Ibotenic acid lesions of the striatum reduce drug-induced rotation in the 6-hydroxydopamine-lesioned rat

Lesions of the dopaminergic nigrostriatal tract produce a range of motor and sensorimotor deficits. One of the simplest and most reliable is the rotational response of the animal following activation with drugs that stimulate the dopaminergic network, most notably amphetamine and apomorphine. Consequently, the rotation test has been extensively used in assessing the success of treatments designed to restore dopaminergic function, including neural transplants. The present study investigates whether rotation induced by 6-hydroxydopamine lesions of the nigrostriatal bundle in rats is modified by additional lesions in the neostriatum. It was found that apomorphine-induced rotation can be reduced by ibotenic acid lesions of the dopamine-deafferented striatum, and that the extent of the reduction was proportional to the size of the lesions. In contrast, such lesions produced a non-significant reduction in amphetamine-induced rotation, although the correlation between the extent of the reduction and the size of the lesion was again apparent. Since the pattern of change was similar in direction, albeit smaller in magnitude, than the previously reported effects of intrastriatal transplantation in rats with similar nigrostriatal lesions, rotation tests alone do not provide an unequivocal test of graft survival and function.     

A multivariable analysis of clinical factors predicting for pathological features associated with local failure after radical prostatectomy for prostate cancer

PURPOSE: A multivariate analysis is used to determine the predictive value of pretreatment clinical indicators on pathologic features associated with local failure after radical prostatectomy in patients with prostate cancer. METHODS AND MATERIALS: A retrospective review of the pathologic findings of 235 patients with adenocarcinoma of the prostate treated between 1990 and 1993 with a radical retropubic prostatectomy was performed. The preoperative clinical data including the serum prostate specific antigen, clinical stage, Gleason sum, and endorectal magnetic resonance scan findings are used to identify patients prior to definitive treatment who would be at high risk for having pathologic features associated with local failure at radical prostatectomy. Outcome prediction curves are constructed from a logistic regression multivariate analysis displaying the probability of pathologic involvement of the seminal vesicle, extracapsular disease, or positive surgical margins as a function of the preoperative prostate specific antigen and Gleason sum for the cases when the endorectal magnetic resonance scan is positive, negative, or not included in the multivariate analysis. RESULTS: Factors identified on multivariate analysis as significant predictors of seminal vesicle invasion include endorectal magnetic resonance scan findings (p < 0.0001), and preoperative prostate specific antigen (p = 0.017). Endorectal magnetic resonance scan findings (p = 0.0016), preoperative prostate specific antigen (p = 0.0002), and Gleason sum (p < 0.0001) were significant predictors of extracapsular extension and preoperative prostate specific antigen (p < 0.0001) and Gleason sum (p = 0.03) were significant predictors of disease extending to the margins of resection. Clinical stage was not a significant predictor (p > 0.05) of pathologic features associated with local failure on multivariate analysis. As a single modality, endorectal surface coil magnetic resonance imaging was accurate 93%, 69%, and 72% of the time for predicting seminal vesicle invasion, transcapsular disease, and final pathologic stage, respectively. Failure to recognize microscopic penetration of the capsule found at the time of pathologic evaluation in a prostate gland with a grossly intact capsule accounts for the majority (70%) of the staging inaccuracies. CONCLUSIONS: The use of the endorectal surface coil magnetic resonance scan findings in conjunction with both the serum prostate specific antigen and Gleason sum improves the clinical accuracy of predicting those patients at high risk for clinically unsuspected extraprostatic disease. In particular, for the subgroup of patients with moderately elevated prostate specific antigen (> 10-20 ng/mL) and intermediate grade clinically organ confined prostate cancer [Gleason sum: 5-7] where the specificity of these tests to predict for occult extraprostatic disease is suboptimal, the additional information obtained from the endorectal coil magnetic resonance scan allows the physician to definitively subgroup these patients into low and high risk for seminal vesicle invasion or transcapsular disease.     

The interferon-induced double-stranded RNA-activated human p68 protein kinase inhibits the replication of vaccinia virus

The interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase (p68 kinase) has long been implicated as one of the antiviral agents responsible for overcoming virus infections. To investigate the antiviral potential of p68 kinase, we have generated a recombinant vaccinia virus that expresses human p68 kinase under the control of lac operator/repressor element. Upon induction of p68 kinase gene with the inducer isopropyl-beta-D-thiogalactoside (IPTG), we observed in cultured cells a severe (> 90%) inhibition of virus protein synthesis; this inhibition correlated with autophosphorylation of p68 kinase. As a result of inhibition in the synthesis of virus polypeptides, there was a 100-fold decrease in virus yields. When cells were infected with the recombinant virus expressing lys296-->arg296 mutant p68 kinase there was no reduction in virus yields. Our findings demonstrate that human p68 kinase once activated severely inhibits vaccinia virus replication as a result of inhibition of protein synthesis.     

A multidimensional measurement model for cardiovascular reactivity: stability and cross-validation in two adult samples

The factor structure for measures of stress-related cardiovascular reactivity was examined in 2 samples: a university campus employee sample (N = 72) and a sample of young adult twins (N = 113). In both samples, 5 noninvasive cardiovascular measures were monitored during a series of challenging laboratory tasks. We developed a 2-factor model depicting vascular and cardiac influences on responding. With confirmatory factor analysis, this model was shown to be consistent with the data across both samples, across 2 testing sessions, and across 2 sets of tasks. Latent variables measuring cardiac and vascular reactivity were highly reliable on retest as well. Individual differences in cardiovascular reactivity to mental stress may be characterized by a stable, 2-dimensional pattern of response.     

Serum immunoglobulin G concentration in goat kids fed colostrum or a colostrum substitute

To determine the suitability of a new colostrum substitute derived from goat serum and to determine the amount of colostral IgG needed to achieve serum IgG concentration > 800 mg/dl, twin kids from 14 does were fed colostrum or a colostrum substitute. The volume of colostrum or colostrum substitute fed was calculated so that half the kids in each group received IgG at a low dosage (1.5 g/kg of body weight) and the other half received IgG at a high dosage (3 g/kg). Kids were bottle fed the colostrum or colostrum substitute and then fed pooled goat's milk until 18 hours old, at which time they were allowed to nurse their dams. Does were milked manually every 2 hours after parturition until specific gravity of mammary secretions was < 1.02, the specific gravity of goat's milk. Serum IgG concentration of each kid was determined by means of single radial immunodiffusion at birth and 12, 18, and 24 hours and 7, 21, and 42 days after birth. Kids were weighed at each blood collection and monitored for illness daily. None of the kids had measurable serum IgG concentrations at birth. Mean serum IgG concentration was significantly higher in kids fed colostrum than in kids fed colostrum substitute at all times, except days 7 and 42 (P < 0.05). By 24 hours after birth, serum IgG concentration was > 800 mg/dl in all kids fed colostrum, in 4 of 7 kids fed the substitute at the higher dosage, and in 2 of 7 kids fed the substitute at the lower dosage.(ABSTRACT TRUNCATED AT 250 WORDS)     

A critical analysis of studies of state drug reimbursement policies: research in need of discipline

Concerns over pharmaceutical costs and appropriateness of medication use have led state Medicaid programs to restrict drug reimbursement. This article critically reviews 20 years of research on cost sharing, drug reimbursement limits, and administrative limitations on access to particular drugs via formularies, category exclusions, or prior authorization requirements; evaluates their methodological rigor; summarizes the state of current knowledge; and proposes future research directions. Drug reimbursement caps and modest cost sharing can reduce the use of both essential and less important drugs in Medicaid populations; severe reimbursement caps may precipitate serious unintended effects. Limitations on access to particular drugs can cause both rational and irrational drug substitution effects; it is unclear whether such limits reduce expenditures either for drugs or for overall health care.     

Dose released and absolute bioavailability of nicotine from a nicotine vapor inhaler

In an open, randomized, three-way crossover study, 14 healthy smokers used one type of nicotine vapor inhaler intensely for 20 minutes every hour for 11 hours (12 administrations). Two different inhalation techniques were applied, shallow frequent sucking (buccal mode) and deep inhalations (pulmonary mode). The determination of nicotine was performed by capillary gas chromatography after single-step liquid-liquid extraction of the plasma sample. Nicotine was detected by means of a nitrogen-sensitive detector, giving high selectivity and sensitivity. The mean (+/- SD) nicotine dose released from each nicotine vapor inhaler unit was estimated at 4.00 +/- 0.60 mg (buccal mode) and 3.87 +/- 0.75 mg (pulmonary mode), inhaled with approximately 15 L of air. Mean (+/- SD) peak plasma level of the last dosing interval was 32.0 +/- 8.7 ng/ml and 34.2 +/- 8.9 ng/ml for the buccal and the pulmonary technique, respectively, achieved after 0.33 and 0.50 (median) hour, respectively. The mean (95% confidence interval [CI]) absolute bioavailability of nicotine was 51 (95% CI, 40 to 65) and 56 (95% CI, 47 to 67) when the buccal and pulmonary techniques were used, respectively. A significant correlation was found between systemically available dose and average steady-state nicotine plasma concentration. Based on the achievement of similar nicotine plasma levels, it may be concluded that the two modes of inhalation appear to be clinically equivalent.