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

Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency

One of the severe combined immunodeficiencies (SCIDs), which is caused by a genetic defect in the signal transduction pathways involved in T-cell activation, is the ZAP70 deficiency. Mutations in ZAP70 lead to both abnormal thymic development and defective T-cell receptor (TCR) signaling of peripheral T-cells. In contrast to the lymphopenia in most SCID patients, ZAP70-deficient patients have lymphocytosis, despite the selective absence of CD8+ T-cells. The clinical presentation is usually before 2 years of age with typical findings of SCID. Here, we present three new ZAP70-deficient patients who vary in their clinical presentation. One of the ZAP70-deficient patients presented as a classical SCID, the second patient presented as a healthy looking wheezy infant, whereas the third patient came to clinical attention for the eczematous skin lesions simulating atopic dermatitis with eosinophilia and elevated immunoglobulin E (IgE), similar to the Omenn syndrome. This study illustrates that awareness of the clinical heterogeneity of ZAP70 deficiency is of utmost importance for making a fast and accurate diagnosis, which will contribute to the improvement of the adequate treatment of this severe immunodeficiency

Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans

Immune genes are under intense, pathogen-induced pressure, which causes these genes to diversify over evolutionary time and become species-specific. Through a forward genetic screen we recently described a C. elegans-specific gene called pals-22 to be a repressor of “Intracellular Pathogen Response” or IPR genes. Here we describe pals-25, which, like pals-22, is a species-specific gene of unknown biochemical function. We identified pals-25 in a screen for suppression of pals-22 mutant phenotypes and found that mutations in pals-25 suppress all known phenotypes caused by mutations in pals-22. These phenotypes include increased IPR gene expression, thermotolerance, and immunity against natural pathogens, including Nematocida parisii microsporidia and the Orsay virus. Mutations in pals-25 also reverse the reduced lifespan and slowed growth of pals-22 mutants. Transcriptome analysis indicates that pals-22 and pals-25 control expression of genes induced not only by natural pathogens of the intestine, but also by natural pathogens of the epidermis. Indeed, in an independent forward genetic screen we identified pals-22 as a repressor and pals-25 as an activator of epidermal defense gene expression. In summary, the species-specific pals-22 and pals-25 genes act as a switch to regulate a program of gene expression, growth, and defense against diverse natural pathogens in C. elegans

The academic backbone: longitudinal continuities in educational achievement from secondary school and medical school to MRCP(UK) and the specialist register in UK medical students and doctors

Background: Selection of medical students in the UK is still largely based on prior academic achievement, although doubts have been expressed as to whether performance in earlier life is predictive of outcomes later in medical school or post-graduate education. This study analyses data from five longitudinal studies of UK medical students and doctors from the early 1970s until the early 2000s. Two of the studies used the AH5, a group test of general intelligence (that is, intellectual aptitude). Sex and ethnic differences were also analyzed in light of the changing demographics of medical students over the past decades. Methods: Data from five cohort studies were available: the Westminster Study (began clinical studies from 1975 to 1982), the 1980, 1985, and 1990 cohort studies (entered medical school in 1981, 1986, and 1991), and the University College London Medical School (UCLMS) Cohort Study (entered clinical studies in 2005 and 2006). Different studies had different outcome measures, but most had performance on basic medical sciences and clinical examinations at medical school, performance in Membership of the Royal Colleges of Physicians (MRCP(UK)) examinations, and being on the General Medical Council Specialist Register. Results: Correlation matrices and path analyses are presented. There were robust correlations across different years at medical school, and medical school performance also predicted MRCP(UK) performance and being on the GMC Specialist Register. A-levels correlated somewhat less with undergraduate and post-graduate performance, but there was restriction of range in entrants. General Certificate of Secondary Education (GCSE)/O-level results also predicted undergraduate and post-graduate outcomes, but less so than did A-level results, but there may be incremental validity for clinical and post-graduate performance. The AH5 had some significant correlations with outcome, but they were inconsistent. Sex and ethnicity also had predictive effects on measures of educational attainment, undergraduate, and post-graduate performance. Women performed better in assessments but were less likely to be on the Specialist Register. Non-white participants generally underperformed in undergraduate and post-graduate assessments, but were equally likely to be on the Specialist Register. There was a suggestion of smaller ethnicity effects in earlier studies. Conclusions: The existence of the Academic Backbone concept is strongly supported, with attainment at secondary school predicting performance in undergraduate and post-graduate medical assessments, and the effects spanning many years. The Academic Backbone is conceptualized in terms of the development of more sophisticated underlying structures of knowledge ('cognitive capital’ and 'medical capital’). The Academic Backbone provides strong support for using measures of educational attainment, particularly A-levels, in student selection

Integrable Models of Internal Gravity Water Waves Beneath a Flat Surface

A two-layer fluid system separated by a pycnocline in the form of an internal wave is considered. The lower layer is bounded below by a flat bottom and the upper layer is bounded above by a flat surface. The fluids are incompressible and inviscid and Coriolis forces as well as currents are taken into consideration. A Hamiltonian formulation is presented and appropriate scaling leads to a KdV approximation. Additionally, considering the lower layer to be infinitely deep leads to a Benjamin-Ono approximation

Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model

Introduction: Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine whether the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues.Methods: In total, 76 male adult Sprague-Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for 4 hours. Cytokines, chemokines, and leukocyte counts from blood, peritoneal cavity, and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the Mann-Whitney U test.Results: Apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid-to-blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid-to-blood chemokine ratios, resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histologic injury in the lung, liver, and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis-treated animals.Conclusions: Our results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung. © 2014 Peng et al

Co-morbidity and polypharmacy in Parkinson's Disease:insights from a large Scottish primary care database

Background: Parkinson’s disease is complicated by comorbidity and polypharmacy, but the extent and patterns of these are unclear. We describe comorbidity and polypharmacy in patients with and without Parkinson’s disease across 31 other physical, and seven mental health conditions. Methods: We analysed primary health-care data on 510,502 adults aged 55 and over. We generated standardised prevalence rates by age-groups, gender, and neighbourhood deprivation, then calculated age, sex and deprivation adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for those with PD compared to those without, for the prevalence, and number of conditions. Results: Two thousand six hundred forty (0.5%) had Parkinson’s disease, of whom only 7.4% had no other conditions compared with 22.9% of controls (adjusted OR [aOR] 0.43, 95% 0.38–0.49). The Parkinson’s group had more conditions, with the biggest difference found for seven or more conditions (PD 12.1% vs. controls 3.9%; aOR 2.08 95% CI 1.84–2.35). 12 of the 31 physical conditions and five of the seven mental health conditions were significantly more prevalent in the PD group. 44.5% with Parkinson’s disease were on five to nine repeat prescriptions compared to 24.5% of controls (aOR 1.40; 95% CI 1.28 to 1.53) and 19.2% on ten or more compared to 6.2% of controls (aOR 1.90; 95% CI 1.68 to 2.15). Conclusions: Parkinson’s disease is associated with substantial physical and mental co-morbidity. Polypharmacy is also a significant issue due to the complex nature of the disease and associated treatments