Antiarrhythmic actions of clemizole as pharmacologic evidence for a circus movement mechanism in atrial flutter

Summary The antihistaminic clemizole was studied as an antiarrhythmic in a preparation in which two arrhythmias of different nature and mechanism were produced in the right atrium of anesthetized dogs. One of the arrhythmias was a circus movement flutter induced by the method of Rosenblueth and García Ramos; the other, an ectopic focus induced by local application of aconitine in the auricular appendage, electrically isolated from the rest of the atrium. Clemizole selectively converted the flutter to sinus rhythm with little action on the coexistent aconitine dysrhythmia. It did not modify arterial pressure. In effective doses the wave length of the impulse was increased by prolongation of the refractory period without significant reduction in conduction velocity. Similarly, in subendocardial cells of isolated rat atria, clemizole in appropriate concentrations retards repolarization with little effect on the rate of depolarization. These results afford pharmacological evidence for the existence of atrial circus movement arrhythmias which can respond to prolongation of the refractory period unaccompanied by effects on other properties of the tissue. Other arrhythmias, self-sustained by the discharge of an ectopic focus, such as the tachysystole produced by aconitine, are not suppressed by similar increase in the refractory period.     

Does prolonged pneumoperitoneum affect oxidative stress compared with open surgical procedures?

BACKGROUND AND PURPOSE: As laparoscopic surgery has evolved, it has become part of the urologic surgical armamentarium and is now used to perform more complex procedures. Carbon dioxide, used to create pneumoperitoneum, produces physiologic changes in various organs, including the kidneys. Such changes are associated with altered redox status because of the release of free radicals and changes in oxidative stress signals. It is unknown whether prolonged pneumoperitoneum is associated with an increase in oxidative stress compared with open surgery. The objective of this study was to compare oxidative stress in patients undergoing urologic laparoscopic and open operations. PATIENTS AND METHODS: Urine samples were obtained immediately preoperatively, immediately postoperatively, and at 6 and 18 hours after surgery from 10 patients who underwent urologic laparoscopic surgery and 10 patients who underwent open surgery. Concentrations of the oxidative stress marker isoprostane (8- iso-prostaglandin F2a) were measured, and the results were analyzed with respect to clinical factors associated with the type of surgery. RESULTS: Urinary isoprostane concentrations (mean +/- SEM) in the laparoscopic and open groups showed an increase immediately after surgery to 189.0 +/- 64.2% and 141.1 +/- 45.8% of the preoperative values, respectively. A decrease in isoprostane was subsequently observed in both groups at 6 hours postoperatively, with preoperative values restored at 18 hours postoperatively (126.3 +/- 19.7% and 89.5 +/- 55.9% at 6 and 18 hours, respectively, in the laparoscopic group and 130.7 +/- 41.6% and 88.7 +/- 20.4% at 6 and 18 hours, respectively, in the open-surgery group). Although in both groups the peak PGF 2a concentration was observed immediately (0 hours) postoperatively, no significant differences were observed between the groups at 0, 6, and 18 hours. In the laparoscopic-surgery group, the mean increase tended to be higher and the decrease to be less prolonged than in the open-surgery group. CONCLUSION: Oxidative stress, as measured by urinary 8-iso-prostaglandin F2a, is produced by both laparoscopic and open urologic surgery. The findings of our nonrandomized study suggest a pattern of increased oxidative stress postoperatively with either type of surgery, with subsequent return almost to preoperative levels. Prolonged laparoscopic operative time did not affect oxidative stress levels.     

Dopaminergic reinnervation of the globus pallidus by fetal nigral grafts in the rodent model of Parkinson's disease

The current neural transplantation strategy for Parkinson's disease (PD) involves the dopaminergic reinnervation of the striatum (STR). Although up to 85% reinnervation of the STR has been attained by neural transplantation, functional recovery in animal models and transplanted patients is incomplete. This limitation may be due to an incomplete restoration of the dopaminergic input to other basal ganglia structures such as the external segment of the globus pallidus (GPe, homologue of the rodent GP), which normally receives dopaminergic input from the substantia nigra (SN). As part of our investigation into a multiple grafting strategy for PD, we have explored the effects of dopaminergic grafts in the GP of rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this experiment, lesioned rats received either 300,000 fetal ventral mesencephalic (FVM) cells or a sham injection into the GP. Functional assessment consisted of rotational behavior at 3 and 6 weeks posttransplantation. A fluorogold tracer study was conducted to rule out any behavioral improvement due to striatal outgrowth of the GP graft. Sections were stained for glial fibrillary acidic protein (GFAP) to assess the degree of trauma in the GP by the graft in comparison to the sham injection. Immunohistochemistry for tyrosine hydroxylase (TH) was performed after transplantation to assess graft survival. Animals with GP grafts demonstrated a significant improvement in rotational behavior at 3 and 6 weeks posttransplantation (p < 0.05) while sham control animals did not improve. All animals receiving FVM cells showed TH-immunoreactive grafts in the GP posttransplantation. TH-positive neurons in the GP showed no double labeling with an intrastriatal injection of fluorogold, indicating that behavioral improvement was not due to striatal innervation by the GP graft. These observations suggest that functional recovery was the result of dopaminergic reinnervation of the GP and that this nucleus may be a potential target for neural transplantation in clinical PD.     

Prevalance of proteinuria in Mexico: a conjunctive consolidation approach with other cardiovascular risk factors: the Mexican Health Survey 2000

BACKGROUND: A number of cross-sectional or serial studies have demonstrated the clinical impact of microproteinuria and macroproteinuria by identifying individuals at risk of both end-stage renal disease and major cardiovascular events. This study focused on the prevalence of proteinuria in Mexico and its relationship with other cardiovascular risk factors such as hypertension, type 2 diabetes mellitus, body mass index, smoking, age, and gender. METHODS: The prevalence of proteinuria in Mexico was obtained from the probabilistic cross-sectional national health survey performed in the year 2000. The proportion of urine dipstick samples that tested positive for protein (defined as > or =1+) in adults from 20 to 69 years of age was determined. The analysis was performed using both algebraic and multicategorical models. Potential interactions between proteinuria and other major cardiovascular risk factors were investigated. RESULTS: A total of 46,523 adult survey participants were included in the analysis. In the general population, 9.2% had proteinuria. By univariate, multivariate, and multicategorical analysis, hypertension, diabetes, obesity, and age were strongly associated with the prevalence of proteinuria (P < 0.001). However, in Mexico, the specific distribution of age groups demonstrated that the absolute number of patients without hypertension that had proteinuria is not irrelevant. To identify 1 case of proteinuria, one would need to screen 3 persons with diabetes mellitus, 5 patients with hypertension without diabetes, or 6 persons over the age of 55 years. When proteinuria is present, the probability of having a noncommunicable chronic disease or other major cardiovascular risk factor is more than 85%. CONCLUSION: Proteinuria is prevalent. When considered together, dipstick-positive proteinuria, blood pressure level, body mass index > or =30 m(2)/kg, and abnormal fasting blood glucose measured on a single occasion identifies different segments of the population. Studies such as this may be a suitable initial clinical approach to general population screening for renal and cardiovascular risk stratification.     

A novel role for parkin in trauma-induced central nervous system secondary injury

Recently, loss-of-function mutations of parkin have been identified as being causally related to autosomal recessive juvenile parkinsonism, the most common form of familial Parkinson's disease. In addition to functioning as an E3 ubiquitin ligase that facilitates the proteasomal degradation of proteins with abnormal conformations, parkin protects dopaminergic neurons from oxidative stress-mediated death by regulating mitochondrial function. Parkin is expressed throughout the brain in a variety of functional and neurochemical systems. We propose that parkin's role in protecting neurons from oxidative stress may extend beyond the nigrostriatal system to include neurons in other regions of the central nervous system. This is relevant for therapeutic strategies for brain and spinal cord injury because oxidative stress leading to lipid peroxidation and protein and nucleic acid oxidation is a significant cause of secondary injury and thus neuronal death following traumatic injuries to the central nervous system. A novel model system to verify the process of oxidative stress as a causative factor in trauma-induced secondary injury mechanisms would be to induce traumatic brain and spinal cord injury in parkin-null mice. This is expected to provide the proof-of-principle that a cascade of oxidative stress is a causal event leading to secondary neuronal injury, that parkin functions outside of the dopaminergic system to protect other neurons from oxidative stress, and that antioxidant pharmacotherapy is a rational therapeutic approach to decrease trauma-induced neuronal injury.     

Reducing hardware-related complications of deep brain stimulation

BACKGROUND: Deep brain stimulation (DBS) is used increasingly worldwide for the treatment of Parkinson's disease, dystonia, tremor and pain. As with any implanted system, however, DBS introduces a new series of problems related to its hardware. Infection, malfunction and lead migration or fracture may increase patient morbidity and should be considered when evaluating the risk/benefit ratio of this therapy. This work highlights several factors felt to increase DBS hardware complications. METHODS: The authors undertook a prospective analysis of their patients receiving this therapy in two Canadian centres, over a four-year period. RESULTS: One hundred and forty-four patients received 204 permanent electrode implants. The average follow-up duration was 24 months. Complications related to the DBS hardware were seen in 11 patients (7.6%). There were two lead fractures (1.4%) and nine infections (6.2%) including two erosions (1.4%). There was a significantly greater risk of infection in patients who underwent staged procedures with externalization. In patients with straight scalp incisions, the rate of infection was higher than that seen with curved incisions. CONCLUSION: Hardware complications were not common. A period of externalization of the electrodes for a stimulation trial was associated with an increased infection rate. It is also possible that a straight scalp incision instead of curvilinear incision may lead to an increase in the rate of infection. With a clear understanding of the accepted DBS device indications and their potential complications, patients may make a truly informed decision about DBS technology.