A Case of Treatment Resistance and Complications in a Patient with Stiff Person Syndrome and Cerebellar Ataxia

Background: Antibodies against glutamic acid decarboxylase (GAD) are associated with Stiff Person Syndrome (SPS). Case report: A 50-year-old woman presented with symptoms progressed over 9 years, resulting in a cerebellar ataxia and right upper limb tremor. Investigations revealed elevated serum and CSF anti-GAD antibody titres (98.6 and 53.4 μ/ml, respectively). Treatment included intravenous immunoglobulin and immunomodulation (infliximab and rituximab), improving her stiffness, but with no impact on the ataxia-related symptoms. Subsequent high-dose steroids led to diabetic ketoacidosis and unmasking of an insulin-dependent diabetes mellitus. Discussion: This case illustrates several key features: (1) the combined clinical picture of SPS and cerebellar ataxia is a rare phenotype associated with anti-GAD antibodies; (2) the cerebellar ataxia described was progressive and poorly responsive to immunomodulatory therapy; and (3) the potential for development of further autoimmune sequelae in response to immunosuppression, namely, the development of insulin-dependent diabetes in response to treatment with high-dose oral steroids

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Current knowledge, status and future for plant and fungal diversity in Great Britain and the UK Overseas Territories

Societal Impact Statement We rely on plants and fungi for most aspects of our lives. Yet plants and fungi are under threat, and we risk losing species before we know their identity, roles, and potential uses. Knowing names, distributions, and threats are first steps toward effective conservation action. Accessible products like field guides and online resources engage society, harnessing collective support for conservation. Here, we review current knowledge of the plants and fungi of the UK and UK Overseas Territories, highlighting gaps to help direct future research efforts toward conserving these vital elements of biodiversity. Summary This review summarizes current knowledge of the status and threats to the plants and fungi of Great Britain and the UK Overseas Territories (UKOTs). Although the body of knowledge is considerable, the distribution of information varies substantially, and we highlight knowledge gaps. The UK vascular flora is the most well studied and we have a relatively clear picture of its 9,001 native and alien taxa. We have seedbanked 72% of the native and archaeophyte angiosperm taxa and 78% of threatened taxa. Knowledge of the UKOTs flora varies across territories and we report a UKOTs flora comprising 4,093 native and alien taxa. We have conserved 27% of the native flora and 51% of the threatened vascular plants in Kew's Millennium Seed Bank, UK. We need a better understanding of the conservation status of plants in the wild, and progress toward completion or updating national red lists varies. Site‐based protection of key plant assemblages is outlined, and progress in identifying Important Plant Areas analyzed. Knowledge of the non‐vascular flora, especially seaweeds remains patchy, particularly in many UKOTs. The biggest gaps overall are in fungi, particularly non‐lichenized fungi. Considerable investment is needed to fill these knowledge gaps and instigate effective conservation strategies

Molecular pathology of human prion disease

Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health

A model for overland flow over agricultural land and application to particle transport (abstract).

Eachyear, millions of tonnes of faecal waste are applied to agricultural land in the UK. Due to their low density and resistance to shear, they may easily be detached and transported to surface waters (Schofield 1988). The potentially harmful microorganisms they contain together with other chemical components and soil particles may seriously endanger the water quality. These elements are mainly transported by overland flow, that is the water running off fields during storms. An event-based model has been developed to simulate the behaviour of surface water and transported particles during a storm. The objective is to apply this model to fields with a surface of up to one square kilometre. As in most fluid applications, the Navier–Stokes equations would provide a valid model for overland flow. However, they are notoriously complex to solve and do not exploit the thin geometry of the film. Our model is based on lubrication theory, an asymptotic simplification of traditional equations (Ockendon & Ockendon 1995, Myers 1998). This results in a single transient non-linear equation for the film thickness, driven by gravity. However, fields are roughsurfaces and this may significantly affect the flow. The equation is then modified to include the soil roughness, through two parameters inherent to the catchment that may be evaluated from the flux and velocity (Myers 2002). Results were compared withsmall-scale experiments. This model of overland flow is then coupled with a transport equation to study the behaviour of soil particles or microorganisms during a storm. The particle detachment is based on a model developed for the EUROSEM code (Morgan et al. 1999). Simulations based on the lubricationEUROSEM transport model are presented for test cases and some real field data. Experiments to evaluate the model are currently underway on a specially designed flume

No behavioral syndromes or sex-specific personality differences in the southern rainforest sunskink (Lampropholis similis)

Behavioral syndromes, when individuals within a population express consistent behavioral differences across time and context, are widespread in animal taxa. For many species, males and females experience different selective pressures after maturation, resulting in the divergence of life-history and behavioral traits. However, the potential for sex-specific differences in individual behaviors and behavioral syndromes has rarely been assessed. Here, we tested for sex-specific differences in behavior (activity, exploration, sociability) and personality in the southern rainforest sunskink, Lampropholis similis. We found that most behaviors in L. similis did not differ between sexes, the exception being sociality which was higher in females than males. In terms of consistency among behaviors, activity and exploration, but not sociability, were repeatable, and there were no sex-specific differences in repeatability of behavioral traits. Although a behavioral syndrome among these three traits is present in a congener (L. delicata), we found no evidence for such a syndrome in either sex of L. similis. Our study is consistent with the results of studies on other Lampropholis skinks that have found only limited sexual differences in behavior. More broadly, our study demonstrates there can be considerable differences in the presence or absence of behavioral syndromes in closely related species