Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms

BACKGROUND: Most disability produced by psychotic illnesses, especially schizophrenia, develops during the prepsychotic period, creating a case for intervention during this period. However, only recently has it been possible to engage people in treatment during this phase. METHODS: A randomized controlled trial compared 2 interventions in 59 patients at incipient risk of progression to first-episode psychosis. We termed this group ultra-high risk to emphasize the enhanced risk vs conventional genetic high-risk studies. Needs-based intervention was compared with specific preventive intervention comprising low-dose risperidone therapy (mean dosage, 1.3 mg/d) and cognitive behavior therapy. Treatment was provided for 6 months, after which all patients were offered ongoing needs-based intervention. Assessments were performed at baseline, 6 months, and 12 months. RESULTS: By the end of treatment, 10 of 28 people who received needs-based intervention progressed to first-episode psychosis vs 3 of 31 from the specific preventive intervention group (P=.03). After 6-month follow-up, another 3 people in the specific preventive intervention group became psychotic, and with intention-to-treat analysis, the difference was no longer significant (P=.24). However, for risperidone therapy-adherent patients in the specific preventive intervention group, protection against progression extended for 6 months after cessation of risperidone use. CONCLUSIONS: More specific pharmacotherapy and psychotherapy reduces the risk of early transition to psychosis in young people at ultra-high risk, although their relative contributions could not be determined. This represents at least delay in onset (prevalence reduction), and possibly some reduction in incidence.     

High-throughput screening for evidence of association by using mass spectrometry genotyping on DNA pools

To facilitate positional cloning of complex trait susceptibility loci, we are investigating methods to reduce the effort required to identify trait-associated alleles. We examined primer extension analysis by matrix-assisted laser desorptionionization time-of-flight mass spectrometry to screen single-nucleotide polymorphisms (SNPs) for association by using DNA pools. We tested whether this method can accurately estimate allele frequency differences between pools while maintaining the high-throughput nature of assay design, sample handling, and scoring. We follow up interesting allele frequency differences in pools by genotyping individuals. We tested DNA pools of 182, 228, and 499 individuals using 16 SNPs with minor allele frequencies 0.026-0.486 and allele frequency differences 0.001-0.108 that we had genotyped previously on individuals and 381 SNPs that we had not. Precision, as measured by the average standard deviation among 16 semidependent replicates, was 0.021 +/- 0.011 for the 16 SNPs and 0.018 +/- 0.008 for the 291381 SNPs used in further analysis. For the 16 SNPs, the average absolute error in predicting allele frequency differences between pools was 0.009; the largest errors were 0.031, 0.028, and 0.027. We determined that compensating for unequal peak heights in heterozygotes improved precision of allele frequency estimates but had only a very minor effect on accuracy of allele frequency differences between pools. Based on these data and assuming pools of 500 individuals, we conclude that at significance level 0.05 we would have 95% (82%) power to detect population allele frequency differences of 0.07 for control allele frequencies of 0.10 (0.50).     

Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis

OBJECTIVE: To determine the relative efficacy of antianginal drugs administered as monotherapy or in combination in patients with chronic stable angina. METHODS: A meta-analysis was performed on randomized trials, published in English between 1980 and 1999, that directly compared combined treatment and monotherapy. Twenty-two articles were included, all on the comparison of -blocker monotherapies to their combination with a calcium antagonist and 10 on the comparison of calcium antagonist monotherapies to their combination with a -blocker. RESULTS: Time to 1 mm ST-segment depression, total exercise duration and time to onset of anginal pain were significantly increased with the combined therapy compared to -blocker alone (by 8, 5 and 12%, respectively). Only time to 1 mm ST-segment depression was significantly increased with the combined therapy compared to calcium antagonist alone (by 9%). For all these parameters, the adjusted differences were significant only within 6 h following drug intake and were not significant after 6 h. No analysis of safety data could be performed. CONCLUSION: As far as exercise testing is concerned, the combination of a calcium antagonist and a -blocker is statistically more effective than either monotherapy. Further studies are needed to confirm the higher efficacy after the first 6 h following drug intake.     

cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO

The nitric oxide (NO)-cGMP signaling cascade has been implicated in synaptic plasticity and, more broadly, in the control of many forms of electrical activity. This raises the issue of how these second messengers regulate ion channels. The field of ion-channel modulation is dominated by G proteins; NO and cGMP are often treated as poor cousins. However, recent advances surveyed here could change this perception. A surprising new dimension to NO signaling is the direct cGMP-independent action of NO on channel proteins through S-nitrosylation. The existence of two effector pathways has important functional implications, expanding and enriching the possibilities for modulating neuronal excitability.     

Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.     

Abnormalities in the recirculation phase of contrast agent bolus passage in cerebral gliomas: comparison with relative blood volume and tumor grade

BACKGROUND AND PURPOSE: Abnormalities in the recirculation phase of the passage of a contrast agent bolus have been identified in tumors and have been suggested to represent vascular tortuosity and hypoperfusion in areas of angiogenic neovascularization. This study was performed to examine the hypothesis that these abnormalities provide information concerning the microcirculation related to tumor grade in patients with cerebral glioma. METHODS: Contrast-enhanced dynamic susceptibility MR imaging was performed in 27 patients with glioma. Residual relaxivity effects were minimized by injection of contrast agent before dynamic imaging. Maps of relative cerebral blood volume (rCBV) and relative recirculation (rR) were calculated, and values from enhancing tumor tissue were compared with tumor grade. RESULTS: Histologic grades were grade II, astrocytoma (n = 3); grade III, anaplastic astrocytoma (n = 10); and grade IV, glioblastoma multiforme (n = 14). rCBV values varied among tumor grades, with higher mean values in higher grade tumors (P <.001). Mean rR values in grade II tumors were not significantly different from those in normal gray and white matter. Mean rR values in grades III and IV tumors were similar and were significantly higher than those in grade II tumors (P <.01). The distribution of the pixel values of rR showed significant differences between grades III and IV tumors (P <.001), with low values of skewness in keeping with a normal distribution in grade III tumors and higher values in grade IV tumors. CONCLUSION: Variation in the recirculation characteristics of a contrast agent bolus is related to tumor grade in gliomas. This supports the hypothesis that abnormalities in contrast agent recirculation provide independent information concerning the microcirculation in imaging studies of angiogenesis and may be of value as surrogate markers in trials of antiangiogenic therapy.     

Hemodynamic responses to stress among black women: fitness and parental hypertension

PURPOSE: We compared hemodynamic aspects of the relationship between cardiorespiratory fitness and blood pressure changes during and after laboratory stress in young black women with or without parental history of hypertension. METHODS: Participants were 30 normotensive, black American women having low to moderate fitness levels (i.e., VO2peak) assessed by cycle ergometry who performed standard active and passive coping laboratory stressors. Blood pressure, heart rate, stroke volume, cardiac output, total peripheral resistance (TPR), calf blood flow (CBF), and calf vascular resistance (CVR) were assessed during exposure to forehead and hand cold pressors, and mental arithmetic, as well as during recovery after the tasks. RESULTS: Fitness was positively related to increases in either TPR or CVR during each stressor. In contrast, fitness was positively related to blunted blood pressure during or after passive stress (i.e., hand or forehead cold) and enhanced recovery of blood pressure and TPR after the active stressor (i.e., mental arithmetic); effects of fitness on the vascular responses during and after mental arithmetic were stronger among women having a negative history of parental hypertension. CONCLUSION: The findings confirm our previous report that fitness blunts systolic blood pressure response during the hand cold pressor in young women. They also suggest that future studies of fitness and blood pressure reactivity during stress should focus on the regulation of vascular responses and their recovery after stress. Weaker effects of VO2peak after mental arithmetic in the positive history group indicate that the level of fitness required to modify recovery from mental stress among black American women may differ according to parental history of hypertension.     

Bile decompression in children with histopathological evidence of pre-existing liver cirrhosis

Although it is agreed upon by most that adequate and timely bile decompression can preserve or even improve existing liver function much debate centers on whether pre-existing liver cirrhosis can also be reversed. To help answer this question we analyzed data on 47 children with choledochal cyst disease (CD) who underwent simultaneous liver biopsy during bile decompression surgery. We collected data on two groups of children with CD spanning two different time periods: January 1985 through November 1994 (Group A) and June 1995 through November 1999 (Group B). In Group A 37 children (16 boys and 21 girls ages 5 days to 10 years) underwent simultaneous liver biopsy during elective definitive surgery for CD. In Group B ten children (five boys and five girls age one month to 7 years) underwent liver biopsy twice: first during initial cyst decompression for acute obstruction and second during elective definitive surgery after resolution of acute disease. Degree of liver cirrhosis was based on a modified World Health Organization classification system (0-IV). In Group A 15/37 (40.5%) had significant liver cirrhosis at time of biopsy (III or IV) with altered liver function in all cases; eight of nine had normal liver function on follow-up, six were lost to follow-up. In Group B seven of ten (70%) had less liver cirrhosis on pathology at second operation with three unchanged; nine of ten (90%) regained normal liver function. We conclude that bile duct obstruction is the main cause of liver cirrhosis in children with CD. Adequate and timely bile decompression can restore normal liver function and even reverse severe cirrhosis.     

Overview of the national spinal cord injury statistical center database

OBJECTIVE: An evaluation of the history, design, and status of the database of the National Spinal Cord Injury Statistical Center (NSCISC) was undertaken to identify its continued relevance. RESEARCH DESIGN: A systematic review was conducted of goals, content, and quality control procedures, as well as its suitability and public availability for conducting future epidemiologic and health services research. RESULTS: The NSCISC database contains information on approximately 29,000 persons injured since 1973 and treated at any regional model spinal cord injury system within 1 year of injury. The NSCISC database is structured longitudinally with data collected at discharge, 1 year after injury, 5 years after injury, and every 5 years thereafter. The database includes information on demographics, injury severity, medical complications, surgical procedures, types and amounts of therapy, length of stay, charges, and both short-term and long-term treatment outcomes. Strengths include large sample size, use of valid and reliable measures, geographic and patient diversity, comprehensiveness, availability of long-term prospective follow-up information, good case identification, and rigorous quality control procedures. Limitations include lack of population basis, inclusion of only model system patients, losses to follow-up, and other missing data. Recent content additions include detailed information on each treatment phase, depression, substance abuse, environmental barriers to community integration, and patient identifying information. A process exists for researchers to gain access to the data. CONCLUSIONS: The database remains a valuable resource. Future plans include linkage to other databases to enhance research capability, a published research compendium, and development of a user's guide to facilitate database usage.