Aggregation of childhood leukemia in geographic areas of Greece)

A total of 872 children aged up to 14 years, who were diagnosed withleukemia in Greece during the decade 1980-89, were allocated by place ofresidence to the 601 administrative districts of the country. Evaluation ofspatial clustering was done using the Potthoff-Whittinghill method, whichvalidly assesses heterogeneity of leukemia risk among districts with variableexpected numbers of cases. There was highly significant evidence for spatialclustering occurring particularly among children living in urban and, to alesser extent, semi-urban areas. The evidence was stronger for childrenyounger than 10 years old, applied also to children in different five-yearage groups, and persisted when cases of acute lymphoblastic leukemia wereanalyzed separately. These findings provide support to the hypothesis thatlocalized environmental exposures could contribute to the etiology ofchildhood leukemia, but they cannot distinguish between exposures of physicalor chemical nature, nor can they exclude socially conditioned patterns ofexposure to infectious agents.     

Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection

Several studies have suggested that respiratory syncytial virus (RSV) bronchiolitis induced the change of cytokine production profile in childhood. We sought to determine whether the RSV-induced cytokine production was affected by the patient's atopic background. We quantified interferon-gamma (IFN-gamma) and interleukin (IL)-4 in the supernatant of peripheral blood mononuclear cells (PBMCs) cultured for 24 h and in the presence of phytohemaglutinin (PHA), IL-12, or IL-18, from 14 infants who were divided into two groups, those who are non-atopic and an atopic group. In RSV-infected infants with atopic diseases, IFN-gamma production from IL-12- or especially IL-18-stimulated PBMCs was subtotally suppressed in the acute phase, whereas in RSV-infected infants without atopic diseases IFN-gamma production was not suppressed on acute phase. The IFN-gamma suppression observed in the atopic group is not caused by the immaturity of an infant's immune system since reduced IFN-gamma production to RSV is not observed in the infants of non-atopic group. IFN-gamma suppression in regard to RSV infection might be caused by some genetic factor involved in the development of atopic disease such as IL-18 signal cascade.     

Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers.

Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites.     

Functional involvement of rat organic anion transporter 2 (Slc22a7) in the hepatic uptake of the nonsteroidal anti-inflammatory drug ketoprofen.

Rat organic anion transporter 2 (rOat2, Slc22a7) is a sinusoidal multispecific organic anion transporter in the liver. The role of rOat2 in the hepatic uptake of drugs has not been thoroughly investigated yet. rOat2 substrates include nonsteroidal anti-inflammatory drugs, such as ketoprofen, indomethacin, and salicylate. In the present study, the uptake of ketoprofen, indomethacin, and salicylate by freshly isolated rat hepatocytes was characterized. The uptake of ketoprofen, indomethacin, and salicylate by hepatocytes was sodium-independent, and the rank order of their uptake activities was indomethacin > ketoprofen > salicylate. Kinetic analysis based on Akaike's Information Criterion suggested that the uptake of ketoprofen and indomethacin by hepatocytes consists of two saturable components and one nonsaturable one. The K(m) and V(max) values for the high- and low-affinity components for ketoprofen uptake were 0.84 and 97 microM and 35 and 1800 pmol/min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 microM and 130 and 16,000 pmol/min/mg protein, respectively. The K(m) values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 microM for ketoprofen and indomethacin, respectively). The uptake of ketoprofen by hepatocytes was significantly inhibited by probenecid and rOat2 inhibitors (indocyanine green, indomethacin, glibenclamide, and salicylate). Other inhibitors of rOatps (taurocholate and pravastatin) and rOat3 (pravastatin and p-aminohippurate) had a slight effect, but digoxin had no effect. These results suggest that rOat2 accounts partly for the hepatic uptake of ketoprofen and, presumably, indomethacin as a high-affinity site and that other transporters, such as rOatps, but not rOatp2, and rOat3, are also involved.     

Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients.

PURPOSE: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy. EXPERIMENTAL DESIGN: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days. RESULTS: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments. CONCLUSIONS: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases.     

Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat.

Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products.     

Maternal death reviews at a rural hospital in Malawi

ObjectiveTo analyze maternal deaths at Nkhoma Church of Central Africa Presbyterian (CCAP) Hospital and identify factors causing delays in care.MethodsMaternal death audits are performed after every maternal death at Nkhoma CCAP Hospital. Information regarding the care provided at the health facility, the referral process, and any delays in the community was collected by an audit team using a structured approach. Data from August 2007 to September 2011 were analyzed retrospectively.ResultsIn total, 61 maternal deaths occurred during the study period, of which 58 were analyzed. Most deaths were categorized as indirect (n = 34 [58.6%]). Non-pregnancy-related infections were the leading cause of indirect death (n = 22), with meningitis the most common (n = 13). Most patients experienced a delay in seeking care (n = 37 [63.8%]), a transport delay (n = 43 [74.1%]), or a delay in receiving adequate care (n = 34 [58.6%]).ConclusionMost maternal deaths had indirect causes and were associated with delays in all phases. An audit makes clear which part of the referral chain needs to be strengthened. Nkhoma CCAP Hospital has taken steps to address all phases of delay.     

Parental loss of family members within two years of offspring birth predicts elevated absorption scores in college

Liotti proposed that interactions during infancy with a parent suffering unresolved loss could lead to vulnerabilities to altered states of consciousness. Hesse and van IJzendoorn provided initial support for Liotti’s hypothesis, finding elevated scores on Tellegen’s Absorption Scale - a normative form of dissociation - for undergraduates reporting that their parents had experienced the loss of family members within two years of their birth. Here, we replicated the above findings in a large undergraduate sample (N = 927). Additionally, we investigated mother’s and father’s losses separately. Perinatal losses, including miscarriage, were also considered. Participants reporting that the mother or both parents had experienced loss within two years of their birth scored significantly higher on absorption than those reporting only perinatal, only father, or no losses. While not applicable to the assessment of individuals, the brief loss questionnaire utilized here could provide a useful addition to selected large-scale studies.     

Epstein–Barr virus positivity among surgically resected intramucosal gastric cancer

Epstein–Barr virus‐associated gastric cancer (EBV‐GC) accounts for approximately 8% of gastric cancers. However, little is known regarding intramucosal EBV‐GC. The present study aimed to evaluate endoscopic and clinicopathological characteristics of intramucosal EBV‐GC. Pathological data of 172 patients with 173 intramucosal gastric cancers who received gastrectomy with lymph node dissection were obtained for review. EBV‐encoded small RNA in situ hybridization (EBER‐ISH) was carried out using a tissue microarray block. Eight intramucosal early gastric cancers (4.6%) were EBER‐ISH positive in which no cases had any lymph node metastasis. Macroscopic types were either depressed or flat, dominant histology was mixed type of moderate and poorly differentiated adenocarcinoma. In detail, histological features of “lace pattern” or “lymphocyte infiltration into the stroma or cancer nests” were observed.