A putative role for hypothalamic glucocorticoid receptors in hypertension induced by prenatal undernutrition in the rat

Prenatal undernutrition induces hypertension later in life, possibly by disturbing the hypothalamo-pituitary-adrenal axis through programming decreased expression of hypothalamic glucocorticoid receptors. We examined the systolic blood pressure, heart rate and plasma corticosterone response to intra-paraventricular dexamethasone, mifepristone and corticosterone in eutrophic and prenatally undernourished young rats. Undernutrition was induced during fetal life by restricting the diet of pregnant mothers to 10 g daily (40% of diet consumed by well-nourished controls). At day 40 of postnatal life (i) intra-paraventricular administration of dexamethasone significantly reduced at least for 24 h both the systolic pressure (−11.6%), the heart rate (−20.8%) and the plasma corticosterone (−40.0%) in normal animals, while producing lower effects (−5.5, −8.7, and −22.3%, respectively) on undernourished rats; (ii) intra-paraventricular administration of the antiglucocorticoid receptor ligand mifepristone to normal rats produced opposite effects (8.2, 20.3, and 48.0% increase, respectively) to those induced by dexamethasone, being these not significant in undernourished animals; (iii) intra-paraventricular corticosterone did not exert any significant effect. Results suggest that the low sensitivity of paraventricular neurons to glucocorticoid receptor ligands observed in prenatally undernourished rats could be due to the already reported glucocorticoid receptor expression, found in the hypothalamus of undernourished animals.     

Maternal near miss and maternal death in the World Health Organization��s 2005 global survey on maternal and perinatal health

Objective

To develop an indicator of maternal near miss as a proxy for maternal death and to study its association with maternal factors and perinatal outcomes.

Methods

In a multicenter cross-sectional study, we collected maternal and perinatal data from the hospital records of a sample of women admitted for delivery over a period of two to three months in 120 hospitals located in eight Latin American countries. We followed a stratified multistage cluster random design. We assessed the intra-hospital occurrence of severe maternal morbidity and the latter’s association with maternal characteristics and perinatal outcomes.

Findings

Of the 97 095 women studied, 2964 (34 per 1000) were at higher risk of dying in association with one or more of the following: being admitted to the intensive care unit (ICU), undergoing a hysterectomy, receiving a blood transfusion, suffering a cardiac or renal complication, or having eclampsia. Being older than 35 years, not having a partner, being a primipara or para > 3, and having had a Caesarean section in the previous pregnancy were factors independently associated with the occurrence of severe maternal morbidity. They were also positively associated with an increased occurrence of low and very low birth weight, stillbirth, early neonatal death, admission to the neonatal ICU, a prolonged maternal postpartum hospital stay and Caesarean section.

Conclusion

Women who survive the serious conditions described could be pragmatically considered cases of maternal near miss. Interventions to reduce maternal and perinatal mortality should target women in these high-risk categories.     

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy

Background:

The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU.

Methods:

Genotyping of TYMS (5′TRP and 3′UTR), UGT1A1^*28, UGT1A9^*22 and UGT1A7^*3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis.

Results:

TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68–20.45; P=0.005). UGT1A1^*28/^*28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09–36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11–37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14–166.67; P=0.008). UGT1A9^*1/^*1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07–6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12–3.98; P=0.02).

Conclusion:

TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.     

Cost-effectiveness analysis of pemetrexed versus docetaxel in the second-line treatment of non-small cell lung cancer in Spain: results for the non-squamous histology population

Background  

The objective of this study was to conduct a cost-effectiveness evaluation of pemetrexed compared to docetaxel in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) for patients with predominantly non-squamous histology in the Spanish healthcare setting.     

Limited role for IVUS in the endovascular repair of aortoiliac aneurysms.

BACKGROUND: To determine the need for routine versus selective intraoperative IVUS during endovascular aortoiliac aneurysm (AIA) repair. METHODS: One-hundred and eighty-eight endovascular AIA repairs performed over a 5-year period were reviewed and included in the study. Surgeon-made aorto-uni-femoral grafts (n=78) and industry-made bifurcated or tube grafts (n=110) were used. In the initial 51 cases IVUS was routinely performed. In the latter 137 cases IVUS was used selectively. In this group graft deformities suspected on completion angiography or pullback pressure measurements were treated with balloon dilatation and stenting. IVUS was then performed only in the presence of a persistent pressure gradient or inconclusive angiographic findings. RESULTS: In the initial 51 cases IVUS revealed 20 lesions of which 8 were not initially detected angiographically and which required further treatment. In the latter 137 cases IVUS was necessary in only 1 case, and guided the treatment of an angiographically undetectable lesion. There have been no late episodes of graft compression, kinking, or thrombosis in the selective IVUS group. CONCLUSIONS: The use of pullback pressure measurements with a low threshold for angioplasty and stenting, especially in unsupported grafts, followed by the selective use of IVUS decreases the overall requirement for IVUS and its associated costs.     

A peptide derived from alpha-fetoprotein inhibits the proliferation induced by estradiol in mammary tumor cells in culture

This study was aimed to obtain additional information on the activity of a cyclized 9-amino acid peptide (cP) containing the active site of alpha fetoprotein, which inhibits the estrogen-stimulated proliferation of tumor cells in culture and of xenografts in immunodeficient mice. Breast cancer cells cultured in the presence of 2 nM estradiol were exposed to cP for different periods and their proliferation, estradiol binding parameters, clustering tendency and expression of E-cadherin and p21Cip1 were analyzed by biochemical and cell biology methods. The proliferation of MCF7 cells was significantly decreased by the addition of 2 microg/ml cP to the medium. cP did not increase cell death rate nor alter the number of binding sites for estradiol nor the endogenous aromatase activity of MCF7 cells. cP also decreased the proliferation of estrogen-dependent ZR75-1 cells but had no effect on estrogen-independent MDA-MB-231 cells. An increased nuclear p21Cip1 expression detected after cP treatment suggests that cP slows MCF7 cell proliferation via this regulator. We propose that cP could represent a novel breast cancer therapeutic agent whose mechanism of action is different from that of tamoxifen or of inhibitors of aromatase.     

A cyclic peptide derived from alpha-fetoprotein inhibits the proliferative effects of the epidermal growth factor and estradiol in MCF7 cells

A cyclic peptide derived from the active domain of alpha-fetoprotein (AFP) significantly inhibited the proliferation of MCF7 cells stimulated with the epidermal growth factor (EGF) or estradiol (E2). The action of these three agents on cell growth was independent of the presence of calf serum in the culture medium. Our results demonstrated that the cyclic peptide interfered markedly with the regulation of MAPK by activated c-erbB2. The cyclic peptide showed no effect on the E2-stimulated release of matrix metalloproteinases 2 and 9 nor on the shedding of heparin-binding EGF into the culture medium. We propose that the AFP-derived cyclic peptide represents a valuable novel antiproliferative agent for treating breast cancer.     

Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Background  

Experimental and clinical studies on sepsis have demonstrated activation of the innate immune response following the initial host–bacterial interaction. In addition, mechanical ventilation (MV) can induce a pulmonary inflammatory response. How these two responses interact when present simultaneously remains to be elucidated. We hypothesized that MV modulates innate host response during sepsis by influencing Toll-like receptor (TLR) signaling.