Diagnosis and treatment of anti-insulin antibody-mediated labile glycaemia in insulin-treated diabetes.

AIMS: Anti-insulin antibodies in insulin-treated diabetes can derange glycaemia, but are under-recognised. Detection of significant antibodies is complicated by antigenically distinct insulin analogues. We evaluated a pragmatic biochemical approach to identifying actionable antibodies, and assessed its utility in therapeutic decision making. METHODS: Forty people with insulin-treated diabetes and combinations of insulin resistance, nocturnal/matutinal hypoglycaemia, and unexplained ketoacidosis were studied using broad-specificity insulin immunoassays, polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC) with or without ex vivo insulin preincubation. RESULTS: Twenty-seven people had insulin immunoreactivity (IIR) below 3000 pmol/L that fell less than 50% after PEG precipitation. Insulin binding by antibodies in this group was low and judged insignificant. In 8 people IIR was above 3000 pmol/L and fell by more than 50% after PEG precipitation. GFC demonstrated substantial high molecular weight (HMW) IIR in 7 of these 8. In this group antibodies were judged likely significant. In 2 people immunosuppression was introduced, with a good clinical result in one but only a biochemical response in another. In 6 people adjustment of insulin delivery was subsequently informed by knowledge of underlying antibody. In a final group of 5 participants IIR was below 3000 pmol/L but fell by more than 50% after PEG precipitation. In 4 of these GFC demonstrated low levels of HMW IIR and antibody significance was judged indeterminate. CONCLUSIONS: Anti-insulin antibodies should be considered in insulin-treated diabetes with unexplained glycaemic lability. Combining immunoassays with PEG precipitation can stratify their significance. Antibody depletion may be beneficial, but conservative measures often suffice.

Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma.

BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Erdheim-Chester disease: expanding the spectrum of cutaneous manifestations.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare condition and there is limited information available regarding its cutaneous manifestations. OBJECTIVES: To describe the clinical and histopathological features of cutaneous involvement in ECD. METHODS: This study is a single-centre retrospective analysis of patients 18 years old and older with biopsy-proven diagnosis of ECD between 1 January 1990 and 1 April 2017. Patients from this cohort were screened for cutaneous manifestations, and BRAF c.1799T>A (p.V600E) mutational analysis was conducted in novel skin manifestations. Primary outcomes included cutaneous manifestations (morphology and topography of lesions) and BRAF mutation status in novel cutaneous findings. RESULTS: Of 71 patients with ECD, 15 patients (21%; median age 52 years) presented with cutaneous manifestations. The most common finding was the presence of xanthelasma-like lesions (n = 8). Two patients had nonfacial cutaneous xanthomas. Seven patients presented with nonxanthomatous cutaneous involvement, with the most common finding being subcutaneous nodules (n = 5). A single patient presented with granuloma annulare-like lesions. Another patient with mixed ECD and Langerhans cell histiocytosis presented with lightly scaling, pink-red macules. In three patients, the appearance of skin lesions was the first manifestation of the disease. Most patients presented with bone/extremity pain, weight loss and other constitutional symptoms at the time of diagnosis. The BRAF V600E mutation was not found in patients with panniculitis-like and granuloma annulare-like lesions. CONCLUSIONS: The most common presentation in ECD is the presence of periorbital xanthelasma-like lesions. Other presentations include nonfacial cutaneous xanthomas, panniculitis-like lesions and granuloma annulare-like lesions. Associated symptoms at presentation include bone/extremity pain and weight loss. What's already known about this topic? Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis characterized by lipid-laden macrophage infiltration of tissue and subsequent fibrosis. Cutaneous involvement is found in approximately 25% of patients, with the majority presenting with periorbital xanthelasma-like lesions. What does this study add? We report two novel cutaneous findings: panniculitis-like lesions and granuloma annulare-like lesions. Associated bone/extremity pain and weight loss should raise suspicion for Erdheim-Chester disease.

Woodhouse-Sakati syndrome in a family is associated with a homozygous start loss mutation in the DCAF17 gene.

BACKGROUND: Woodhouse-Sakati syndrome (WSS) is a rare neuroendocrine and ectodermal disorder inherited in an autosomal recessive pattern. The syndrome presents prominent clinical features, including alopecia, neuroendocrine defects, neurological findings and progressive hearing loss. The condition results from mutations in the DCAF17 gene. AIMS: To search for the underlying genetic defect in a Pakistani family with WSS phenotypes. METHODOLOGY: Whole exome sequencing was used to search for the disease-causing variant. RESULTS: Analysis of the exome data revealed a start loss sequence variant (c.1A>G, p.M1?) in DCAF17. CONCLUSION: This variant is predicted to abolish translation of the DCAF17 polypeptide. To our knowledge, this is the first start loss variant identified in the DCAF17.

The value of international volunteers experience to the NHS.

BACKGROUND: Global Engagement works with health partnerships to establish workforce and educational translation on a global scale to support the National Health Service (NHS). There is growing evidence on how international experiences (through volunteering, exchanges and placements) benefit the NHS through an innovative workforce that develops international best practice and promotes lifelong learning. Most of this evidence has been captured though surveys to returned international volunteers. However, there is limited evidence about how to quantify the value that returned international healthcare volunteers bring back to their country of residence. METHODS: This paper identifies the various benefits to the NHS from returned international healthcare volunteers. The outcomes from returned international volunteers, which have been identified as relevant form a NHS perspective, are linked to three key areas in a multisector analytical framework used by the World Bank to evaluate labour market programmes: (1) Investment climate and Infrastructure, (2) Labor market regulations and institutions, and (3) Education and skills development. The monetary value of these outcomes is quantified through productivity indices which capture the economic value that the achievement of these outcomes have on the quality of the NHS labor force. This model is applied to a dataset of international volunteers provided by the Global Engagement health partnerships. RESULTS: The results suggest that international volunteering generates average productivity gains of up to 37% for doctors and up to 62% for nurses. Average productivity gains estimated from health partnerships data vary depending on duration of volunteering periods and occupational category mix. CONCLUSIONS: Our analysis offers a value for money rationale for international volunteering programmes purely from a domestic and NHS perspective. The valuation method considers only one of the aims of international volunteering programmes: the development of the existing and future NHS workforce. Broader benefits for health system strengthening at a global level are acknowledged but not accounted for. Overall, we conclude that if the acquisition of volunteering outcomes is realised, the NHS can accrue a productivity increase of between 24 and 41% per volunteer, with a value ranging from £13,215 to £25,934 per volunteer.

Impact of peripheral immune status on central molecular responses to facial nerve axotomy.

When facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2-/-) mice, there is greater facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2-/- mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2-/- mice with lymphocytes from the mutant superoxide dismutase (mSOD1) mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways. Gene expression profiles of the axotomized facial motor nucleus were assessed from RAG-2-/- mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2-/- + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.

Setting the top 10 research priorities to improve the health of people with Type 2 diabetes: a Diabetes UK-James Lind Alliance Priority Setting Partnership.

AIMS: To describe processes and outcomes of a priority setting partnership to identify the 'top 10 research priorities' in Type 2 diabetes, involving people living with the condition, their carers, and healthcare professionals. METHODS: We followed the four-step James Lind Alliance Priority Setting Partnership process which involved: gathering uncertainties using a questionnaire survey distributed to 70 000 people living with Type 2 diabetes and their carers, and healthcare professionals; organizing the uncertainties; interim priority setting by resampling of participants with a second survey; and final priority setting in an independent group of participants, using the nominal group technique. At each step the steering group closely monitored and guided the process. RESULTS: In the first survey, 8227 uncertainties were proposed by 2587 participants, of whom 18% were from black, Asian and minority ethnic groups. Uncertainties were formatted and collated into 114 indicative questions. A total of 1506 people contributed to a second survey, generating a shortlist of 24 questions equally weighted to the contributions of people living with diabetes and their carers and those of healthcare professionals. In the final step the 'top 10 research priorities' were selected, including questions on cure and reversal, risk identification and prevention, and self-management approaches in Type 2 diabetes. CONCLUSION: Systematic and transparent methodology was used to identify research priorities in a large and genuine partnership of people with lived and professional experience of Type 2 diabetes. The top 10 questions represent consensus areas of research priority to guide future research, deliver responsive and strategic allocation of research resources, and improve the future health and well-being of people living with, and at risk of, Type 2 diabetes.

Saliva testing for human papilloma virus in oropharyngeal squamous cell carcinoma: A diagnostic accuracy study.

BACKGROUND: New cases of oropharyngeal squamous cell carcinoma (OPSCC) are routinely tested for HPV. HPV in saliva can be detected with PCR, but its clinical applicability in the context of OPSCC remains unknown. METHODS: Forty-six consecutive patients diagnosed with OPSCC had pre-treatment saliva specimens collected. PCR for HPV on saliva was compared to p16 IHC and HPV DNA in situ hybridisation (ISH) on surgical biopsies. RESULTS: The sensitivity and specificity of saliva testing when compared to the reference test of p16 IHC and HPV DNA ISH were 72.2% and 90%, and positive and negative predictive values were 96.3% and 47.4%. There were no adverse events. Time from last meal, smoking, alcohol drinking and physical exercise did not impact on results. CONCLUSIONS: Saliva testing is a promising test to detect HPV in patients with OPSCC. A positive result could avoid the need for surgical biopsies, thereby reducing costs, patient morbidity and expedite treatment.

Safety and collection efficiency with a lower transfusion threshold for extracorporeal photopheresis in adult patients with graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) is an established treatment for graft-versus-host disease (GVHD). Various haematocrit thresholds have been used to trigger red blood cells transfusion prior to ECP. Moderate-to-severe GVHD is frequently complicated by anaemia; the safety and collection efficiency with a lower haematocrit for ECP is unknown. METHODS: We prospectively enrolled 26 consecutive adult GVHD patients with haematocrits between 25% and 28·9% who received ECP on the CELLEX system. Preprocedural transfusion was withheld. We monitored the adverse events and transfusions avoided. A complete blood cell count with differential was performed on preprocedural peripheral blood and buffy coat collected. Lymphocyte fold enrichment (LFE) was compared between this cohort and two historical control groups with haematocrits of 29% or higher. RESULTS: Red Blood Cells transfusion was avoided in the lower-haematocrit cohort without adverse events. The median LFE was 4·5 (95%CI, 3·1-5·7) in the lower-haematocrit cohort and 5·2 (95%CI, 4·1-6·5) in the higher-haematocrit CELLEX-treated control group. The median difference was 0·7 (95%CI, -0·3 to 2·0, P = 0·14). It could not be established that the lower-haematocrit cohort was non-inferior to the higher-haematocrit control group with a prespecified non-inferiority margin of 1·3. However, LFE was significantly higher in the lower-haematocrit cohort than the higher-haematocrit UVAR XTS-treated control group (P < 0·01). CONCLUSION: Buffy coat can be collected for ECP using CELLEX in GVHD patients with a haematocrit of 25% or higher, with a collection efficiency superior to that in patients with higher haematocrits but treated using UVAR XTS. No increase in adverse events was observed at these lower haematocrits.

The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE).

BACKGROUND: Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: Evaluate efficacy and safety of apremilast vs. placebo in biologic-naive patients with moderate-to-severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo-controlled study (NCT01690299). METHODS: Two hundred and fifty patients were randomized to placebo (n = 84), apremilast 30 mg BID (n = 83) or etanercept 50 mg QW (n = 83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104. The primary efficacy endpoint was achievement of PASI-75 at Week 16 with apremilast vs. placebo. Secondary endpoints included achievement of PASI-75 at Week 16 with etanercept vs. placebo and improvements in other clinical endpoints vs. placebo at Week 16. Outcomes were assessed through Week 52. This study was not designed for apremilast vs. etanercept comparisons. RESULTS: At Week 16, PASI-75 achievement was greater with apremilast (39.8%) vs. placebo (11.9%; P < 0.0001); 48.2% of patients achieved PASI-75 with etanercept (P < 0.0001 vs. placebo). PASI-75 response was maintained in 47.3% (apremilast/apremilast), 49.4% (etanercept/apremilast) and 47.9% (placebo/apremilast) of patients at Week 52. Most common adverse events (≥5%) with apremilast, including nausea, diarrhoea, upper respiratory tract infection, nasopharyngitis, tension headache and headache, were mild or moderate in severity; diarrhoea and nausea generally resolved in the first month. No new safety or tolerability issues were observed through Week 52 with apremilast. CONCLUSION: Apremilast demonstrated significant efficacy vs. placebo at Week 16 in biologic-naive patients with psoriasis, which was sustained over 52 weeks, and demonstrated safety consistent with the known safety profile of apremilast. Switching from etanercept to apremilast did not result in any new or clinically significant safety findings, and efficacy was maintained with apremilast through Week 52.

A systematic review and network meta-analysis of post-imatinib therapy in advanced gastrointestinal stromal tumour.

BACKGROUND: The standard first-line systemic therapy for advanced gastrointestinal stromal tumour (gist) is imatinib. However, most gists develop imatinib resistance, highlighting the need for new agents in the imatinib-refractory setting. Currently, no randomized studies have directly compared the available post-first-line treatments. METHODS: In a systematic review, the medline, embase, and central databases, and American Society of Clinical Oncology abstracts to July 2014 were searched to identify randomized controlled trials that included gist patients treated with post-first-line therapies. Hazard ratios (hrs) for progression-free (pfs) and overall survival (os) were extracted. Direct pairwise meta-analyses and indirect comparisons using the Butcher method were performed. RESULTS: Four studies were identified for the systematic review. One study showed that sunitinib in the second-line setting (vs. placebo) was associated with improved pfs, but not improved os. Three studies examined the third-line setting (imatinib resumption vs. placebo, regorafenib vs. placebo, nilotinib vs. best supportive care). In the third-line settings, the two placebo-controlled and the non-placebo-controlled trials showed significant heterogeneity (I2 = 98%). Indirect comparisons of imatinib resumption and regorafenib suggested that the hr for pfs was 0.59 (95% confidence interval: 0.31 to 1.12; p = 0.10), trending in favour of regorafenib. Indirect comparisons found that toxicities were higher in the regorafenib group, with a risk difference of 27.8% for any-grade toxicities and 19.5% for grades 3 and 4 toxicities. CONCLUSIONS: Because a head-to-head study of imatinib resumption compared with regorafenib is unlikely ever to be conducted, our study suggests that, in terms of pfs, regorafenib might be the preferred treatment. However, given the increased toxicity observed with regorafenib, clinicians should interpret that evidence with caution at an individual patient level.

Exome sequencing revealed a novel biallelic deletion in the DCAF17 gene underlying Woodhouse Sakati syndrome.

Woodhouse Sakati syndrome (WSS, MIM 241080) is a rare autosomal recessive genetic condition characterized by alopecia, hypogonadism, hearing impairment, diabetes mellitus, learning disabilities and extrapydamidal manifestations. Sequence variants in the gene DCAF17, encoding nucleolar substrate receptor, were identified as the underlying cause of inherited WSS. Considerable phenotypic heterogeneity exists in WSS with regard to severity, organs involvement and age of onset, both in inter-familial and intra-familial cases. In this study, the genetic characterization of a consanguineous pedigree showing mild features of WSS was performed, followed by structural analysis of truncated protein. Exome sequencing identified a novel single base deletion variant (c.270delA; K90Nfs8*) in third exon of the gene DCAF17 (RefSeq; NM_025000), resulting in a truncated protein. Structural analysis of truncated DCAF17 revealed absence of amino acid residues crucial for interaction with DDB1. Taken together, the data confirmed the single base pair deletion as the underlying cause of this second report of WSS from Pakistan. This signifies the vital yet unexplored role of DCAF17 both in development and maintenance of adult tissues homeostasis.

A novel homozygous mutation disrupting the initiation codon in the SLURP1 gene underlies mal de Meleda in a consanguineous family.

Mal de Meleda (MDM) is a palmoplantar keratoderma (PPK), characterized by hyperkeratosis of the palms and soles, and keratotic skin lesions. Patients with MDM can develop perioral erythema, keratotic and lichenoid plaques over the joints (including the elbows and knees), nail abnormalities, joint contractures and stiffness, brachydactyly, sclerodactyly, pseudoainhum, and malodorous maceration. MDM is associated with mutations in the SLURP1 gene. We report a consanguineous family in which MDM was inherited in an autosomal recessive manner. Genotyping using microsatellite markers established linkage in the family to the SLURP1 gene, which has been mapped previously to chromosome 8q24.3. Sequence analysis revealed a homozygous missense mutation (c.2T>C, p.Met1Thr) in affected family members. Molecular docking studies using a ZDOCK server predicted disruption of binding of the mutant variant to its target α7-nAChR. This study further supports the previously reported findings that homozygous mutations in the SLURP1 gene cause MDM.

The effect of prolonged of warm ischaemic injury on renal function in an experimental ex vivo normothermic perfusion system.

BACKGROUND: Donation after circulatory death (DCD) kidney transplants inevitably sustain a degree of warm ischaemic injury, which is manifested clinically as delayed graft function. The aim of this study was to define the effects of prolonged periods of warm ischaemic injury on renal function in a normothermic haemoperfused kidney model. METHODS: Porcine kidneys were subjected to 15, 60, 90 (n = 6 per group) and 120 min (n = 4) of in situ warm ischaemia (WI) and then retrieved, flushed with cold preservation fluid and stored in ice for 2 h. Kidneys then underwent 3 h of normothermic reperfusion with a whole blood-based perfusate using an ex vivo circuit developed from clinical grade cardiopulmonary bypass technology. RESULTS: Creatinine clearance, urine output and fractional excretion of sodium deteriorated sequentially with increasing warm time. Renal function was severely compromised after 90 or 120 min of WI but haemodynamic, metabolic and histological parameters demonstrated the viability of kidneys subjected to prolonged warm ischaemia. CONCLUSIONS: Isolated kidney perfusion using a warm, oxygenated, red cell-based perfusate allows an accurate ex vivo assessment of the potential for recovery from warm ischaemic injury. Prolonged renal warm ischaemic injury caused a severe decrement in renal function but was not associated with tissue necrosis.

Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2).

BACKGROUND: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. OBJECTIVES: ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. METHODS: This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. RESULTS: The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks.

Magnetic resonance diffusion metrics indexing high focal cellularity and sharp transition at the tumour boundary predict poor outcome in glioblastoma multiforme.

AIM: To investigate the prognostic power of intra-tumoural and gradient magnetic resonance imaging (MRI) diffusion metrics in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: Forty-six consecutive patients with histologically confirmed GBM who had undergone preoperative diffusion tensor imaging at 3 T were included. Mean diffusivity (MD) and MD gradient maps were computed. Regions of interest were analysed to determine the minimum MD within the enhancing tumour (minMD). MD gradients were calculated along the enhancing tumour boundary and subjected to histogram analysis. Overall survival (OS) and time to progression (TTP) were derived and survival analysis was undertaken. RESULTS: There were 31 deaths and 37 patients progressed during the study period. Multivariate survival analysis, controlling for treatment and gender, showed that minMD values<6.1×10(-4) mm(2)/s predicted shorter OS (hazard ratio [HR]=2.82, 1.25-6.34; p=0.012) and TTP (HR=5.43, 1.96-15.05; p=0.001). Higher MD gradient values of the tumour boundary predicted shorter survival: MD gradient values >4.7×10(-5) mm(2)/s (10(th) centile) had a significantly shorter OS with a HR of 0.43 (0.19-0.96; p=0.04). Similarly, a value above 1.4×10(-4) mm(2)/s (75(th) centile) was a significant predictor for shorter OS (HR=0.39, 0.17-0.89; p=0.03). CONCLUSIONS: Lower minMD and higher MD gradient values for the 10(th) and 75(th) percentile of the tumour boundary demonstrated prognostic value in preoperative GBM. This suggests that MRI diffusion metrics indicative of higher focal cellularity and steeper transition from high cellular tumour edge to low cellular oedema define more aggressive glioblastoma subtypes with a poorer prognosis.

Weight loss, exercise or both and cardiometabolic risk factors in obese older adults: results of a randomized controlled trial.

BACKGROUND: Obesity exacerbates the age-related decline in insulin sensitivity and is associated with risk for cardiometabolic syndrome in older adults; however, the appropriate treatment for obese older adults is controversial. OBJECTIVE: To determine the independent and combined effects of weight loss and exercise on cardiometabolic risk factors in obese older adults. DESIGN: One-hundred and seven obese (body mass index (BMI)≥30 kg m(-2)) older (≥65 years) adults with physical frailty were randomized to control group, diet group, exercise group and diet-exercise group for 1 year. Outcomes for this study included changes in insulin sensitivity index (ISI), glucose tolerance, central obesity, adipocytokines and cardiometabolic syndrome. RESULTS: Although similar increases in ISI occurred in the diet-exercise and diet groups at 6 months, the ISI improved more in the diet-exercise than in the diet group at 12 months (2.4 vs 1.2; between-group difference, 1.2; 95% confidence interval, 0.2-2.1); no changes in ISI occurred in both exercise and control groups. The diet-exercise and diet groups had similar improvements in insulin area under the curve (AUC) (-2.9 and -2.9 × 10(3) mg min dl(-1)), glucose AUC (-1.4 and -2.2 × 10(3)mg min dl(-1)), visceral fat (-787 and -561 cm(3)), tumor necrosis factor (-17.0 and -12.8 pg ml(-1)), adiponectin (5.0 and 4.0 ng ml(-1)), waist circumference (-8.2 and -8.4 cm), triglyceride (-30.7 and -24.3 g dl(-1)) and systolic/diastolic blood pressure (-15.9 and -13.1/-4.9 and -6.7 mm Hg), while no changes in these parameters occurred in both exercise and control groups. The cardiometabolic syndrome prevalence decreased by 40% in the diet-exercise and by 15% in the diet group. Body weight decreased similarly in the diet-exercise and diet groups (-8.6 and -9.7 kg) but not in the exercise and control groups. CONCLUSIONS: In frail, obese older adults, lifestyle interventions associated with weight loss improve insulin sensitivity and other cardiometabolic risk factors, but continued improvement in insulin sensitivity is only achieved when exercise training is added to weight loss.

Changes in thigh muscle volume predict bone mineral density response to lifestyle therapy in frail, obese older adults.

UNLABELLED: We studied the relationships among strength, muscle mass, and bone mineral density (BMD) with lifestyle change. Lifestyle therapy consisted of exercise, diet, and diet plus exercise. Diet was by caloric restriction to induce and maintain a weight loss of 10 % from baseline body weight. Exercise attenuated weight loss-induced muscle and bone losses. Exercise improved strength despite muscle loss in patients on diet and exercise. Changes in strength did not correlate with changes in BMD. However, changes in thigh muscle volume correlated with, and predicted changes in hip BMD. INTRODUCTION: Losses of hip BMD and lean body mass are major complications of lifestyle therapy in frail, obese older adults; however, the contribution of mechanical strain loss from muscle loss is poorly defined. We determined the effect of changes in thigh muscle volume and muscle strength on BMD in frail, obese older adults undergoing lifestyle therapy aimed at intentional weight loss with or without exercise. METHODS: One hundred seven obese older adults were randomized to control, diet, exercise, and diet-exercise groups for 1 year. Thigh muscle volume was measured by magnetic resonance imaging, BMD by DXA, knee strength by dynamometry, total strength by one-repetition maximum (1-RM), and bone markers by immunoassay. RESULTS: Thigh muscle volume decreased in the diet group (-6.2 ± 4.8 %) and increased in the exercise group (2.7 ± 3.1 %), while it was not significantly different from the control in the diet-exercise group. Changes in hip BMD followed similar pattern as those in thigh muscle volume. Knee extension and flexion increased in the exercise group (23 ± 20 %; 25 ± 19 %) and diet-exercise group (20 ± 19 %; 20.6 ± 27 %) but were unchanged in the control and diet groups. Changes in thigh muscle volume correlated with changes in hip BMD (r = 0.55, P = <0.001) and were an independent predictor of changes in hip BMD (ß = 0.12, P = 0.03) in the multiple regression analyses after accounting for demographic factors and changes in weight and physical activity. There were no correlations between BMD changes and knee strength, 1-RM, and sclerostin changes. CONCLUSIONS: Changes in thigh muscle volume predict hip BMD changes in obese older patients undergoing lifestyle therapy. The effect of exercise in attenuating thigh muscle loss when added to diet may in part account for the reduction in weight loss-induced bone loss in the diet-exercise group.

Protonation favors aggregation of lysozyme with SDS.

Different proteins have different amino acid sequences as well as conformations, and therefore different propensities to aggregate. Electrostatic interactions have an important role in the aggregation of proteins as revealed by our previous report (J. M. Khan et al., PLoS One, 2012, 7, e29694). In this study, we designed and executed experiments to gain knowledge of the role of charge variations on proteins during the events of protein aggregation with lysozyme as a model protein. To impart positive and negative charges to proteins, we incubated lysozyme at different pH values of below and above the pI (∼11). Negatively charged SDS was used to 'antagonize' positive charges on lysozyme. We examined the effects of pH variations on SDS-induced amyloid fibril formation by lysozyme using methods such as far-UV circular dichroism, Rayleigh scattering, turbidity measurements, dye binding assays and dynamic light scattering. We found that sub-micellar concentrations of SDS (0.1 to 0.6 mM) induced amyloid fibril formation by lysozyme in the pH range of 10.0-1.0 and maximum aggregation was observed at pH 1.0. The morphology of aggregates was fibrillar in structure, as visualized by transmission electron microscopy. Isothermal titration calorimetry studies demonstrated that fibril formation is exothermic. To the best of our current understanding of the mechanism of aggregation, this study demonstrates the crucial role of electrostatic interactions during amyloid fibril formation. The model proposed here will help in designing molecules that can prevent or reverse the amyloid fibril formation or the aggregation.

Appendicocalicostomy: A case of mistaken identity.

Anatomical structures with similar appearance may at times be confused for each other. This situation can be compounded by lack of normal anatomical planes. We did ureterocalicostomy on a 32-year-female with secondary pelvi-ureteral junction obstruction. Post-operatively, it was discovered that she had a long appendix running parallel to ureter in retroperitoneum, which was misidentified as ureter and anastomosed to the lower pole of the kidney. She was re-explored, appendix was removed, ureter was identified and ureterocalicostomy was done. Patient is asymptomatic at 1 year follow-up.