Cellular Receptors Involved in KSHV Infection

The process of Kaposi’s Sarcoma Herpes Virus’ (KSHV) entry into target cells is complex and engages several viral glycoproteins which bind to a large range of host cell surface molecules. Receptors for KSHV include heparan sulphate proteoglycans (HSPGs), several integrins and Eph receptors, cystine/glutamate antiporter (xCT) and Dendritic Cell-Specific Intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This diverse range of potential binding and entry sites allows KSHV to have a broad cell tropism, and entry into specific cells is dependent on the available receptor repertoire. Several molecules involved in KSHV entry have been well characterized, particularly those postulated to be associated with KSHV-associated pathologies such as Kaposi’s Sarcoma (KS). In this review, KSHV infection of specific cell types pertinent to its pathogenesis will be comprehensively summarized with a focus on the specific cell surface binding and entry receptors KSHV exploits to gain access to a variety of cell types. Gaps in the current literature regarding understanding interactions between KSHV glycoproteins and cellular receptors in virus infection are identified which will lead to the development of virus infection intervention strategies.     

Reduction in Virulence over Time in Ostreid herpesvirus 1 (OsHV-1) Microvariants between 2011 and 2015 in Australia

Microvariant genotypes of Ostreid herpesvirus 1 (OsHV-1) are associated with mass mortality events of Pacific oysters in many countries. The OsHV-1 microvariant (µVar) emerged in France 2008 and caused significant economic losses as it became endemic and displaced the previously dominant OsHV-1 reference genotype. Recently, considerable genotypic variation has been described for OsHV-1 microvariants, however, less is known about variation in viral phenotype. This study used an in vivo laboratory infection model to assess differences in total cumulative mortality, peak viral load, transmissibility, and dose-response for three OsHV-1 isolates obtained between 2011 and 2015 from endemic waterways in Australia. This followed field observations of apparent reductions in the severity of mass mortalities over this time. Significantly higher hazard of death and cumulative mortality were observed for an isolate obtained in 2011 compared to isolates from 2014–2015. In keeping with other studies, the hazard of death was higher in oysters challenged by injection compared to challenge by cohabitation and the mortality was higher when the initial dose was 1 × 10⁴ OsHV-1 DNA copies per oyster injection compared to 1 × 10² DNA copies. There was no difference in the quantity of OsHV-1 DNA at time of death that could be related to isolate or dose, suggesting similar pathogenetic processes in the individual oysters that succumbed to end-stage disease. While the isolates examined in this study were biased towards pathogenic types of OsHV-1, as they were collected during disease outbreaks, the variation in virulence that was observed, when combined with prior data on subclinical infections, suggests that surveillance for low virulence genotypes of OsHV-1 would be rewarding. This may lead to new approaches to disease management which utilize controlled exposure to attenuated strains of OsHV-1.     

rHuEpo administration in patients with low-risk myelodysplastic syndromes: evaluation of erythroid precursors' response by fluorescence in situ hybridization on May-Grunwald-Giemsa-stained bone marrow samples

The issue of whether, in patients affected by myelodysplastic syndromes (MDS), haematological response to cytokines, particularly to recombinant human erythropoietin (rHuEpo), is a phenomenon related to the stimulation of normal haemopoietic cells or to the differentiation of cells belonging to the abnormal clone remains an open question. To assess the pattern of response to rHuEpo treatment of bone marrow (BM) cells, we evaluated in 13 low-risk MDS patients with known cytogenetic abnormalities the number of cytogenetically normal and abnormal cells by conventional cytogenetic analysis (CCA) and by a fluorescence in situ hybridization (FISH) technique, enabling the simultaneous visualization of FISH chromosomal abnormalities in morphologically and immunophenotypically identifiable BM elements. Patients responding to rHuEpo presented a lower number of abnormal metaphases at diagnosis in comparison with patients who did not respond (22.74% vs 76.23%, P = < 0.001). This was confirmed by the combined morphological FISH analysis, showing that, before treatment, BM samples from patients responding to rHuEpo had a lower proportion of both FISH abnormal erythroid (36.48% vs 66.93%, P = 0.002) and myeloid (40.76% vs 67.70%, P = 0.014) elements than unresponsive patients. After rHuEpo treatment, responding patients presented a significantly lower proportion of FISH abnormal erythroid precursors than observed before treatment (16.93%vs 36.48%, P = 0.017). Likewise, in responding patients, a significantly lower proportion of FISH abnormal erythroid elements (16.93% vs 66.30%, P < 0.001) was detected in comparison with unresponsive patients. These findings provide evidence that, in low-risk MDS patients with known cytogenetic abnormalities, response to rHuEpo may be due to the proliferation of karyotypically normal erythroid precursors, possibly representing residual normal erythroid elements.     

Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inflammatory bowel disease

PURPOSE: 6-Mercaptopurine (6-MP) has proven efficacy in the therapy of inflammatory bowel disease. Its teratogenicity is demonstrated in animal studies when used at very high doses, whereas human data suggest that 6-MP at maintenance doses is safe. We report the outcome of 72 pregnancies in patients with inflammatory bowel disease who were previously treated with 6-MP with three different doses of 50, 75, and 100 mg/d, for a median duration of 18 months, along with long-term follow-up of the children. METHODS: We have compared the outcome of pregnancies and development of the offspring in the following two groups: group 1, patients with inflammatory bowel disease who conceived 6 months to 22 years after stopping 6-MP (median 72 months); and group 2, patients with inflammatory bowel disease who never received 6-MP prior to conception. All pregnancies were evaluated in terms of outcome: live full-term birth, premature delivery, stillbirth, spontaneous abortion, ectopic pregnancy, and therapeutic dilatation and curettage. Data on children were obtained regarding birth weight, congenital anomalies, and development. RESULTS: Group 1 included 72 pregnancies carried by 29 women. There were 51 live births (4 premature), 16 spontaneous abortions, 1 stillbirth, 2 therapeutic abortions due to abnormal amniocentesis, and 2 ectopic pregnancies. The total incidence of fetal loss was 29.2%. In group 2, 75 women had 140 pregnancies resulting in 120 live births (8 premature), 18 spontaneous abortions, and 2 stillbirths. There were no cases of ectopic pregnancies or abnormal amniocentesis. The total incidence of fetal loss was 14.3%. There was no increase in the incidence of developmental defects when the mothers had been treated with 6-MP prior to pregnancy. CONCLUSIONS: The incidence of fetal loss is higher in women with inflammatory bowel disease who had been previously treated with 6-MP compared with those who had not. Whether this was related to the older age at conception in 6-MP group, longer duration of disease, initially more severe disease, or use of 6-MP we cannot tell.     

Clinical usefulness of electrophysiologic testing in patients with ventricular tachycardia and chronic chagasic cardiomyopathy treated with amiodarone or sotalol

INTRODUCTION: This study assessed the role of electrophysiologic testing to identify therapeutic strategies for the treatment of patients with sustained ventricular tachycardia (VT) and chronic chagasic cardiomyopathy treated with amiodarone or sotalol. METHODS AND RESULTS: One hundred fifteen patients [69 men (60%); mean age 52 +/- 10 years] with chagasic cardiomyopathy presenting with symptomatic VT were studied after loading with Class III antiarrhythmic drugs; 78 had a history of sustained VT, and 37 with symptomatic nonsustained VT had sustained VT induced at baseline electrophysiologic study. All but 12 patients also underwent baseline electrophysiologic study. Mean left ventricular ejection fraction was 0.49 +/- 0.14. Based on results of electrophysiologic study after loading with Class III drugs, patients were divided into three groups: group 1 (n = 23) had no sustained VT induced; group 2 (n = 45) had only tolerated sustained VT induced; and group 3 (n = 47) had hemodynamically unstable sustained VT induced. After a mean follow-up of 52 +/- 32 months, total mortality rate was 39.1%; it was significantly higher in group 3 than in groups 2 and 1 [69%, 22.2%, and 26%, respectively, P < 0.0001, hazard ratio (HR) 10.4, 95% confidence interval (CI) 3.8, 21.8]. There was no significant difference in total mortality rate between groups 1 and 2 (P = 0.40, HR 1.5, 95% CI 0.75, 4.58). Cardiac mortality and sudden cardiac death rates also were higher in group 3 patients. CONCLUSION: In patients with chagasic cardiomyopathy and sustained VT, electrophysiologic testing can predict long-term efficacy of Class III antiarrhythmic drugs. This may help in the selection of patients for implantable cardioverter defibrillator therapy.     

Clinical characteristics of familial versus sporadic Crohn's disease using the Vienna Classification

BACKGROUND: The etiology of Crohn's disease, an illness protean in its manifestations, may be better resolved through studies involving more homogenous subgroups of patients. Because a strong genetic influence exists, family history of inflammatory bowel disease may be a useful variable for patient classification if patients with familial and sporadic Crohn's disease are clinically different. Our study attempted to define any possible differences. METHODS: The medical records of 552 patients were reviewed, and patients were classified according to guidelines of the Vienna Classification. Patients were then divided based on family history of inflammatory bowel disease, and the familial and sporadic groups were compared. RESULTS: Overall, 422 (78.9%) patients were diagnosed before age 40 years (A1) and 114 (21.1%) at age 40 years or older (A2). There were 141 (26.3%) patients with disease involving the terminal ileum only (L1), 211 (39.4%) in the colon only (L2), 117 (21.9%) in the terminal ileum and colon (L3), and 66 (12.3%) in the upper gastrointestinal tract (L4). Disease behavior, as determined at the time of last visit or telephone contact, was nonstricturing, nonpenetrating (B1) in 149 (27.9%) patients, stricturing (B2) in 50 (9.3%) patients, and penetrating (B3) in 336 (62.8%) patients. Comparisons among the groups of 53 patients with first-degree relatives only, the 96 patients with either first-, second-, or third-degree relatives (familial CD group), and the 439 patients with sporadic disease demonstrated no differences in sex, age at diagnosis, or disease location. There was a difference in disease behavior between the familial and sporadic groups (p = 0.048) that failed to exist when nonstricturing, nonpenetrating cases were excluded. No such difference was observed between the first-degree relatives only group and the sporadic group (p > 0.10). CONCLUSIONS: Using the Vienna Classification, familial and sporadic Crohn's disease differed only in disease behavior. However, this difference failed to exist after patients with nonstricturing, nonpenetrating disease were excluded. Therefore, familial and sporadic groups appear to be quite similar clinically, and family history does not appear to be a variable useful for disease subclassification.     

Stress hyperglycemia in general surgery: Why should we care?

Aims

To determine the frequency of increasing levels of stress hyperglycemia and its associated complications in surgery patients without a history of diabetes.

Validity of the multidimensional fatigue symptom inventory-short form in an African-American community-based sample

Objectives. This study examined the psychometric properties of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) in a community-based sample of African-Americans.

Design. A sample of 340 African-Americans (116 men, 224 women) ranging in age from 18–81 years were recruited from the community (e.g., churches, health fairs, and beauty salons). Participants completed a brief demographic survey, the MFSI-SF and the Positive and Negative Affect Schedule.

Results. The structural validity of the MFSI-SF for a community-based sample of African-Americans was not supported. The five dimensions of fatigue (General, Emotional, Physical, Mental, Vigor) found for Whites in prior research were not found for African-Americans in this study. Instead, fatigue, while multidimensional for African-Americans, was best represented by a unique four-four profile in which general and emotional fatigue are collapsed into a single dimension and physical fatigue, mental fatigue, and vigor are relatively distinct. Hence, in the absence of modifications, the MFSI-SF cannot be considered to be structurally invariant across ethnic groups. A modified four-factor version of the MFSI-SF exhibited excellent internal consistency reliability and evidence supports its convergent validity. Using the modified four-factor version, gender, and age were not meaningfully associated with MFSI-SF scores.

Conclusion. Future research should further examine whether modifications to the MFSI-SF would, as the findings suggest, improve its validity as a measure of multidimensional fatigue in African-Americans.