Evidence for the preventive effect of the polyunsaturated phytol side chain in tocotrienols on 17beta-estradiol epoxidation

BACKGROUND: We found that 17beta-estradiol (E2) could be activated by epoxidation to bind DNA and to inhibit nuclear RNA synthesis. Vitamin E compounds are powerful antioxidants and chain-breaking free radical scavengers. The chromanol ring in Vitamin E is believed to be involved in these reactions. METHODS: Here, we examined the preventive effect of alpha-tocopherol, alpha-, gamma- and delta-tocotrienols on E2 activation. RESULTS: We found that when any one of these Vitamin E compounds was mixed with E2 for epoxidation by the epoxide-forming oxidant dimethyldioxirane (DMDO), alpha-tocopherol was the least effective as compared with the tocotrienols against the formation of E2 epoxide as reflected by the loss of the ability of E2 to inhibit nuclear RNA synthesis. This conclusion was further confirmed by the binding studies of [3H] labeled E2 to DNA using either DMDO or liver microsomes activation system. CONCLUSIONS: Since the chromanol ring is shared by both tocopherols and tocotrienols and the only difference between these two subgroups of Vitamin E is the phytol side chain, we conclude that the polyunsaturated phytol group in tocotrienols plays a key preventive role in E2 epoxidation. This is the first report showing that the polyunsaturated phytol side chain in tocotrienols is involved in an antioxidative activity and it may also have a preventive effect against the E2 epoxide induced breast cancer carcinogenesis at the initiation.     

Synchronized network activity in developing rat hippocampus involves regional hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function

The principal form of synchronized network activity in neonatal hippocampus consists of low frequency 'giant depolarizing potentials' (GDPs). Whereas contribution of both GABA and glutamate to their generation has been demonstrated, full understanding of the mechanisms underlying these synchronized activity bursts remains incomplete. A contribution of the h-current, conducted by HCN channels, to GDPs has been a topic of substantial interest. Here we focus on HCN1, the prevalent HCN channel isoform in neonatal hippocampus, and demonstrate an HCN1 spatiotemporal expression pattern in both CA3 principal cells and interneurons that correlates with the developmental profile of GDPs. Abrogation of HCN physiological function in CA3, via the selective I(h)-blocker ZD7288, disrupts GDP generation. Furthermore, ZD7288 specifically abolishes spontaneous bursting of the CA3 pyramidal cells at frequencies typical of GDPs without major influence on interneuronal firing. These findings support a pivotal role for HCN channels expressed by CA3 neurons, and particularly CA3 pyramidal cells, in GDP-related network synchronization.     

Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia

OBJECTIVE: This randomized double-blind multicenter trial evaluated the effects of olanzapine vs. clozapine on subjective well-being, quality of life (QOL) and clinical outcome. METHOD: The primary objective was to demonstrate non-inferiority of olanzapine, mean dosage 16.2 +/- 4.8 (5-25 mg/day) vs. clozapine, mean dosage 209 +/- 91 (100-400 mg/day) regarding improvement on the 'Subjective Well-Being under Neuroleptic Treatment' (SWN) Scale after 26 treatment weeks in 114 patients with schizophrenia. Secondary outcome parameters included: Munich QOL Dimension List (MLDL), Positive and Negative Symptom Scale (PANSS), Clinical Global Impression (CGI). RESULTS: SWN scores improved significantly in both groups, olanzapine was non-inferior to clozapine (group difference 3.2 points in favor of olanzapine; 95% CI: 4.2;10.5). MLDL-satisfaction, PANSS and CGI-S improved similarly, olanzapine yielded a higher CGI Therapeutic Index. Individual SWN and PANSS changes correlated only moderately (r = -0.45). CONCLUSION: Olanzapine was non-inferior to clozapine. The lack of a marked correlation between PANSS and SWN improvements indicates that patients and psychiatrists perceive treatment differently.     

Dimensional representations of DSM-IV personality disorders: relationships to functional impairment

OBJECTIVE: This study compared three-dimensional representations of DSM-IV personality disorders and standard categories with respect to their associations with psychosocial functioning. METHOD: Six hundred sixty-eight patients with semistructured interview diagnoses of schizotypal, borderline, avoidant, or obsessive-compulsive personality disorders or with major depressive disorder and no personality disorder completed questionnaires assessing three-factor and five-factor dimensional models of personality. Personality disorder categories, dimensional representations of the categories based on criteria counts, and three- and five-factor personality dimensions were compared on their relationships to impairment in seven domains of functioning, as measured by the Longitudinal Interval Follow-up Evaluation-Baseline Version. RESULTS: Both the categorical and dimensional representations of DSM-IV personality disorders had stronger relationships to impairment in functioning in the domains of employment, social relationships with parents and friends, and global social adjustment and to DSM-IV axis V ratings than the three- and five-factor models. DSM-IV dimensions predicted functional impairment best of the four approaches. Although five-factor personality traits captured variance in functional impairment not predicted by DSM-IV personality disorder dimensions, the DSM-IV dimensions accounted for significantly more variance than the measures of personality. CONCLUSIONS: Scores on dimensions of general personality functioning do not appear to be as strongly associated with functional impairment as the psychopathology of DSM personality disorder. A compromise in the ongoing debate over categories versus dimensions of personality disorder might be the dimensional rating of the criteria that comprise traditional categories.     

CT fluoroscopy-guided biopsy of the lung or upper abdomen with a breath-hold monitoring and feedback system: a prospective randomized controlled clinical trial

PURPOSE: To prospectively determine the clinical effectiveness of a breath-hold monitoring and feedback system in computed tomographic (CT) fluoroscopy-guided biopsies in which respiratory motion is a problem. MATERIALS AND METHODS: Institutional review board approval and oral and written informed consent were obtained. This study was HIPAA compliant. A bellows-based system was used to monitor respiration and provide patient feedback. A randomized controlled clinical trial compared intermittent mode CT fluoroscopy-guided biopsies of the lung or upper abdomen performed with (n = 56) and without (n = 57) the bellows system. Inclusion criteria for 113 patients were lesions 6 cm or smaller in maximum dimension that were not affixed to the chest or abdominal wall. Primary outcome measurements were CT fluoroscopy exposure time and patient dose. Wilcoxon rank sum, chi(2), and Fisher exact tests were used for statistical analysis. RESULTS: Median CT fluoroscopy exposure time was 12.6 seconds (range, 2.4-44.4 seconds) for the bellows group and 18.0 seconds (range, 6.0-118.0 seconds) for the nonbellows group (P = .004). Patient dose was decreased in the bellows group (median dose, 29.5 mGy; range, 4.7-135.8 mGy) versus the nonbellows group (median, 41.3 mGy; range, 11.8-155.9 mGy) (P = .01). Lesions were accessed successfully with one needle puncture attempt in 43 of 56 patients (77%) in the bellows group and 30 of 57 patients (53%) in the nonbellows group (P = .007). Pneumothorax developed in 11 of 50 patients (22%) in the bellows group who underwent lung biopsy compared with 16 of 50 (32%) patients in the nonbellows group. CONCLUSION: A breath-hold monitoring and feedback system allows depiction of mobile target lesions throughout CT fluoroscopy-guided biopsy of the lung and upper abdomen.     

Children's physical activity: using accelerometers to validate a parent proxy record

INTRODUCTION: The purpose of this study was to validate a parent proxy record of children's physical activity with CSA Model 7164 accelerometers. METHODS: A parent proxy record was developed to record children's activity after school on weekdays and all day long on weekends for 7 d. Parents recorded both duration and intensity of activity (light, medium, hard and very hard). Children simultaneously wore a CSA-7164 accelerometer around their right hip, which served as the objective measurement against which the proxy record was validated. Sixty-five parent/child dyads participated in the study. RESULTS: The overall activity level of the children was low (<3 METs). Spearman-rho analyses indicated that the accelerometer and proxy record showed poor to fair agreement for the entire monitoring period, with parents consistently overreporting their child's activity levels. Correlation between the two instruments was highest at midday on weekends (0.383) and immediately after school on weekdays (0.267). CONCLUSION: Due to the low correlation between this proxy record and the accelerometer, the need still exists for a valid measurement of child physical activity that is both inexpensive and easy to employ in larger community-based interventions.     

Long-term care liability for pressure ulcers

More than 20% of residents who have been in long-term care (LTC) facilities for 2 or more years will develop at least one pressure ulcer (PU). Residents suffer pain, disfigurement, and decreased quality of life, and their risk of illness and death increases. LTC facilities face censure from residents, their families, and surveyors and the threat of expensive lawsuits. Lawsuits are typically based on contentions of residents with a PU--or their advocates--that the LTC facility was negligent and failed to provide the care that, by industry standards, it must provide to prevent or manage such wounds (managing pressure, incontinence, and nutrition). In this article, data from 1999 and 2002 are presented, showing that lawsuits related to PUs are increasingly common and costly for LTC owners and care providers. Residents realized some type of recovery against the facility in 87% of the cases (verdicts for the resident plus settlements) and were awarded amounts as high as $312 million in damages. Even LTC administrators who believe that care in their facility equals or exceeds industry standards often settle lawsuits out of court to avoid jury verdicts. The data also show that jury awards were highest for PUs caused by multiple factors and that the highest awards for PUs caused by a single factor were seen when that factor was inadequate nutrition. LTC providers can help improve the health and quality of life of their residents, improve survey results, and minimize their risk of expensive lawsuits by developing, implementing, and documenting a plan of basic measures to prevent PUs.