Developmental plasticity shapes synaptic phenotypes of autism-associated neuroligin-3 mutations in the calyx of Held.

Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Mutations in neuroligin-3 predispose to autism, but how such mutations affect synaptic function remains incompletely understood. Here we systematically examined the effect of three autism-associated mutations, the neuroligin-3 knockout, the R451C knockin, and the R704C knockin, on synaptic transmission in the calyx of Held, a central synapse ideally suited for high-resolution analyses of synaptic transmission. Surprisingly, germline knockout of neuroligin-3 did not alter synaptic transmission, whereas the neuroligin-3 R451C and R704C knockins decreased and increased, respectively, synaptic transmission. These puzzling results prompted us to ask whether neuroligin-3 mutant phenotypes may be reshaped by developmental plasticity. Indeed, conditional knockout of neuroligin-3 during late development produced a marked synaptic phenotype, whereas conditional knockout of neuroligin-3 during early development caused no detectable effect, mimicking the germline knockout. In canvassing potentially redundant candidate genes, we identified developmentally early expression of another synaptic neurexin ligand, cerebellin-1. Strikingly, developmentally early conditional knockout of cerebellin-1 only modestly impaired synaptic transmission, whereas in contrast to the individual single knockouts, developmentally early conditional double knockout of both cerebellin-1 and neuroligin-3 severely decreased synaptic transmission. Our data suggest an unanticipated mechanism of developmental compensation whereby cerebellin-1 and neuroligin-3 functionally occlude each other during development of calyx synapses. Thus, although acute manipulations more likely reveal basic gene functions, developmental plasticity can be a major factor in shaping the overall phenotypes of genetic neuropsychiatric disorders.

Sirolimus for rescue of steroid and anti-thymocyte globulin-resistant recurrent acute rejection after liver transplantation: report of one case.

Sirolimus (SRL) not only displays prophylactic activity, it also reverses acute rejection (AR) in humans with ongoing refractory renal allograft rejection and chronic liver allograft rejection. The present case of a human liver allograft recipient documents the utility of SRL therapy for a patient experiencing ongoing resistant recurrent AR just after orthotopic liver transplantation (OLT) and liver dysfunction that had not abated after treatment with corticosteroids and antilymphocyte globulin. SRL was added to the mycophenolate mofetil/steroid regimen to treat the ongoing rejection. The patient was rescued with SRL, not experiencing AR again. To date the patient has exhibited no significant side effects after more than 6 months of SRL therapy and his clinical and general condition have been good; he is completely involved in daily life. SRL is a new and safe immunosuppressive agent for rescue in patients with early OLT and recurrent AR.

Modified quantitative subjective global assessment of nutrition in patients on the renal transplant waiting list.

Subjective global assessment (SGA) of nutritional status is a widely used and validated method for identifying and classifying malnutrition. It has been thought that this semiquantitative feature restricts the reliability and precision of the SGA. Recently, in an effort to assess nutritional status, a modified quantitative SGA system has been devised in which scores are assigned for items or components of the SGA. This prospective study evaluated the correlation of the quantitative SGA with objective nutritional parameters and compared this method with conventional SGA in a group of patients on the renal transplant waiting list.

A new flap technique to treat pilonidal sinus.

BACKGROUND: Failures of flap rotation, flap necrosis, recurrence of the disease, maceration at the incisional line and insufficient or late healing of flap corners which can be associated with ischemia appear to be the main problems associated with the closing techniques during the surgical treatment of this disease. We describe a simple, effective and incision protective repair method for excision of the pilonidal cyst. METHODS: Data from 17 (12 males and 5 females) consecutive patients who had elective surgery for chronic pilonidal sinus disease with wide excision of all the sinuses and a new flap technique closure with adipo-fascio-cutaneous flaps which was used in our series for the treatment of pilonidal sinus disease were retrospectively analyzed. RESULTS: Satisfactory results were achieved with this flap rotation technique in 17 patients. There were no flap rotation failures, flap necrosis, disease recurrence, incisional line maceration, or delayed wound healing. CONCLUSION: As a result, presented technique provides avoidance of flap necrosis, maceration on the incision and insufficient or late healing of the flap. We describe a technique which has a minimal amount of scar across the midline natal cleft and fewer flap corners resulting in a lower chance of margin necrosis.

Thermally induced shape memory behavior, enzymatic degradation and biocompatibility of PLA/TPU blends: "Effects of compatibilization".

Poly(lactic acid) (PLA)/thermoplastic polyurethane (TPU) blends were melt-mixed and compatibilized to investigate their biocompatibility, biodegradability and thermally induced shape memory properties. The blend compositions were PLA/TPU: 80/20 (20TPU) and PLA/TPU: 50/50 (50TPU). 1,4-phenylene diisocyanate (PDI) was used in order to compatibilize the components reactively. The PDI composition was 0.5, 1, 3% by weight. Biodegradability was assessed by enzymatic degradation tests. Biocompatibility was investigated through in-vitro cell-culture experiments. Shape memory tests exhibited that 20TPU blends have higher recovery ratio than that of 50TPU blends. It was observed that the shape recovery ratio was enhanced by the addition of PDI. The highest shape recovery ratio was obtained at 3%PDI in 20TPU blends. Enzymatic biodegradability tests showed that the increasing TPU content decreased the biodegradability of the blends. It was found that compatibilization slowed down the enzymatic degradation of PLA/TPU blends. In-vitro cell-culture experiments indicated that all blends were biocompatible, and no evidence of cytotoxicity was observed.

Tribenoside and lidocaine in the local treatment of hemorrhoids: an overview of clinical evidence.

OBJECTIVE: The combination of tribenoside+lidocaine (Procto-Glyvenol®) is a medical preparation for the local treatment of hemorrhoids, delivered as a suppository or rectal cream. This product has been used for decades in the therapy of hemorrhoids. This review discusses available evidence on the use of tribenoside/lidocaine in clinical practice. MATERIALS AND METHODS: Papers were retrieved by a PubMed search, using different combinations of pertinent keywords (e.g. tribenoside AND hemorrhoids), without any limitations in terms of publication date and language. Documents from Authors' personal collection of literature could also be considered. Papers were selected for inclusion according to their relevance for the topic, as judged by the Authors. RESULTS: The efficacy of the combination of tribenoside+lidocaine in relieving symptoms caused by hemorrhoids and its safety have been assessed in several clinical studies on patients of either gender, either versus its two individual components (tribenoside and lidocaine) or versus steroids in the same setting. Five studies compared the combination treatment with each of its single components, and of these, three studies compared tribenoside+ lidocaine with a tribenoside-free semi-placebo preparation containing only lidocaine, and two studies compared this combination with lidocaine-free preparations containing only tribenoside. Tribenoside+lidocaine was compared with steroid-containing preparations in six studies. Last, two studies evaluated the efficacy and tolerability of the tribenoside+lidocaine combination in women with hemorrhoids as a consequence of pregnancy or delivery. All the above-mentioned studies were well-conducted and can provide a comprehensive evaluation of tribenoside+lidocaine in the treatment of hemorrhoids. CONCLUSIONS: Enough evidence exists to recommend the use of this combination therapy as a fast, effective and safe option for the local treatment of low-grade hemorrhoids.

Use of random urine samples to estimate total urinary calcium and phosphate excretion.

Calcium-to-creatinine and phosphate-to-creatinine ratios in random single-voided urine specimens were compared with 24-hour calcium and phosphate excretions, respectively, in 67 subjects who were selected prospectively to represent a wide range of renal and parathyroid function as well as urinary calcium and phosphate loss. Simple linear regression analysis revealed significant correlation between the spot urine calcium-to-creatinine ratio and 24-hour total calcium excretion and between the spot urine phosphate-to-creatinine ratio and 24-hour phosphate excretion. Calculating these simple ratios permits easy, rapid, correct, and inexpensive estimation of the daily urinary calcium and phosphate excretion.

The effects of increased intraabdominal pressure on colonic anastomoses.

BACKGROUND: This experimental, randomized, controlled study was designed to investigate the effects of increased intraabdominal pressure (IAP) on colocolic anastomoses. To our knowledge, this is the first study to address this important issue. METHODS: For this study, 50 Wistar albino rats were randomized into five groups. The animals in all the groups underwent laparotomy and colocolic anastomosis. The rats in the control group were not subjected to increased IAP. Accordingly, IAP's of 14, 20, 25, and 30 mmHg were established by carbon dioxide insufflation and maintained for 60 min in study groups 1, 2, 3 and 4, respectively. Colocolic anastomosis was realized after these periods of IAP in the study groups. Half of the surviving rats in all the groups were sacrificed on postoperative days 7 and 14 to allow comparison between the control and study groups with respect to their mean body weights, mean anastomosis bursting pressures, and histopathologic characteristics of their anastomosis sites. RESULTS: The mean body weights of all the groups were comparable at all times during the study. The anastomosis bursting pressures of the animals subjected to increased IAP were lower than that of the control group, with the differences reaching statistical relevance for the animals subjected to an IAP of 20 mmHg or higher on postoperative day 7 (p <0.0005 for study groups 2, 3, and 4 vs the control group) and becoming more pronounced by the day 14 (p <0.0005 for study groups 2, 3, and 4 vs the control group). The anastomosis bursting pressure showed an inverse correlation with IAP. The adequacy of mucosal layer formation at the anastomosis line was lower and the degree of inflammation was higher in the groups exposed to an IAP of 20 mmHg or higher in the control group (p <0.05 for both comparisons among study groups 2, 3 and 4 vs the control group). CONCLUSIONS: An IAP increased to 20 mmHg and higher was found to result in impaired strength and wound healing in colocolic anastomoses, as reflected by the decreased bursting pressure and mucosal layer formation, and by the increased inflammation at the anastomosis sites of animals subjected to high IAP values.

The oxidative effect of prolonged CO2 pneumoperitoneum on renal tissue of rats.

BACKGROUND: Despite its advantages, laparoscopic donor nephrectomy is associated with prolonged operation time, which could potentially increase oxidative stress in the graft. We performed the first experimental, randomized, controlled study with blind assessment of outcome to address this possibility. METHODS: Wistar-Albino rats were randomized into three groups. The animals in the control group were subjected to a sham operation under anesthesia; the animals in the other two groups were subjected to CO(2) pneumoperitoneum (Pp) for 120 and 240 min, respectively. The kidneys were removed at the end of each experiment. The concentrations of protein carbonyl and sulfhydryl (SH) groups and the activities of superoxide dismutase (SOD) were measured in renal tissue samples as markers of oxidative stress. Renal tissue samples were also evaluated histopathologically using light microscopy. RESULTS: Exposure to 120 min of Pp significantly increased the finding of oxidative stress in renal tissue samples, with an increase in protein carbonyl content and a decrease in protein sulfhydryls and tissue (SOD) activities. When exposure to Pp was prolonged from 120 min to 240 min, Pp associated oxidative stress was found to be increased. These changes occurred in the absence of light microscopical evidence of overt tissue damage. CONCLUSIONS: In an experimental model resembling laparoscopic donor nephrectomy, we found that exposure of pneumoperitoneum prolonged from 120 min to 240 min acts as an additive factor with respect to causing increased oxidative stress in renal tissue. Because these effects imply subtle tissue injury that may contribute to the chronic demise of renal grafts obtained laparoscopically, avoiding the use of Pp if possible and keeping operation time less than 120 min during laparoscopic donor nephrectomy appear to be advisable.

Can preconditioning reduce laparoscopy-induced tissue injury?

BACKGROUND: Pneumoperitoneum (P) created to facilitate laparoscopy (L) is associated with splanchnic perfusion, ischemia/reperfusion (I/R) injury, and oxidative stress. In this randomized controlled experimental study with blind outcome assessment, we evaluated the effect of preconditioning (PRE) on L-induced I/R injury. METHODS: The subjects were 40 Sprague-Dawley male rats. P was created in all except controls, using carbondioxide (CO2) insufflation under a pressure of 15 mmHg. PRE consisted of 10 min of P, followed by 10 min of deflation (D). The rats were randomized to the following groups: Group P was subjected to 60 min of P. Group P/D was subjected to 60 min of P, followed by 45 min of D. Group PRE/P was subjected to PRE, followed by 60 min of P. Group PRE/P/D was subjected to PRE, followed by 60 min of P and 45 min of D. Group C (control) was subjected to a sham operation, without P. Its anesthesia time was equal to that for group PRE/P/D. At the end of the experiments, the rats were killed; blood, liver, and kidney samples were then obtained and coded. Plasma alanine aminotransferase (ALT) and malondialdehyde (MDA), as well as homogenized tissue MDA levels and glutathione (GSH) activities, were measured; tissue samples were assessed for histopathological evidence of injury; all assessments were done by investigators blinded to the study design. The results were decoded and analyzed statistically with the Kruskal-Wallis and Mann Whitney tests. A p <0.05 was considered significant. RESULTS: Plasma ALT as well as plasma, liver, and kidney MDA levels and liver and kidney injury scores were increased, whereas liver and kidney GSH values were decreased in groups P and P/D, as compared to group C. Rats subjected to PRE before P had plasma ALT, kidney MDA, and kidney and liver GSH levels comparable to controls; their kidney and liver injury scores were higher than controls but significantly lower than nonpreconditioned animals. PRE enabled decreased plasma, kidney, and liver MDA as well as increased kidney GSH if applied before P; its efficacy on oxidative stress was limited to providing decreased kidney MDA and increased kidney GSH if applied before P/D. However, PRE significantly attenuated kidney and liver injury after P as well as P/D. CONCLUSION: PRE consisting of 10 min of P followed by 10 min of D decreases the oxidative stress induced by sustained P in the plasma, liver, and kidney. PRE significantly limits liver and kidney injury after prolonged P and P/D. After further studies to define its ideal timing, PRE before L incorporating P may have clinical relevance, especially for elderly patients or those with impaired hepatic and/or renal function or perfusion.

Ischemic preconditioning decreases laparoscopy-induced oxidative stress in small intestine.

BACKGROUND/AIMS: Laparoscopy is advantageous but its adverse effects have not yet been completely elucidated. Pneumoperitoneum performed to facilitate laparoscopy causes the organ perfusion decrease such as in the intestine. Oxidative stress reflects the tissue injury related to ischemia and reperfusion. We previously showed that laparoscopy causes oxidative stress in intestinal tissues. To assess whether the preconditioning phenomenon could be taken advantage of during laparoscopy we designed this randomized, controlled, experimental study with blind outcome assessment. We evaluated the effect of preconditioning, including sequential periods of pneumoperitoneum and desufflation on laparoscopy-induced tissue injury of small bowel with the help of two important markers of oxidative stress, thiobarbituric acid reactive substances and reduced glutathione. METHODOLOGY: Forty Sprague-Dawley male rats were used. After anesthesia, an intraperitoneal catheter was inserted. Pneumoperitoneum was created in all except controls, by CO2 insufflation under a pressure of 15 mmHg. The rats were randomized into the groups below: Group P was subjected to 60 minutes of pneumoperitoneum; Group P/D was subjected to 60 minutes of pneumoperitoneum followed by 45 minutes of desufflation; Group IP + P was subjected to 10 minutes of pneumoperitoneum, 10 minutes of desufflation and 60 minutes of pneumoperitoneum; Group IP + P/D was subjected to 10 minutes of pneumoperitoneum, 10 minutes of desufflation, 60 minutes of pneumoperitoneum and 45 minutes of desufflation; Group C (Control) was subjected to a sham operation, without pneumoperitoneum. Small bowel tissue malondialdehyde and reduced glutathione activities were measured, as applicable, by investigators blinded to the study design. The results were decoded and statistically analyzed with Kruskal-Wallis test. Mann-Whitney U test was used to compare the paired groups. p < 0.05 was considered significant. RESULTS: Small bowel tissue malondialdehyde levels were increased, whereas glutathione values were decreased in Groups P and P/D, as compared to Groups PRE/P and PRE/P/D; the latter two groups had results similar to the Control Group. CONCLUSIONS: Laparoscopic preconditioning may reduce the oxidative injury in intestine following laparoscopic procedures.

Calcium oxalate crystals in benign cyst fluid from the breast. A case report.

BACKGROUND: Two types of calcification have been observed in breast lesions. The more common is composed mostly of calcium phosphate and is detected in routine histologic tissue sections of frequently malignant lesions. The rare type is calcium oxalate and is found exclusively in benign cysts. CASE: In a 47-year-old female, strongly birefringent polyhedral crystals of calcium oxalate were detected in benign breast cyst fluid. CONCLUSION: Calcium oxalate is not clearly visible on routine histologic sections, and examination of the cytologic specimens under polarized light reveals them. Awareness of this potential pitfall might lead to conservative management.

A comparison of the oxidative stress response and antioxidant capacity of open and laparoscopic hernia repairs.

BACKGROUND: Free radical-induced lipid peroxidation that is associated with a decrease in the antioxidant status of plasma occurs in many kinds of surgical procedures. In this study, we aimed to investigate markers of oxidative stress--malondialdehyde (as thiobarbituric acid reactive substances), protein carbonyls, and protein sulfhydryls--in patients undergoing Lichtenstein tension-free hernioplasty (LH) or laparoscopic preperitoneal hernia (LPPH) repair. METHODS: Seventeen patients with unilateral inguinal hernia and no complications or recurrence were included in this study. Ten were randomized to undergo LH and seven to LPPH repair. Heparinized blood samples were taken to measure the levels of oxidative stress markers in the patients undergoing hernia repair. Levels of malondialdehyde, protein carbonyls, and protein sulfhydryls were measured preoperatively and at 6 and 24 hours postoperatively in all patients. RESULTS: Both types of hernia repair caused a significant increase in the oxidative stress response and a decrease in antioxidant activity. Plasma levels of malondialdehyde and carbonyls (indicators of oxidant activity) were significantly higher in the LH than in the LPPH repair group (P<.05), and plasma sulfhydryl levels (indicators of antioxidant activity) were significantly lower in the LH than in the LPPH group (P<.05). In both groups, significant differences were also found between the preoperative levels and the postoperative levels 6 and 24 hours (P<.05). CONCLUSIONS: These data demonstrate that both LH and LPPH repair cause a significant increase in markers of oxidative stress; however, the oxidative stress response associated with LH is greater than that associated with LPPH repair.

Current value of peritoneal tap in blunt abdominal trauma.

This study aimed to establish the diagnostic value of paracentesis (peritoneal tap) in the assessment of patients with blunt abdominal trauma. Paracentesis, using a four-quadrant puncture technique, was performed in blunt abdominal trauma victims presenting to the emergency department of a tertiary-care university medical centre. Pregnant patients, those under 18 or those having an abdominal scar were excluded from the study. All patients then underwent one of the following procedures as indicated: emergency ultrasound, abdominal computed tomography scan, diagnostic peritoneal lavage or laparotomy. Paracentesis results were compared with the results of other tests and surgery in diagnosing haemoperitoneum. Haemoperitoneum was confirmed surgically in six of the seven patients with a positive paracentesis. Nine out of 65 patients with positive clinical findings but negative taps underwent surgical intervention, and abdominal bleeding was confirmed in eight. Three seriously injured patients died before diagnostic studies or laparotomy could be performed. In conclusion, a positive paracentesis result may be used to guide decision-making in the setting of blunt abdominal trauma if other diagnostic methods are unavailable. Its high false-negative rate limits its overall usefulness.

The effect of NG-nitro L-arginine methyl ester on colonic anastomosis after increased intra-abdominal pressure.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) is associated with augmented nitric oxide (NO) production. Increased intra-abdominal pressure (IAP) during surgical pneumoperitoneum (P) facilitates I/R injury. We previously demonstrated decreased strength and healing of colocolic anastomoses after high IAPs. The effect of an NO synthase inhibitor, N (G)-nitro-arginine methyl ester (L: -NAME), on anastomoses realized in colonic tissue exposed to high IAPs was investigated in this study, a randomized, controlled, and experimental study with blind outcome assessment. METHOD: Fifty Wistar-albino rats were randomized to five groups; all underwent colocolic anastomosis. P was maintained for 60 min at IAPs of 14, 20, 25, and 30 mmHg in study groups 1, 2, 3, and 4, respectively; P was preceded by intraperitoneal L: -NAME (2.5 mg/kg) and followed by anastomosis. The control group was not subjected to IAP or L: -NAME. RESULTS: Anastomosis bursting pressure (ABP) values and histopathological findings were determined on the 7th-14th postoperative days. The ABPs of groups 3-4 were significantly lower than the others. Groups 1-2 had results similar to controls. Histopathological findings of the groups were consistent with their ABPs. CONCLUSION: Administration of a 2.5-mg/kg intraperitoneal L: -NAME dose was found to provide a beneficial role, implying a role in impaired anastomotic healing after IAPs of 14 and 20 mmHg.

Preventive effect of nicardipine on hyperplastic changes in venous bypass grafts.

Nicardipine is a relatively new calcium channel blocker with important properties that could result in attenuation of the adverse proliferative changes in autogenous vein bypass grafts. In this experimental, randomized, controlled study, the effect of nicardipine on the pathologic findings in aortoaortic bypass graft was assessed. Forty-two male rabbits (Orycytolagus cuniculus) were randomized to three groups: group 1 received nicardipine and groups 2 and 3 placebo for 4 weeks, after which an aortaortic bypass was realized with an autogenous inferior vena cava segment. During the following 4 weeks, groups 1 and 2 received nicardipine, and placebo was continued in group 3. The animals were sacrificed at the end of the study to permit removal and evaluation of the bypass grafts. The mean intimal and medial thickness values for groups 1 and 2 were lower than those for group 3, indicating that nicardipine has a significant preventive effect on the hyperplastic changes in venous bypass grafts compared to placebo. The mean intimal and medial thickness values of group 1 were also lower than those of group 2, and the differences carried statistical relevance, suggesting that the use of nicardipine before grafting could potentiate its protective effect. To provide stimulus for further research, an attempt is made to relate the hyperplasia-preventing effect of nicardipine to possible mechanisms.