The expression of activin-betaA- and -betaB-subunits, follistatin, and activin type II receptors in fallopian tubes bearing an ectopic pregnancy

CONTEXT: Ectopic pregnancy is a major cause of maternal morbidity and mortality with increasing incidence worldwide. OBJECTIVE: We investigated whether epithelia from Fallopian tubes (FTs) bearing an ectopic pregnancy differ from normal tubes in expression of TGF-beta family and related proteins and their receptors. METHODOLOGY: Because it is not possible to collect FTs from women carrying a healthy pregnancy, we studied tissue collected at the time of hysterectomy for benign disease. Women were injected with human chorionic gonadotropin in the days leading up to hysterectomy to produce a state of pseudopregnancy. Pseudopregnancy status was confirmed by the presence of high serum progesterone levels and the decidualization of the endometrium. Fifteen FTs bearing ectopic pregnancy and six pseudopregnant tubes were collected and examined using immunohistochemistry and quantitative RT-PCR. RESULTS: Immunohistochemistry demonstrated clear staining for the betaA- and betaB-subunits, type II receptor group comprising the activin type IIA and type IIB receptors, and follistatin, which increased in intensity from the isthmus to the ampulla in both models. However, the intensity of expression of these molecules was stronger in the ectopic pregnancy group when compared with the pseudopregnant group. Quantitative RT-PCR showed significant decrease in mRNA levels of betaA-subunit, activin type IIA and IIB receptors, and follistatin in ectopic group (P < 0.05) but no changes in betaB-subunit (P > 0.05). Overall, there was an apparent paradox of high concentration of protein but low mRNA expression. CONCLUSION: Activin-A may stimulate tubal decidualization and trophoblast invasion. A better understanding of the mechanism by which an embryo implants in the tubal epithelium may lead to improved methods for early diagnosis and/or management of ectopic pregnancy.     

The impact of metabolic syndrome and prevalent liver disease on living donor liver transplantation: a pressing need to expand the pool

Background and aims

Organ shortage has been the ongoing obstacle to expanding liver transplantation worldwide. Living donor liver transplantation (LDLT) is hoped to improve this shortage. The aim of the present study is to analyze the impact of metabolic syndrome and prevalent liver disease on living donations.

Methods

From July 2007 to May 2012, 1065 potential living donors were evaluated according to a stepwise evaluation protocol. The age of the worked-up donors ranged from 18 to 45 years.

Results

Only 190 (18 %) were accepted for donation, and 875 (82 %) were rejected. In total, 265 (24.9 %) potential donors were excluded because of either diabetes or a body mass index >28. Some potential donors were excluded at initial screening because of incompatible blood groups (115; 10.8 %), social reasons (40; 3.8 %), or elevated liver enzymes (9; 1 %). Eighty-five (8 %) donors were excluded because of positive hepatitis serology. Steatosis resulted in the exclusion of 84 (8 %) donors. In addition, 80 (7.5 %) potential donors were rejected because of variations in biliary anatomy, and 20 (2 %) were rejected because of aberrant vascular anatomy. Rejection due to biliary-related aberrancy decreased significantly in the second half of our program (11 vs. 4 %, p = 0.001). In total, 110 (10.3 %) potential donors were rejected because of insufficient remnant volume (<30 %) as determined by CT volumetry, whereas 24 (2.2 %) were rejected because of a graft-to-recipient body weight ratio less than 0.8 %.

Conclusion

Metabolic syndrome and viral hepatitis negatively impacted our living donor pool. Expanding the donor pool requires the implementation of new strategies.

     

The development of epithelial phenotypes in the human fetal and infant breast

In order to explain the molecular events that contribute to benign and malignant breast disease, it is essential to understand the cellular context in which these are occurring. This study describes a detailed analysis of the epithelial phenotypes in the human fetal and infant breast and provides a starting point for such consideration. Using methacarn-fixed, paraffin sections from ten fetal and 45 infant breast, immunostained with a panel of antibodies to cytoskeletal proteins and κ-casein, it has been possible to define in detail the chronological evolution of the major cell types in the human breast from 16 weeks of intrauterine life to 2 years of age, in both sexes. Cells at the tips of the lobular buds and terminal end buds have a characteristic cytoskeletal protein profile, suggesting that they may have the capacity to generate both basal cells and luminal cells. Based on the expression of cytoskeletal proteins in the developing fetal and infant breast, a model system has been proposed for mammary epithelial differentiation. © 1998 John Wiley & Sons, Ltd.     

Assessment of the effect of interval from presentation to surgery on outcome in patients with peri-ampullary malignancy

BackgroundDelay between diagnosis of peri-ampullary cancer (PC) and surgery may allow tumour progression and affect outcome. The aim of this study was to explore associations of interval to surgery (IS) with pathological outcomes and survival in patients with PC.MethodA database review of all patients undergoing surgery between 2006 and 2014 was undertaken. IS was measured from diagnosis by imaging. Potential association between IS and survival was measured using Cox regression analysis, and between IS and pathological outcome with multivariate logistic analysis.Results388 patients underwent surgery. The median IS was 49 days (1–551 days), and was not associated with any of the evaluated outcomes in patients with pancreatic (149) or distal bile duct (46) cancer. For patients with ampullary cancer (71) longer IS was associated with improved survival, with median survival of 27.5 months for patients waiting ≤ median IS (35) and 38.3 months for patients waiting > median IS (36) for surgery (p = 0.041). A higher rate of margin positivity (31.4%) was also noted among patients who waited less than the median IS compared to those waiting longer than this interval (11.4%) (p = 0.032).ConclusionFor patients with ampullary cancer there is a paradoxical improvement in outcome among those with a longer IS, which may be explained by progression to inoperability of more aggressive lesions.     

Hyperuricemia,Hypertension, and Chronic Kidney Disease: an Emerging Association

Uric acid is a product of purine metabolism and has been linked to gout and kidney calculi. Chronic kidney disease (CKD) and hypertension (HTN) are two major public health problems, and both are associated with increased risk of cardiovascular events. Emerging evidence suggests a pathogenic role of hyperuricemia in the development of HTN and CKD, in addition to progression of CKD, by inducing renal inflammation, endothelial dysfunction, and activation of the renin-angiotensin system. In addition, several epidemiological studies have linked hyperuricemia with an increased risk of HTN and CKD. A few clinical trials have assessed the use of uric acid-lowering therapies such as allopurinol and febuxostat in the management of HTN and delaying progression of CKD. To date, most of these trials are short-term with a small sample size; however, their results are encouraging and provide a rationale for larger randomized controlled trials to establish the role of uric acid-lowering therapies in the management of HTN, in addition to prevention of CKD progression and cardiovascular events.     

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar^?) and Europe (Evoltra^?) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2?h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7?h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3?years old weighing 16?kg with an eCrCL of 138?mL/min/1.73?m², the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3?L/h (1.14?L/h/kg) and 92.9?L (5.81?L/kg), respectively. ??- and ??-half-life were 0.9 and 4.4?h, respectively. For an elderly patient 82?years old weighing 96?kg with an eCrCL of 46?mL/min/1.73?m², the population estimates for CL and Vdss were 21.5?L/h (0.22?L/h/kg) and 257.4?L (268?L/kg), respectively. ??- and ??-half-life were 0.5 and 10.6?h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60?mL/min/1.73?m²) and severe (eCrCL <30?mL/min/1.73?m²) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1?h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9?h (range 3.9 to 6.2?h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies.