Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study.

BACKGROUND: Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. OBJECTIVE: The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. METHOD: This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. RESULTS: A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.6 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. >5% for >6 months) or BMI <20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. CONCLUSION: Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

Estimating the Prevalence of Muscle Wasting, Weakness, and Sarcopenia in Hemodialysis Patients.

OBJECTIVES: Haemodialysis (HD) patients suffer from nutritional problems, which include muscle wasting, weakness, and cachexia, and are associated with poor clinical outcomes. The European Working Group for Sarcopenia in Older People (EWGSOP) and Foundations for the National Institute of Health (FNIH) have developed criteria for the assessment of sarcopenia, including the use of non-invasive techniques such as bioelectrical impedance assessment (BIA), anthropometry, and hand grip strength (HGS) dynamometry. This study investigated the prevalence of muscle wasting, weakness, and sarcopenia using the EWGSOP and FNIH criteria. METHODS: BIA was performed in 24 females (f) and 63 males (m) in the post-dialysis period. Total skeletal muscle mass and appendicular skeletal muscle mass were estimated and index values (i.e., muscle mass divided by height2 [kg/m2]) were calculated (Total Skeletal Muscle Index (TSMI) and Appendicular Skeletal Muscle Index (ASMI)). Mid-arm circumference and triceps skin-fold thickness were measured and mid-upper arm muscle circumference (MUAMC) calculated. HGS was measured using a standard protocol and Jamar dynamometer. Suggested cut-points for low muscle mass and grip strength were utilized using the EWGSOP and FNIH criteria with prevalence estimated, including sarcopenia. RESULTS: The prevalence varied depending on methodology: low TSMI (moderate and severe sarcopenia combined) was 55% for whole group: 21% (f) and 68% (m). Low ASMI was 32% for whole group: 25% (f) and 35% (m). Low MUAMC was 25% for whole group: 0% (f) and 30% (m). ASMI highly correlated with Body Mass Index (r = 0.78, P < .001) and MUAMC (r = 0.68, P < .001). Muscle weakness was high regardless of cut-points used (50-71% (f); 60-79% (m)). CONCLUSIONS: Internationally, this is the first study comparing measures of muscle mass (TSMM and ASMM by BIA and MUAMC) and muscle strength (HGS) using this specific methodology in a hemodialysis population. Future work is required to confirm findings.

Establishing a clinical phenotype for cachexia in end stage kidney disease - study protocol.

BACKGROUND: Surveys using traditional measures of nutritional status indicate that muscle wasting is common among persons with end-stage kidney disease (ESKD). Up to 75% of adults undergoing maintenance dialysis show some evidence of muscle wasting. ESKD is associated with an increase in inflammatory cytokines and can result in cachexia, with the loss of muscle and fat stores. At present, only limited data are available on the classification of wasting experienced by persons with ESKD. Individuals with ESKD often exhibit symptoms of anorexia, loss of lean muscle mass and altered energy expenditure. These symptoms are consistent with the syndrome of cachexia observed in other chronic diseases, such as cancer, heart failure, and acquired immune deficiency syndrome. While definitions of cachexia have been developed for some diseases, such as cardiac failure and cancer, no specific cachexia definition has been established for chronic kidney disease. The importance of developing a definition of cachexia in a population with ESKD is underscored by the negative impact that symptoms of cachexia have on quality of life and the association of cachexia with a substantially increased risk of premature mortality. The aim of this study is to determine the clinical phenotype of cachexia specific to individuals with ESKD. METHODS: A longitudinal study which will recruit adult patients with ESKD receiving haemodialysis attending a Regional Nephrology Unit within the United Kingdom. Patients will be followed 2 monthly over 12 months and measurements of weight; lean muscle mass (bioelectrical impedance, mid upper arm muscle circumference and tricep skin fold thickness); muscle strength (hand held dynamometer), fatigue, anorexia and quality of life collected. We will determine if they experience (and to what degree) the known characteristics associated with cachexia. DISCUSSION: Cachexia is a debilitating condition associated with an extremely poor outcome. Definitions of cachexia in chronic illnesses are required to reflect specific nuances associated with each disease. These discrete cachexia definitions help with the precision of research and the subsequent clinical interventions to improve outcomes for patients suffering from cachexia. The absence of a definition for cachexia in an ESKD population makes it particularly difficult to study the incidence of cachexia or potential treatments, as there are no standardised inclusion criteria for patients with ESKD who have cachexia. Outcomes from this study will provide much needed data to inform development and testing of potential treatment modalities, aimed at enhancing current clinical practice, policy and education.

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

BACKGROUND: Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. METHODS: A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. RESULTS: Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. CONCLUSION: The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.

Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.

Childhood sexual trauma, cannabis use and psychosis: statistically controlling for pre-trauma psychosis and psychopathology.

PURPOSE: Recurring evidence seems to suggest that sexual trauma in childhood may moderate associations between cannabis consumption and psychosis. It has also been suggested, however, that poor childhood mental health may explain linkages between these phenomena. METHODS: The current study, using data from the National Comorbidity Survey-Replication (N = 2,355), sought to revaluate the stability of the childhood trauma-cannabis interaction while statistically controlling for pre-trauma psychotic experiences and psychopathology in childhood. RESULTS: Psychotic experiences that occurred before childhood sexual trauma significantly influenced adult psychosis symptomatology (psychosis pre-rape B = 0.10; psychosis pre-sexual assault B = 0.23). Social phobia (B = 0.07) also conferred risk for adult psychosis. Pre-trauma childhood psychopathology, however, did not account for the interaction between childhood sexual trauma and cannabis consumption in a multivariate model. Childhood experiences of rape (B = 0.15) and an interaction between cannabis use and childhood sexual assault (B = 0.05) independently contributed to adult psychosis. Cannabis use conferred no independent risk. CONCLUSIONS: With specific regard to research methodology, the current findings offer further justification for the inclusion of childhood sexual trauma in analyses investigating associations between cannabis use and psychosis.

Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.

Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.

FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.

Attitudes and intentions to performing testicular self-examination: utilizing an extended theory of planned behavior.

This study examined the ability of an extended theory of planned behavior (TPB) to predict 500, 17- to 35-year-old male students' intentions to perform testicular self-examination (TSE). In a hierarchical regression analysis TPB components attitude, subjective norm and self-efficacy and the added constructs, past behavior, and anticipated regret all emerged as significant independent predictors of TSE intention. Overall, 64% of the variance in TSE intention was explained. Although prospective research is needed to confirm these preliminary findings, they suggest that an extended TPB might be a useful framework to guide interventions aimed at promoting TSE.

Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.

BACKGROUND: Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD). METHODS: We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection. FINDINGS: The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease. INTERPRETATION: The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.

Assessing the general health of diagnostic orphans using the Short Form Health Survey (SF-12v2): a latent variable modelling approach.

AIMS: Research has demonstrated that diagnostic orphans (i.e. individuals who experience only one to two criteria of DSM-IV alcohol dependence) can encounter significant health problems. Using the SF-12v2, this study examined the general health functioning of alcohol users, and in particular, diagnostic orphans. METHODS: Current drinkers (n = 26,913) in the National Epidemiologic Survey on Alcohol and Related Conditions were categorized into five diagnosis groups: no alcohol use disorder (no-AUD), one-criterion orphans, two-criterion orphans, alcohol abuse and alcohol dependence. Latent variable modelling was used to assess the associations between the physical and mental health factors of the SF-12v2 and the diagnosis groups and a variety of background variables. RESULTS: In terms of mental health, one-criterion orphans had significantly better health than two-criterion orphans and the dependence group, but poorer health than the no-AUD group. No significant differences were evident between the one-criterion orphan group and the alcohol abuse group. One-criterion orphans had significantly poorer physical health when compared to the no-AUD group. One- and two-criterion orphans did not differ in relation to physical health. CONCLUSION: Consistent with previous research, diagnostic orphans in the current study appear to have experienced clinically relevant symptoms of alcohol dependence. The current findings suggest that diagnostic orphans may form part of an alcohol use disorders spectrum severity.

The distribution of positive psychosis-like symptoms in the population: a latent class analysis of the National Comorbidity Survey.

OBJECTIVE: Previous research has suggested that psychosis is better described as a continuum rather than a dichotomous entity. This study aimed to describe the distribution of positive psychosis-like symptoms in the general population by means of latent class analysis. METHOD: Latent class analysis was used to identify homogeneous sub-types of psychosis-like experiences. Multinomial logistic regression models were used to interpret the nature of the latent classes, or groups, by estimating the associations with demographic factors, clinical variables, and experiences of traumatic events. RESULTS: The best fitting latent class model was a four-class solution: a psychosis class, a hallucinatory class, an intermediate class, and a normative class. The associations between the latent classes and the demographic risk factors, clinical variables, and experiences of traumatic events showed significantly higher risks for the psychosis class, the hallucinatory class, and the intermediate class compared to the normative class. Furthermore there appeared to be a grading in the magnitude of the odds ratios: the odds ratios for the psychosis group were generally higher than those for the hallucinatory class, and the odds ratios for the hallucinatory class were generally higher than those for the intermediate class. CONCLUSIONS: The latent class analysis showed that psychosis-like symptoms at the population level could be best explained by four groups that appeared to represent an underlying continuum.