Dramatic clinical response to ultra-high dose IVIg in otherwise treatment resistant inflammatory neuropathies

Background Intravenous immunoglobulin (IVIg) has short and long-term efficacy in both chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). There is potential for under and over-treatment if trial regimens are strictly adhered to in clinical practice where titrating dose to clinical response is recommended. Methods We report the response to high-dose IVIg (>2 g/kg/6 weeks) in a subgroup of patients with definite CIDP or MMNCB who were unresponsive to ‘usual’ dosing. IVIg frequency and dosing was determined for each individual by subjective and objective outcome measures for impairment, grip strength, and activity and participation. Results Six patients (three with chronic inflammatory demyelinating polyneuropathy (CIDP), three with MMN) were included. Two patients (one CIDP and one MMNCB) returned to full-time work on fractionated IVIg doses of 5 g/kg/month and 9 g/kg/month. Patient three (CIDP) failed numerous other immunosuppressants but responded to short-term fractionated 4 g/kg/month of IVIg. Patient four has severe, refractory, childhood-onset CIDP, remains stable but dependent currently on 6.9 g/kg/month of IVIg. Patients five and six, both with MMNCB, required short term 4.5–5 g/kg/month to recover significant bilateral hand strength. No IVIg-related adverse events occurred in any individual. Conclusions These six cases demonstrate the safety and effectiveness of a treatment approach that includes individualised but evidence-based clinical assessment and, when necessary, high-doses of IVIg to restore patients’ strength and ability to participate in activities of daily activities. Careful patient selection is important

A pragmatic randomised controlled trial of hydrotherapy and land exercises on overall well being and quality of life in rheumatoid arthritis

Background \ud Hydrotherapy is highly valued by people with rheumatoid arthritis yet few studies have compared the benefits of exercises in heated water against exercises on land. In particular, data on quality of life is rarely reported. This is especially important because patients treated with hydrotherapy often report an enhanced sense of well-being. We report a randomised controlled trial in which we compared the effects of hydrotherapy with exercises on land on overall response to treatment, physical function and quality of life in patients with rheumatoid arthritis. \ud \ud Methods \ud One hundred and fifteen patients with RA were randomised to receive a weekly 30-minute session of hydrotherapy or similar exercises on land for 6 weeks. Our primary outcome was a self-rated global impression of change – a measure of treatment effect on a 7-point scale ranging from 1(very much worse) to 7 (very much better) assessed immediately on completion of treatment. Secondary outcomes including EuroQol health related quality of life, EuroQol health status valuation, HAQ, 10 metre walk time and pain scores were collected at baseline, after treatment and 3 months later. Binary outcomes were analysed by Fisher's exact test and continuous variables by Wilcoxon or Mann-Whitney tests. \ud \ud Results \ud Baseline characteristics of the two groups were comparable. Significantly more patients treated with hydrotherapy (40/46, 87%) were much better or very much better than the patients treated with land exercise (19/40, 47.5%), p < 0.001 Fisher's exact test. Eleven patients allocated land exercise failed to complete treatment compared with 4 patients allocated hydrotherapy (p = 0.09). Sensitivity analyses confirmed an advantage for hydrotherapy if we assumed non-completers would all not have responded (response rates 70% versus 38%; p < 0.001) or if we assumed that non-completers would have had the same response as completers (response rates 82% versus 55% p = 0.002). Ten metre walk time improved after treatment in both cases (median pre-treatment time for both groups combined 10.9 seconds, post-treatment 9.1 s, and 3 months later 9.6 s). There was however no difference between treatment groups. Similarly there were no significant differences between groups in terms of changes to HAQ, EQ-5D utility score, EQ VAS and pain VAS. \ud \ud Conclusion \ud Patients with RA treated with hydrotherapy are more likely to report feeling much better or very much better than those treated with land exercises immediately on completion of the treatment programme. This perceived benefit was not reflected by differences between groups in 10-metre walk times, functional scores, quality of life measures and pain scores

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-β-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways

Design and methods of a longitudinal study investigating the impact of antiretroviral treatment on the partnerships and sexual behaviour of HIV-infected individuals in rural KwaZulu-Natal, South Africa

BACKGROUND: Diagnosed HIV-infected people form an increasingly large sub-population in South Africa, one that will continue to grow with widely promoted HIV testing and greater availability of antiretroviral therapy (ART). For HIV prevention and support, understanding the impact of long-term ART on family and sexual relationships is a health research priority. This includes improving the availability of longitudinal demographic and health data on HIV-infected individuals who have accessed ART services but who are not yet ART-eligible.DESIGN AND METHODS: The aim of the study is to investigate the impact of ART on family and partner relationships, and sexual behaviour of HIV-infected individuals accessing a public HIV treatment and care programme in rural South Africa. HIV-infected men and women aged 18 years or older attending three clinics are screened. Those people initiating ART because they meet the criteria of WHO stage 4 or CD4 ? 200 cells/?L are assigned to an 'ART initiator' group. A 'Monitoring' group is composed of people whose most recent CD4 count was &gt;500 cells/?L and are therefore, not yet eligible for ART. During the four-year study, data on both groups is collected every 6 months during clinic visits, or where necessary by home visits or phone. Detailed information is collected on social, demographic and health characteristics including living arrangements, past and current partnerships, sexual behaviour, HIV testing and disclosure, stigma, self-efficacy, quality of family and partner relationships, fertility and fertility intentions, ART knowledge and attitudes, and gender norms. Recruitment for both groups started in January 2009. As of October 2010, 600 participants have been enrolled; 386 in the ART initiator group (141, 37% male) and 214 in the Monitoring group (31, 14% male). Recruitment remains open for the Monitoring group.DISCUSSION: The data collected in this study will provide valuable information for measuring the impact of ART on sexual behaviour, and for the planning and delivery of appropriate interventions to promote family and partner support, and safe sexual behaviour for people living with HIV in this setting and elsewhere in sub-Saharan Africa

The differential hormonal milieu of morning versus evening, may have an impact on muscle hypertrophic potential

Substantial gains in muscle strength and hypertrophy are clearly associated with the routine performance of resistance training. What is less evident is the optimal timing of the resistance training stimulus to elicit these significant functional and structural skeletal muscle changes. Therefore, this investigation determined the impact of a single bout of resistance training performed either in the morning or evening upon acute anabolic signalling (insulin-like growth factor-binding protein-3 (IGFBP-3), myogenic index and differentiation) and catabolic processes (cortisol). Twenty-four male participants (age 21.4±1.9yrs, mass 83.7±13.7kg) with no sustained resistance training experience were allocated to a resistance exercise group (REP). Sixteen of the 24 participants were randomly selected to perform an additional non-exercising control group (CP) protocol. REP performed two bouts of resistance exercise (80% 1RM) in the morning (AM: 0800 hrs) and evening (PM: 1800 hrs), with the sessions separated by a minimum of 72 hours. Venous blood was collected immediately prior to, and 5 min after, each resistance exercise and control sessions. Serum cortisol and IGFBP-3 levels, myogenic index, myotube width, were determined at each sampling period. All data are reported as mean ± SEM, statistical significance was set at P≤0.05. As expected a significant reduction in evening cortisol concentration was observed at pre (AM: 98.4±10.5, PM: 49.8±4.4 ng/ml, P0.05). Timing of resistance training regimen in the evening appears to augment some markers of hypertrophic potential, with elevated IGFBP-3, suppressed cortisol and a superior cellular environment. Further investigation, to further elucidate the time course of peak anabolic signalling in morning vs evening training conditions, are timely

Norwegian Physicians' Knowledge of and Opinions about Evidence-Based Medicine: Cross-Sectional Study

Objective: To answer five research questions: Do Norwegian physicians know about the three important aspects of EBM? Do they use EBM methods in their clinical practice? What are their attitudes towards EBM? Has EBM in their opinion changed medical practice during the last 10 years? Do they use EBM based information sources? Design: Cross sectional survey in 2006. Setting: Norway. Participants: 966 doctors who responded to a questionnaire (70% response rate). Results: In total 87% of the physicians mentioned the use of randomised clinical trials as a key aspect of EBM, while 53% of them mentioned use of clinical expertise and only 19% patients' values. 40% of the respondents reported that their practice had always been evidence-based. Many respondents experienced difficulties in using EBM principles in their clinical practice because of lack of time and difficulties in searching EBM based literature. 80% agreed that EBM helps physicians towards better practice and 52% that it improves patients' health. As reasons for changes in medical practice 86% of respondents mentioned medical progress, but only 39% EBM. Conclusions: The results of the study indicate that Norwegian physicians have a limited knowledge of the key aspects of EBM but a positive attitude towards the concept. They had limited experience in the practice of EBM and were rather indifferent to the impact of EBM on medical practice. For solving a patient problem, physicians would rather consult a colleague than searching evidence based resources such as the Cochrane Library

Foot posture in people with medial compartment knee osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Foot posture has long been considered to contribute to the development of lower limb musculoskeletal conditions as it may alter the mechanical alignment and dynamic function of the lower limb. This study compared foot posture in people with and without medial compartment knee osteoarthritis (OA) using a range of clinical foot measures. The reliability of the foot measures was also assessed.</p> <p>Methods</p> <p>The foot posture of 32 patients with clinically and radiographically-confirmed OA predominantly in the medial compartment of the knee and 28 asymptomatic age-matched healthy controls was investigated using the foot posture index (FPI), vertical navicular height and drop, and the arch index. Independent t tests and effect size (Cohen's d) were used to investigate the differences between the groups in the foot posture measurements.</p> <p>Results</p> <p>Significant differences were found between the control and the knee OA groups in relation to the FPI (1.35 ± 1.43 vs. 2.46 ± 2.18, p = 0.02; <it>d </it>= 0.61, medium effect size), navicular drop (0.02 ± 0.01 vs. 0.03 ± 0.01, p = 0.01; <it>d </it>= 1.02, large effect size) and the arch index (0.22 ± 0.04 vs. 0.26 ± 0.04, p = 0.04; <it>d </it>= 1.02, large effect size). No significant difference was found for vertical navicular height (0.24 ± 0.03 vs. 0.23 ± 0.03, p = 0.54; <it>d </it>= 0.04, negligible effect size).</p> <p>Conclusion</p> <p>People with medial compartment knee OA exhibit a more pronated foot type compared to controls. It is therefore recommended that the assessment of patients with knee OA in clinical practice should include simple foot measures, and that the potential influence of foot structure and function on the efficacy of foot orthoses in the management of medial compartment knee OA be further investigated.</p