Gsx1 expression defines neurons required for prepulse inhibition.

In schizophrenia, cognitive overload is thought to reflect an inability to suppress non-salient information, a process which is studied using prepulse inhibition (PPI) of the startle response. PPI is reduced in schizophrenia and routinely tested in animal models and preclinical trials of antipsychotic drugs. However, the underlying neuronal circuitry is not well understood. We used a novel genetic screen in larval zebrafish to reveal the molecular identity of neurons that are required for PPI in fish and mice. Ablation or optogenetic silencing of neurons with developmental expression of the transcription factor genomic screen homeobox 1 (gsx1) produced profound defects in PPI in zebrafish, and PPI was similarly impaired in Gsx1 knockout mice. Gsx1-expressing neurons reside in the dorsal brainstem and form synapses closely apposed to neurons that initiate the startle response. Surprisingly, brainstem Gsx1 neurons are primarily glutamatergic despite their role in a functionally inhibitory pathway. As Gsx1 has an important role in regulating interneuron development in the forebrain, these findings reveal a molecular link between control of interneuron specification and circuits that gate sensory information across brain regions.

Poly(A)-binding protein 1 partially relocalizes to the nucleus during herpes simplex virus type 1 infection in an ICP27-independent manner and does not inhibit virus replication.

Infection of cells by herpes simplex virus type 1 (HSV-1) triggers host cell shutoff whereby mRNAs are degraded and cellular protein synthesis is diminished. However, virus protein translation continues because the translational apparatus in HSV-infected cells is maintained in an active state. Surprisingly, poly(A)-binding protein 1 (PABP1), a predominantly cytoplasmic protein that is required for efficient translation initiation, is partially relocated to the nucleus during HSV-1 infection. This relocalization occurred in a time-dependent manner with respect to virus infection. Since HSV-1 infection causes cell stress, we examined other cell stress inducers and found that oxidative stress similarly relocated PABP1. An examination of stress-induced kinases revealed similarities in HSV-1 infection and oxidative stress activation of JNK and p38 mitogen-activated protein (MAP) kinases. Importantly, PABP relocalization in infection was found to be independent of the viral protein ICP27. The depletion of PABP1 by small interfering RNA (siRNA) knockdown had no significant effect on viral replication or the expression of selected virus late proteins, suggesting that reduced levels of cytoplasmic PABP1 are tolerated during infection.

Characterizing Sleep in Adolescents and Adults with Autism Spectrum Disorders.

We studied 28 adolescents/young adults with autism spectrum disorders (ASD) and 13 age/sex matched individuals of typical development (TD). Structured sleep histories, validated questionnaires, actigraphy (4 weeks), and salivary cortisol and melatonin (4 days each) were collected. Compared to those with TD, adolescents/young adults with ASD had longer sleep latencies and more difficulty going to bed and falling asleep. Morning cortisol, evening cortisol, and the morning-evening difference in cortisol did not differ by diagnosis (ASD vs. TD). Dim light melatonin onsets (DLMOs) averaged across participants were not different for the ASD and TD participants. Average participant scores indicated aspects of poor sleep hygiene in both groups. Insomnia in ASD is multifactorial and not solely related to physiological factors.

Monitoring interfacial bioelectrochemistry using a FRET switch.

Generation of functionally active biomolecular monolayers is important in both analytical science and biophysical analyses. Our ability to monitor the redox-active state of immobilized proteins or enzymes at a molecular level, from which stochastic and surface-induced variations would be apparent, is impeded by comparatively slow electron-transfer kinetics and associated signal:noise difficulties. We demonstrate herein that by covalently tethering an appropriate dye to the copper protein azurin a highly oxidation-state-sensitive FRET process can be established which enables redox switching to be optically monitored at protein levels down to the zeptomolar limit. The surface-potential-induced cycling of emission enables the redox potential of clusters of a few hundred molecules to be determined.

A field worker's guide to a nutritional status survey.

This guide has been prepared specifically for the medical worker in a developing country who has little experience for survey methodology and few outside sources on which to draw. All, or only portions of the guide, may be used as local needs dictate. It provides an outline of necessary preparations, sampling, field organization, measuring techniques and recording form. To aid the statistical treatment and presentation of the data, a sample recording form is given together with coding instructions and output table layout.

Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra.

To investigate the effect on the sleep EEG, a 1-mg oral dose of SR 46349B, a novel 5-HT2 antagonist, was administered three hours before bedtime. The drug enhanced slow wave sleep (SWS) and reduced stage 2 without affecting subjective sleep quality. In nonREM sleep (NREMS) EEG slow-wave activity (SWA; power within 0.75-4.5 Hz) was increased and spindle frequency activity (SFA; power within 12.25-15 Hz) was decreased. The relative NREMS power spectrum showed a bimodal pattern with the main peak at 1.5 Hz and a secondary peak at 6 Hz. A regional analysis based on bipolar derivations along the antero-posterior axis revealed significant 'treatment' x 'derivation' interactions within the 9-16 Hz range. In enhancing SWA and attenuating SFA, the 5-HT2 receptor antagonist mimicked the effect of sleep deprivation, whereas the pattern of the NREMS spectrum differed.

The relationship between slow-wave activity, body temperature, and cardiac activity during nighttime sleep.

STUDY OBJECTIVES: Recent work indicates that cardiac sympathetic activity is not influenced by the circadian system and instead decreases after sleep onset. However, little is known about the pattern of change in cardiac sympathetic activity during NREM/REM sleep cycles and whether this is associated with alterations in slow-wave activity (SWA). To address these questions, we examined SWA, cardiac sympathetic activity, heart rate and rectal and foot temperatures during the first three NREM/REM sleep cycles and during transitions between NREM and REM sleep. DESIGN: Subjects were required to maintain a constant sleep-wake cycle for at least a week and have at least one adaptation night, before their night of recording. SETTING: Individual temperature controlled bedrooms. PARTICIPANTS: 10 young healthy males and females. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: All variables showed the greatest change in the first NREM cycle. Specifically, SWA, sympathetic activity, heart rate and foot temperature increased while rectal temperature decreased. After the initial increase, cardiac sympathetic activity decreased across the sleep phase, in association with a decrease in heart rate. Cardiac sympathetic activity did not significantly alter across NREM-REM cycles. CONCLUSIONS: The results suggest that increases in heart rate and cardiac sympathetic activity early in the sleep period are, in part, a compensatory reaction to the concomitant thermoregulatory changes observed. These results also indicate that the effect of time asleep on cardiac sympathetic activity may be greater than the influence of sleep cycles. These results are discussed with reference to the recuperative value of naps.

Effects of bright light and melatonin on sleep propensity, temperature, and cardiac activity at night.

Melatonin increases sleepiness, decreases core temperature, and increases peripheral temperature in humans. Melatonin may produce these effects by activating peripheral receptors or altering autonomic activity. The latter hypothesis was investigated in 16 supine subjects. Three conditions were created by using bright light and exogenous melatonin: normal endogenous, suppressed, and pharmacological melatonin levels. Data during wakefulness from 1.5 h before to 2.5 h after each subject's estimated melatonin onset (wake time + 14 h) were analyzed. Respiratory sinus arrhythmia (cardiac parasympathetic activity) and preejection period (cardiac sympathetic activity) did not vary among conditions. Pharmacological melatonin levels significantly decreased systolic blood pressure [5.75 +/- 1.65 (SE) mmHg] but did not significantly change heart rate. Suppressed melatonin significantly increased rectal temperature (0.27 +/- 0.06 degrees C), decreased foot temperature (1.98 +/- 0.70 degrees C), and increased sleep onset latency (5.53 +/- 1.87 min). Thus melatonin does not significantly alter cardiac autonomic activity and instead may bind to peripheral receptors in the vasculature and heart. Furthermore, increases in cardiac parasympathetic activity before normal nighttime sleep cannot be attributed to the concomitant increase in endogenous melatonin.

The relative bioavailability of paracetamol after rectal administration of suppositories containing a mixture of paracetamol, codeine phosphate and buclizine hydrochloride in healthy volunteers.

'New' and 'old' suppositories (6 months and 30 months since manufacture) containing 800 mg paracetamol, 16 mg codeine phosphate and 12.5 mg buclizine hydrochloride in an identical base were administered to 10 normal volunteers at an interval of 2 weeks. Blood samples were taken at intervals up to 300 minutes after administration for estimation of paracetamol plasma concentrations using high pressure liquid chromatography. Mean peak concentrations were obtained of 4.75 +/- 0.74 mg/ml at 1.75 hours with the new suppositories and of 4.6 +/- 0.67 mg/ml at 2.0 hours with the old suppositories. The difference was not significant. Mean elimination half-life was 4.4 +/- 0.42 hours and 3.73 +/- 0.28 hours, respectively. Again, the difference was not significant, indicating that the absorption characteristics for the suppositories did not appear to deteriorate with ageing for 24 months. Bioavailability data for paracetamol derived from the results were similar to those reported by other workers who studied suppositories containing paracetamol as the only active ingredient. This indicates that the inclusion of codeine phosphate and buclizine hydrochloride in the suppository formulation investigated in the present study did not affect adversely the absorption of paracetamol.

The effect of mycoplasma on the autocrine stimulation of human small cell lung cancer in vitro by bombesin and beta-endorphin.

The tumor stem cell clonogenic assay was utilized to investigate the autocrine growth response of small cell lung cancer (SCLC) to bombesin (BN) and beta-endorphin (beta-E). Mycoplasma contamination was detected in the human SCLC cell line NCl-H345 by a nucleic acid hybridization assay which detects mycoplasma ribosomal RNA. Clonogenic assays of mycoplasma (+) cells were compared to assays of the same cell line following treatment for mycoplasma. Concentrations of beta-E ranging from 0.1nM to 25nM or BN (0.1nM-100nM) were added to cells, media and agarose and applied to prepared base layers. Following incubation for 12-14 days at 37 degrees C, the degree of clonal growth stimulation was determined by colony counts greater than or equal to 42 mu. The non-infected cell population grew in the presence of 25nM BN up to 69% over control growth. The infected cells, however, did not grow more than 27% above control. In the presence of 10nM beta-E, colony counts of non-infected cells exceeded the control values by up to 187% whereas the mycoplasma (+) colonies did not grow more than 20% over the control values. These results indicate a marked reduction in the response of SCLC cell lines to the peptides BN and beta-E when infected with mycoplasma. Since infecting mycoplasma typically adhere to cellular membranes, these adherent mycoplasma may interfere with membrane receptors or alter signal transduction, thus, inhibiting the development of the autocrine response.

The impact of a week of simulated night work on sleep, circadian phase, and performance.

AIMS: To investigate factors that may contribute to performance adaptation during permanent night work. METHODS: Fifteen healthy subjects participated in an adaptation and baseline night sleep, directly followed by seven simulated eight-hour night shifts (2300 to 0700 hours). At the end of each shift they were taken outside and exposed to natural light for 20 minutes. They then slept from approximately 0800 hours until they naturally awoke. RESULTS: There was a significant increase in mean performance on a visual psychomotor vigilance task across the week. Daytime sleep quality and quantity were not negatively affected. Total sleep time (TST) for each of the daytime sleeps was reduced, resulting in an average cumulative sleep debt of 3.53 hours prior to the final night shift. TST for each of the daytime sleep periods did not significantly differ from the baseline night, nor did TST significantly vary across the week. There was a significant decrease in wake time after sleep onset and sleep onset latency across the week; sleep efficiency showed a trend towards greater efficiency across the consecutive daytime sleeps. Hours of wakefulness prior to each simulated night shift significantly varied across the week. The melatonin profile significantly shifted across the week. CONCLUSIONS: Results suggest that under optimal conditions, the sleep debt that accumulates during consecutive night shifts is relatively small and does not exacerbate decrements in night-time performance resulting from other factors. When sleep loss is minimised, adaptation of performance during consecutive night shifts can occur in conjunction with circadian adaptation.

Parameters of normotensive women and women with pregnancy induced hypertension (PIH) in Lusaka.

This paper reports results of a survey of mean arterial pressures (MAP) in a population of 125 control patients and 30 cases who developed pregnancy induced hypertension. The investigation was carried out to see if MAP would be a useful addition to methods used to screen for PIH. More of the cases had elevated MAP than did the controls, suggesting that use of this easily obtainable information may be helpful in identifying patients at risk for pregnancy--induced hypertension. Addition baseline information on the 155 patients and their pregnancy outcome is also presented.

PIP: 35 cases of pregnancy-induced-hypertension (PIH) and 125 controls taken on nonconsecutive days from 792 deliveries during the period June-August 1988 at the University Teaching Hospital, Lusaka, Zambia, were analyzed for mean arterial pressure (MAP), and contributing factors. Data were taken from delivery logs and patients' antenatal cards. The cases were women diagnosed with PIH or a history of seizures. Controls were the 5 preceding deliveries with adequate data. Results for MAP were presented as a matrix showing good outcome controls, poor outcome controls, and cases, by MAP at antenatal visits 1-4, with numbers of women in groupings by MAP ranges. There were more high MAP values for cases than for controls. Over 25% of both groups were women aged 17-19. 64.7% of cases were primigravida, compared to 43% of controls. Data on weight gain were not consistently available, but a higher proportion of cases gained 20 pounds than controls. Most women gained 0 or 1-10 pounds. 44% of cases and 41% of controls had hemoglobin 10 mg/dl. There were 4 positive VDRLs among 34 women tested. 4% of the control infants were stillborn; 7% died in hospital. Among the cases there were 1 fetal death, 2 stillborns, 4 hospital deaths, 20% pregnancy loss overall. Apgar scores were lower among cases, with 25% 4-6, compared to 3.3% of controls. These results did not indicate that MAP would be useful in comparison with blood pressure and other risk factors in monitoring pregnant women for PIH.

A note on some reinforcing properties of university lectures.

Contingency management systems in university courses have sometimes assigned the role of reinforcing stimulus to lectures and demonstrations. Attending a lecture was made contingent upon having previously finished certain course assignments. The present paper investigated some variables that control student attendance at lectures. Attendance remained high throughout each course at those class meetings where quizzes contributing to course grades were given or where impending quizzes were discussed. Attendance at lectures over the reading assignments or over material unrelated to course quizzes rapidly declined. When students were given course credit for attending these lectures, or when the lectures included information for future quizzes, attendance increased. When attending these lectures was made contingent upon having completed certain assignments the prior week, no increase in assignment completion was noted and the attendance at the lectures decreased even further. All lectures were given during one class meeting each week. Attendance at the other class meetings during the week remained stable.

Response of bone subjected to optimized high dose irradiation.

Allograft tissues are used in over one million musculoskeletal procedures per year. Consequently, it is crucial tissue banks use procedures to militate against allograft associated bacterial and viral infections. Recent studies have identified an important pathogen inactivation technology for musculoskeletal allografts that utilizes high-dose gamma irradiation (50 kGy) under controlled conditions. A total dose of 50 kGy assures that the current standard for medical devices for a microbial sterility assurance level of 10(- 6) is met. Furthermore, the pathogen inactivation technology results in a greater than four log inactivation of enveloped and nonenveloped viruses. Efficacious clinical outcome from musculoskeletal allografts exposed to this innovative sterilization procedure will require that there is no performance decrement in the allograft's biological properties. Therefore, to validate this objective, we executed a study focusing on remodeling and osteoconduction of bone allografts treated with a high dose of gamma irradiation (50 kGy), radioprotectants and well-defined operating parameters of temperature and water content. A rabbit calvarial model was used to test the hypothesis that remodeling and osteoconduction of allogeneic bone treated with the new pathogen inactivation technology would be equivalent to nontreated allogeneic bone. Results indicated treated bone allografts were comparable to nontreated allografts. We conclude, therefore, that based on this outcome and other reports, that high doses of gamma irradiation under optimized conditions designed to reduce free radical damage to tissue will provide safer allografts.

Organisational culture: variation across hospitals and connection to patient safety climate.

CONTEXT: Bureaucratic organisational culture is less favourable to quality improvement, whereas organisations with group (teamwork) culture are better aligned for quality improvement. OBJECTIVE: To determine if an organisational group culture shows better alignment with patient safety climate. DESIGN: Cross-sectional administration of questionnaires. Setting 40 Hospital Corporation of America hospitals. PARTICIPANTS: 1406 nurses, ancillary staff, allied staff and physicians. MAIN OUTCOME MEASURES: Competing Values Measure of Organisational Culture, Safety Attitudes Questionnaire (SAQ), Safety Climate Survey (SCSc) and Information and Analysis (IA). RESULTS: The Cronbach alpha was 0.81 for the group culture scale and 0.72 for the hierarchical culture scale. Group culture was positively correlated with SAQ and its subscales (from correlation coefficient r = 0.44 to 0.55, except situational recognition), ScSc (r = 0.47) and IA (r = 0.33). Hierarchical culture was negatively correlated with the SAQ scales, SCSc and IA. Among the 40 hospitals, 37.5% had a hierarchical dominant culture, 37.5% a dominant group culture and 25% a balanced culture. Group culture hospitals had significantly higher safety climate scores than hierarchical culture hospitals. The magnitude of these relationships was not affected after adjusting for provider job type and hospital characteristics. CONCLUSIONS: Hospitals vary in organisational culture, and the type of culture relates to the safety climate within the hospital. In combination with prior studies, these results suggest that a healthcare organisation's culture is a critical factor in the development of its patient safety climate and in the successful implementation of quality improvement initiatives.