Masculinization of the European sea bass (Dicentrarchus labrax) by treatment with an androgen or aromatase inhibitor involves different gene expression and has distinct lasting effects on maturation

The objective of this study was to contribute to our understanding of the role of sex steroids in fish sex differentiation and male maturation. Sexually undifferentiated sea bass were administered 17α-methyldihydrotestosterone (MDHT), estradiol-17β (E₂), fadrozole (Fz), cyproterone acetate (CPA) or tamoxifen (Tx). MDHT produced 100% males whereas E₂ and Tx resulted in 100% females. Fz produced 95% males while CPA did not alter sex ratios. E₂ treatment did not affect gonadal aromatase (cyp19a) expression levels, supporting the possibility that the feminizing effect of exogenous E₂ are not directly related to cyp19a regulation. Both MDHT and Fz decreased cyp19a expression. Moreover, androgen receptor (ar) expression levels increased during development in all but the MDHT group, suggesting that early exposure to an androgen down-regulates subsequent ar expression in males and that Fz does not interact with the androgen receptor. Together, these observations indicate that although MDHT and Fz result in a similar phenotype, the molecular pathways involved are likely different, and show that Fz masculinization is the consequence of inhibited ovarian differentiation rather than of a direct androgenic effect. Further, since CPA did not alter sex ratios when administered during the period of highest androgen sensitivity, we suggest that androgens are not required for initial testicular differentiation in the sea bass. MDHT and Fz did not alter the number of precocious males but reduced and increased, respectively, their gonadosomatic index (GSI). In addition, Fz had lasting effects on the GSI of precocious and non-precocious males, probably due to alterations of estrogen function in the testis.     

Autologous blood stem cell transplantation for acute myeloblastic leukemia in first complete remission. Intensification therapy before transplantation does not prolong disease-free survival

BACKGROUND AND OBJECTIVE: To compare the clinical results of two consecutive therapeutic protocols including autologous blood stem cell transplantation (ABSCT) for patients with de novo acute myeloblastic leukemia (AML) in first complete remission (CR1). DESIGN AND METHODS: Between November 1989 and January 1997, 50 patients with AML in CR1 underwent ABSCT using two consecutive protocols. In the first one (Group A, 25 patients) peripheral blood stem cells (PBSC) were collected after induction and consolidation chemotherapy courses, and ABSCT was performed immediately thereafter. In the subsequent 25 patients (Group B), PBSC were collected after consolidation alone, and a further chemotherapy course with intermediate dose cytarabine (Ara-C 1 g/m2/12 h x3 days) and mitoxantrone (12 mg/m2/d x3 days) was administered as early intensification. The conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) in every case. RESULTS: Hematopoietic engraftment was slightly quicker in Group B, with median times to reach 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L being 13 and 12 days in Group A and 12 and 11 days in Group B, respectively. There were three graft failures (8%) (2 in Group A and 1 in Group B) and three transplant-related deaths (8%) (2 in Group A and 1 in Group B). No significant differences were observed between the groups in terms of relapse (64% at 4-years in Group A and 81% in Group B). Likewise, the actuarial 4-year disease-free survival (DFS) was not significantly different between the two groups (32% v 18%). INTERPRETATION AND CONCLUSIONS: Our study confirms that AML patients in CR1 receiving ABSCT have rapid engraftment with low mortality. However, autologous transplants with PBSC collected after consolidation chemotherapy were still associated with a high rate of relapse (RR). This RR was not apparently reduced by the administration of intermediate dose Ara-C before transplantation.     

Human papillomavirus distribution in invasive cervical carcinoma in sub‐Saharan Africa: could HIV explain the differences?

Objectives To describe human papillomavirus (HPV) distribution in invasive cervical carcinoma (ICC) from Mali and Senegal and to compare type‐specific relative contribution among sub‐Saharan African (SSA) countries. Methods A multicentric study was conducted to collect paraffin‐embedded blocks of ICC. Polymerase chain reaction, DNA enzyme immunoassay and line probe assay were performed for HPV detection and genotyping. Data from SSA (Mozambique, Nigeria and Uganda) and 35 other countries were compared. Results One hundred and sixty‐four ICC cases from Mali and Senegal were tested from which 138 were positive (adjusted prevalence = 86.8%; 95% CI = 79.7–91.7%). HPV16 and HPV18 accounted for 57.2% of infections and HPV45 for 16.7%. In SSA countries, HPV16 was less frequent than in the rest of the world (49.4%vs. 62.6%; P < 0.0001) but HPV18 and HPV45 were two times more frequent (19.3%vs. 9.4%; P < 0.0001 and 10.3%vs. 5.6%; P < 0.0001, respectively). There was an ecological correlation between HIV prevalence and the increase of HPV18 and the decrease of HPV45 in ICC in SSA (P = 0.037 for both). Conclusion HPV16/18/45 accounted for two‐thirds of the HPV types found in invasive cervical cancer in Mali and Senegal. Our results suggest that HIV may play a role in the underlying HPV18 and HPV45 contribution to cervical cancer, but further studies are needed to confirm this correlation.     

Nocardiosis pulmonar en pacientes con EPOC: características y factores pronósticos

Introduction

Pulmonary nocardiosis (PN) is a severe infection with a high morbidity and mortality that mainly affects immunocompromised patients. In recent years, an increase in PN cases has been detected among patients with chronic obstructive pulmonary disease (COPD). The factors that are associated with its presence and determine its prognosis remain unknown.

Methods

Retrospective study of COPD patients diagnosed with PN over the period from 1997-2009 at the Hospital de la Santa Creu i Sant Pau, in Barcelona (Spain). Demographic, clinical, microbiological and evolution data were evaluated in all cases

Results

Thirty patients were identified with PN and COPD. Mean age (standard deviation) was 76 (7) years and the mean FEV₁ was 40 (14)%. Chronic respiratory failure was observed in 56,7% patients and 51,7% had received systemic corticosteroid therapy previous to the PN diagnosis. The most common symptoms were cough and dyspnea (90%). Alveolar infiltrates were observed in 60% of the cases. The most frequently isolated Nocardia species was N. cyriacigeorgica (68%). The one-month mortality rate was 17%, while the one-year mortality rate was 33%. The factors associated with mortality within the first year included previous systemic corticosteroid treatment, less than three months of specific antibiotic therapy and active associated neoplasm.

Conclusions

PN affects patients with moderate-severe COPD and has high short- and mid-term mortality rates. Previous corticosteroid treatment, specific antibiotic therapy for less than 3 months and active neoplasia were factors associated with mortality.     

Effect of bariatric surgery on cardiac structure and function in obese patients: Role of the renin‐angiotensin system

Echocardiographic alterations have been described in obesity, but their modifications after bariatric surgery (BS) and mechanisms are little known, mostly in normotensive patients. We aimed to analyze cardiac changes 1 year post‐BS and to explore possible mechanisms. A cohort of patients with severe obesity (58% normotensives) were prospectively recruited and examined before surgery and after 12 months. Clinical and echocardiographic data, 24 h BP, renin‐angiotensin‐aldosterone system (RAAS) components, cytokines, and inflammatory markers were analyzed at these two time points. Overall reduction in body weight was mean (IQR) = 30.0% (25.9–33.8). There were statistically significant decreases in left ventricle mass index^2.7(LVMI)^2.7, septum thickness (ST), posterior wall thickness (PWT), relative wall thickness (RWT), and E/e’, both in the whole cohort and in patients without RAAS blockers (p ≤ .04 for all). Plasma renin activity (PRA) decreased from (median, IQR) = 0.8 (0.3;1.35) to 0.4 (0.2;0.93) ng/ml/h, plasma aldosterone from 92 (58.6;126) to 68.1 (56.2;83.4) ng/dl, and angiotensin‐converting enzyme (ACE)‐2 activity from 7.7 (5.7;11.8) to 6.8 (5.3;11.2) RFU/µl/h, p < .05. The body weight loss correlated with a decrease in both 24 h SBP and 24 h DBP (Pearson''s coefficient 0.353, p = .022 and 0.384, p = .012, respectively). Variation (Δ) of body weight correlated with ΔE/e’ (Pearson''s coeff. 0.414, p = .008) and with Δ lateral e’ (Pearson''s coeff. = −0.363, p = .018). Generalized linear models showed that ΔPRA was an independent variable for the final (12‐months post‐BS) LVMI^2.7 (p = .028). No other changes in cardiac parameters correlated with ΔBP. In addition to the respective baseline value, final values of PWT and RWT were dependent on 12‐month Δ of PRA, ACE, and ACE/ACE2 (p < .03 for all). We conclude that there are cardiac changes post‐BS in patients with severe obesity, normotensives included. Structural changes appear to be related to modifications in the renin‐angiotensin axis.     

Organ damage changes in patients with resistant hypertension randomized to renal denervation or spironolactone: The DENERVHTA (Denervación en Hipertensión Arterial) study

Renal denervation and spironolactone have both been proposed for the treatment of resistant hypertension, but their effects on preclinical target organ damage have not been compared. Twenty‐four patients with 24‐hour systolic blood pressure ≥140 mm Hg despite receiving three or more full‐dose antihypertensive drugs, one a diuretic, were randomized to receive spironolactone or renal denervation. Changes in 24‐hour blood pressure, urine albumin excretion, arterial stiffness, carotid intima‐media thickness, and left ventricular mass index were evaluated at 6 months. Mean baseline‐adjusted difference between the two groups (spironolactone vs renal denervation) at 6 months in 24‐hour systolic blood pressure was −17.9 mm Hg (95% confidence interval [CI], −30.9 to −4.9; P = .01). Mean baseline‐adjusted change in urine albumin excretion was −87.2 (95% CI, −164.5 to −9.9) and −23.8 (95% CI, −104.5 to 56.9), respectively (P = .028). Mean baseline‐adjusted variation of 24‐hour pulse pressure was −13.5 (95% CI, −18.8 to −8.2) and −2.1 (95% CI, −7.9 to 3.7), respectively (P = .006). The correlation of change in 24‐hour systolic blood pressure with change in log‐transformed urine albumin excretion was r = .713 (P < .001). At 6 months there was a reduction in albuminuria in patients with resistant hypertension treated with spironolactone as compared with renal denervation.     

Effects of <Emphasis Type="Italic">S</Emphasis>-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback

Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca²⁺ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n?=?10); (b) S-nitrosoglutathione 10 µM (n?=?11); and (c) S-nitrosoglutathione 50 µM (n?=?11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 µM did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6?±?1.7 vs. 21.3?±?3.8 Hz; p?<?0.0001) and reduction of percentile 5 of the activation intervals (42?±?3 vs. 38?±?4 ms; p?<?0.05) induced by stretch. In contrast, at baseline using the 50 µM concentration, percentile 5 was shortened (38?±?6 vs. 52?±?10 ms; p?<?0.005) and the complexity index increased (1.77?±?0.18 vs. 1.27?±?0.13; p?<?0.0001). The greatest complexity indices (1.84?±?0.17; p?<?0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 µM attenuates the effects of mechanoelectric feedback, while at a concentration of 50 µM the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.