Understanding the pathogenesis of complex immunologic disorders such as multiple sclerosis (MS) is challenging. Abnormalities in many different cell types are observed in the immune system and CNS of ...patients with MS and the identification of the primary and secondary events is difficult. Recent studies suggest that the model of MS as a disorder mediated only by T cells is overly simplistic and propose an important role for B cells in the propagation of the disease. B-cell activation in the form of oligoclonal bands (OCB) production is the most consistent immunologic finding in patients with MS. Notably, markers of B-cell activation within the CSF of patients with MS predict conversion from clinically isolated syndrome to clinically definite MS and correlate with MRI activity, onset of relapses, and disability progression. In addition, the main genetic risk factor in MS is associated with OCB production, and environmental agents associated with MS susceptibility (vitamin D and the Epstein-Barr virus) influence B-cell proliferation and function. Finally, the only cell-specific treatments that are effective in patients with MS are monoclonal antibodies targeting the B-cell antigen CD20, suggesting a potentially causative role for B cells. Based on current evidence there is no longer doubt that B cells are relevant to the etiology and pathogenesis of MS. Elucidating the role of B cells in MS will be a fruitful strategy for disease prevention and treatment.
Comprehensive global climate models are the only tools that account for the complex set of processes which will determine future climate change at both a global and regional level. Planners are ...typically faced with a wide range of predicted changes from different models of unknown relative quality, owing to large but unquantified uncertainties in the modelling process. Here we report a systematic attempt to determine the range of climate changes consistent with these uncertainties, based on a 53-member ensemble of model versions constructed by varying model parameters. We estimate a probability density function for the sensitivity of climate to a doubling of atmospheric carbon dioxide levels, and obtain a 5-95 per cent probability range of 2.4-5.4 °C. Our probability density function is constrained by objective estimates of the relative reliability of different model versions, the choice of model parameters that are varied and their uncertainty ranges, specified on the basis of expert advice. Our ensemble produces a range of regional changes much wider than indicated by traditional methods based on scaling the response patterns of an individual simulation.
Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and ...antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage-gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen-onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N-methyl-d-aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell-mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N-methyl-d-aspartate receptors antibody encephalitis is intriguing and requires further study.
Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from ...multiple sclerosis. We describe the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. Our findings support autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. Adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab.
Diabetes is on the rise as the worldwide population ages. While physical activity can help protect against diabetes, ageing is commonly associated with reduced physical activity. This study aimed to ...examine if physical activity differs by diabetes status in mid-aged adults, how this association changes over time, and whether physical activity-related sociodemographic factors and health indicators differ in those with and without diabetes. Data came from four waves of the How Areas in Brisbane Influence HealTh and AcTivity (HABITAT), a longitudinal study of mid-age adults living in Brisbane, Australia. Random effects/Expectation-maximisation (RE-EM) regression trees were used to identify factors affecting physical activity among those with and without diabetes, both separately and combined. At study entry, those with diabetes had a higher median age of 58 years (95% CI: 57–60) and a lower median physical activity of 699 MET.min/week (95% CI: 599–799) than people without diabetes (53 years (95% CI: 53–53) and 849 MET.min/week (95% CI: 799–899)). However, the strongest factors influencing physical activity were BMI and gender, not diabetes status. It is vital to promote physical activity among adults, in particular among those with high BMI and women, as well as those with and at high risk of diseases like diabetes.
Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether ...quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials.
To determine whether computer-derived CT measures, specifically measures of pulmonary vessel-related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations.
Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER Computer-Aided Lung Informatics for Pathology Evaluation and Rating software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria.
In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%.
Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria-the VRS score-that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.
Myelitis and optic neuritis are prototypic clinical presentations of both multiple sclerosis and neuromyelitis optica. Once considered a subtype of multiple sclerosis, neuromyelitis optica, is now ...known to have a discrete pathogenesis in which antibodies to the water channel, aquaporin 4, play a critical role. Timely differentiation of neuromyelitis optica from MS is imperative, determining both prognosis and treatment strategy. Early, aggressive immunosuppression is required to prevent the accrual of severe disability in neuromyelitis optica; conversely, MS-specific therapies may exacerbate the disease. The diagnosis of neuromyelitis optica requires the integration of clinical, MR imaging, and laboratory data, but current criteria are insensitive and exclude patients with limited clinical syndromes. Failure to recognize the expanding spectrum of cerebral MR imaging patterns associated with aquaporin 4 antibody seropositivity adds to diagnostic uncertainty in some patients. We present the state of the art in conventional and nonconventional MR imaging in neuromyelitis optica and review the place of neuroimaging in the diagnosis, management, and research of the condition.
Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of ...immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil®. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case–control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil® vaccine may provide relevant safety data in this population.
Background and Aims:
It has become clear that vein resection and reconstruction for pancreatic ductal adenocarcinoma (PDAC) is the standard of care as supported by multiple guidelines. However, ...resection of large peri-pancreatic arteries remains debatable.
Materials and Methods:
This review examines the current state of vascular resection with curative intent for PDAC in the last 5 years. Herein, we consider venous (superior mesenteric vein, portal vein), as well as arterial (superior mesenteric artery, celiac trunk, hepatic artery) resection or both with or without reconstruction.
Results:
Improvement of multidrug chemotherapy has revolutionized care for PDAC that should shift traditional surgical thinking from an anatomical classification of resectability to a prognostic and biological classification.
Conclusion:
The present review gives an overview on the results of pancreatectomy associated with vascular resection, with consideration of new perspectives offered by the availability of better systemic therapies.
Debris-induced osteolysis due to surface wear of ultra high molecular weight polyethylene (UHMWPE) bearings is a potential long-term failure mechanism of total knee replacements (TKR). This study ...investigated the effect of prosthesis design, kinematics and bearing material on the wear of UHMWPE bearings using a physiological knee simulator. The use of a curved fixed bearing design with stabilised polyethylene bearings reduced wear in comparison to more flat-on-flat components which were sterilised by gamma irradiation in air. Medium levels of crosslinking further improved the wear resistance of fixed bearing TKR due to resistance to strain softening when subjected to multidirectional motion at the femoral–insert articulating interface. Backside motion was shown to be a contributing factor to the overall rate of UHMWPE wear in fixed bearing components. Wear of fixed bearing prostheses was reduced significantly when anterior–posterior displacement and internal–external rotation kinematics were reduced due to decreased cross shear on the articulating surface and a reduction in AP displacement. Rotating platform mobile bearing prostheses exhibited reduced wear rates in comparison to fixed bearing components in these simulator studies due to redistribution of knee motion to two articulating interfaces with more linear motions at each interface. This was observed in two rotating platform designs with different UHMWPE bearing materials. In knee simulator studies, wear of TKR bearings was dependent on kinematics at the articulating surfaces and the prosthesis design, as well as the type of material.
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