as Prevention (TasP) using directly-acting antivirals has been advocated for Hepatitis C Virus (HCV) in people who inject drugs (PWID), but treatment is expensive and TasP’s effectiveness is uncertain. Previous modelling has assumed a homogeneously-mixed population or a static network lacking turnover in the population and injecting partnerships. We developed a transmission-dynamic model on a dynamic network of injecting partnerships using data from survey of injecting behaviour carried out in London, UK. We studied transmission on a novel exponential-clustered network, as well as on two simpler networks for comparison, an exponential unclustered and a random network, and found that TasP’s effectiveness differs markedly. With respect to an exponential-clustered network, the random network (and homogeneously-mixed population) overestimate TasP’s effectiveness, whereas the exponential-unclustered network underestimates it. For all network types TasP’s effectiveness depends on whether treated patients change risk behaviour, and on treatment coverage: higher coverage requires fewer total treatments for the same health gain. Whilst TasP can greatly reduce HCV prevalence, incidence of infection, and incidence of reinfection in PWID, assessment of TasP’s effectiveness needs to take account of the injecting-partnership network structure and post-treatment behaviour change, and further empirical study is required

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome

Medicalising the moral: the case of depression as revealed in internet blogs

Depression is regularly declared to be equivalent to a bodily illness, yet critics have long contested this ‘medical’ view of mental disorders. Following the ideas of Szasz and Foucault, we describe an alternative ‘moral’ view of depression, which emphasises the agency of the individual and presents depression as a potentially problematic but meaningful response that can be regarded as an aspect of character. We use popular internet blogs by people with depression to explore these contrasting conceptions, which can also be found in other research and information on depression. In blogs, the medical view is used to challenge what bloggers perceive as a persistently influential moral view, by deflecting criticism and responsibility and disowning unwanted aspects of the self. At the same time, bloggers make positive use of the moral concept of depression when discussing recovery. The moral view enables people to take active steps to address their difficulties and to integrate the experience of depression into their understanding of themselves in a challenging yet rewarding process of personal development. We suggest that the moral view of depression represents an enduring aspect of our understanding of ourselves, which the medical view has been superimposed onto, but has not managed to suppress

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Social Identity Mapping and Psychotic Disorders: Understanding the Relationships Between Social Identity Features, Self-Esteem, and Quality of Life

Having more social connections is related to better quality of life in people with psychosis. However, little is known about the nature of these social connections or whether the personal significance of social connections matters for quality of life. We aimed to fill this gap by surveying 200 people with psychosis using social identity mapping (SIM), which allows people to name their groups, roles, and relationships and how they feel about these. SIM names were categorized into 10 groups, with “activities” (39%) and “family” (14%) being most common; “patient” (3%), “politics” (2%), and “local residence” (1%) were least common. Hierarchical regression revealed that the only variable associated with better quality of life was having a greater number of highly important connections. This was mediated by self-esteem. Clinicians and researchers should examine the potential of social identification, the internalization of social connections, as a means of improving quality of life

Hoof lesions in partly housed pasture-based dairy cows

Lameness is a symptom of a painful disorder affecting the limbs, which impacts dairy cow welfare and productivity. Lameness is primarily caused by hoof lesions. The prevalence of different lesion types can differ depending on environmental conditions and farm management practices. The aims of this observational study were to establish the cow-level and herd-level lesion prevalence during both housing and grazing periods in a partly housed, pasture-based system, establish the prevalence of lesions always associated with pain (“alarm” lesion), identify the lesions associated with a higher lameness score, determine relationships between lesions, and identify risk factors for digital dermatitis. On 98 farms during the grazing period and on 74 of the same farms during the housing period, every cow was lameness scored (0–3 lameness scoring scale), and the hind hooves of lame cows (score 2 and 3) were examined (maximum 20 cows per visit) and the prevalence of each lesion type recorded. To gather data on potential predictors for the risk factor analysis, a questionnaire with the farmer was conducted on lameness management practices and infrastructure measurements were taken at each visit. Cow-level data were also collected (e.g., parity, breed, milk yield, and so on). Noninfectious lesions were found to be more prevalent than infectious lesions in this system type. The most prevalent lesion types during both grazing and housing periods were white line separation, sole hemorrhages and overgrown claws; all remaining lesions had a cow-level prevalence of less than 15%. The cow-level prevalence of alarm lesions was 19% during the grazing period and 25% during the housing period; the most prevalent alarm lesion was sole ulcers during both periods. We found significantly more foreign bodies within the hoof sole (grazing = 14%, housing = 7%) and overgrown claws (grazing = 71%, housing = 55%) during the grazing period compared with the housing period. Cows with foul of the foot, sole ulcer, white line abscess, toe necrosis or an amputated claw had higher odds of being more severely lame, compared with mildly lame. The strongest correlation between lesions were between toe necrosis and digital dermatitis (r = 0.40), overgrown claws and corkscrew claws (r = 0.33), and interdigital hyperplasia and digital dermatitis (r = 0.31) at herd level. At the cow level, the strongest correlation was between overgrown claws and corkscrew claws (r = 0.27), and digital dermatitis and heel erosion (r = 0.22). The farmers' perception of the presence of digital dermatitis (and lameness) was significantly correlated with the actual presence of digital dermatitis recorded. Additional risk factors for the presence of digital dermatitis were cow track and verge width near the collecting yard, and stone presence on the cow tracks. Results from this study help further our understanding of the causes of lameness in partly housed, pasture-based dairy cows, and can be used to guide prevention and treatment protocols