WHOOPING CRANE TITERS TO EASTERN EQUINE ENCEPHALITIS VACCINATIONS

In 1984 an epizootic of eastern equine encephalitis (EEE) virus killed 7 of 39 (18%) whooping cranes in captivity at the Patuxent Wildlife Research Center in Laurel, Maryland, USA. Since that time whooping cranes have been vaccinated with a human EEE vaccine. This vaccine was unavailable for several years, necessitating use of an equine vaccine in the cranes. This study compared the antibody titers measured for three years using the human vaccine with those measured for two years using the equine form. Whooping cranes developed similarly elevated titers in one year using the human vaccine and both years using the equine vaccine. However, in two years where the human vaccine was used, the whooping cranes developed significantly lower titers compared to other years

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding

Calcium and Vitamin D increase mRNA levels for the growth control hIK1 channel in human epidermal keratinocytes but functional channels are not observed

BACKGROUND: Intermediate-conductance, calcium-activated potassium channels (IKs) modulate proliferation and differentiation in mesodermal cells by enhancing calcium influx, and they contribute to the physiology of fluid movement in certain epithelia. Previous reports suggest that IK channels stimulate proliferative growth in a keratinocyte cell line; however, because these channels indirectly promote calcium influx, a critically unique component of the keratinocyte differentiation program, an alternative hypothesis is that they would be anti-proliferative and pro-differentiating. This study addresses these hypotheses. METHODS: Real-time PCR, patch clamp electrophysiology, and proliferation assays were used to determine if human IK1 (hIK1) expression and function are correlated with either proliferation or differentiation in cultured human skin epidermal keratinocytes, and skin biopsies grown in explant culture. RESULTS: hIK1 mRNA expression in human keratinocytes and skin was increased in response to anti-proliferative/pro-differentiating stimuli (elevated calcium and Vitamin D). Correspondingly, the hIK1 agonist 1-EBIO inhibited keratinocyte proliferation suggesting that the channel could be anti-proliferative and pro-differentiating. However, this proliferative inhibition by 1-EBIO was not reversed by a panel of hIK1 blockers, calling into question the mechanism of 1-EBIO action. Subsequent patch clamp electrophysiological analysis failed to detect hIK1 channel currents in keratinocytes, even those expressing substantial hIK1 mRNA in response to calcium and Vitamin D induced differentiation. Identical electrophysiological recording conditions were then used to observe robust IK1 currents in fibroblasts which express IK1 mRNA levels comparable to those of keratinocytes. Thus, the absence of observable hIK1 currents in keratinocytes was not a function of the electrophysiological techniques. CONCLUSION: Human keratinocyte differentiation is stimulated by calcium mobilization and influx, and differentiation stimuli coordinately upregulate mRNA levels of the calcium-activated hIK1 channel. This upregulation is paradoxical in that functional hIK1 channels are not observed in cultured keratinocytes. It appears, therefore, that hIK1 does not contribute to the functional electrophysiology of primary human keratinocytes, nor intact human skin. Further, the results indicate caution is required when interpreting experiments utilizing pharmacological hIK1 modulators in human keratinocytes

Potential risk factors associated with human encephalitis: application of canonical correlation analysis

<p>Abstract</p> <p>Background</p> <p>Infection of the CNS is considered to be the major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. Despite being identified worldwide as an important public health concern, studies on encephalitis are very few and often focus on particular types (with respect to causative agents) of encephalitis (e.g. West Nile, Japanese, etc.). Moreover, a number of other infectious and non-infectious conditions present with similar symptoms, and distinguishing encephalitis from other disguising conditions continues to a challenging task.</p> <p>Methods</p> <p>We used canonical correlation analysis (CCA) to assess associations between set of exposure variable and set of symptom and diagnostic variables in human encephalitis. Data consists of 208 confirmed cases of encephalitis from a prospective multicenter study conducted in the United Kingdom. We used a covariance matrix based on Gini's measure of similarity and used permutation based approaches to test significance of canonical variates.</p> <p>Results</p> <p>Results show that weak pair-wise correlation exists between the risk factor (exposure and demographic) and symptom/laboratory variables. However, the first canonical variate from CCA revealed strong multivariate correlation (ρ = 0.71, se = 0.03, p = 0.013) between the two sets. We found a moderate correlation (ρ = 0.54, se = 0.02) between the variables in the second canonical variate, however, the value is not statistically significant (p = 0.68). Our results also show that a very small amount of the variation in the symptom sets is explained by the exposure variables. This indicates that host factors, rather than environmental factors might be important towards understanding the etiology of encephalitis and facilitate early diagnosis and treatment of encephalitis patients.</p> <p>Conclusions</p> <p>There is no standard laboratory diagnostic strategy for investigation of encephalitis and even experienced physicians are often uncertain about the cause, appropriate therapy and prognosis of encephalitis. Exploration of human encephalitis data using advanced multivariate statistical modelling approaches that can capture the inherent complexity in the data is, therefore, crucial in understanding the causes of human encephalitis. Moreover, application of multivariate exploratory techniques will generate clinically important hypotheses and offer useful insight into the number and nature of variables worthy of further consideration in a confirmatory statistical analysis.</p

Advances in Pediatric Neurovirology

Viral infections of the pediatric central nervous system (CNS) encompass a broad spectrum of both perinatally and postnatally acquired diseases with potentially devastating effects on the developing brain. In children, viral infections have been associated with chronic encephalopathy, encephalitis, demyelinating disease, tumors, and epilepsy. Older diagnostic techniques of biopsy, viral culture, electron microscopy, gel-based polymerase chain reaction (PCR), and viral titer quantification are being replaced with more rapid, sensitive, and specific real-time and microarray-based PCR technologies. Advances in neuroimaging technologies have provided for earlier recognition of CNS injury without elucidation of specific viral etiology. Although the mainstay therapy of many pediatric neurovirologic diseases, aside from HIV, includes intravenous acyclovir, much work is being done to develop novel antiviral immunotherapies aimed at both treating and preventing pediatric CNS viral disease

Viral Etiology of Encephalitis in Children in Southern Vietnam: Results of a One-Year Prospective Descriptive Study

Viral encephalitis is associated with high morbidity and mortality in Vietnam. However little is known about the causes of the disease due to a lack of diagnostic facilities in this relatively resource-poor setting. Knowledge about the etiologies and clinical outcome of viral encephalitis is necessary for future design of intervention studies targeted at improvement of clinical management, treatment and prevention of the disease. We report the viral agents, clinical outcome and prognostic factors of mortality of encephalitis in children admitted to a referral hospital for children in southern Vietnam. We show that about one third of the enrolled patients die acutely, and that mortality is independently associated with patient age and Glasgow Coma Scale on admission. Japanese encephalitis, dengue virus and enterovirus (including enterovirus 71) are the major viruses detected in our patients. However, more than half of the patients remain undiagnosed, while mortality in this group is as high as in the diagnosed group. This study will benefit clinicians and public health in terms of clinical management and prevention of childhood encephalitis in Vietnam

Evidence and rationale for the World Health Organization recommended standards for Japanese encephalitis surveillance

<p>Abstract</p> <p>Background</p> <p>Japanese encephalitis (JE) is the most important form of viral encephalitis in Asia. Surveillance for the disease in many countries has been limited. To improve collection of accurate surveillance data in order to increase understanding of the full impact of JE and monitor control programs, World Health Organization (WHO) Recommended Standards for JE Surveillance have been developed. To aid acceptance of the Standards, we describe the process of development, provide the supporting evidence, and explain the rationale for the recommendations made in the document.</p> <p>Methods</p> <p>A JE Core Working Group was formed in 2002 and worked on development of JE surveillance standards. A series of questions on specific topics was initially developed. A literature review was undertaken and the findings were discussed and documented. The group then prepared a draft document, with emphasis placed on the feasibility of implementation in Asian countries. A field test version of the Standards was published by WHO in January 2006. Feedback was then sought from countries that piloted the Standards and from public health professionals in forums and individual meetings to modify the Standards accordingly.</p> <p>Results</p> <p>After revisions, a final version of the JE surveillance standards was published in August 2008. The supporting information is presented here together with explanations of the rationale and levels of evidence for specific recommendations.</p> <p>Conclusion</p> <p>Provision of the supporting evidence and rationale should help to facilitate successful implementation of the JE surveillance standards in JE-endemic countries which will in turn enable better understanding of disease burden and the impact of control programs.</p

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible