Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats

The prevalence of major depressive disorder (MDD) in adult men is roughly half that of women. Clinical evidence supports a protective effect of androgens against depressive disorders in men. The developing brain is subject to androgen exposure but a potential role for this in depression during adulthood has not been considered. In order to explore this question we treated newborn male rat pups with the androgen receptor antagonist flutamide to block endogenous androgen action and then conducted behavioral tests prior to puberty. Depression-like behaviors were assessed with the Forced Swim Test (FST) and the Sucrose Preference Test (SPT), and anxiety-like behaviors were assessed with the Open Field Test (OFT) and the Novelty-Suppressed Feeding Test (NSFT). Compared to the vehicle-treated controls, neonatal-flutamide treatment caused a significant increase in depression-like behaviors in preadolescent male rats but did not cause any significant difference in anxiety-like behaviors. In separate experiments, male pups with and without flutamide treatment were injected with 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU) from postnatal day (PND) 1 to 4 to label newly produced cells or the hippocampi were Golgi-Cox imbedded and pyramidal neurons visualized. Three lines of evidence indicate neonatal flutamide treatment inhibits hippocampal neurogenesis and neuronal dendritic spine formation in preadolescent male rats. Compared to vehicle controls, flutamide treatment significantly decreased (1) the number of microtubal associated protein-2+ (MAP-2) neurons in the CA1 region, (2) the number of MAP-2+ neurons in the dentate gyrus (DG) region of the hippocampus, and (3) the density of dendritic spines of pyramidal neurons in the CA1 region. However, there was no effect of flutamide treatment on the number of glial fibrillary acidic protein (GFAP)+ or GFAP+/BrdU+ cells in the hippocampus. This study suggests that the organizational effect of androgen-induced hippocampal neurogenesis is antidepressant.     

De novo chromosomal abnormalities and month of conception

OBJECTIVES: We set out to study the possible relationship between the occurrence of chromosomal abnormalities and the month of conception using data from 7 years of prenatal diagnosis. METHODS: The sample included 7439 cytogenetic analyses from amniocentesis performed for conceptions between 1997 and 2003. The monthly prevalence of all de novo chromosomal abnormalities, trisomies, including trisomy 21, and Robertsonian translocations was investigated. RESULTS: Two hundred and four de novo numerical and structural chromosomal abnormalities (2.7%) were detected. A significant decrease in the frequencies of all de novo chromosomal abnormalities for June conceptions, as well as lower summer occurrences of trisomy 21, were found. In addition, de novo Robertsonian translocations were unexpectedly detected only among December conceptions. CONCLUSIONS: The relationship between chromosomal abnormalities and the month of conception could turn out to be useful in estimating the actual risk in pregnancy, if confirmed by other studies. The observed June lowest rate might indicate an association between chromosomal abnormalities and the maximum number of daylight hours throughout the year (summer solstice). We cannot explain the unusual findings concerning Robertsonian translocations that were only found for conceptions in December. This may be related to the annual minimum daylight hours (winter solstice) as opposed to the summer solstice.     

Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome

AIM:To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.METHODS:Between January 1992 and June 2012,28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1(MEN1)syndrome underwent surgery at our institution.This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome(ZES).Surgical treatment consisted of duodenopancreatectomy(DP)or total pancreatectomy(TP).Regional lymphadenectomy was always performed.Any hepatic tumoral lesions found were removed during surgery.In MEN1 patients,removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia.One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors.This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.RESULTS:Seventeen MEN1 patients affected with ZES were analyzed.The mean age was 40 years.Fifteen patients underwent DP and two TP.On histopathological examination,duodeno pancreatic endocrine tumors were found in all 17 patients.Eighty-one gastrinomas were detected in the first three portions of the duodenum.Only one gastrinoma was found in the pancreas.The mean number of gastrinomas per patient was 5(range 1-16).Malignancy was established in 12 patients(70.5%)after lymph node,liver and omental metastases were found.Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s).In two cases,the ectopic gastrinoma was removed at the same time as pancreatic surgery,while in the third case,the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.CONCLUSION:These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.     

Maxillary sinus augmentation with platelet-rich plasma and fibrinogen cryoprecipitate: a tomographic pilot study

The purpose of this study was to evaluate the clinical efficacy of platelet-rich plasma, autologous bone, and autologous fibrinogen as cryoprecipitate in maxillary sinus augmentation procedures. Six patients (age range, 29-58) undergoing sinus augmentation procedures were included in the study. Platelet-rich plasma and autologous fibrinogen in the form of cryoprecipitate were prepared from 300 ml of blood. Sinus augmentation was performed with intraoral bone grafts, platelet-rich plasma, and cryoprecipitate. The amount of regeneration was then evaluated quantitatively and qualitatively with Spiral TC (Dentascan) pre- and postoperatively 6 months after the intervention. Orthopantomography was performed preoperatively 3 and 6 months after the surgery. A mean platelet concentration of 320.5% was obtained from the baseline platelet blood count. The tomographic analysis indicated an average bone augmentation of 6.27 mm (range, 3.5-10 mm). Radiologically, a satisfactory morphological recovery of the maxillary jaw was obtained. No graft resorption was noticed. Orthopantomography indicated mineralization as early as 3 months postoperatively in the entire study population. This technique appeared to be safe and effective. Our preliminary results encourage the clinical use of platelet-rich plasma associated with cryoprecipitate.     

Etanercept as a salvage treatment for refractory aplastic anemia

About 10–15% of patients with acquired aplastic anemia (AAA) have resistant/recurrent disease not eligible for standard treatment like hematopoietic stem cell transplantation and/or combined immunosuppression. We report a 17‐year‐old male with an 11 years history of AAA who, after two courses of immunosuppression, was red cell transfusion‐dependent, severely thrombocytopenic, refractory to platelet transfusion, had iron overload and post‐transfusion HCV infection. This patient achieved transfusion independence from platelets and normalized Hb after treatment with the anti‐TNF agent Etanercept. Over a 12 months follow‐up he experienced only transient increase of liver transaminases. Pediatr Blood Cancer 2009;52:522–525. © 2008 Wiley‐Liss, Inc.     

Screening for subclinical stenosis in native vessel arteriovenous fistulae.

Guidelines recommend the use of ultrasound dilution techniques (UDT), including measurement of access recirculation (AR) and access blood flow (Q(a)), to screen for subclinical vascular access dysfunction. Although these techniques are efficacious in polytetrafluoroethylene grafts, data in native vessel arteriovenous fistulae (AVF) are lacking. A prospective observational study was conducted to evaluate the utility of UDT screening in AVF. Q(a) and AR were measured bimonthly. Positive studies required fistulograms and were defined by Q(a) < 500 ml/min, DeltaQ(a) > 20% from baseline or AR > 5%. Accesses with stenosis underwent percutaneous angioplasty. After 1 yr, there were 1355 mo of follow-up in 177 patients. There were 44 positive studies in 40 patients. Q(a) was <500 ml/min in 36 (82%), DeltaQ(a) was >20% in 5 (11%), and AR was >5% in 6 (14%). Of patients with Q(a) < 500 ml/min, 29 (81%) had stenosis. Only two patients (40%) with DeltaQ(a) > 20% but Q(a) > 500 ml/min had stenosis. No patient with AR > 5% had stenosis unless Q(a) was also <500 ml/min. Immediate patency rate was 93% post-PTA. Mean Q(a) increased from 303 +/- 154 ml/min to 602 +/- 220 ml/min (P < 0.0001), and mean urea reduction ratio increased from 70.4 +/- 8.4% to 74.6 +/- 6.5% (P = 0.003) post-PTA. The results demonstrate that UDT could detect subclinical stenoses in AVF, and most lesions were amenable to angioplasty. AVF that underwent PTA delivered higher Q(a) and urea reduction ratio, and immediate patency rates were acceptable. Access failure after negative UDT was unusual. Measuring AR increases the time required to perform UDT but does not improve utility. Serial measurements of Q(a) alone may be the best strategy for screening AVF.     

Effect of alpha-fluorination of valproic acid on valproyl-S-acyl-CoA formation in vivo in rats.

Studies designed to compare valproic acid (VPA) with its alpha-fluorinated derivative (F-VPA) for their abilities to form acyl-CoA thioester derivatives in vivo are described. Recent studies have shown that alpha-fluorination of a hepatotoxic metabolite of VPA (Delta(4)-VPA) resulted in a nonhepatotoxic derivative. We hypothesize that the decrease in hepatotoxicity may be related to a lack of formation of the intermediary acyl-CoA thioester. To determine the effect of alpha-fluoro substitution on acyl-CoA formation, we synthesized F-VPA and compared it with VPA for its ability to form the acyl-CoA thioester derivative in vivo in rat liver. Thus, after dosing rats with VPA or F-VPA, animals were sacrificed (0.05-, 0.5-, 1-, 2-, and 5-h postadministration) for the analysis of liver tissue. High-performance liquid chromatography (HPLC) and electrospray ionization/tandem mass spectrometry analysis of liver extracts from VPA-dosed rats showed the presence of VPA-CoA that was maximal after 0.5 h (185 nmol/g of liver) and was still measurable 5-h postadministration (90 nmol/g of liver). In agreement with our hypothesis, F-VPA did not form the corresponding acyl-CoA derivative as determined by the absence of F-VPA-CoA upon HPLC analysis of liver extracts from F-VPA-dosed rats. Further examination of liver tissue for the presence of free acids revealed that the differences in acyl-CoA formation cannot be explained by differences in VPA and F-VPA free acid concentrations. From these observations and related studies showing the lack of toxicity due to alpha-fluoro substitution, we propose that metabolism of VPA by acyl-CoA formation may mediate the hepatotoxicity of the drug.     

Serum protein binding of a new oral cephalosporin, CL 284,635, in various species

CL 284,635 is a new third generation oral cephalosporin. Its serum protein binding was investigated in the human, monkey, dog, rat, and rabbit. This study was performed by using an equilibrium dialysis and ultrafiltration method, using radiolabeled and cold CL 284,635. In humans, CL 284,635 was found to have a mean free fraction [fu = concentration of unbound (free) drug divided by total concentration of unbound plus bound to serum proteins] of 31.3 +/- 3.3% with no serum concentration dependency in a range of 0.5 to 26 micrograms/ml. The drug was mainly bound to albumin. In rabbits and monkeys the protein binding profile of CL 284,635 was found to be 36.1 +/- 2.3% and 33.9 +/- 1.5% with no serum concentration dependency. In rats and dogs a non-concentration-dependent fu was observed at serum concentrations ranging from 0.5 to 30 micrograms/ml. A gradual increase in fu values was observed at higher serum concentrations of CL 284,635. Overall, the protein binding profile of CL 284,635 was found to be different in the five investigated species. The protein binding of CL 284,635 in monkeys and rabbits was most similar to that in humans. These species differences in protein binding may have an impact on the disposition of the drug in different species.