Single dose methodology to assess the influence of an alpha1-adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia

AIMS: To establish methodology which rapidly and reliably assesses the effect of an alpha1-adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH. METHODS: Twenty-five patients with BPH enrolled in a double-blind, placebo-controlled, two-period crossover study. Patients were either withdrawn from their current alpha1-adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s-1 off therapy (or < 10 ml s-1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s-1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two-period crossover. Uroflowmetry was performed predose and once postdose (4.5-5.5 h postdose) on day 1, and once postdose (4.5-5.5 h postdose) on day 8 of each treatment period. RESULTS: After a single dose of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s-1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s-1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference). CONCLUSIONS: Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for 'responsiveness' to an alpha1-adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.     

Parent-Child Interaction and Developmental Outcomes in Medically Fragile, High-Risk Children

We examined the relation between parents' responsiveness and directiveness with their 2-year-olds and the children's developmental outcomes at age 5 1/2 in 88 preterm children with intraventricular hemorrhage. At age 2, each participant was videotaped in a free-play setting with the primary caregiver. These videotapes were evaluated and coded using the Maternal Behavior Rating Scale (MBRS) and the Parent/Caregiver Involvement Scale (P/CIS). The Stanford-Binet Intelligence Scale, Fourth Edition (SB-IV) was administered to the children at age 5 1/2. Evidence of statistically and clinically significant relations between interaction at age 2 and development at school age was yielded. Higher rates of responsiveness on all measures were associated with favorable developmental outcomes on the SB-IV. Greater amounts of directiveness on both the MBRS and the P/CIS were related to less favorable developmental outcomes. Findings suggest that the critical aspects of directiveness may lie in the appropriateness of the directives for the individual child and in the manner in which the directives are given. Implications for intervention with parents of medically fragile infants are discussed.     

Bone scan findings in hypervitaminosis D: case report

Bone scans in three patients showed generalized symmetrical increased uptake of radiopharmaceutical by the skeleton and absent or faint kidney images. It is thought that these appearances may be attributable to excess vitamin D, but other possible contributing factors, including the presence of renal osteodystrophy, are discussed.     

Life events, social support, and cardiovascular reactivity in adolescence

Physiologic responses to environmental stress show striking interindividual differences, beginning early in life. Whereas cardiovascular reactivity (CVR) to stress has been linked to short- and long-term changes in health, little previous work has addressed reactivity in children, and no past studies have investigated the relationship of reactivity to psychosocial factors, such as stressful life events (LE) and social support (SS). We therefore studied cardiovascular response to psychologically and physically stressful laboratory tasks in 25 adolescent boys. The degree of individual CVR was examined cross-sectionally in relationship to LE, SS, and "sense of permanence" (SP), a construct reflecting the stability or continuity in the child's life experience. Heart rate reactivity (HRR) and mean arterial pressure reactivity (BPR) were bimodally distributed, with a subpopulation of approximately 20% of subjects demonstrating an exaggerated cardiovascular response. SP was related to BPR at a borderline level of significance (R = 0.33, p less than 0.10), whereas SS was unrelated to either reactivity variable. Unexpectedly, LE was strongly and inversely related to both HRR and BPR (R = -0.40 and -0.47, respectively, p less than 0.05). Subjects reporting low numbers of previous stressful life events had the highest level of cardiovascular reactivity. Possible explanations for this finding included (1) the development of a hyperdynamic response as a consequence of avoiding or denying stressful experience, (2) an effect of exaggerated CVR on cognition and the reporting of stressful events, or, most plausibly, (3) an 'inoculation effect,' in which previous LE facilitate the development of effective coping strategies, thereby diminishing responses to stressful laboratory tasks.     

Pharmacologic C5-complement suppression reduces blood loss during on-pump cardiac surgery

BACKGROUND: Inflammation contributes to morbidity following on-pump cardiac surgery. Complement activation during cardiopulmonary bypass has been associated with the postoperative bleeding and tissue injury. This study examines the pharmacology and impact on blood loss of complement C5 suppression with pexelizumab in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: Pexelizumab, a humanized monoclonal antibody single-chain fragment that binds to the human C5 complement component, was studied in a Phase II multicentered clinical trial. CABG (n = 800) and CABG with concomitant valve surgery (n = 114) patients were evaluated. Patients were randomized to either: pexelizumab bolus (2.0 mg/kg) + placebo infusion; pexelizumab bolus (2.0 mg/kg) + pexelizumab infusion (0.05 mg/kg/hour for 24 hours); or placebo bolus + placebo infusion. Pharmacology, chest tube drainage, and transfusion requirements were assessed. RESULTS: Mean maximum pexelizumab serum concentration was similar for bolus and bolus + infusion-treated patients. Complement-dependent serum hemolytic activity was completely suppressed within 1 hour following pexelizumab bolus, however, suppression was maintained for a longer duration in the bolus + infusion compared to the bolus-only treated patients. A reduction in chest tube drainage was observed for all pexelizumab-treated patients, although transfusion of blood products was similar across all study groups. CONCLUSION: Pexelizumab administration inhibits complement-dependent hemolytic activity and is associated with a reduction in postoperative chest tube drainage in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Further, clinical studies are needed to assess the value of complement attenuation in this setting.     

Three dimensional reconstruction of a human breast carcinoma using routine laboratory equipment and immunohistochemistry

AIMS: To establish a three dimensional reconstruction of an invasive breast carcinoma using basic laboratory equipment to evaluate and characterise the spatial arrangement of the parenchymal cells of the breast. METHODS: One hundred and twenty eight sequential 4 microm sections (20 microm apart) of the tumour were stained immunohistochemically with an epithelial specific marker (AE1/AE3) or tumour specific marker (c-erbB-2) to reconstruct two different three dimensional images of the normal and malignant parenchymal cells. Sections were digitally imaged using a microscope, scanner, and digital camera linked to a conventional personal computer. Accurate alignment of the digitalised images was carried out using a semiautomatic graphical method of manual interaction, using the cross correlation coefficient as a goodness of fit measure, and an automatic search algorithm using the Fibonacci search algorithm for automatic alignment. The volume was reconstructed using maximum, minimum point projection and "back to front" opacity blending. RESULTS: The quality of the reconstructed images was distinct and perfect, providing a comprehensive and explicit view of the normal and malignant parenchymal tissues of the breast that is not possible by viewing two dimensional histological sections. Specifically, this approach showed the spatial arrangement of the tumour cells and their relation to the surrounding tissues at a high resolution. CONCLUSION: This simple and reproducible approach enables the spread and infiltration of invasive carcinoma to be understood and could also be used to analyse the spatial relation between atypical hyperplastic and malignant in situ lesions of the breast.