Web-based physiotherapy for people affected by multiple sclerosis: a single blind, randomized controlled feasibility study

Objective: To examine the feasibility of a trial to evaluate web-based physiotherapy compared to a standard home exercise programme in people with multiple sclerosis. Design: Multi-centre, randomized controlled, feasibility study. Setting: Three multiple sclerosis out-patient centres. Participants: A total of 90 people with multiple sclerosis (Expanded Disability Status Scale 4–6.5). Interventions: Participants were randomized to a six-month individualized, home exercise programme delivered via web-based physiotherapy (n = 45; intervention) or a sheet of exercises (n = 45; active comparator). Outcome measures: Outcome measures (0, three, six and nine months) included adherence, two-minute walk test, 25 foot walk, Berg Balance Scale, physical activity and healthcare resource use. Interviews were undertaken with 24 participants and 3 physiotherapists. Results: Almost 25% of people approached agreed to take part. No intervention-related adverse events were recorded. Adherence was 40%–63% and 53%–71% in the intervention and comparator groups. There was no difference in the two-minute walk test between groups at baseline (Intervention-80.4(33.91)m, Comparator-70.6(31.20)m) and no change over time (at six-month Intervention-81.6(32.75)m, Comparator-74.8(36.16)m. There were no significant changes over time in other outcome measures except the EuroQol-5 Dimension at six months which decreased in the active comparator group. For a difference of 8(17.4)m in two-minute walk test between groups, 76 participants/group would be required (80% power, P > 0.05) for a future randomized controlled trial. Conclusion: No changes were found in the majority of outcome measures over time. This study was acceptable and feasible by participants and physiotherapists. An adequately powered study needs 160 participants

Recent trends and future directions for lung cancer mortality in Europe

Lung cancer mortality patterns throughout Europe are very heterogeneous and largely reflect past smoking habits. In order to clarify the changing patterns of lung cancer in Europe we have plotted the overall lung cancer trends among men and women for 20 countries from 1950 up to1998. Furthermore, using a Bayesian age-period-cohort approach, we have calculated 5 year projections of lung cancer rate up to 2003. Finally, we make some comments on probable future trends by analysing recent trends in adults aged <55 years. Lung cancer mortality rates up to age 75 years portray a general trend of decreasing lung cancer rates among men and increasing lung cancer rates among women. Exceptions to this decrease among men include Hungary where not only are current mortality rates much higher than previously observed in any other country (at 76.7 out of 100 000 in 1998) but they are projected to increase further in the short term. Rates among adults aged <55 years have recently peaked, indicating that overall rates are likely to peak in the next decade. Among women, rapid increases have been observed in Denmark, Netherlands, Hungary, Ireland and UK. Whereas Ireland and UK rates have started to decrease and are projected to continue falling, rates in the other three countries are projected to increase further. Trends in women aged <55 years indicate that rates in Danish women will peak in the next decade, whereas lung cancer rates among Dutch women are likely to continue increasing. Rates in Hungarian women are likely to increase and will surpass the current high rate observed in Denmark

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection

Die Rangfolge psychischer und sozialer Prädiktoren und Kriterien für die Prognose Herztransplantierter

Bei 44 Herztransplantierten wurden präoperativ und bis zu einem und drei Jahre postoperativ psychiatrisch/psychologische Untersuchungen durchgeführt und psychosoziale Daten erhoben. Die Prädiktoren und Kriterien für eine gute Prognose wurden ihrer Rangfolge nach hierarchisiert. Es ergab sich folgende Prädiktorrangfolge: 1. die eindeutige Motivation und der unauffällige psychopathologische Befund, 2. der gute soziale Rückhalt und die vor der Transplantation zum Ausdruck gebrachte positive Berufsperspektive, 3. das Bewußtsein der Geborgenheit durch die Familie und die reife psychologische Verarbeitung der Herzerkrankung und der bevorstehenden Herztransplantation, 4. der fortgeschrittene Schweregrad der Herzerkrankung (Schweregrad IV NYHA), 5. der relativ geringe Fernsehkonsum (weniger als an 4 Abenden), und 6. u. a. noch lebende Eltern und das Vorhandensein von Kindern. Für die 7 prognostischen Kriterien ließ sich folgendeKriterienrangfolge ermitteln: 1. die soziale Reintegration, 2. die Lebenszufriedenheit, 3. die Compliance und der psychopathologische Befund, 4. die berufliche Rehabilitation, und 5. die körperliche Belastbarkeit und der körperliche Zustand. Die Studie zeigt, daß es eine unterschiedliche Gewichtung psychosozialer Faktoren vor und nach der Herztransplantation gibt, und daß die soziale Reintegration der beste Indikator für eine erfolgreiche Herztransplantation ist.44 patients underwent psychiatric/psychological and psychosocial examinations before and for one to three years after heart transplantation. Predictors and prognostic criteria for a good result were established according to the rank of their significance. The rank sequence for the predictors were 1. strong motivation and absence of psychiatric symptomatology, 2. good social support and determination to return to work after transplantation, 3. the feeling of being cared for by the family and a mature psychological coping with the heart disease and the expected transplantation, 4. advanced heart failure (stage IV NYHA), 5. watching TV less than 4 evenings a week, 6. parents still living and having one’s own children. The rank sequence for the 7 prognostic criteria for a good result after heart transplantation were 1. social reintegration, 2. being content with life. 3. good compliance and absence of psychopathology, 4. returning to work, and 5. physical exercise tolerance and general physical condition. The study shows that there is a different magnitude of significance for psychosocial factors before and after heart transplantation and that social reintegration is the best indicator for a good result after heart transplantation

HIV Types, Groups, Subtypes and Recombinant Forms: Errors in Replication, Selection Pressure and Quasispecies

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1{*}1303, KIR and PARD3B. Copyright (C) 2012 S. Karger AG, Base

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Physicians and Drug Representatives: Exploring the Dynamics of the Relationship

BACKGROUND: Interactions between physicians and drug representatives are common, even though research shows that physicians understand the conflict of interest between marketing and patient care. Little is known about how physicians resolve this contradiction. OBJECTIVE: To determine physicians’ techniques for managing cognitive inconsistencies within their relationships with drug representatives. DESIGN, SETTING, AND PARTICIPANTS: Six focus groups were conducted with 32 academic and community physicians in San Diego, Atlanta, and Chicago. MEASUREMENTS: Qualitative analysis of focus group transcripts to determine physicians’ attitudes towards conflict of interest and detailing, their beliefs about the quality of information conveyed and the impact on prescribing, and their resolution of the conflict between detailers’ desire to sell product and patient care. RESULTS: Physicians understood the concept of conflict of interest and applied it to relationships with detailers. However, they maintained favorable views of physician–detailer exchanges. Holding these mutually contradictory attitudes, physicians were in a position of cognitive dissonance. To resolve the dissonance, they used a variety of denials and rationalizations: They avoided thinking about the conflict of interest, they disagreed that industry relationships affected physician behavior, they denied responsibility for the problem, they enumerated techniques for remaining impartial, and they reasoned that meetings with detailers were educational and benefited patients. CONCLUSIONS: Although physicians understood the concept of conflict of interest, relationships with detailers set up psychological dynamics that influenced their reasoning. Our findings suggest that voluntary guidelines, like those proposed by most major medical societies, are inadequate. It may be that only the prohibition of physician–detailer interactions will be effective