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Purpose: Incidence of status epilepticus (SE) ranges from 6.8 to 41.0 per 100,000 population. Although SE is associated with significant morbidity and mortality, the temporal relationship between SE, epilepsy, and mortality is less clear. The risk of all-cause mortality following SE with and without prior epilepsy was investigated., Method: This study identified hospitalizations and emergency department visits for persons with SE and persons with epilepsy between 2000 and 2013. Excluded were those with epilepsy subsequent to SE, epilepsia partialis continua, less than 90days follow-up, and less than 2 years of data prior to first diagnosis. The cohort was grouped into: 1) SE only, 2) post-epilepsy SE (PES), and 3) epilepsy only. The risk of mortality was estimated using Cox proportional hazard models adjusting for potential confounders., Results: The cohort (N=82,331) consisted of 1296 SE only cases (1.6%); 2136 PES cases (2.6%); and 78,899 epilepsy only controls (95.8%) with 24.9%, 29.2% and 20.0% mortality, respectively. Compared with controls, the hazard of mortality was increased for those with SE only (hazard ratio [HR]=1.61, 95% CI=1.41-1.82) and PES (HR=1.16, 95% CI=1.07-1.25) after adjustment for demographic and clinical factors. Prior stroke, central nervous system infection, and brain tumor increased the mortality hazard., Conclusion: There is a statistically significant increased risk of all-cause mortality with SE. The risk is stronger in those with no prior epilepsy. Specific etiologies increase mortality risk in those with SE warranting further investigation of the complex associations between these etiologies and SE., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Few studies of sport-related traumatic brain injury (TBI) are population-based or rely on directly observed data on cause, demographic characteristics, and severity. This study addresses the epidemiology of sport-related TBI in a large population., Methods: Data on all South Carolina hospital and emergency department encounters for TBI, 1998-2011, were analyzed. Annual incidence rate of sport-related TBI was calculated, and rates were compared across demographic groups. Sport-related TBI severity was modeled as a function of demographic and TBI characteristics using logistic regression., Results: A total of 16,642 individuals with sport-related TBI yielded an average annual incidence rate of 31.5/100,000 population with a steady increase from 19.7 in 1998 to 45.6 in 2011. The most common mechanisms of sport-related TBI were kicked in football (38.1%), followed by fall injuries in sports (20.3%). Incidence rate was greatest in adolescents ages 12-18 (120.6/100,000/persons). Severe sport-related TBI was strongly associated with off-road vehicular sport (odds ratio [OR], 4.73; 95% confidence interval [95% CI], 2.92-7.67); repeated head trauma (OR, 4.36; 95% CI, 3.69-5.15); equestrian sport (OR, 2.73; 95% CI, 1.64-4.51); and falls during sport activities (OR, 2.72; 95% CI, 1.67-4.46)., Conclusions: The high incidence of sport-related TBI in youth, potential for repetitive mild TBI, and its long-term consequences on learning warrants coordinated surveillance activities and population-based outcome studies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Increased cardiovascular risk has been associated with high levels of serum antibodies to citrullinated proteins (ACPA) in patients with rheumatoid arthritis (RA). Citrullination is part of many chronic inflammatory processes and we therefore investigated whether ACPA might be associated with coronary artery disease, in the absence of RA., Methods: To maximize the potential predictive value of this retrospective study we included sera from a cohort of 3052 healthy male individuals, subsequently followed for the development of coronary artery disease, and documented for other disease risk factors. With each case event (myocardial infarction; n = 144), 2 matched controls were assigned., Results: We found 10.4% of cases were ACPA positive compared to 3.8% of controls (odds ratio (95% CI) = 3.26 (1.36-7.80), p = 0.008), remaining significant after adjustment for classical risk factors including smoking and CRP (4.23 (1.22-14.61) p = 0.02)., Conclusion: The genesis and fine specificity of ACPA in patients with atherosclerosis, in the absence of Rheumatoid arthritis, may prove worthy of further investigation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Cutaneous wound healing is a complex process involving blood clotting, inflammation, migration of keratinocytes, angiogenesis, and, ultimately, tissue remodeling and wound closure. Many of these processes involve transforming growth factor-β (TGF-β) signaling, and mice lacking components of the TGF-β signaling pathway are defective in wound healing. We show herein that CLIC4, an integral component of the TGF-β pathway, is highly up-regulated in skin wounds. We genetically deleted murine CLIC4 and generated a colony on a C57Bl/6 background. CLIC4(NULL) mice were viable and fertile but had smaller litters than did wild-type mice. After 6 months of age, up to 40% of null mice developed spontaneous skin erosions. Reepithelialization of induced full-thickness skin wounds and superficial corneal wounds was delayed in CLIC4(NULL) mice, resolution of inflammation was delayed, and expression of β4 integrin and p21 was reduced in lysates of constitutive and wounded CLIC4(NULL) skin. The induced level of phosphorylated Smad2 in response to TGF-β was reduced in cultured CLIC4(NULL) keratinocytes relative to in wild-type cells, and CLIC4(NULL) keratinocytes migrated slower than did wild-type keratinocytes and did not increase migration in response to TGF-β. CLIC4(NULL) keratinocytes were also less adherent on plates coated with matrix secreted by wild-type keratinocytes. These results indicate that CLIC4 participates in skin healing and corneal wound reepithelialization through enhancement of epithelial migration by a mechanism that may involve a compromised TGF-β pathway., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Chloride intracellular channel (CLIC) proteins are proposed to have numerous functions, including chloride channel activity, regulation of gene expression, and serving as a component of the cytoskeleton. Pierchala et al. have identified CLIC5A in podocytes, where it is complexed with ezrin, podocalyxin, and the actin cytoskeleton. Absence of CLIC5A results in altered podocyte morphology and proteinuria. Exactly how CLIC5A supports podocyte function is unclear. Potential mechanisms in which cytoskeletal interactions could regulate other functions of CLIC5A are discussed.

Epidemiologic data on convulsive status epilepticus (CSE) is needed to develop preventative strategies. Epilepsy is one of the known risk factors for CSE. A systematic review of epidemiologic studies on status epilepticus (SE) completed in the United States and Europe reports that people with epilepsy account for less than 50% of cases of SE in all age groups. Less is known about the epidemiology of SE in developing countries including those in Central America. A high incidence of epilepsy, widespread non-adherence to anti-epileptic drugs (AED), and common use of complementary and alternative medicines have been shown in all ages in the developing country of Honduras, Central America. In 2003, an epidemiologic study of CSE in Honduran children demonstrated it is common and exhibits a long duration until onset of treatment. The etiologies, treatment, and outcomes of CSE in Honduran adults have not been thoroughly studied. This study is a consecutive case series of 31 adult patients presenting with CSE to the adult medicine emergency department of the tertiary care "Hospital Escuela" in the capital city Tegucigalpa, Honduras. The majority (77.4%) of patients had a prior history of epilepsy. Non-adherence to AED was the most common etiology of CSE (75.0%). The mortality rate in this pilot CSE study was 14.8%, which is similar to studies from industrialized countries where mortality from status epilepticus ranged from 7.6 to 22% for all age groups. However, this rate is concerning given that CSE from epilepsy and AED non-adherence generally carries a good prognosis. Improving AED adherence in this population appears to be the most effective approach in decreasing the rate, and possibly the mortality of Honduran adult CSE., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Endothelial cells form capillary tubes through the process of intracellular tubulogenesis. Chloride intracellular channel (CLIC) family proteins have been previously implicated in intracellular tubulogenesis, but their specific role has not been defined. In this study, we show that disruption of the Clic4 gene in mice results in defective angiogenesis in vivo as reflected in a Matrigel plug angiogenesis assay. An angiogenesis defect is also apparent in the retina, both in the decreased spontaneous development of retinal vasculature of unstressed mice and in the dramatically decreased angiogenic response of retinal vessels to an oxygen toxicity challenge. We found that endothelial cells derived from Clic4(-/-) mice demonstrated impaired tubulogenesis in three-dimensional fibrin gels compared with cells derived from wild-type mice. Furthermore, we found that tubulogenesis of wild-type cells in culture was inhibited by both an inhibitor of CLICs and an inhibitor of the vacuolar proton ATPase. Finally, we showed that vacuoles along the endothelial tubulogenesis pathway are acidic in wild-type cells, and that vacuolar acidification is impaired in Clic4(-/-) cells while lysosomal acidification is intact. We conclude that CLIC4 plays a critical role in angiogenesis by supporting acidification of vacuoles along the cell-hollowing tubulogenic pathway.

Background: There is growing recognition that the health care delivery system in the United States must make major changes. Intervention projects focusing on quality and patient safety offer the potential for reshaping the future of medicine. Sustainability of the Partnerships for Quality (PFQ) projects and other patient safety and quality improvement projects that provide evidence of effectiveness is essential if progress is to be made., Methods: For the purposes of these projects, a conceptual framework and a checklist for sustainability were developed. The framework consists of two dimensions: (1) the goals--what is to be sustained--and (2) elements for sustainability--infrastructure, incentives, incremental opportunities for involvement, and integration. The checklist is designed to trigger planning for sustainability early in a project's design. Specific questions about each of the elements can cue planners and project leaders to build in the goals for sustainability and change processes., Results: A pilot test showed that the framework and checklist are relevant and helpful across a variety of projects., Discussion and Conclusion: Two extended examples of planning and action for sustainability from the PFQ projects are described. It is too early to claim sustainability for these project. However, continued monitoring for at least three years with the checklist could result in valuable national data with which to design and implement future projects.

Background: Translating research into practice and policy is a complex process that links the research enterprise and health care delivery system of the United States. The Agency for Healthcare Research and Quality (AHRQ) Partnerships for Quality (PFQ) initiative expanded the scope of research translation beyond clinical practice, highlighting the role of strategic partners. A work group of AHRQ grantees developed a framework for systematic evaluation of the impact of strategic partnerships on research translation., Methods: The evaluation framework posits a hierarchy of impacts that cumulatively lead to observable patient outcomes. The evaluation framework captures (1) health care outcomes improvement, (2) clinical practice changes, (3) policies, procedures, and protocols, and (4) research and knowledge. After the framework and tool were subjected to face-validity critique among PFQ investigators, the concept of synergy was added. PFQ investigators pilot-tested the evaluation framework, and the PFQ tool was refined further., Results: Early feedback from PFQ grantees suggested that the framework is generalizable and potentially useful to guide investigators in capturing impacts of their work that might otherwise go unrecognized or trivialized., Discussion: The PFQ Evaluation Tool, a pragmatic approach for evaluating the impact of partnership-driven translation projects, provides a comprehensive evaluation of impacts, including synergistic outcomes.

B cell depletion therapy was introduced for auto-antibody associated rheumatic disease in 1998. Encouraging pilot studies in rheumatoid arthritis were followed by randomised controlled trials confirming major benefit. Licensing for use in patients unable to benefit from tumour necrosis factor alpha (TNFalpha) neutralising agents is envisaged shortly. Open studies in other disorders, in particular systemic lupus erythematosus (SLE), have also suggested benefit and its use in life-threatening situations is becoming widespread. Toxicity appears to compare favourably with other agents, but respiratory problems may be more common. Repeated therapy is effective, but may lead to hypogammaglobulinemia. Rituximab is currently the main agent used but other agents are in development. Optimal protocols are not well characterised and will probably be different for different conditions.

B lymphocyte depletion therapy in rheumatoid arthritis can provide major clinical benefits. Widespread use in the future will depend on continued evidence of safety, particularly in the context of long term use. Rituximab is a highly effective agent, but it may be best used in combination with other agents. Substantial improvement following a single course of therapy has been found to last up to 42 months, and it is reasonable to hope that further development of strategies targeting B cells will extend this toward the original aim of truly long-term remission.

Conversion of fibroblasts into myofibroblasts as mediated by transforming growth factor-beta1 (TGF-beta1) is the most prominent stromal reaction to a number of epithelial lesions including breast cancer. To identify genes which are regulated during this process, the mRNA profiles from primary breast fibroblasts treated with or without TGF-beta1 were analyzed by differential display. Ninety-five differentially expressed transcripts were PCR-cloned and sequenced, and 28 clones were selected for verification in a hybridization array. By use of gene-specific sequence tags, nine differentially expressed genes were identified. One of the clones, identified as CLIC4, a member of the CLIC family of chloride channels, was up-regulated more than 16 times in myofibroblasts and was therefore chosen for further analysis. Using RT-PCR, comparison with CLIC1, CLIC2, CLIC3, and CLIC5 demonstrated that CLIC4 was unique by being up-regulated by TGF-beta1 in myofibroblasts. Immunohistochemistry showed a hitherto unknown, distinctive pattern of CLIC4 expression in breast stroma. Whereas normal breast fibroblasts were devoid of CLIC4 protein expression, myofibroblasts of breast carcinomas were strongly CLIC4-positive. The functional significance of CLIC4 was analyzed in MEF/3T3 fibroblasts by conditional expression using the tetracycline-repressive gene regulation system. In a migration assay, we found that CLIC4 inhibited cell motility by 27%. These results suggest that CLIC4 is differentially regulated in fibroblasts and that its expression contributes to a collective stationary myofibroblast phenotype.

We have previously employed scanning force microscopy (SFM) to study antibody-antigen molecular interactions on microtiter wells used for enzyme linked immunosorbant assays (ELISA). Here we demonstrate the ability of SFM to image and discriminate different types of antibody and antibody fragments bound to an ELISA well surface. The samples studied include a type IgG antibody with a proportion of bound IgM and two-dimensional films of whole IgG antibody, and Fab' and F(ab)2 antibody fragments. Molecular resolution is achieved in each case despite the size of substrate features exceeding most of the molecular dimensions observed. Analysis of the data shows that the SFM overestimates molecular dimensions by an approximately constant amount, which is proposed to principally result from the effects of a finite probe size and not from deformation of the molecular species due to the imaging forces employed.

A range of partial denaturation antibody pre-treatments that affect immunoassay performance have been evaluated. Monoclonal anti-ferritin antibody was either partially denatured by heat, urea or pH pre-treatment or left untreated and then passively adsorbed to polystyrene microtiter wells. The adsorption characteristics and functionality of the different surfaces produced have been evaluated by dynamic contact angle (DCA) analysis and scanning tunnelling microscopy (STM) imaging respectively. The DCA data show that the effect of partial denaturation is to change the wetting characteristics of the antibody surfaces, while, in addition, STM imaging reveals marked effects seen in the aggregation properties of the denatured antibodies.

An accurate diagnosis of an isolated PCL injury may be difficult, especially in the acute setting. A detailed history emphasizing the mechanism of injury is crucial as is a careful, complete examination of the knee. Plain and stress radiographs may be helpful in establishing the diagnosis; however, MR imaging is currently the most sensitive ancillary study available to evaluate the integrity of the posterior cruciate ligament. Failure to recognize and treat appropriately an isolated PCL disruption may result in the development of symptomatic irreversible articular surface injury.

An antiferritin antibody was either, (a) passively adsorbed to microwells or (b) biotinylated and immobilised to streptavidin coated microwells. Scanning tunnelling microscope (STM) imaging of these well surfaces coated with a platinum (95%) carbon (5%) coating (Pt/C) conductive layer showed a randomly oriented array of antibodies for passive adsorption whereas for biotin-streptavidin immobilisation there was a more uniform and even distribution of antibodies on the well surface. On further incubation with ferritin STM imaging showed that for passive adsorption approximately 5% of the surface was functional, while for the biotinylated antibody it was greater than 60%. The images presented in this paper show graphically the loss of functionality that occurs using passive adsorption and, conversely, the preservation of antibody functionality using the biotin-streptavidin linkage for antibody immobilisation. These results correlate well with the work of others in the field.

The role of leukocytes in tissue damage in the liposclerotic skin of venous disease has been investigated. Twenty-eight skin biopsy specimens were obtained from 23 patients with varicose veins of the lower limb, with a spectrum of skin injury ranging from normal to severe liposclerosis. In no patient was a venous ulcer present. Immunohistochemistry was used to determine the cell types present and provide an indication of their activity. The predominant infiltrating cell types present were T lymphocytes and macrophages. B cells and neutrophils were rarely seen. As described previously, the capillaries were greatly increased in number in the papillary dermis and exhibited grossly increased expression of factor VIII-related antigen and major histocompatibility complex class II. Surprisingly, expression of adhesion molecules endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule were not elevated, but intercellular adhesion molecule-1 expression did increase in more severely diseased skin. Perivascular fibrin was seen occasionally, but there was no evidence of microvascular occlusion. Staining for the cytokine tumor necrosis factor-alpha was not increased in liposclerotic skin. Dermal staining for both interleukin (IL)-1 alpha and IL-1 beta was increased in severely liposclerotic skin, but this was not seen at an early stage. Epidermal staining for IL-1 alpha and IL-1 beta was not increased. All changes were confined to the subpapillary region of the skin. These findings demonstrate that accumulation of macrophages and T cells is an event associated with the development of liposclerotic skin changes that may lead to ulceration in venous disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The unsaturated fatty acyl residues of egg yolk lecithin are selectively removed when bilayer dispersions of the lipid are exposed to decomposing peroxychromate at pH 7.6 or pH 9.0. Mannitol (50 mM or 100 mM)partially prevents the oxidation of the phospholipid due to decomposing peroxychromate at pH 7.6 and the amount of lipid lost is inversely proportional to the concentration of mannitol. N,N-Dimethyl-p-nitrosoaniline, mixed with the lipid in a molar ratio of 1.3:1, completely prevents the oxidation of lipid due to decomposing peroxychromate at pH 9.0, but some linoleic acid is lost if the incubation is done at pH 7.6. If the concentration of this quench reagent is reduced tenfold, oxidation of linoleic acid by decomposing peroxychromate at pH 9.0 is observed. Hydrogen peroxide is capable of oxidizing the unsaturated fatty acids of lecithin dispersions. Catalase or boiled catalase (2 mg/ml) protects the lipid from oxidation due to decomposing peroxychromate at pH 7.6 to approximately the same extent, but their protective effect is believed to be due to the non-specific removal of .OH. It is concluded that .OH is the species responsible for the lipid oxidation caused by decomposing peroxychromate. This is consistent with the observed bleaching of N,N-dimethyl-p-nitrosoanaline and the formation of a characteristic paramagnetic .OH adduct of the spin trap, 5,5-dimethylpyrroline-1-oxide.

Type A synovial lining cells resemble macrophages in their ultrastructure. Type B lining cells, in contrast, resemble tissue fixed synthetic cells such as fibroblasts. Although cells with intermediate features are well recognised, recent evidence suggests that types A and B cells have different origins. Experiments on mouse radiation chimeras suggest a bone marrow derivation for the type A cells, but not for the type B. Esterase activity, surface Ia, and immunoglobulin receptors have been demonstrated in relation to a proportion of lining cells. It seems reasonable at the present time to consider type A lining cells as belonging to the Mononuclear Phagocyte System.

Patients who had received halothane within a periof of one year and who required another anaesthetic were allocated at random to be given halothane or a control anaesthetic, the control being fiben using halothane-free apparatus. There were 76 patients entries in each group. Serum-glutamic-oxaloacetic-transaminase (S.G.O.T.) levels were measured before the anaesthetics and serially postoperatively for two to three weeks. The S.G.O.T. levels in the halothane group were significantly higher than in the controls. High levels were confined to patients who had had less than four previous halothane anaesthetics, increases above normal in the remainder and in the controls being rate. 1 patient in the halothane group had an S.G.O.T. of 440 I.U. per litre and hepatocellular necrosis on liver biopsy. 2 patients in the halothane group whose S.G.O.T.s rose to more than twice normal showed a similar reaction to re-exposure to halothane, although they had not shown a reaction to an intervening control anaesthetic.