Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom.\ud \ud PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed.\ud \ud RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation.\ud \ud CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.\ud \u

The influence of statins on the free intracellular calcium concentration in human umbilical vein endothelial cells

BACKGROUND: Statins are cholesterol-lowering drugs that are widely used to reduce the risk of cardiac infarction. Their beneficial clinical effects, however, are not restricted to their influence on cholesterol production. As several studies have shown that they have a potency of relaxing blood vessels. METHODS: We measured the effects of statins on the intracellular free calcium concentration ([Ca(2+)](i)) in human umbilical vein endothelial cells (HUVEC) after acute application and 24-h-preincubation of statins. RESULTS: Incubation of the cells for 24 h with cerivastatin or fluvastatin significantly increased the resting [Ca(2+)](i). For cerivastatin this effect manifested at a concentration of 1 μM. Increase of resting [Ca(2+)](i )in the presence of cerivastatin also occurred when the nitric oxide synthase was inhibited. Transient Ca(2+ )release induced by histamine was not affected. CONCLUSIONS: The increase of resting [Ca(2+)](i )after incubation with cerivastatin or fluvastatin may provide an explanation for the direct effects of statins on the endothelial-dependent vasodilatation and restoration of endothelial activity in vivo

Continuous Interaction with a Virtual Human

Attentive Speaking and Active Listening require that a Virtual Human be capable of simultaneous perception/interpretation and production of communicative behavior. A Virtual Human should be able to signal its attitude and attention while it is listening to its interaction partner, and be able to attend to its interaction partner while it is speaking – and modify its communicative behavior on-the-fly based on what it perceives from its partner. This report presents the results of a four week summer project that was part of eNTERFACE’10. The project resulted in progress on several aspects of continuous interaction such as scheduling and interrupting multimodal behavior, automatic classification of listener responses, generation of response eliciting behavior, and models for appropriate reactions to listener responses. A pilot user study was conducted with ten participants. In addition, the project yielded a number of deliverables that are released for public access

Beckman Access versus the Bayer ACS:180 and the Abbott AxSYM cardiac Troponin-I real-time immunoassays: an observational prospective study

BACKGROUND: Reliability of cardiac troponin-I assays under real-time conditions has not been previously well studied. Most large published cTnI trials have utilized protocols which required the freezing of serum (or plasma) for delayed batch cTnI analysis. We sought to correlate the presence of the acute ischemic coronary syndrome (AICS) to troponin-I values obtained in real-time by three random-mode analyzer immunoassay systems: the Beckman ACCESS (BA), the Bayer ACS:180 (CC) and the Abbott AxSYM (AX). METHODS: This was an observational prospective study at a university tertiary referral center. Serum from a convenience sampling of telemetry patients was analyzed in real-time for troponin-I by either the BA-CC (Arm-1) or BA-AX (Arm-2) assay pairs. Presence of the AICS was determined retrospectively and then correlated with troponin-I results. RESULTS: 100 patients were enrolled in Arm-1 (38 with AICS) and 94 in Arm-2 (48 with AICS). The BA system produced 51% false positives in Arm-1, 44% in Arm-2, with negative predictive values of 92% and 100% respectively. In Arm-1, the BA and the CC assays had sensitivities of 97% and 63% and specificities of 18% and 87%. In Arm-2, the BA and the AX assays had sensitivities of 100% and 83% and specificities of 11% and 78%. CONCLUSIONS: In real-time analysis, the performance of the AxSYM and ACS:180 assay systems produced more accurate troponin-I results than the ACCESS system

Predictors of Hospitalization for Injection Drug Users Seeking Care for Soft Tissue Infections

BACKGROUND: Soft tissue infections (STIs) from injection drug use are a common cause of Emergency Department visits, hospitalizations, and operating room procedures, yet little is known about factors that may predict the need for these costly medical services. OBJECTIVE: To describe a cohort of injection drug users seeking Emergency Department care for STIs and to identify risk factors associated with hospitalization. We hypothesized that participants who delayed seeking care would be hospitalized more often than those who did not. DESIGN: Cohort study using in-person structured interviews and medical record review. Logistic regression assessed the association between hospital admission and delay in seeking care as well as other demographic, clinical, and psychosocial factors. PARTICIPANTS: Injection drug users who sought Emergency Department care for STIs from May 2001 to March 2002. RESULTS: Of the 136 participants, 55 (40%) were admitted to the hospital. Delay in seeking care was not associated with hospital admission. Participants admitted for their infection were significantly more likely to be living in a shelter (P = .01) and to report being hospitalized 2 or more times in the past year (P < .01). CONCLUSIONS: We identified a subpopulation of injection drug users, mostly living in shelters, who were hospitalized frequently in the past year and who were more likely to be hospitalized for their current infections compared to others. As members of this subpopulation can be easily identified and located, they may benefit from interventions to reduce the health care utilization resulting from these infections

Orlistat after initial dietary/behavioural treatment: changes in body weight and dietary maintenance in subjects with sleep related breathing disorders

<p>Abstract</p> <p>Background</p> <p>Sleep related breathing disorders (SRBD) are associated with increased morbidity and mortality and weight loss is recommended to overweight or obese patients with SRBD. However, maintenance of weight loss is difficult to achieve and strategies for weight loss maintenance is needed. Orlistat is a pharmacological agent that reduces the intestinal absorption of fat and may favour long-term weight maintenance.</p> <p>Objective</p> <p>To examine the change in body weight and dietary intake during a 1-year treatment with orlistat after an initial weight loss in obese subjects with SRBD. Furthermore, to explore the dietary determinants of weight maintenance during treatment with orlistat.</p> <p>Methods</p> <p>Men and women with SRBD aged 32-62 years (n = 63) participated in a 3-month dietary intervention to increase intake of vegetables and fruit. After an initial weight loss of 3.4 kg they achieved a mean body mass index of 34.3 ± 4.7 kg/m2. Subsequently they were treated with orlistat for 1 year. During this year, dietary and behavioural interventions to attain weight loss were provided in the course of 14 group sessions. Dietary intake, energy density and food choices were assessed with a food frequency questionnaire before and after orlistat treatment.</p> <p>Results</p> <p>With orlistat, body weight decreased by a mean of 3.5 kg (95% CI 1.5, 5.5). The dietary E% from saturated fat, intake of fatty dairy products and energy density increased after 1 year while intakes of oils, fish and vegetables decreased (all P < 0.05). After multivariate adjustments, weight loss was associated with E% protein (R2_adj= 0.19 [95% CI 0.10, 0.46]), and inversely associated with E% saturated fat (R2_adj= 0.20 [95% CI 0.12, 0.47]) and fatty dairy products (R2_adj= 0.23 [95% CI 0.12, 0.49]).</p> <p>Conclusions</p> <p>Orlistat induced further weight loss, but dietary compliance declined with time. Increasing dietary protein and restricting saturated fat and fatty dairy products may facilitate weight loss with orlistat.</p

Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy

HisAK70: Progress towards a vaccine against different forms of leishmaniosis

Background: Leishmania major and Leishmania infantum are among the main species that are responsible for cutaneous leishmaniosis (CL) and visceral leishmaniosis (VL), respectively. The leishmanioses represent the second-largest parasitic killer in the world after malaria. Recently, we succeeded in generating a plasmid DNA (pCMV-HISA70m2A) and demonstrated that immunized mice were protected against L. major challenge. The efficacy of the DNA-vaccine was further enhanced by the inclusion of KMP-11 antigen into the antibiotic-free plasmid pVAX1-asd. Methods: Here, we describe the use of a HisAK70 DNA-vaccine encoding seven Leishmania genes (H2A, H2B, H3, H4, A2, KMP11 and HSP70) for vaccination of mice to assess the induction of a resistant phenotype against VL and CL. Results: HisAK70 was successful in vaccinated mice, resulting in a high amount of efficient sterile hepatic granulomas associated with a hepatic parasite burden fully resolved in the VL model; and resulting in 100 % inhibition of parasite visceralization in the CL model. Conclusions: The results suggest that immunization with the HisAK70 DNA-vaccine may provide a rapid, suitable, and efficient vaccination strategy to confer cross-protective immunity against VL and CL.This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (AGL2010-17394 and AGL2013-44100R) and PLATESA (P2013/ABI-2906) from the Comunidad de Madrid (Spain).Peer Reviewe

Degradation of Host Sphingomyelin Is Essential for Leishmania Virulence

In eukaryotes, sphingolipids (SLs) are important membrane components and powerful signaling molecules. In Leishmania, the major group of SLs is inositol phosphorylceramide (IPC), which is common in yeast and Trypanosomatids but absent in mammals. In contrast, sphingomyelin is not synthesized by Leishmania but is abundant in mammals. In the promastigote stage in vitro, Leishmania use SL metabolism as a major pathway to produce ethanolamine (EtN), a metabolite essential for survival and differentiation from non-virulent procyclics to highly virulent metacyclics. To further probe SL metabolism, we identified a gene encoding a putative neutral sphingomyelinase (SMase) and/or IPC hydrolase (IPCase), designated ISCL (Inositol phosphoSphingolipid phospholipase C-Like). Despite the lack of sphingomyelin synthesis, L. major promastigotes exhibited a potent SMase activity which was abolished upon deletion of ISCL, and increased following over-expression by episomal complementation. ISCL-dependent activity with sphingomyelin was about 20 fold greater than that seen with IPC. Null mutants of ISCL (iscl−) showed modest accumulation of IPC, but grew and differentiated normally in vitro. Interestingly, iscl− mutants did not induce lesion pathology in the susceptible BALB/c mice, yet persisted indefinitely at low levels at the site of infection. Notably, the acute virulence of iscl− was completely restored by the expression of ISCL or heterologous mammalian or fungal SMases, but not by fungal proteins exhibiting only IPCase activity. Together, these findings strongly suggest that degradation of host-derived sphingomyelin plays a pivotal role in the proliferation of Leishmania in mammalian hosts and the manifestation of acute disease pathology

Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins