Preclinical Characterization of GSK2336805, a Novel Inhibitor of Hepatitis C Virus Replication That Selects for Resistance in NS5A

GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons and exhibits a modest serum shift. GSK2336805 was not active on 22 RNA and DNA viruses that were profiled. We have identified changes in the N-terminal region of NS5A that cause a decrease in the activity of GSK2336805. These mutations in the genotype 1b replicon showed modest shifts in compound activity (<13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.     

Investigation of Kawasaki syndrome risk factors in Colorado

Risk factors for Kawasaki syndrome (KS) were evaluated through a case-control study during an investigation of a KS cluster in Denver, CO. KS was associated with a humidifier in the child's room (odds ratio, 7.3; 95% confidence interval, 1.8 to 29.3) and possibly with an antecedent respiratory illness. The use of humidifiers should be further investigated as part of future studies of KS.     

Metastatic pure small-cell carcinoma of prostate

Extrapulmonary small-cell carcinoma arising in the prostate gland has been described in several case series and case reports. However, pure small-cell carcinoma of the prostate is rare, and there are only a few reports in literature describing the clinical features and management of this neoplasm. These tumors are highly aggressive and commonly manifest with visceral metastasis at the time of diagnosis. We report a case of metastatic pure prostatic small-cell carcinoma and an associated paraneoplastic polyneuropathy.     

Chronic wasting disease and potential transmission to humans

Chronic wasting disease (CWD) of deer and elk is endemic in a tri-corner area of Colorado, Wyoming, and Nebraska, and new foci of CWD have been detected in other parts of the United States. Although detection in some areas may be related to increased surveillance, introduction of CWD due to translocation or natural migration of animals may account for some new foci of infection. Increasing spread of CWD has raised concerns about the potential for increasing human exposure to the CWD agent. The foodborne transmission of bovine spongiform encephalopathy to humans indicates that the species barrier may not completely protect humans from animal prion diseases. Conversion of human prion protein by CWD-associated prions has been demonstrated in an in vitro cell-free experiment, but limited investigations have not identified strong evidence for CWD transmission to humans. More epidemiologic and laboratory studies are needed to monitor the possibility of such transmissions     

Field evaluation of FD-DAT, rK39 dipstick and KATEX (urine latex agglutination) for diagnosis of visceral leishmaniasis in northwest Ethiopia

Three novel diagnostic tests for visceral leishmaniasis (VL), namely FD-DAT, rK39 dipstick and KATEX, were evaluated under field conditions using 101 clinical cases suspected of having VL enrolled in a trial either by active (63 patients) or passive (38 patients) surveillance. VL was confirmed in 49 patients: 35 by both aspirate smear microscopy and NNN culture, 10 by NNN culture alone and 4 by aspirate smear microscopy alone. Based on tests performed in the field, sensitivity for FD-DAT, rK39 dipstick and KATEX was determined to be 95.3% (95% CI 82.9-99.2%), 71.7% (95% CI 56.3-83.5%) and 57.4% (95% CI 42.3-71.4%), respectively. Similarly, the specificity was determined to be 62.7% (95% CI 48.1-75.5%), 82.4% (95% CI 68.6-91.1%) and 84.3% (95% CI 70.9-92.5%), respectively. A higher sensitivity of KATEX (73.9% vs. 41.7%) and higher specificity of FD-DAT (100.0% vs. 48.6%) were demonstrated under passive case detection compared with active case detection. FD-DAT is recommended for confirmation of VL diagnosis in hospital settings, whereas its use in the field will be limited to exclude VL in clinical suspects. The sensitivity of KATEX and rK39 dipstick tests needs to be improved to promote their use as first-line diagnostic tests in the field setting of northwestern Ethiopia.     

Kawasaki syndrome in Denmark

OBJECTIVE: To describe the epidemiologic characteristics of Kawasaki syndrome (KS) and to estimate national KS incidence rates among children in Denmark. METHODS: A retrospective population-based study using hospital discharge records with a KS diagnosis for children younger than 15 years selected from the Danish National Hospital Register for 1981-2004. Incidence rates were calculated using the number of KS patients and corresponding census data. RESULTS: During 1981-2004, 360 children younger than 15 years were hospitalized with KS in Denmark, with 73% younger than 5 years. In this age group, the average annual incidence of KS gradually increased from 1981 to 1999 and thereafter stabilized at 4.5 to 5.0 per 100,000 person-years. The incidence was greater for boys than for girls (RR = 1.6, 95% CI = 1.2-2.0) and was highest among infants younger than 1 year (4.5), declining with increasing age (P = 0.03). However, the age-specific decline in incidence was only observed for boys, whereas the incidence for girls remained unchanged by age. The median length of hospital stay was 12 days, and the incidence peaked in the winter months. CONCLUSIONS: Major epidemiologic characteristics identified among Danish childhood KS are consistent with those described in previous studies, such as highest incidence among young children and winter-seasonality. The KS incidence rate among children younger than 5 years in Denmark increased steadily during the early study period (coinciding with global recognition of KS) and seems to have stabilized from 1998-1999 onwards. Although the incidence among Danish children was lower than that reported for several other European countries, differences in methodology challenge definite comparisons.     

Kawasaki Syndrome and Factors Associated With Coronary Artery Abnormalities in California

BACKGROUND:: Kawasaki syndrome (KS) occurs in children <18 years of age and is the leading cause of acquired heart disease among children in the United States. Understanding the epidemiology of KS and factors associated with coronary artery abnormalities (CAA) may lead to timely diagnosis and treatment of KS and could limit CAA. METHODS:: Epidemiologic characteristics, including risk factors for the development of CAA, among KS and incomplete KS patients <18 years of age with onset during 2000-2009 reported by the California Department of Public Health to the Centers for Disease Control and Prevention's national KS surveillance system were analyzed. RESULTS:: A total of 2056 KS and incomplete KS patients <18 years of age were reported during 2000-2009. The median age of patients was 2 years; 60% of patients were male. Of 1818 patients with race information reported, 56% were white and 28% were Asian/Pacific Islander. Ninety-eight percent of patients received intravenous immunoglobulin. Of 1843 patients with information on cardiac complications, 89 (5%) had coronary artery aneurysms and 341 (19%) had CAA. Characteristics associated with the occurrence of CAA in KS patients were male sex, Asian/Pacific Islander race, age <1 year or 9-17 years, and not receiving intravenous immunoglobulin treatment before the fifth day of illness. CONCLUSIONS:: This study suggests that intravenous immunoglobulin treatment before the fifth day of illness may reduce CAA among KS patients. Timely diagnosis and treatment of KS continue to be important in reducing the occurrence of cardiac complications.