Comparative in vivo uroselectivity profiles of anticholinergics, tested in a novel anesthetized rabbit model

The aim of this study was to describe a new experimental animal model for simultaneous measurement of carbachol-induced increase in intravesical pressure and salivary secretion in rabbits. Further, we also compared the in vivo potency and urinary bladder versus salivary gland selectivity profiles of Oxybutynin, Tolterodine, Solifenacin and Darifenacin. The intravesical pressure and salivary secretion were evoked by intra-arterial injection of carbachol (1.5 microg/kg). The carbachol-induced increase in intravesical pressure and salivation was simultaneously recorded before and after increasing doses of test drugs administered intravenously. The basal mean changes in intravesical pressure and salivation subsequent to carbachol administration were in the range of 6.7-7.5 mm Hg and 0.5-0.7 g respectively. Repeated administration of vehicle did not elicit any appreciable changes in intravesical pressure and salivary secretion to carbachol administration from the basal values till 3 h. All the test drugs exhibited a dose-dependent inhibition of carbachol-induced increase in intravesical pressure and salivary secretion. Darifenacin demonstrated a greater potency compared to other muscarinic receptor antagonists for inhibiting carbachol-induced increase in intravesical pressure. It also exhibited functional selectivity for the urinary bladder versus salivary gland. In contrast, Oxybutynin was functionally more selective in inhibiting carbachol-induced increase in salivary secretion. The observed urinary bladder versus salivary selectivity values were 0.6+/-0.2, 1.1+/-0.2, 1.7+/-0.5, and 2.3+/-0.5 for Oxybutynin, Tolterodine, Solifenacin and Darifenacin respectively. These results suggest that the functional selectivity of muscarinic receptor antagonists between urinary bladder and salivary glands can be readily detected in this model. Thus rabbits may represent a useful animal model for evaluating putative bladder selective muscarinic receptor antagonists for the treatment of overactive bladder.     

A peri-trigonal giant tumefactive cavernous malformation: case report and review of literature

Introduction  

Giant cavernous malformations (GCMs) constitute an uncommon entity in the diagnostic armamentarium of the neurosurgeon. We report a 3-year-old boy with a GCM in the peri-trigonal region and review 13 other paediatric cases previously reported in literature.     

The operant training and generalization of pronouns and a verb form in a language delayed child.

The purpose of the present investigation was to train the correct use of three pronouns and the verb from "are" in a language delayed child and to assess the generalization of these trained responses to untrained stimuli. Within a multiple base-line design the four selected behaviors were sequentially trained using the techniques of positive reinforcement, modeling, and punishment for inappropriate responses. At succeding stages of training, probe trials were conducted to assess the extent of generalization of trained responses to untrained stimuli. A 100% generalization of trained responses to untrained stimuli was obtained for each of the four linguistic behaviors.     

An analysis of discrepancy between point-of-care and central laboratory international normalized ratio testing in ED patients with cerebrovascular disease

Objective

Our objective was to identify demographic, clinical, and operational variables associated with discrepancy between point-of-care (POC) and central laboratory international normalized ratio (INR) results in emergency department (ED) patients with acute cerebrovascular disease.

Methods

We conducted a retrospective, observational cohort study of a series of 637 patients with acute cerebrovascular disease over 30 months who underwent simultaneous POC, using the i-STAT POC analyzer (Abbott, Princeton, NJ), and central laboratory INR testing at ED presentation. Point-of-care INR results greater than ± 0.25 INR units from the central laboratory INR value were considered discrepant. We analyzed potential predictors of POC INR discrepancy from demographic, clinical, and operational variables using multivariable logistic regression. We evaluated the change in POC INR discrepancy incidence over the study interval using analysis of variance methodology.

Results

The final diagnoses of the 637 subjects were acute ischemic stroke (n = 427), transient ischemic attack (n = 105), and intracranial hemorrhage (n = 105). Discrepant POC INR results occurred in 21.5% (137/637) of subjects. The mean bias between POC and central laboratory INR was 0.24 ± 0.69 (range, 0-11.3). Significant covariates of POC INR discrepancy were oral anticoagulant use (odds ratio, 3.03; confidence interval, 1.37-6.68) and increasing activated partial thromboplastin time (aPTT) (odds ratio, 1.07; confidence interval, 1.02-1.12). We observed a significant reduction trend in the incidence of POC-central laboratory discrepancy over the study period, decreasing on average at 0.42% per month (F = 5.59, P = .025).

Conclusion

In this retrospective study, oral anticoagulant use and increasing aPTT were significantly associated with POC INR discrepancy in ED patients with acute cerebrovascular disease. Point-of-care INR discrepancy incidence decreased over the study interval.     

Cardiovascular surgical outcomes in patients with the antiphospholipid syndrome--a case-series

BACKGROUND: Patients with the antiphospholipid syndrome (APLS) have severe involvement of the cardiovascular apparatus and often need surgical interventions to correct these manifestations. Few studies that have looked at the outcomes of cardiothoracic surgeries in APLS patients have reported high rates of perioperative mortality and thromboembolic events. OBJECTIVE: Our goal was to examine the outcomes of adult APLS patients undergoing coronary artery bypass surgery (CABG) and/or valvular surgery. We also wanted to determine whether aggressive anticoagulation therapy could prevent life threatening thromboembolic complications in these patients. METHODS: We retrospectively reviewed medical records of nine patients with primary APLS undergoing cardiothoracic surgery between 1985 and 2005 at our institution. Patient demographics, operative procedures and one-year clinical outcomes were obtained. RESULTS: Forty-five percent of our patients had more than three cardiovascular risk factors other than APLS. There were no mortalities in our case series. However, 89% of our patients developed major complications. Despite aggressive anticoagulation, 37.5% developed thromboembolic events including cerebrovascular accidents, myocardial infarctions and vena caval thrombosis. Other complications included heparin-induced thrombocytopenia, redo of CABG surgery and sepsis. CONCLUSION: Despite aggressive anticoagulation and lack of significant pre-operative co-morbidities, APLS patients undergoing cardiothoracic surgery appear to have high rates of post-operative clinical events.     

Comparative study of perioperative infusion of diltiazem and nicorandil on myocardial protection during OPCAB surgery

We compared the effects of continuous intravenous infusions of nicorandil and diltiazem on left ventricular function, haemodynamics and as anti-ischaemic and anti-arrhythmic agents in 50 patients undergoing off pump coronary artery bypass surgery using arterial conduits. The patients were randomized into two equal groups to receive diltiazem or nicorandil. Both the drugs were given as a continuous infusion in the dose of 1microg/kg/min starting at induction and continued for 24 hours postoperatively. Haemodynamic parameters, cardiac enzyme levels and use of vasoactive agents were studied and compared using ANOVA, unpaired "t" and Fisher's exact tests. The two groups did not differ with respect to preoperative and operative data. Diltiazem group showed lower cardiac index (2.66+/-0.8 and 2.27+/-0.89 L/min/m2) as compared with nicorandil group (3.16+/-0.79 and 2.97+/-1.01 L/min/m2) during revascularisation of anterior (P=0.03) and inferior (P=0.01) circulation respectively. The systemic vascular resistance index was higher (2290+/-699 and 2545+/-911 dync.sec.cm-5.m2) in diltiazem group as compared with nicorandil group (1822+/-532 and 1877+/-548 dyne. sec.cm-5.m2) during revascularization of anterior (P=0.01) and inferior (P=0.002) circulation respectively. The mean pulmonary artery pressure was significantly higher in nicorandil group as compared with diltiazem group during revascularisation of anterior circulation (22.5+/-4.9 and 18.1+/-6.8 mmHg, P=0.01). The patients in the diltiazem group maintained a lower heart rate throughout the study period, but the difference was not statistically significant. None of the patients exhibited any arrhythmia except one in nicorandil group, who developed supraventricular arrhythmia 24 hours postoperatively. Cardiac enzyme levels were found to be similar in the two groups. The present study demonstrates that the anti-ischemic and antiarrythmic effects of diltiazem and nicorandil are comparable, but diltiazem causes a decrease in cardiac index and increase in systemic vascular resistance index during revascularization of anterior and inferior circulation.     

Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB--expressed by adenovirus vectors or after HCMV infection--and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells.