Alcohol and benzodiazepines: recent mechanistic studies

The phospholipid headgroup mobility of small unilamellar vesicles composed of different mixtures of phosphatidyl-L-serine (PS) and phosphatidylcholine is characterized by the solvent relaxation behavior of the polarity sensitive dyes 6-propionyl-2-(dimethylamino)naphthalene (Prodan) and 6-palmitoyl-2-[trimethylammoniumethyl]-methylamino]naphthalene chloride (Patman). If the PS content exceeds 10%, the addition of calcium leads to a substantial deceleration of the solvent relaxation of both dyes, indicating the formation of Ca(PS)2 complexes. Addition of prothrombin and its fragment 1 leads to a further decrease of the headgroup mobility, as explained by the binding of more than two PS-molecules by a single protein molecule. Prodan monitors the outermost region of the bilayer and it clearly distinguishes between the binding of prothrombin and its fragment 1. The deeper incalated Patman does not distinguish between both proteins. The validity of the solvent relaxation technique for the investigation of the membrane binding of peripheral proteins is demonstrated by the studies of prothrombin induced changes in the steady-state fluorescence anisotropies of 1,6-diphenyl-1,3, 5-hexatriene.     

Adolescent sexual and reproductive behavior: a review of the evidence from India

Despite the fact that adolescents represent almost one quarter of the Indian population, their reproductive health needs are poorly understood and ill served. This paper documents the existing research on sexual and reproductive health, explores the knowledge and attitudes among this population in India, and highlights limitations of methodologies currently employed in research on adolescent reproductive health in India. One serious limitation is the lack of attention in almost every dimension of their reproductive health, including sexuality, reproductive morbidity, abortion-seeking and reproductive choice. What is needed is more behavioral research that explores the levels, patterns, and sociocultural factors underlying adolescents' reproductive health; assesses adolescent reproductive health needs and ways in which health and information services can be structured to respond to these needs in light of the social, cultural and economic constraints that adolescents face; and explores appropriate methodological alternatives, recognizing the need for community-based research, as well as the difficulties of conducting such research under the sociocultural constraints prevailing in India. At the same time, this review argues for far more attention within programs to address adolescent reproductive health service and information needs.     

Electrophysiological evidence for a postperceptual locus of suppression during the attentional blink

When an observer detects a target in a rapid stream of visual stimuli, there is a brief period of time during which the detection of subsequent targets is impaired. In this study, event-related potentials (ERPs) were recorded from normal adult observers to determine whether this "attentional blink" reflects a suppression of perceptual processes or an impairment in postperceptual processes. No suppression was observed during the attentional blink interval for ERP components corresponding to sensory processing (the P1 and N1 components) or semantic analysis (the N400 component). However, complete suppression was observed for an ERP component that has been hypothesized to reflect the updating of working memory (the P3 component). Results indicate that the attentional blink reflects an impairment in a postperceptual stage of processing.     

Columnar alteration with prominent apical snouts and secretions: a spectrum of changes frequently present in breast biopsies performed for microcalcifications

OBJECTIVE: To examine the effect of treatment with an inactivated, gp120-depleted, HIV-1 immunogen (Remune) in 30 Thai subjects infected with HIV-1 subtype E. DESIGN: Sixty-week open-label study. METHODS: Thirty HIV-positive volunteers with CD4 cell counts > or = 300 x 10(6)/l were given intramuscular injections of Remune into the triceps muscle on day 1 and then at weeks 4, 8, 12, 24, 36, 48 and 60. RESULTS: Treatment with Remune was well-tolerated and augmented HIV-1-specific immune responses. Furthermore, subjects had a significant increase in CD4 cell count (P < 0.0001), CD4 cell percentage (P < 0.0001), CD8 cell percentage (P < 0.0001), and body weight (P < 0.0001) compared with pretreatment levels. Fourteen subjects with detectable viral load at day 1 showed a decrease at week 60 (P=0.04). Retrospective Western blot analysis showed 23 subjects with increased intensity of antibody bands and 15 patients showed development of new reactivities to HIV proteins, especially towards p17 and p15. CONCLUSION: These results indicate that HIV-specific immune-based therapeutic approaches such as Remune should be further examined in countries with different clades of HIV-1 and where access to antiviral drug therapies is limited.     

Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices

STUDY OBJECTIVES: To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. DESIGN: Two randomized, three-way crossover studies. SETTING: Clinical research laboratory. PARTICIPANTS: Healthy, nonsmoking volunteers. INTERVENTIONS: In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). MEASUREMENTS AND RESULTS: Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). CONCLUSION: The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.     

Substance abuse and the emergency room: programmatic implications

A literature review (1984 to 1995) was conducted to identify cost effective policy implications regarding substance use in the emergency room (ER) and trauma unit. Prevalence rates, ranging from 9% to 47%, vary according to where, when and who is tested. Other drugs, most commonly marijuana, benzodiazepines and cocaine, follow a similar pattern to alcohol. The optimal method of measuring substance use depends on the goal of the assessment and a combination of clinical, self-report and biochemical markers is recommended. Simple screening questions such as the TWEAK or AUDIT should be routinely used with all attendants and further assessment provided only when high risk factors have been identified. These include: males, younger patients, metropolitan centres, after midnight and on weekends, injury from violence, accidents including MVAs, high acuity and psychiatric morbidity. Further, this screening should be complimented by an intervention, referral and treatment resource for those in need.     

An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency

OBJECTIVES: Nitric oxide (NO), a highly reactive species produced by the activity of NO synthases (NOS), is normally present in the exhaled air of humans and animals. Exhaled NO concentration increases significantly in humans with sepsis and animals, but neither the source nor NOS isoforms responsible for this rise in pulmonary NO production are known. The main objective of this study is to determine the sites and the mechanisms of enhanced NO production in the exhaled air of endotoxemic pigs. DESIGN: Randomized, controlled, animal study. SETTING: University-based animal research facility. SUBJECTS: Thirteen pathogen-free adult female pigs (22 to 27 kg). INTERVENTIONS: Anesthetized pigs were divided into two groups: control and lipopolysaccharides (LPS) (septic) groups. In both groups, extrathoracic (upper airways, nasal, and paranasal) and intrathoracic (bronchi, bronchioles, and alveoli) compartments were ventilated equally with two separate ventilators connected to two tracheal tubes. The LPS group received slow infusion (over 2 h) of Escherichia coli endotoxin (10 microg/kg/h), whereas saline solution was infused into the control group. Expired air of the two compartments was collected throughout the 2-h observation period. The animals were then killed and the lungs were quickly excised and frozen. MEASUREMENTS: Hemodynamic variables were measured in both groups. NO concentration in the exhaled air of both compartments was measured with a chemiluminescence analyser. Pulmonary NOS activity was evaluated by measuring the conversion of L-[2,3H]-arginine to L-[2,3H]-citrulline, and pulmonary expression of NOS was evaluated by immunoblotting. RESULTS: Baseline NO concentration in both groups was significantly higher in the extrathoracic vs intrathoracic compartment (average of 5.2 vs 3.4 parts per billion). Endotoxin infusion elicited a significant and early (after 45 min) rise in exhaled NO concentration in the extrathoracic compartment. Exhaled NO in the intrathoracic compartment also rose significantly but after 90 min of endotoxin infusion. Measurement of lung NOS activity showed a substantial rise in Ca++/calmodulin-dependent activity in the LPS group with no rise in Ca++/calmodulin-independent activity. Immunoblotting of lung tissue samples indicated the absence of the inducible isoform in both groups of animals. Moreover, LPS injection elicited no significant alterations in the pulmonary expression of the endothelial and the neuronal isoforms. CONCLUSIONS: Both extrathoracic and intrathoracic compartments contribute to the rise in exhaled NO production in experimental septic shock. The rise in exhaled NO production is due to increased activity of constitutive NOS isoforms as a result of increased cofactor availability and/or downregulation of the endogenous inhibitors of NOS.     

Limb reduction defects in the A/J mouse strain associated with maternal blood loss

We previously described a high incidence of digit/limb anomalies in the offspring of A/J mice subjected to surgery on day 12.5 postconception (p.c.), but not in the offspring of untreated control mice. To investigate the cause of these defects, we compared the offspring of mice in experimental groups involving adrenalectomy, sham adrenalectomy, blood sampling, and anesthesia with the offspring of control mice. All treatments significantly reduced fetal weight and increased resorptions as compared with the controls. The highest incidence of digit anomalies occurred in the offspring of dams from which blood samples had been drawn on days 12.5, 14.5, and 15.5 p.c. The incidence of isolated cleft palate was also increased in the offspring of mice that had been subjected to blood sampling. We conclude that digit anomalies in the offspring of A/J mice result from fetal vascular disruptive phenomena subsequent to maternal blood loss induced hypovolemia and hypoperfusion to the uterus and placenta as has been suggested for uterine vascular clamping, misoprostol, chorionic villus sampling, and cocaine teratogenesis. The etiology for cleft lip in these mice may involve mechanisms unrelated to uterine/placental hypoperfusion.