Spatial memory extinction differentially affects dorsal and ventral hippocampal metabolic activity and associated functional brain networks

Previous studies showed the involvement of brain regions associated with both spatial learning and associative learning in spatial memory extinction, although the specific role of the dorsal and ventral hippocampus and the extended hippocampal system including the mammillary body in the process is still controversial. The present study aimed to identify the involvement of the dorsal and ventral hippocampus, together with cortical regions, the amygdaloid nuclei, and the mammillary bodies in the extinction of a spatial memory task. To address these issues, quantitative cytochrome c oxidase histochemistry was applied as a metabolic brain mapping method. Rats were trained in a reference memory task using the Morris water maze, followed by an extinction procedure of the previously acquired memory task. Results show that rats learned successfully the spatial memory task as shown by the progressive decrease in measured latencies to reach the escape platform and the results obtained in the probe test. Spatial memory was subsequently extinguished as shown by the descending preference for the previously reinforced location. A control naïve group was added to ensure that brain metabolic changes were specifically related with performance in the spatial memory extinction task. Extinction of the original spatial learning task significantly modified the metabolic activity in the dorsal and ventral hippocampus, the amygdala and the mammillary bodies. Moreover, the ventral hippocampus, the lateral mammillary body and the retrosplenial cortex were differentially recruited in the spatial memory extinction task, as shown by group differences in brain metabolic networks. These findings provide new insights on the brain regions and functional brain networks underlying spatial memory, and specifically spatial memory extinction. © 2016 Wiley Periodicals, Inc.     

Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C(0) )/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C(0) /dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28±26.45, 59.12±24.00, 62.43±41.12, and 57.01±17.34 vs. 112.37± 76.60, 123.21±59.57, 163.34±76.23, and 183.07±107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose-corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01±17.34 vs. 100.09±24.78; P=0.016). Only the ABCB1 TGC (3435-2677-1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR=4.73; CI: 1.3-16.7; P=0.02). Our findings indicate that the CYP3A4*1B-CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.     

Human cord blood-derived mesenchymal stem cells home and survive in the marrow of immunodeficient mice after systemic infusion

Bone marrow is the residence site of mesenchymal stem cells (MSC), which upon commitment and maturation develop into several mesenchymal phenotypes. Recently, we have described the presence of MSC in human cord blood (cbMSC) and informed that their properties are the same as those for MSC obtained from adult bone marrow. In this study we have investigated the capability of transplanted cbMSC to home and survive in the marrow of unconditioned nude mice. cbMSC utilized for transplantation studies were characterized by morphology, differentiation potential, and immunophenotype. After transplantation by systemic infusion, human DNA (as detected by PCR amplification of human-specific beta-globin gene) was detected in the marrow of recipients as well as in ex vivo-expanded stromal cells prepared from the marrow of transplanted animals. These results demonstrate homing and survival of cbMSC into the recipient marrow and also suggest a mesenchymal-orientated fate of engrafted cells, because human DNA was also detected in cells of other recipient tissues, like cardiac muscle, teeth, and spleen.     

Is the levator–urethra gap helpful for diagnosing avulsion?

Introduction and hypothesis

Levator avulsion is a risk factor for female pelvic organ prolapse (POP) and recurrence after POP surgery. Imaging diagnosis requires the observation of an abnormal muscle insertion on tomographic ultrasound imaging (TUI). This study was designed to compare the diagnostic performance of the qualitative diagnosis (visual qualitative assessment) to measurement of the distance between muscle insertion and urethra [levator–urethra gap; (LUG)].

Methods

This was a retrospective analysis of data obtained in a tertiary urogynecological unit. All patients presented with symptoms of pelvic floor dysfunction and underwent 4D translabial pelvic floor ultrasound (US), supine, and after voiding. Avulsion was defined qualitatively as abnormal muscle insertion and quantitatively as LUG ≥25 mm on at least three consecutive central axial plane slices, with one examiner using both methods. We examined the correlation between both methods and validated them against clinical prolapse, significant organ descent on US, and hiatal ballooning.

Results

Between January and July 2013, 233 patients were seen, of whom 202 had complete volume data sets. The qualitative method diagnosed avulsion in 22 % and the quantitative method in 24.3 %. Agreement was good, with a kappa of 0.79 (0.70–0.87). Avulsion diagnosed by either method was associated with clinical and sonographic prolapse and hiatal ballooning, with odds ratios nonsignificantly higher for the quantitative method.

Conclusion

Qualitative analysis of slices on TUI and a method using LUG measurement show good agreement for the diagnosis of avulsion. The LUG method is at least equally as valid in its capacity to predict significant prolapse on clinical examination and US, as well as ballooning of the levator hiatus.

     

Long-term Experience with the Laparoscopic Approach to Perforated Diverticulitis plus Generalized Peritonitis

Background  The treatment of perforated diverticulitis is changing form the current standard of laparotomy with resection, Hartmann procedure, and colostomy to a minimally invasive technique. In patients with complicated acute diverticulitis and peritonitis without gross fecal contamination, laparoscopic peritoneal lavage, inspection of the colon, and intraoperative drain placement of the peritoneal cavity appears to alleviate morbidity and improve the outcome. In this article, we report our experience of a laparoscopic peritoneal lavage technique with delayed definitive resection when necessary. Method and materials  Records of patients who underwent intraoperative peritoneal lavage for purulent diverticulitis at the Texas Endosurgery Institute from April 1991 to September 2006 were retrospectively reviewed. Results  Forty patients were included in the study, with a male/female ratio of 26:14. The average age was 60 years. Many had associated co-morbidities. The average operating time was 62 minutes. There were no conversions to an open procedure. Apart from mild postoperative paralytic ileus in six patients and chest infections in two, there were no significant peroperative or postoperative complications. Just over 50% underwent elective interval laparoscopic sigmoid colectomy. During the mean follow-up of 96 months, none of the other patients required further surgical intervention. Conclusion  Laparoscopic lavage of the peritoneal cavity and drainage is a safe alternative to the current standard of treatment for the management of perforated diverticulitis with or without gross fecal contamination. It is associated with a decrease in the overall cost of treatment; the use of a colostomy is avoided; patient improvement is immediate; and there is a reduction in mortality and morbidity as definitive laparoscopic resection can be performed in a nonemergent fashion. Perhaps the most important benefit, other than avoiding a colostomy, is the association of fewer wound complications such as dehiscence, wound infection, and the high risk of hernia formation. Laparoscopic lavage and drainage should be considered in all patients in whom medical and/or percutaneous treatment is not feasible. It carries minimal morbidity and should be considered the standard of care.     

Intralesional administration of epidermal growth factor‐based formulation (Heberprot‐P) in chronic diabetic foot ulcer: treatment up to complete wound closure

Previous studies have shown that an epidermal growth factor‐based formulation (Heberprot‐P) can enhance granulation of high‐grade diabetic foot ulcers (DFU). The aim of this study was to explore the clinical effects of this administration up to complete wound closure. A pilot study in 20 diabetic patients with full‐thickness lower extremity ulcers of more than 4 weeks of evolution was performed. Mean ulcer size was 16·3 ± 21·3 cm². Intralesional injections of 75 μg of Heberprot‐P three times per week were given up to complete wound healing. Full granulation response was achieved in all 20 patients in 23·6 ± 3·8 days. Complete wound closure was obtained in 17 (85%) cases in 44·3 ± 8·9 days. Amputation was not necessary in any case and only one relapse was notified. The most frequent adverse events were tremors, chills, pain and ardour at site of administration and local infection. The therapeutic scheme of intralesional Heberprot‐P administration up to complete closure can be safe and suitable to improve the therapeutic goal in terms of healing of chronic DFU.     

Results of gastric bypass plus resection of the distal excluded gastric segment in patients with morbid obesity

Surgical treatment is the procedure of choice for morbidly obese patients. Gastric bypass with a long limb Roux-en-Y anastomosis is the "gold standard" technique for these patients. We sought to determine the early and late results of open gastric bypass with resection of the distal excluded stomach in patients with morbid obesity. We included in this prospective study 400 patients who were seen from September 1999 through August 2003 (311 women and 89 men; mean age, 38.5 years). The mean body mass index of the patients was 46 kg/m2. All underwent 95% distal gastrectomy, with resection of the bypassed stomach, leaving a small gastric pouch of 15 to 20 ml. An end-to-side gastrojejunostomy was performed with circular stapler No. 25. The length of the Roux-en-Y loop was 125 to 150 cm. In all patients, a biopsy was taken from the liver and routine cholecystectomy was performed. Follow-up was as long as 36 months. A barium study was performed in all patients at 5 days after surgery. Mortality and postoperative morbidity rates were 0.5% and 4.75%, respectively, mainly due to anastomotic leak in 10 patients (2.5%). Hospital length of stay was 7 days for 95% of the patients. Follow-up data for longer than 12 months were available in 184 patients. There was excess body weight loss of 70% at 24 and 36 months, and there was an inverse correlation among preoperative body mass index and the loss of weight. Anemia was present in 10%, and incisional hernia was present in 10.2%. At 1 year after surgery, the BAROS index demonstrated very good or excellent index in 96.6% of the patients. Gastric bypass with resection of the distal excluded segment has results very similar to those of gastric bypass alone but eliminates the potential risks of gastric bypass such as anastomotic ulcer, gastrogastric fistula, postoperative bleeding due to peptic ulcer and gastritis, and the eventual future development of gastric cancer. It is also possible to perform via laparoscopy, as we started to do recently.     

Sodium retention in cirrhotic rats is associated with increased renal abundance of sodium transporter proteins

BACKGROUND: Liver cirrhosis with ascites is associated with a decrease in renal sodium excretion and therefore sodium retention. METHODS: In this paper, we utilize transporter-specific antibodies to address the hypothesis that dysregulation of one or more sodium transporters or channels is associated with sodium chloride (NaCl) retention in a rat model of cirrhosis induced by repeated exposure to carbon tetrachloride. Age-matched controls and cirrhotic rats were pair fed to ensure identical NaCl and water intake for 4 days prior to euthanasia for quantitative immunoblotting studies. RESULTS AND CONCLUSION: The rats manifested marked extracellular fluid volume expansion with massive ascites. Plasma aldosterone levels were markedly elevated. Analysis of immunoblots revealed marked increases in the abundances of both of the major aldosterone-sensitive apical transport proteins of the renal tubule, namely the thiazide-sensitive NaCl cotransporter NCC and the epithelial sodium channel alpha subunit (alpha-ENaC). These results are consistent with an important role for hyperaldosteronism in the pathogenesis of sodium retention and ascites formation in cirrhosis. In addition, we observed a large decrease in cortical NHE3 abundance (proximal tubule) and a large increase in NKCC2 abundance (thick ascending limb), potentially shifting premacula densa sodium absorption from proximal tubule to loop of Henle (which powers urinary concentration and dilution).