Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus

The effects of cibenzoline on transmembrane action potentials were examined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea-pig hearts. In papillary muscles, cibenzoline > or = 3 microM caused a significant decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the action potential duration. The inhibition of Vmax was enhanced at higher stimulation frequencies. In the presence of cibenzoline, trains of stimuli at rates > or = 0.2 Hz led to a use-dependent inhibition of Vmax. The time constant for Vmax recovery (tauR) from the use-dependent block was 26.2 s. The use-dependent block of Vmax with cibenzoline was enhanced and tauR was shortened when the resting potential was depolarized by high (8, 10 mM) [K+]o. The curve relating membrane potential and Vmax in single myocytes was shifted by cibenzoline (10 microM) in a hyperpolarizing direction by 7.1 mV. In myocytes treated with cibenzoline (10 microM), a 10-ms conditioning clamp to 0 mV caused a significant decrease in Vmax of the subsequent test action potential; the Vmax inhibition was enhanced modestly in association with a prolongation of the 0 mV clamp pulse duration. In the presence of cibenzoline (3 microM), application of a train of depolarizing pulses (10 ms, 200 ms) to myocytes from the resting level (-80 mV) to 0 mV resulted in a progressive Vmax reduction in a pulse number-dependent manner. Unlike glibenclamide (30 microM), cibenzoline (10 microM) did not prevent the hypoxia-induced shortening of action potential duration in papillary muscles. These findings indicate that the onset and offset kinetics of use-dependent Na+ channel block by cibenzoline are slow. Given its state dependence, cibenzoline may be a blocker of activated Na+ channels. The inhibitory action of this compound on the ATP-sensitive K+ current (I(K), ATP) would be minimal or negligible at concentrations causing sufficient Na+ channel block.     

Angiotensin II receptor type 1 mRNA is upregulated in atria of patients with end-stage heart failure

There is increasing evidence that pathological changes in the myocardium during chronic heart failure (CHF) are partly regulated through the activation of the renin-angiotensin system (RAS), an effect mediated by the angiotensin II type 1 receptor (AT1R). We examined the expression of cardiac AT1R mRNA in normal (atria, n=7; ventricle, n=3) and end-stage CHF human hearts (atria, n=8; ventricle, n=14). Tissue was snap-frozen immediately after explantation during orthotopic cardiac transplantation; control specimens were obtained from healthy donor hearts rejected for technical reasons. Northern blots of purified total mRNA from each tissue were hybridized with a random primed radiolabeled probe for the coding sequence of AT1R. Stringent conditions were used for both hybridization (5X SSC, 65 degrees C) and washing (0.5X SSC, 0.1% SDS, 65 degrees C) of the membrane. Left and right atrial tissue showed low levels of AT1R mRNA expression in the controls, with statistically significant upregulation of expression in tissue from pathological hearts; CHF atria 1.28+/-0.86 optical density (OD) units, control atria 0.56+/-0.31 OD units, P=0.05 (mean+/-s.d.). There were undetectable levels in ventricles from either control (2/2) or dilated hearts (7/7). The results were independent of the etiology of the heart failure and suggest that increased levels of atrial AT1R mRNA may occur in response to elevated atrial pressures in heart failure.     

On the effectiveness of early life cycle defect prediction with Bayesian Nets

Standard practice in building models in software engineering normally involves three steps: collecting domain knowledge (previous results, expert knowledge); building a skeleton of the model based on step 1 including as yet unknown parameters; estimating the model parameters using historical data. Our experience shows that it is extremely difficult to obtain reliable data of the required granularity, or of the required volume with which we could later generalize our conclusions. Therefore, in searching for a method for building a model we cannot consider methods requiring large volumes of data. This paper discusses an experiment to develop a causal model (Bayesian net) for predicting the number of residual defects that are likely to be found during independent testing or operational usage. The approach supports (1) and (2), does not require (3), yet still makes accurate defect predictions (an R ² of 0.93 between predicted and actual defects). Since our method does not require detailed domain knowledge it can be applied very early in the process life cycle. The model incorporates a set of quantitative and qualitative factors describing a project and its development process, which are inputs to the model. The model variables, as well as the relationships between them, were identified as part of a major collaborative project. A dataset, elicited from 31 completed software projects in the consumer electronics industry, was gathered using a questionnaire distributed to managers of recent projects. We used this dataset to validate the model by analyzing several popular evaluation measures (R ², measures based on the relative error and Pred). The validation results also confirm the need for using the qualitative factors in the model. The dataset may be of interest to other researchers evaluating models with similar aims. Based on some typical scenarios we demonstrate how the model can be used for better decision support in operational environments. We also performed sensitivity analysis in which we identified the most influential variables on the number of residual defects. This showed that the project size, scale of distributed communication and the project complexity cause the most of variation in number of defects in our model. We make both the dataset and causal model available for research use.     

Polyenes and vision

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT, E.C.2.4.2.8) from Artemia cysts exhibits maximum activity at 70 degrees C. Its thermal stability has been examined following enzymatic activity as a function of temperature. Cold-induced renaturation experiments of samples heated at increasing temperatures showed that reversibility of thermal inactivation depends on the incubation time and final temperature. Prolonged incubation of the thermoinactivated enzyme at 0 degree C did not afford any further increase of the catalytic activity at 37 degrees C. The complex substrate PRPP:Mg protects HGPRT from thermal inactivation. However, incubations with hypoxanthine rendered a less thermostable enzyme at any temperature tested. The irreversible inactivation of HGPRT proceeds in two exponential steps. The analysis of the apparent rate constants for the fast and the slow phases, lambda 1 and lambda 2 as per the Lumry and Eyring model suggests the existence of more than three states in the thermal denaturation pathway of the free enzyme. In the presence of PRPP:Mg the irreversible process follows a single exponential and proceeds very slowly below 70 degrees C. PRPP:Mg also protects the enzyme from inactivation by NEM and pCMB, suggesting that -SH groups may be in the vicinity of the active site.     

Noninvasive assessment of regional ventilation in the human lung using oxygen-enhanced magnetic resonance imaging

The imaging of regional ventilation in the lungs is essential for the evaluation of a variety of pathological conditions, such as emphysema, pneumonia and pulmonary embolism. We propose a novel approach for ventilation scanning, using magnetic resonance imaging (MRI) and inhaled molecular oxygen as a contrast agent, that directly depicts transfer of oxygen across the alveolus into the pulmonary vasculature. Molecular oxygen is only weakly paramagnetic but produces substantial signal changes in the lungs because of their large surface area. Ventilation defects were shown in a patient with bullous emphysema, and ventilation-perfusion mismatches were shown in two patients with pulmonary embolism.     

Renal osteodystrophy in diabetic patients

To assess the effects of diabetes mellitus on renal osteodystrophy, we examined the database of 256 patients (45% on hemodialysis and 55% on peritoneal dialysis) who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. All patients had serial documentation of their clinical, laboratory and risk parameters of bone disease, and completed a series of investigations that included the deferoxamine test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Twenty-five percent of these patients were diabetic. When compared to non-diabetic patients, they were on dialysis for a shorter duration (2.4 +/- 0.3 vs. 4.7 +/- 0.3 years; P < 0.0002), used calcium carbonate as the only phosphate binder more frequently (40 vs. 25%; P < 0.007), and had lower parathyroid hormone levels (12 +/- 1.4 vs. 24 +/- 2.3 pmol/liter; P < 0.002). High-turnover bone disorders (that is, osteitis fibrosa and mixed disorder) were distinctly uncommon (8 vs. 33%; P < 0.01 by Fisher's exact test), while the mild (19 vs. 9%; P = NS) and the aplastic disorders (with mean stainable bone surface aluminum of 6.5 +/- 0.7%) (46 vs. 31%; P = NS) tended to be more common in diabetic patients. The prevalence of aluminum bone disease was the same in both groups (27%). Diabetic patients ingested a smaller cumulative dose of aluminum gels (3.7 +/- 0.6 vs. 9.3 +/- 1.1 kg; P < 0.005), yet had a higher rate of aluminium accumulation on bone surfaces than non-diabetic patients (1.5 +/- 0.19 vs. 0.96 +/- 0.10% per month on dialysis; P < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)     

Implanted functional electrical stimulation hand system in adolescents with spinal injuries: an evaluation

OBJECTIVE: To study the utility and functional benefits of an implanted functional electrical stimulation (FES) system for hand grasp and release in adolescents with tetraplegia secondary to spinal cord injuries. DESIGN: Intervention study with before-after trial measurement with each subject as his or her own control. SETTING: Nonprofit pediatric orthopedic rehabilitation facility specializing in spinal cord injury. PARTICIPANTS: A convenience sample of five adolescents between 16 and 18 years of age with C5 or C6 level tetraplegia at least 1 year after traumatic spinal cord injury. Key muscles for palmar and lateral grasp and release were excitable by electrical stimulation. INTERVENTIONS: A multichannel stimulator/receiver and eight electrodes were surgically implanted to provide stimulated palmar and lateral grasp and release. In conjunction with implantation of the FES hand system, surgical reconstruction in the form of tendon transfers, tendon lengthenings and releases, and joint arthrodeses was performed to augment stimulated hand function. Rehabilitation of the tendon transfers and training in the use of the FES hand system were provided. MAIN OUTCOME MEASURES: Measurements of pinch and grasp force, the Grasp and Release Test (GRT), and an assessment of six activities of daily living (ADL) were administered before implantation of the FES hand system and at regular follow-up intervals. Results of the stimulated response of individual muscles and surgical reconstruction were evaluated using standard and stimulated muscle testing techniques and standard assessment of joint range of motion. All subjects completed followup testing. RESULTS: Lateral and palmar forces were significantly greater than baseline forces (p = .043). Heavy objects on the GRT could only be manipulated with FES, and FES increased the level of independence in 25 of 30 ADL comparisons (5 subjects, 6 activities) as compared to baseline. After training, FES was preferred in 21 of 30 comparisons over the typical means of task completion. Of the 40 electrodes implanted, 37 continue to provide excellent stimulated responses and all of the implanted stimulators have functioned without problems. The surgical reconstruction procedures greatly enhanced FES hand function by either expanding the workspace in which to utilize FES (deltoid to triceps transfer), stabilizing the wrist (brachioradialis to wrist extensor transfer), or stabilizing joints (intrinsic tenodesis transfer, FPL split transfer). CONCLUSION: For five adolescents with tetraplegia, the combination of FES and surgical reconstruction provided active palmar and lateral grasp and release. Laboratory-based assessments demonstrated that the FES system increased pinch force, improved the manipulation of objects, and typically increased independence in six standard ADL as compared to pre-FES hand function. The study also showed that the five adolescents generally preferred FES for most of the ADL tested. Data on the benefits of the implanted FES hand system outside of the laboratory are needed to understand the full potential of FES.