An updated physiologically based pharmacokinetic model for hexachlorobenzene: incorporation of pathophysiological states following partial hepatectomy and hexachlorobenzene treatment.

Physiologically based pharmacokinetic (PBPK) modeling is generally used for describing xenobiotic disposition in animals and humans with normal physiological conditions. We describe here an updated PBPK model for hexachlorobenzene (HCB) in male F344 rats with the incorporation of pathophysiological conditions. Two more features contribute to the distinctness of this model from the earlier published versions. This model took erythrocyte binding into account, and a particular elimination process of HCB, the plasma-to-gastrointestinal (GI) lumen passive diffusion (i.e., exsorption), was incorporated. Our PBPK model was developed using data mined from multiple pharmacokinetic studies in the literature, and then modified to simulate HCB disposition under the conditions of our integrated pharmacokinetics/liver foci bioassay. This model included plasma, erythrocytes, liver, fat, rapidly and slowly perfused compartments, and GI lumen. To account for the distinct characteristics of HCB absorption, the GI lumen was split into an upper and a lower part. HCB was eliminated through liver metabolism and the exsorption process. The pathophysiological changes after partial hepatectomy, such as alterations in the liver and body weights and fat volume, were incorporated in our model. With adjustment of the transluminal diffusion-related parameters, the model adequately described the data from the literature and our bioassay. Our PBPK model simulation suggests that HCB absorption and exsorption processes depend on exposure conditions; different exposure conditions dictate different absorption and exsorption rates. This model forms a foundation for our further exploration of the quantitative relationship between HCB exposure and development of preneoplastic liver foci.     

Absorption, distribution, metabolism, and elimination of 8-2 fluorotelomer alcohol in the rat.

The absorption, distribution, metabolism, and elimination of [3-14C] 8-2 fluorotelomer alcohol (8-2 FTOH, C7F1514CF2CH2CH2OH) following a single oral dose at 5 and 125 mg/kg in male and female rats have been determined. Following oral dosing, the maximum concentration of 8-2 FTOH in plasma occurred by 1 h postdose and cleared rapidly with a half-life of less than 5 h. The internal dose to 8-2 FTOH, as measured by area under the concentration-time curve to infinity, was similar for male and female rats and was observed to increase in a dose-dependent fashion. The majority of the 14C 8-2 FTOH (> 70%) was excreted in feces, and 37-55% was identified as parent. Less than 4% of the administered dose was excreted in urine, which contained low concentrations of perfluorooctanoate (approximately 1% of total 14C). Metabolites identified in bile were principally composed of glucuronide and glutathione conjugates, and perfluorohexanoate was identified in excreta and plasma, demonstrating the metabolism of the parent FTOH by sequential removal of multiple CF2 groups. At 7 days postdose, 4-7% of the administered radioactivity was present in tissues, and for the majority, 14C concentrations were greater than whole blood with the highest concentration in fat, liver, thyroid, and adrenals. Distribution and excretion of a single 125-mg/kg [3-14C] 8-2 FTOH dermal dose following a 6-h exposure in rats was also determined. The majority of the dermal dose either volatilized from the skin (37%) or was removed by washing (29%). Following a 6-h dermal exposure and a 7-day collection period, excretion of total radioactivity via urine (< 0.1%) and feces (< 0.2%) was minor, and radioactivity concentrations in most tissues were below the limit of detection. Systemic availability of 8-2 FTOH following dermal exposure was negligible.     

Assessing the feasibility of harm reduction services for MSM: the late night breakfast buffet study

Background  

Despite the leveling off in new HIV infections among men who have sex with men (MSM) in San Francisco, new evidence suggests that many recent HIV infections are linked with the use of Methamphetamine (MA). Among anonymous HIV testers in San Francisco, HIV incidence among MA users was 6.3% compared to 2.1% among non-MA users. Of particular concern for prevention programs are frequent users and HIV positive men who use MA. These MSM pose a particular challenge to HIV prevention efforts due to the need to reach them during very late night hours.     

Maternal pre-pregnancy overweight status and obesity as risk factors for cesarean delivery.

OBJECTIVE: To determine the extent to which, if at all, maternal pre-pregnancy adiposity and other anthropometric factors are related to risk of cesarean delivery. METHODS: This hospital-based prospective cohort study included 738 nulliparous women who initiated prenatal care prior to 16 weeks gestation. Participants provided information about their pre-pregnancy weight and height and other sociodemographic and reproductive covariates. Labor and delivery characteristics were obtained from maternal and infant medical records. Risk ratios (RR) and 95% CI were estimated by fitting generalized linear models. RESULTS: The proportion of cesarean deliveries in this population was 26%. Women who were overweight (BMI 25.00-29.99 kg/m2) were twice as likely to deliver their infants by cesarean section as lean women (BMI<20.00 kg/m2) (RR=2.09; 95% CI 1.27-3.42). Obese women (BMI>or=30.00 kg/m2) experienced a three-fold increase in risk of cesarean delivery when compared with this referent group (RR=3.05; 95% CI 1.80-5.18). The joint association between maternal pre-pregnancy overweight status and short stature was additive. When compared with tall (height>or=1.63 m), lean women, short (<1.63 m), overweight (BMI>or=25.00 kg/m2) women were nearly three times as likely to have a cesarean delivery (RR=2.79; 95% CI 1.72-4.52). CONCLUSION: Our findings suggest that nulliparous women who are overweight or obese prior to pregnancy, and particularly those who are also short, have an increased risk of delivering their infants by cesarean section.     

Chemoprevention of colorectal cancer by inhibition of cyclooxygenase-2 derived prostaglandin E2 signaling: Recent advances in basic biology

Experimental evidence collected over the past decade has revealed that targeting cyclooxygenase-2 (COX-2) may have some efficacy for chemoprevention of cancer. However, recent safety concerns over the long-term use of COX-2 selective inhibitors are prompting research aimed at identifying other specific targets downstream of COX-2. In this regard, several groups have found that NSAIDs and COX-2 selective inhibitors primarily reduce the production of prostaglandin (PG) E2, a biologically active lipid product of the COX-2 enzyme, which results in attenuation of PGE2 signaling in the tumor microenvironment. Therefore, a detailed understanding of the PGE2 signaling pathway in transformed cells is critical to help identify novel and safer targets for effective prevention and/or treatment of cancer. Here we review the recent advances in elucidating the molecular mechanisms by which PGE2 promotes carcinogenesis.     

眼眶硬化性骨髓外造血细胞瘤

骨髓外造血细胞瘤可发生于包括骨髓纤维化、慢性骨髓性门血病和非常少见的红细胞增多症等骨髓增殖紊乱时。当纤维巨细胞增值伴有坚硬肿块形成时，该区域被称为硬化性骨髓外造血细胞瘤（SEMHTs），据我们所知．我们描述的是第一例发生于双侧眼眶SEMHTs的多发性骨髓纤维变中性。     

Intracystic Breast Carcinoma with Giant Axillary Metastasis: A Case Report

Abstract: Cystic breast disease is the most frequent cause of benign breast masses. While breast cysts are common, intracystic lesions, especially intracystic carcinomas, are rare. Furthermore, while breast carcinoma is the most common cancer in women, intracystic breast cancers are rare. Most intracystic breast carcinomas have been described as either papillary or medullary subtypes with infiltrating ductal carcinomas being much less common. The literature has shown their incidence to range from 0.3% to 7% of all breast carcinomas. We describe an interesting case of a premenopausal woman with a large cystic breast carcinoma and review the literature.     

Predictors of smoking initiation and cessation among childhood cancer survivors: a report from the childhood cancer survivor study.

PURPOSE: To examine the determinants of smoking behavior among participants in the Childhood Cancer Survivors Study (CCSS). METHODS: This retrospective cohort survey study was conducted among 9,709 childhood cancer survivors. Main outcomes included smoking initiation and cessation. RESULTS: Twenty-eight percent of patients reported ever smoking and 17% reported being current smokers. Standardized to United States population rates, the observed to expected (O/E) ratios and corresponding 95% confidence limits (95% CL) of cigarette smoking were 0.72 (95% CL, 0.69, 0.75) among all survivors and 0.71 (95% CL, 0.68 to 0.74) and 0.81 (95% CL, 0.70, 0.93) among whites and nonwhites, respectively. Significantly lower O/E ratios were present among both males (O/E, 0.73) and females (O/E, 0.70). Factors independently associated with a statistically significant relative risk of smoking initiation included older age at cancer diagnosis, lower household income, less education, not having had pulmonary-related cancer treatment, and not having had brain radiation. Blacks were less likely to start smoking. Survivors who smoked were significantly more likely to quit (O/E, 1.22; 95% CL, 1.15, 1.30). Among ever-smokers, factors associated with the likelihood of being a current smoker included age less than 13 years at smoking initiation, less education, and having had brain radiation; those age less than 3 years at cancer diagnosis were significantly more likely to be ex-smokers. CONCLUSIONS: Although survivors in the CCSS cohort seem to be smoking at rates below the general population, interventions are needed to prevent smoking initiation and promote cessation in this distinct population.