The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Uneven focal shoe deterioration in Tourette syndrome.

A 31-year-old single man (AB) sought neuropsychiatric consultation for treatment-resistant motor and vocal tics. He described himself expressing a total of 24 different tics, mainly facial twitches (eye blinking, raising eyebrows, mouth opening, lips licking, stereotyped grimacing) and inappropriate utterances (grunting, throat clearing, sniffing), since the age of 7. There appeared to be no family history of tic disorder. He reported occasional utterance of swear words in contextually inappropriate situations (coprolalia), and the urge to copy other people’s movements (echopraxia). Other tic-associated symptoms included self-injurious behaviours and forced touching of objects. A.B. met both DSM-IV-tr and ICD-10 criteria for Tourette syndrome, and also DSM-IV-tr criteria for attention deficit hyperactivity disorder (combined type) in childhood

Ketamine: stimulating antidepressant treatment?

SUMMARY: The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations. DECLARATION OF INTERESTS: G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013

WHEDA study: Effectiveness of occupational therapy at home for older people with dementia and their caregivers - the design of a pragmatic randomised controlled trial evaluating a Dutch programme in seven German centres

Contains fulltext : 80941.pdf (publisher's version ) (Open Access)BACKGROUND: A recent Dutch mono-centre randomised controlled trial has shown that occupational therapy improves daily functioning in dementia. The aim of this present study is to compare the effects of the Dutch community occupational therapy programme with a community occupational therapy consultation on daily functioning in older people with mild or moderate dementia and their primary caregivers in a German multi-centre context. METHODS/DESIGN: A multi-centre single blind randomised controlled trial design is being used in seven health care centres (neurological, psychiatric and for older people) in urban regions. Patients are 1:1 randomised to treatment or control group. Assessors are blind to group assignment and perform measurements on both groups at baseline, directly after intervention at 6 weeks and at 16, 26 and 52 weeks follow-up. A sample of 140 community dwelling older people (aged >65 years) with mild or moderate dementia and their primary caregivers is planned. The experimental intervention consists of an evidence-based community occupational therapy programme including 10 sessions occupational therapy at home. The control intervention consists of one community occupational therapy consultation based on information material of the Alzheimer Society. Providers of both interventions are occupational therapists experienced in treatment of cognitively impaired older people and trained in both programmes. 'Community' indicates that occupational therapy intervention occurs in the person's own home. The primary outcome is patients' daily functioning assessed with the performance scale of the Interview for Deterioration in Daily Living Activities in Dementia and video tapes of daily activities rated by external raters blind to group assignment using the Perceive, Recall, Plan and Perform System of Task Analysis. Secondary outcomes are patients' and caregivers' quality of life, mood and satisfaction with treatment; the caregiver's sense of competence, caregiver's diary (medication, resource utilisation, time of informal care); and the incidence of long-term institutionalisation. Process evaluation is performed by questionnaires and focus group discussion. DISCUSSION: The transfer from the Dutch mono-centre design to the pragmatic multi-site trial in a German context implicates several changes in design issues including differences in recruitment time, training of interventionists and active control group treatment.The study is registered under DRKS00000053 at the German register of clinical trials, which is connected to the International Clinical Trials Registry Platform

Toll-Like Receptor 3 Signaling on Macrophages Is Required for Survival Following Coxsackievirus B4 Infection

Toll-like receptor 3 (TLR3) has been proposed to play a central role in the early recognition of viruses by sensing double stranded RNA, a common intermediate of viral replication. However, several reports have demonstrated that TLR3 signaling is either dispensable or even harmful following infection with certain viruses. Here, we asked whether TLR3 plays a role in the response to coxsackievirus B4 (CB4), a prevalent human pathogen that has been associated with pancreatitis, myocarditis and diabetes. We demonstrate that TLR3 signaling on macrophages is critical to establish protective immunity to CB4. TLR3 deficient mice produced reduced pro-inflammatory mediators and are unable to control viral replication at the early stages of infection resulting in severe cardiac damage. Intriguingly, the absence of TLR3 did not affect the activation of several key innate and adaptive cellular effectors. This suggests that in the absence of TLR3 signaling on macrophages, viral replication outpaces the developing adaptive immune response. We further demonstrate that the MyD88-dependent signaling pathways are not only unable to compensate for the loss of TLR3, they are also dispensable in the response to this RNA virus. Our results demonstrate that TLR3 is not simply part of a redundant system of viral recognition, but rather TLR3 plays an essential role in recognizing the molecular signatures associated with specific viruses including CB4

Melanoma Differentiation-Associated Gene 5 (MDA5) Is Involved in the Innate Immune Response to Paramyxoviridae Infection In Vivo

The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to paramyxovirus infection and provide the first evidence of MDA5-dependent containment of in vivo infections caused by (−) sense RNA viruses

Predicting complete loss to follow-up after a health-education program: number of absences and face-to-face contact with a researcher

<p>Abstract</p> <p>Background</p> <p>Research on health-education programs requires longitudinal data. Loss to follow-up can lead to imprecision and bias, and <it>complete </it>loss to follow-up is particularly damaging. If that loss is predictable, then efforts to prevent it can be focused on those program participants who are at the highest risk. We identified predictors of complete loss to follow-up in a longitudinal cohort study.</p> <p>Methods</p> <p>Data were collected over 1 year in a study of adults with chronic illnesses who were in a program to learn self-management skills. Following baseline measurements, the program had one group-discussion session each week for six weeks. Follow-up questionnaires were sent 3, 6, and 12 months after the baseline measurement. A person was classified as completely lost to follow-up if none of those three follow-up questionnaires had been returned by two months after the last one was sent.</p> <p>We tested two hypotheses: that complete loss to follow-up was directly associated with the number of absences from the program sessions, and that it was less common among people who had had face-to-face contact with one of the researchers. We also tested predictors of data loss identified previously and examined associations with specific diagnoses.</p> <p>Using the unpaired t-test, the U test, Fisher's exact test, and logistic regression, we identified good predictors of complete loss to follow-up.</p> <p>Results</p> <p>The prevalence of complete loss to follow-up was 12.2% (50/409). Complete loss to follow-up was directly related to the number of absences (odds ratio; 95% confidence interval: 1.78; 1.49-2.12), and it was inversely related to age (0.97; 0.95-0.99). Complete loss to follow-up was less common among people who had met one of the researchers (0.51; 0.28-0.95) and among those with connective tissue disease (0.29; 0.09-0.98). For the multivariate logistic model the area under the ROC curve was 0.77.</p> <p>Conclusions</p> <p>Complete loss to follow-up after this health-education program can be predicted to some extent from data that are easy to collect (age, number of absences, and diagnosis). Also, face-to-face contact with a researcher deserves further study as a way of increasing participation in follow-up, and health-education programs should include it.</p

Enhanced relapse prevention for bipolar disorder – ERP trial. A cluster randomised controlled trial to assess the feasibility of training care coordinators to offer enhanced relapse prevention for bipolar disorder

BACKGROUND: Bipolar Disorder (BD) is a common and severe form of mental illness characterised by repeated relapses of mania or depression. Pharmacotherapy is the main treatment currently offered, but this has only limited effectiveness. A recent Cochrane review has reported that adding psycho-social interventions that train people to recognise and manage the early warning signs of their relapses is effective in increasing time to recurrence, improving social functioning and in reducing hospitalisations. However, the review also highlights the difficulties in offering these interventions within standard mental health services due to the need for highly trained therapists and extensive input of time. There is a need to explore the potential for developing Early Warning Sign (EWS) interventions in ways that will enhance dissemination. METHODS AND DESIGN: This article describes a cluster-randomised trial to assess the feasibility of training care coordinators (CCs) in community mental health teams (CMHTs) to offer Enhanced Relapse Prevention (ERP) to people with Bipolar Disorder. CMHTs in the North West of England are randomised to either receive training in ERP and to offer this to their clients, or to continue to offer treatment as usual (TAU). The main aims of the study are (1) to determine the acceptability of the intervention, training and outcome measures (2) to assess the feasibility of the design as measured by rates of recruitment, retention, attendance and direct feedback from participants (3) to estimate the design effect of clustering for key outcome variables (4) to estimate the effect size of the impact of the intervention on outcome. In this paper we provide a rationale for the study design, briefly outline the ERP intervention, and describe in detail the study protocol. DISCUSSION: This information will be useful to researchers attempting to carry out similar feasibility assessments of clinical effectiveness trials and in particular cluster randomised controlled trials

Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection with RABV. Our results indicate that BMDC activation and type I IFN production following a RABV infection is independent of TLR signaling. However, IPS-1 is essential for both BMDC activation and IFN production. Interestingly, we see that the BMDC activation is primarily due to signaling through the IFNAR and only marginally induced by the initial infection. To further identify the receptor recognizing RABV infection, we next analyzed BMDC from Mda-5−/− and RIG-I−/− mice. In the absence of either receptor, there is a significant decrease in BMDC activation at 12h post infection. However, only RIG-I−/− cells exhibit a delay in type I IFN production. In order to determine the role that IPS-1 plays in vivo, we infected mice with pathogenic RABV. We see that IPS-1−/− mice are more susceptible to infection than IPS-1+/+ mice and have a significantly increased incident of limb paralysis

Calcium and copper transport ATPases: analogies and diversities in transduction and signaling mechanisms

The calcium transport ATPase and the copper transport ATPase are members of the P-ATPase family and retain an analogous catalytic mechanism for ATP utilization, including intermediate phosphoryl transfer to a conserved aspartyl residue, vectorial displacement of bound cation, and final hydrolytic cleavage of Pi. Both ATPases undergo protein conformational changes concomitant with catalytic events. Yet, the two ATPases are prototypes of different features with regard to transduction and signaling mechanisms. The calcium ATPase resides stably on membranes delimiting cellular compartments, acquires free Ca2+ with high affinity on one side of the membrane, and releases the bound Ca2+ on the other side of the membrane to yield a high free Ca2+ gradient. These features are a basic requirement for cellular Ca2+ signaling mechanisms. On the other hand, the copper ATPase acquires copper through exchange with donor proteins, and undergoes intracellular trafficking to deliver copper to acceptor proteins. In addition to the cation transport site and the conserved aspartate undergoing catalytic phosphorylation, the copper ATPase has copper binding regulatory sites on a unique N-terminal protein extension, and has also serine residues undergoing kinase assisted phosphorylation. These additional features are involved in the mechanism of copper ATPase intracellular trafficking which is required to deliver copper to plasma membranes for extrusion, and to the trans-Golgi network for incorporation into metalloproteins. Isoform specific glyocosylation contributes to stabilization of ATP7A copper ATPase in plasma membranes