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

Phosphorylation of Puma modulates its apoptotic function by regulating protein stability

Puma is a potent BH3-only protein that antagonises anti-apoptotic Bcl-2 proteins, promotes Bax/Bak activation and has an essential role in multiple apoptotic models. Puma expression is normally kept very low, but can be induced by several transcription factors including p53, p73, E2F1 and FOXO3a, whereby it can induce an apoptotic response. As Puma can to bind and inactivate all anti-apoptotic members of the Bcl-2 family, its activity must be tightly controlled. We report here, for the first time, evidence that Puma is subject to post-translational control through phosphorylation. We show that Puma is phosphorylated at multiple sites, with the major site of phosphorylation being serine 10. Replacing serine 10 with alanine causes reduced Puma turnover and enhanced cell death. Interestingly, Puma turnover occurs through the proteasome, and substitution of serine 10 causes elevated Puma levels independently of macroautophagy, Bcl-2 family member binding, caspase activity and apoptotic death. We conclude, therefore, that phosphorylation of Puma at serine 10 promotes Puma turnover, represses Puma's cell death potential and promotes cell survival. Owing to the highly pro-apoptotic nature of Puma, these studies highlight an important additional regulatory step in the determination of cellular life or death

Holographic rho mesons in an external magnetic field

We study the rho meson in a uniform magnetic field eB using a holographic QCD-model, more specifically a D4/D8/Dbar8 brane setup in the confinement phase at zero temperature with two quenched flavours. The parameters of the model are fixed by matching to corresponding dual field theory parameters at zero magnetic field. We show that the up- and down-flavour branes respond differently to the presence of the magnetic field in the dual QCD-like theory, as expected because of the different electromagnetic charge carried by up- and down-quark. We discuss how to recover the Landau levels, indicating an instability of the QCD vacuum at eB = m_rho^2 towards a phase where charged rho mesons are condensed, as predicted by Chernodub using effective QCD-models. We improve on these existing effective QCD-model analyses by also taking into account the chiral magnetic catalysis effect, which tells us that the constituent quark masses rise with eB. This turns out to increase the value of the critical magnetic field for the onset of rho meson condensation to eB = 1.1 m_rho^2 = 0.67 GeV^2. We briefly discuss the influence of pions, which turn out to be irrelevant for the condensation in the approximation made.Comment: 26 pages, 10 .pdf figures, v2: version accepted for publication in JHE

Sentinel surveillance for human enterovirus 71 in Sarawak, Malaysia: lessons from the first 7 years

BACKGROUND: A major outbreak of human enterovirus 71-associated hand, foot and mouth disease in Sarawak in 1997 marked the beginning of a series of outbreaks in the Asia Pacific region. Some of these outbreaks had unusually high numbers of fatalities and this generated much fear and anxiety in the region. METHODS: We established a sentinel surveillance programme for hand, foot and mouth disease in Sarawak, Malaysia, in March 1998, and the observations of the first 7 years are described here. Virus isolation, serotyping and genotyping were performed on throat, rectal, vesicle and other swabs. RESULTS: During this period Sarawak had two outbreaks of human enterovirus 71, in 2000 and 2003. The predominant strains circulating in the outbreaks of 1997, 2000 and 2003 were all from genogroup B, but the strains isolated during each outbreak were genetically distinct from each other. Human enterovirus 71 outbreaks occurred in a cyclical pattern every three years and Coxsackievirus A16 co-circulated with human enterovirus 71. Although vesicles were most likely to yield an isolate, this sample was not generally available from most cases and obtaining throat swabs was thus found to be the most efficient way to obtain virological information. CONCLUSION: Knowledge of the epidemiology of human enterovirus 71 transmission will allow public health personnel to predict when outbreaks might occur and to plan interventions in an effective manner in order to reduce the burden of disease

Are Algae Relevant to the Detritus-Based Food Web in Tank-Bromeliads?

We assessed the occurrence of algae in five species of tank-bromeliads found in contrasting environmental sites in a Neotropical, primary rainforest around the Nouragues Research Station, French Guiana. The distributions of both algal abundance and biomass were examined based on physical parameters, the morphological characteristics of bromeliad species and with regard to the structure of other aquatic microbial communities held in the tanks. Algae were retrieved in all of the bromeliad species with mean densities ranging from ∼102 to 104 cells/mL. Their biomass was positively correlated to light exposure and bacterial biomass. Algae represented a tiny component of the detrital food web in shaded bromeliads but accounted for up to 30 percent of the living microbial carbon in the tanks of Catopsis berteroniana, located in a highly exposed area. Thus, while nutrient supplies are believed to originate from wind-borne particles and trapped insects (i.e., allochtonous organic matter), our results indicate that primary producers (i.e., autochtonous organic matter) are present in this insectivorous bromeliad. Using a 24-h incubation of size-fractionated and manipulated samples from this plant, we evaluated the impact of mosquito foraging on algae, other microorganisms and rotifers. The prey assemblages were greatly altered by the predation of mosquito larvae. Grazing losses indicated that the dominant algal taxon, Bumilleriopsis sp., like protozoa and rotifers, is a significant part of the diet of mosquito larvae. We conclude that algae are a relevant functional community of the aquatic food web in C. berteroniana and might form the basis of a complementary non-detrital food web

Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes

BACKGROUND: Early clinical trials, mostly in the setting of melanoma, have shown that dendritic cells (DCs) expressing tumor antigens induce some immune responses and some clinical responses. A major difficulty is the extension to other tumors, such as breast carcinoma, for which few defined tumor-associated antigens are available. We have demonstrated, using both prostate carcinoma and melanoma as model systems, that DCs loaded with killed allogeneic tumor cell lines can induce CD8(+ )T cells to differentiate into cytotoxic T lymphocytes (CTLs) specific for shared tumor antigens. METHODS: The present study was designed to determine whether DCs would capture killed breast cancer cells and present their antigens to autologous CD4(+ )and CD8(+ )T cells. RESULTS: We show that killed breast cancer cells are captured by immature DCs that, after induced maturation, can efficiently present MHC class I and class II peptides to CD8(+ )and CD4(+ )T lymphocytes. The elicited CTLs are able to kill the target cells without a need for pretreatment with interferon gamma. CTLs can be obtained by culturing the DCs loaded with killed breast cancer cells with unseparated peripheral blood lymphocytes, indicating that the DCs can overcome any potential inhibitory effects of breast cancer cells. CONCLUSION: Loading DCs with killed breast cancer cells may be considered a novel approach to breast cancer immunotherapy and to identification of shared breast cancer antigens