Jagged1 (JAG1) mutations in patients with tetralogy of fallot or pulmonic stenosis

Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right‐sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right‐sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation. Hum Mutat 31:594–601, 2010. © 2010 Wiley‐Liss, Inc.     

Moderate caloric restriction increases diaphragmatic antioxidant enzyme mRNA, but not when combined with lifelong exercise

Diaphragmatic antioxidant enzymes are upregulated following acute and long-term treadmill exercise, but the effect of lifelong voluntary exercise (E) on diaphragmatic antioxidants is unknown. Therefore, 10-week old Fisher 344 rats were assigned to either: (a) sedentary ad libitum (AL) fed (24AL; n = 6); (b) E + 8% caloric restriction (24ECR; n = 9); or (c) sedentary + 8% caloric restriction (24CR; n = 9) groups. Diaphragms were harvested from animals at 24 months of age. Heme oxygenase-1 (HO-1) mRNA in addition to catalase (CAT), glutathione peroxidase (GPX), copper-zinc superoxide dismutase (Cu-ZnSOD) and manganese superoxide dismutase (MnSOD) mRNA and protein levels were measured. Reduced glutathione (GSH) and citrate synthase (CS) activity were measured to assess antioxidant status and oxidative capacity, respectively. The 24CR group demonstrated increased GPX, HO-1, MnSOD, and CAT mRNA compared to 24AL and 24ECR. Interestingly, the increased mRNA in 24CR animals did not result in elevated protein levels. No group differences in Cu-ZnSOD mRNA, CS activity, or GSH were observed, although GSH was 30% greater in 24CR animals (p = 0.085). In summary, although CR elevated the mRNA of key antioxidant enzymes in the diaphragm, lifelong CR alone or in combination with voluntary exercise did not alter diaphragm CS activity, antioxidant protein quantity, or GSH levels.     

Evaluation of 100 laparoscopic varicocele operations with preservation of testicular artery and ligation of collateral vein in children and adolescents

OBJECTIVES: To introduce a useful technique for identifying any collateral veins during laparoscopic varicocele operation and to evaluate our long-term results with this technique after 100 cases. METHODS: A new method was used to detect an incidental collateral vein. During surgery the patient was placed in anti-Trendelenburg position after introducing laparoscopic instruments until the dilated scrotal varicose filled up with blood. The main spermatic vein was then grasped atraumatically and the blood was pressed out manually from the scrotum. During this manoeuvre any existing collateral vein/veins became dilated and could be easily identified. The dilated spermatic vein and also any collateral vessel were first prepared then clipped. RESULTS: Out of the 100 patients, collateral veins were detected and ligated in 19 cases. In 15 cases a single collateral, in 4 cases two collaterals, and in the remaining 81 children no collateral veins were found. The testicular artery was identified in all operations as a pulsatile vessel. At a mean of 24 months (range 6-60 months) follow-up recurrence occurred in one patient and in five children hydrocele developed postoperatively. Testicular atrophy and severe intra- or postoperative complication did not occur in any patient of this series. CONCLUSION: The identification of incidental collateral vein by this method and preservation of the testicular artery resulted in a very good success rate in children and adolescents treated by laparoscopic varicocele operation.     

High-speed videotopographic measurement of tear film build-up time

PURPOSE: To detect tear film regularity changes in the 15 seconds after a blink, by using a new high-speed videotopographic method. METHODS: The new system, based on a standard corneal topograph, allows registration of four photokeratoscopic images per second. Altogether, 15 eyes of 15 healthy volunteers and 7 eyes of 7 patients with dry eye were examined in this prospective preliminary study. The main outcome measures were changes in surface regularity index (SRI), surface asymmetry index (SAI), and corneal power. RESULTS: The corneal surface became more regular in the first few seconds after a blink. In healthy eyes, the trend line of SRI and SAI decreased (improved) significantly (P < 0.001) after a blink, in 10 of 15 eyes for the SRI and in 13 of 15 for the SAI. In the typical cases, the trend line for SRI reached its minimum level, on average, at 7.1 +/- 3.9 seconds after a blink and that for the SAI at 5.4 +/- 2.7 seconds. Similar trends were found in the dry-eye group. The changes in keratometric measures were small (mean range, <1.5% of the absolute value) and showed no definite trends. CONCLUSIONS: High-speed videotopography provides the possibility of quantitative measurement of tear-film dynamics and may have clinical value in the management of ocular surface disorders. After a blink, it takes the tear film approximately 3 to 10 seconds (tear film build-up time) to reach the most regular state. However, despite surface-regularity changes, the measured corneal powers are stable.     

New trends in the development of oral antidiabetic drugs

A large number of oral antidiabetic agents are available today. This article provides a short review of the pharmacology and some clinical aspects of various oral antidiabetic drugs. It focuses mainly on the newest developing drugs (therapy of the near future) and on the most commonly used older groups for the common approach of every-day practice (sulphonylureas). The primary goal of this review is to compare the electrophysiological effects of glibenclamide in isolated normal and streptozotocin induced diabetic rats and alloxan induced rabbits ventricular preparations, while on the other hand to differentiate the hypoglycaemic sulphonylureas (0.1-1000 mmol/kg) according to their cardiovascular activity in healthy and diabetic animals. In vitro (1-100 micromol/l) as well as chronically treated (5 mg/kg for 10 weeks) glibenclamide prolonged the action potential duration in normal but failed to affect it in diabetic ventricular preparations. Our results suggest that the sensitivity to glibenclamide of K(ATP) channels in diabetic ventricular fibers is drastically decreased. The effects of different sulphonylureas (tolbutamide, glibenclamide, gliclazide, glimepiride) on ventricular ectopic beats as well as the duration of ventricular fibrillation induced by 10 min ischemia/50 min reperfusion in healthy and diabetic rats were compared. Tolbutamide and gliclazide dose-dependently enhanced both parameters both in healthy and diabetic groups. Glibenclamide in healthy rats increased, while in diabetic rats it decreased the arrhythmogenicity. Glimepiride depressed the arrhythmogenicity in both healthy and diabetic animals. Glimepiride proved to dose-dependently enhance the myocardial tissue flow in dog in contrast to glibenclamide. These results confirm that glimepiride has less cardiovascular actions than other sulphonylureas. From the newest oral antidiabetics this review tries to emphasize the most important basic pharmacological properties, mechanism of action, therapeutic use.     

3H]Dopamine release in striatum in response to cortical stimulation in a corticostriatal slice preparation

A new method has been developed to investigate corticostriatal glutamatergic influence on [3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate-dopamine-GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.     

Dalteparin sodium treatment during resuscitation inhibits hemorrhagic shock-induced leukocyte rolling and adhesion in the mesenteric microcirculation

BACKGROUND: Ischemia/reperfusion-induced polymorphonuclear neutrophil leukocyte (PMN) adhesion and extravasation are pivotal for the development of postinjury multiple organ failure. We hypothesized that the deleterious microcirculatory consequences of hemorrhagic shock (HS) could be altered by low-molecular-weight heparin (LMWH) therapy. Our aim was to investigate the effects of dalteparin sodium on leukocyte-endothelial cell interactions when LMWH treatment was initiated before HS or during resuscitation. METHODS: Anesthetized dogs underwent HS (40 mm Hg mean arterial pressure for 60 minutes) and resuscitation either with shed blood or with lactated Ringer's (LR) solution. LMWH or conventional heparin sodium pretreatment was administered subcutaneously before hemorrhage; or LMWH was given intravenously during resuscitation. Mesenteric postcapillary venules were observed by intravital video microscopy before and after HS, and 60 minutes, 120 minutes, and 180 minutes after resuscitation, and leukocyte rolling and firm adherence were determined. RESULTS: HS significantly increased PMN rolling and adhesion in the mesenteric microcirculation. LMWH, but not heparin sodium pretreatment, significantly inhibited both primary and secondary interactions. LMWH treatment was also effective when initiated during resuscitation. LMWH exerted the same inhibitory effect regardless of the type of resuscitation. CONCLUSION: LMWH treatment during resuscitation effectively inhibits PMN rolling and adhesion.     

Reconstruction of cervical esophageal anastomosis using median sternotomy

We performed cervical oesophageal anastomosis in 153 patients in 10 years. In 11 patients reconstruction or delayed anastomosis was performed through median sternotomy because cervical approach was not suitable. Reoperations were the following: 7 oesophageal stenosis which couldn't be dilated, 2 necrosis of the transplanted organ and 2 because of delayed anastomosis. 8 patients had oesophageal tumors and 3 erosive fluid reflux. During median sternotomy the transplanted organ was injured twice. In 9 patients after reconstruction dysphagia disappeared, in one pharyngo-ileostomy stenosis was noticed and one of the patients died because of ARDS after a leak.     

Late reconstructive surgery for cloaca malformations

The rarity of cloacal anomalies, the wide range of anatomical variants, and the number of different operations mean that successful management of a patient (neonate or child) with this condition is one of the greatest challenges for paediatric surgeons. The authors describe the complex corrections of 3 patients with cloacal malformation (age 10-13 years). The cloacal malformations were not diagnosed at neonatal age and therefore only the anorectal agenesis was corrected at the first stage. The authors strongly recommend that all components of this anomaly (urethra, vagina and anorectum) should be managed in one step. Because of the rarity and complexity of cloacal malformations, the anomaly should be operated on only in specialised centres.