Evaluation of the role of P-glycoprotein in the uptake of paroxetine, clozapine, phenytoin and carbamazapine by bovine retinal endothelial cells

Expression of the drug transport proteins, including P-glycoprotein (Pgp), in the brain vascular endothelium represents a challenge for the effective delivery of drugs for the treatment of several central nervous system (CNS) disorders including depression, schizophrenia and epilepsy. It has been hypothesized that Pgp plays a major role in drug efflux at the blood-brain barrier, and may be an underlying factor in the variable responses of patients to CNS drugs. However, the role of Pgp in the transport of many CNS drugs has not been directly demonstrated. To explore the role of Pgp in drug transport across an endothelial cell barrier derived from the central nervous system, the expression and activity of Pgp in bovine retinal endothelial cells (BRECs) and the effects of representative CNS drugs on Pgp activity were examined. Significant Pgp expression in BRECs was demonstrated by western analyses, and expression was increased by treatment of the cells with hydrocortisone. Intracellular accumulation of the well-characterized Pgp-substrate Taxol was markedly increased by the non-selective transporter inhibitor verapamil and the Pgp-selective antagonist PGP-4008, demonstrating that Pgp is active in these endothelial cells. In contrast, neither verapamil nor PGP-4008 affected the intracellular accumulation of [3H]paroxetine, [14C]phenytoin, [3H]clozapine or [14C]carbamazapine, indicating that these drugs are not substrates for Pgp. Paroxetine, clozapine and phenytoin were shown to be Pgp inhibitors, while carbamazapine did not inhibit Pgp at any concentration tested. These results indicate that Pgp is not likely to modulate patient responses to these drugs.     

Optimal control of redundant muscles in step-tracking wrist movements

An important question in motor neuroscience is how the nervous system controls the spatiotemporal activation patterns of redundant muscles in generating accurate movements. The redundant muscles may not only underlie the flexibility of our movements but also pose the challenging problem of how to select a specific sequence of muscle activation from the huge number of possible activations. Here, we propose that noise in the motor command that has an influence on task achievement should be considered in determining the optimal motor commands over redundant muscles. We propose an optimal control model for step-tracking wrist movements with redundant muscles that minimizes the end-point variance under signal-dependent noise. Step-tracking wrist movements of human and nonhuman primates provide a detailed data set to investigate the control mechanisms in movements with redundant muscles. The experimental EMG data can be summarized by two eminent features: 1) amplitude-graded EMG pattern, where the timing of the activity of the agonist and antagonist bursts show slight variations with changes in movement directions, and only the amplitude of activity is modulated; and 2) cosine tuning for movement directions exhibited by the agonist and antagonist bursts, and the discrepancy found between a muscle's agonist preferred direction and its pulling direction. In addition, it is also an important observation that subjects often overshoot the target. We demonstrate that the proposed model captures not only the spatiotemporal activation patterns of wrist muscles but also trajectory overshooting. This suggests that when recruiting redundant muscles, the nervous system may optimize the motor commands across the muscles to reduce the negative effects of motor noise.     

The value of computed tomography in the diagnosis of intracranial lipomata.

Intracranial lipomata can be found in both symptomatic and asymptomatic patients. The tumors, which are rare, can be diagnosed by computed tomography without further investigative procedures.     

Transcatheter Embolization of Hypogastric Artery Aneurysms: Lessons Learned

Transcatheter embolization of hypogastric artery aneurysms has become an attractive therapeutic alternative for many patients with this difficult lesion. Because of the increasing use of stent grafting for treatment of abdominal aortic aneurysms, transcatheter embolization of normal-caliber hypogastric arteries has become an almost routine procedure, usually accomplished with little morbidity. Applying this treatment to aneurysmal hypogastric arteries, however, involves greater technical complexity and a significantly higher risk of ischemic complications. We present three cases to illustrate the technical challenges of hypogastric aneurysm embolization, the potentially devastating ischemic complications, and the clinical situations that may predispose to poor outcomes.A preliminary version of this paper was presented at the 27th Annual Meeting of the New England Surgical Society, Boston, MA, October 5, 2000.     

Morbidity and mortality associated with renal insufficiency and endovascular repair of abdominal aortic aneurysms: a 5-year experience

To evaluate the outcome of patients with renal insufficiency undergoing endovascular repair of abdominal aortic aneurysm (AAA), data were prospectively collected between 1998 and 2003 on patients undergoing elective repair of their AAA with a stent graft. The patients were divided into 2 groups: those with serum creatinine (Crs) concentrations <1.2 (Group A) and those with Crs > or =1.2 mg/dL not requiring hemodialysis (Group B). The outcomes of the procedure for these 2 groups were compared. Different variables that existed between the 2 groups and contributed to mortality included estimated blood loss (EBL), volume of contrast used in the operating room, incidence of diabetes (DM), tobacco use, and history of myocardial infarction (MI). In total, 213 patients underwent elective repair of their AAA with use of a stent graft: 61% who had a Crs <1.2 mg/dL (Group A) and 39% who had a Crs > or =1.2 mg/dL not requiring dialysis (Group B). Among 129 patients with normal renal function there was an 18.6% complication rate and 1.6% mortality rate. Of 83 patients with renal insufficiency not on hemodialysis 30.1% (Fisher's Exact Test = 0.076) had 1 or more complications and there was a 6% (Fisher's Exact Test = 0.166) mortality rate. One patient in Group A (0.8%) progressed to hemodialysis and 5 (6%) patients in Group B progressed to end-stage renal disease requiring hemodialysis (p=0.068). A statistically significant higher proportion of the patients in Group B had a history of MI (p<0.001). There was no difference in the amount of EBL between the 2 groups, but a significantly lower amount of contrast (p<0.05) was used in patients with renal insufficiency.     

Adaptation to a visuomotor shift depends on the starting posture

Previous studies have shown that human subjects can adapt to a new visuomotor relationship that depends on the trajectory of the arm. However, these studies have not distinguished between hand- and joint-based learning models. We have examined whether different endpoint kinematics are necessary to obtain a differential visuomotor shift. The joint trajectory was varied by changing the initial posture, while maintaining a similar finger trajectory. After learning, maximum after-effects were found when movement began with the posture used during exposure to the visuomotor shift and decreased with the difference between initial and trained posture. This was shown to be independent of the final posture attained. Our results show that adaptation to a visual remapping cannot be due to the recoding of a desired final posture and depends on the arm trajectory in joint space.     

Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod=3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several crossovers in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus. Electronic Publication     

St John's wort: a potential therapy for elderly depressed patients?

St John's wort (Hypericum perforatum) has a 2000-year history of use as a medicinal herb. Its modern application as a plant extract for treating depression has undergone scientific investigation over the last decade, and its effectiveness has been shown in studies comparing it with placebo and reference antidepressants. Our own work supports the contention that LI 160, the best-documented St John's wort medication, is effective at a high dosage even in patients with severe depression. Since the new Berlin Aging Study revealed significant treatment deficiencies among elderly depressive patients, St John's wort extracts may be a useful alternative to benzodiazepines to avoid nontreatment of early depression. Because St John's wort preparations have better tolerability than tricyclic antidepressants, elderly people in particular, can benefit from their use.     

Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome

Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. Methods and Results: Pinacidil, an I_K‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I_Kr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization. Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.