Pre-erythrocytic T cell immunity in malaria exposed Africans

Many believe that vaccines are the intervention with the greatest chance of reducing the worldwide burden of malaria. Irradiated sporozoites protect against subsequent malaria challenge, and a vaccine that mimics this stage might be effective. CD4 and CDS T cells are thought to be crucial in protection, but studies of T cell immunity in malaria exposed donors are hampered by widespread nonresponsiveness, to malaria antigens. Most studies of natural T cell immunity measured lymphoproliferation alone, but I found that if 3 T cell assays were employed simultaneously (proliferation, overnight IFN-y ELISPOT, and IFN-y ELISPOT after 14 days culture), that T cell reactivity to circumsporozoite protein (CS) was considerably higher than when using proliferation alone. Responses to individual epitopes failed to correlate over the 3 assays, suggesting that they detect different memory T cell subsets. I investigated the nature of responder cells in the 3 assays, and found ex- vivo ELISPOT responses were mediated by CCR7+ and cultured ELISPOT by CCR7+ cells. I also found a CD4+CD38+ T cell subset that suppressed lymphoproliferation, and might contribute to malaria immunosuppression. The immunodominant T cell epitope regions of CS are highly polymorphic, and I found that altered peptide ligand antagonism operated for variants of a CD4 T cell site. Less polymorphic antigens might be better vaccine candidates, one promising candidate being thrombospondin related adhesive protein (TRAP). I mapped novel CD4 T cell epitopes in TRAP, 16 of which were conserved. I found differences in TRAP T cell reactivity between East and West Africans, and adults and children, which is important since these populations will be recipients of future malaria vaccines. I investigated whether IFN-y ELISPOT responses to TRAP correlated with protection, since IFN-y is thought to be the mechanism by which T cells exert their protective effect, but no protection was found

Glycerol monolaurate inhibits lipase production by clinical ocular isolates without affecting bacterial cell viability

PURPOSE. We sought to determine the relative lipase production of a range of ocular bacterial isolates and to assess the efficacy of glycerol monolaurate (GML) in inhibiting this lipase production in high lipase-producing bacteria without affecting bacterial cell growth. METHODS. Staphylococcus aureus, Staphylococcus epidermidis, Propionibacterium acnes, and Corynebacterium spp. were inoculated at a density of 106/mL in varying concentrations of GML up to 25 μg/mL for 24 hours at 378C with constant shaking. Bacterial suspensions were centrifuged, bacterial cell density was determined, and production of bacterial lipase was quantified using a commercial lipase assay kit. RESULTS. Staphylococcus spp. produced high levels of lipase activity compared with P. acnes and Corynebacterium spp. GML inhibited lipase production by Staphylococcal spp. in a dosedependent manner, with S. epidermidis lipase production consistently more sensitive to GML than S. aureus. Glycerol monolaurate showed significant (P \u3c 0.05) lipase inhibition above concentrations of 15 μg /mL in S. aureus and was not cytotoxic up to 25 μg /mL. For S. epidermidis, GML showed significant (P \u3c 0.05) lipase inhibition above 7.5 μg /mL. CONCLUSIONS. Lipase activity varied between species and between strains. Staphylococcal spp. produced higher lipase activity compared with P. acnes and Corynebacterium spp. Glycerol monolaurate inhibited lipase production by S. aureus and S. epidermidis at concentrations that did not adversely affect bacterial cell growth. GML can be used to inhibit ocular bacterial lipase production without proving detrimental to commensal bacteria viability

Experiences of Establishing an Academic Early Phase Clinical Trials Unit

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This paper describes an approach to establishing an academically-led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009 the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focusing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article

Metabolisable energy content in canine and feline foods is best predicted by the NRC2006 equation

Although animal trials are the most accurate approach to determine the metabolisable energy (ME) content of pet food, these are expensive and labour-intensive. Instead, various equations have been proposed to predict ME content, but no single method is universally recommended. Data from canine and feline feeding studies, conducted according to Association of American Feed Control Officials recommendations, over a 6-year period at a single research site, were utilised to determine the performance of different predictive equations. Predictive equations tested included the modified Atwater (MA equation), NRC 2006 equations using both crude fibre (NRC 2006cf) and total dietary fibre (NRC 2006tdf), and new equations reported in the most recent study assessing ME predictive equations (Hall equations; PLoS ONE 8(1): e54405). Where appropriate, equations were tested using both predicted gross energy (GE) and GE measured by bomb calorimetry. Associations between measured and predicted ME were compared with Deming regression, whilst agreement was assessed with Bland-Altman plots. 335 feeding trials were included, comprising 207 canine (182 dry food; 25 wet food) and 128 feline trials (104 dry food, 24 wet food). Predicted ME was positively associated with measured ME whatever the equation used (P<0.001 for all). Agreement between predicted and actual ME was worst for the MA equation, for all food types, with evidence of both a systematic bias and proportional errors evident for all food types. The NRC 2006cf and Hall equations were intermediate in performance, whilst the NRC 2006tdf equations performed best especially when using measured rather than predicted GE, with the narrowest 95% limits of agreement, minimal bias and proportional error. In conclusion, when predicting ME content of pet food, veterinarians, nutritionists, pet food manufacturers and regulatory bodies are strongly advised to use the NRC 2006tdf equations and using measured rather than predicted GE

Cut-off scores for mild and moderate dementia on the Addenbrooke's Cognitive Examination-III and the Mini-Addenbrooke's Cognitive Examination compared with the Mini-Mental State Examination

Aims and method We aimed to establish cut-off scores to stage dementia on the Addenbrooke's Cognitive Examination-III (ACE-III) and the Mini-Addenbrooke's Cognitive Examination (M-ACE) compared with scores traditionally used with the Mini-Mental State Examination (MMSE). Our cross-sectional study recruited 80 patients and carers from secondary care services in the UK. Results A score ≤76 on the ACE-III and ≤19 on the M-ACE correlated well with MMSE cut-offs for mild dementia, with a good fit on the receiver operating characteristic analysis for both the ACE-III and M-ACE. The cut-off for moderate dementia had lower sensitivity and specificity. There were low to moderate correlations between the cognitive scales and scales for everyday functioning and behaviour. Clinical implications Our findings allow an objective interpretation of scores on the ACE-III and the M-ACE relative to the MMSE, which may be helpful for clinical services and research trials

Cut-off scores for mild and moderate dementia on the Addenbrooke's Cognitive Examination-III and the Mini-Addenbrooke's Cognitive Examination compared with the Mini-Mental State Examination

Aims and method: We aimed to establish cut-off scores to stage dementia on the Addenbrooke's Cognitive Examination-III (ACE-III) and the Mini-Addenbrooke's Cognitive Examination (M-ACE) compared with scores traditionally used with the Mini-Mental State Examination (MMSE). Our cross-sectional study recruited 80 patients and carers from secondary care services in the UK. Results: A score ≤76 on the ACE-III and ≤19 on the M-ACE correlated well with MMSE cut-offs for mild dementia, with a good fit on the receiver operating characteristic analysis for both the ACE-III and M-ACE. The cut-off for moderate dementia had lower sensitivity and specificity. There were low to moderate correlations between the cognitive scales and scales for everyday functioning and behaviour. Clinical implications: Our findings allow an objective interpretation of scores on the ACE-III and the M-ACE relative to the MMSE, which may be helpful for clinical services and research trials

Attitudes of US medical trainees towards neurology education: "Neurophobia" - a global issue

<p>Abstract</p> <p>Background</p> <p>Several studies in the United Kingdom and Asia have suggested that medical students and residents have particular difficulty in diagnosing and managing patients with neurological problems. Little recent information is available for US trainees. We examined whether students and residents at a US university have difficulty in dealing with patients with neurological problems, identified the perceived sources of these difficulties and provide suggestions for the development of an effective educational experience in neurology.</p> <p>Methods</p> <p>A questionnaire was administered to third and fourth year medical students at a US school of medicine and to residents of an internal medicine residency program affiliated with that school. Perceived difficulties with eight medical specialties, including neurology, were examined. Methods considered to be most useful for learning medicine were documented. Reasons why neurology is perceived as difficult and ways to improve neurological teaching were assessed.</p> <p>Results</p> <p>152 surveys were completed. Participation rates varied, with medical students having higher response rates (> 50%) than medical residents (27%-48%). Respondents felt that neurology was the medical specialty they had least knowledge in (p < 0.001) and was most difficult (p < 0.001). Trainees also felt they had the least confidence when dealing with patients with neurological complaints (p < 0.001). Residents felt more competent in neurology than students (p < 0.001). The paramount reasons for perceived difficulties with neurology were the complexity of neuroanatomy, limited patient exposure and insufficient teaching. Transition from pre-clinical to clinical medicine led to a doubling of "poor" ratings for neurological teaching. Over 80% of the respondents felt that neurology teaching could be improved through greater exposure to patients and more bedside tutorials.</p> <p>Conclusions</p> <p>Medical students and residents at this US medical university found neurology difficult. Although this is consistent with prior reports from Europe and Asia, studies in other universities are needed to confirm generalizability of these findings. The optimal opportunity for improvement is during the transition from preclinical to clinical years. Enhanced integration of basic neurosciences and clinical neurology with emphasis on increased bedside tutorials and patient exposure should improve teaching. Studies are needed to quantify the effect of these interventions on confidence of trainees when dealing with patients presenting with neurological complaints.</p

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

OBJECTIVES: ‘Persistent cloaca’ is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice. PATIENTS AND METHODS: We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association. RESULTS: Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation. CONCLUSION: Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca

SELIMETRY- a multicentre I-131 dosimetry trial: a clinical perspective

Treatment options for patients with thyroid cancer that is no longer sensitive to iodine therapy are limited. Those treatments which currently exist are associated with significant toxicity. The SELIMETRY trial (EudraCT No 2015-002269-47) aims to investigate the role of the MEK inhibitor Selumetinib in resensitizing advanced iodine refractory differentiated thyroid cancer to radioiodine therapy. Patients deemed to have sufficient iodine uptake in previously iodine refractory lesions after 4 weeks of Selumetinib therapy will be given an empirical activity of 5.5 GBq I-131, and response to therapy will be assessed. The trial presents an opportunity to investigate the dosimetric aspects of radioiodine therapy for advanced thyroid cancer. Patients will undergo serial I-123 single-photon emission CT (SPECT)/CT scans following Selumetinib therapy to determine whether there has been a change in the degree of iodine uptake to justify further I-131 therapy, and to allow dosimetric calculations to predict absorbed dose to target lesions following therapy. Patients receiving I-131 therapy will undergo a further series of post-therapy SPECT/CT scans to allow dosimetric calculations. We describe the challenges in setting up a multicentre trial in a relatively underinvestigated field, describing the work that has been carried out to calibrate and validate measurements to ensure that standardized image data are collected at each site. We hope that this trial will lead to individualization and optimization of therapy for patients with advanced thyroid cancer and that the ground work carried out in setting up a network of centres capable of standardized molecular radiotherapy dosimetry will lead to further clinical trials in this field

The Protection of the Rights of Migrant Domestic Workers in a Country of Origin and a Country of Destination: Case Studies of the Philippines and Kuwait

During the spring semester of 2013, the SAIS International Human Rights Clinic researched the protection and promotion of the rights of migrant domestic workers in a country of origin and a country of destination by example of the Philippines and Kuwait. The students embarked on a weeklong fact-finding mission to gain insights into (a) the underlying causes and social consequences of labor migration, (b) the mechanisms to protect migrant domestic workers from abuse and exploitation, and (c) the preventive activities carried out in the two countries. The findings of the two fact-finding missions, supported by academic research and scholarship, policy papers, and press releases, are published in this report. The report describes the situation of migrant domestic workers from the start of their journey in the Philippines, through their arrival and work in Kuwait, and through their repatriation. The report aims (a) to raise public awareness about the rights of migrant domestic workers; (b) to offer practical solutions to policymakers in countries of origin and destination; and (c) to offer practical solutions specifically to the Kuwaiti and Philippine governments to take decisive action to better prevent human rights abuses, punish human rights violators, and protect vulnerable populations. By focusing on Filipino migrant domestic workers, the report aims to facilitate the further development of Kuwait–Philippines intergovernmental cooperation that may serve as a model for labor-receiving and labor-sending countries