A follow-up study of the first 70 admissions to a general purpose adolescent unit

A follow-up study of the first 70 admissions to a general purpose adolescent unit. The adolescentS and their families were given individual interviews. The outcome, which was assessed on the basis of these interviews, included psychiatric symptomatology and three basic areas of functioning: social, sexual and work adjustments. A global rating of the general level of function, relative to normality, was given for each adolescent. One third of the adolescents were functioning at a high level, one third were functioning at a moderate level and one third were severely handicapped in the most essential areas of functioning. The study group appeared to be disadvantaged socially and in the work situation. Results suggested that the optimum length of stay was 5-25 weeks. The nature of discharge was important: those adolescents who completed treatment were more likely to have a better outcome than those discharged prematurely.     

Influence of altitude training modality on performance and total haemoglobin mass in elite swimmers

We compared changes in performance and total haemoglobin mass (tHb) of elite swimmers in the weeks following either Classic or Live High:Train Low (LHTL) altitude training. Twenty-six elite swimmers (15 male, 11 female, 21.4 ± 2.7 years; mean ± SD) were divided into two groups for 3 weeks of either Classic or LHTL altitude training. Swimming performances over 100 or 200 m were assessed before altitude, then 1, 7, 14 and 28 days after returning to sea-level. Total haemoglobin mass was measured twice before altitude, then 1 and 14 days after return to sea-level. Changes in swimming performance in the first week after Classic and LHTL were compared against those of Race Control (n = 11), a group of elite swimmers who did not complete altitude training. In addition, a season-long comparison of swimming performance between altitude and non-altitude groups was undertaken to compare the progression of performances over the course of a competitive season. Regardless of altitude training modality, swimming performances were substantially slower 1 day (Classic 1.4 ± 1.3% and LHTL 1.6 ± 1.6%; mean ± 90% confidence limits) and 7 days (0.9 ± 1.0% and 1.9 ± 1.1%) after altitude compared to Race Control. In both groups, performances 14 and 28 days after altitude were not different from pre-altitude. The season-long comparison indicated that no clear advantage was obtained by swimmers who completed altitude training. Both Classic and LHTL elicited ~4% increases in tHb. Although altitude training induced erythropoeisis, this physiological adaptation did not transfer directly into improved competitive performance in elite swimmers.     

Attitudes of Medical Students,Clinicians and Sports Scientists Towards Exercise Counselling

We compared the amount of exercise undertaken by medical students, clinicians, and sport scientists with the National Australian Physical Activity (NAPA) Guidelines. A second aim was to compare attitudes to exercise counselling as preventive medicine between university- and clinic-based professionals. The research setting was a university medical school and a sports science sports medicine centre. A 20-item questionnaire was completed by 216 individuals (131 medical students, 43 clinicians and 37 sports scientists). Self-reported physical activity habits, exercise counselling practices and attitudes towards preventive medicine were assessed. The physical activity undertaken by most respondents (70%) met NAPA Guidelines. General practitioners had significantly lower compliance rates with NAPA Guidelines than other professionals. More than half of clinicians and medical students (54%) were less active now compared with levels of activity undertaken prior to graduate training. Most physicians (68%) reported they sometimes discuss physical activity with patients. In contrast, the majority of non-medically qualified respondents (60%) said they never discuss physical activity with their doctor. Most respondents (70%) had positive attitudes to exercise counselling. Sports scientists and respondents who were highly active in childhood had more positive attitudes to exercise counselling than others. Health professionals in this study were more active than the general population, however healthy exercise habits tend to deteriorate after the commencement of medical training. Despite the important role of doctors in health promotion, the degree of exercise counselling to patients is low.

Key points

• The rate of exercise counselling by doctors to patients is low
• Sports physicians and scientists have substantially more positive attitudes to exercise counselling than clinicians and medical students
• Medical schools have a responsibility to promote physical activity of students and improve training in exercise counselling

Key words: Physical activity, exercise, counselling, university, medical school, attitudes.     

Automated high-dimensional flow cytometric data analysis

Flow cytometric analysis allows rapid single cell interrogation of surface and intracellular determinants by measuring fluorescence intensity of fluorophore-conjugated reagents. The availability of new platforms, allowing detection of increasing numbers of cell surface markers, has challenged the traditional technique of identifying cell populations by manual gating and resulted in a growing need for the development of automated, high-dimensional analytical methods. We present a direct multivariate finite mixture modeling approach, using skew and heavy-tailed distributions, to address the complexities of flow cytometric analysis and to deal with high-dimensional cytometric data without the need for projection or transformation. We demonstrate its ability to detect rare populations, to model robustly in the presence of outliers and skew, and to perform the critical task of matching cell populations across samples that enables downstream analysis. This advance will facilitate the application of flow cytometry to new, complex biological and clinical problems.     

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

Background and purpose:

This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.

Experimental approach:

Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg⁻¹ of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg⁻¹ oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.

Results:

A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT₀/(1 +MED). LT₀ is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL⁻¹.

Conclusions:

The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.     

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

Waanders E, Venselaar H, te Morsche RHM, de Koning DB, Kamath PS, Torres VE, Somlo S, Drenth JPH. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation‐sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, Poly Phen , and p Mut and sift . We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non‐sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.     

Evaluation of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 Test and Identification of Rare Polymorphisms Potentially Affecting Assay Performance

We evaluated the FDA-approved Roche Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) HIV-1 viral load assay for sensitivity, reproducibility, linearity, HIV-1 subtype detection, and correlation to the Roche Amplicor HIV-1 monitor test, version 1.5 (Amplicor). The limit of detection calculated by probit analysis was 23.8 copies/ml using the 2nd International WHO Standard and 30.8 copies/ml using Viral Quality Assurance (VQA) standard material. Serial dilutions of six patient samples were used to determine inter- and intra-assay reproducibility and linearity, which were very good (<8% coefficient of variation [CV]; between ∼1.7 and 7.0 log₁₀ copies/ml). Subtype detection was evaluated in the CAP/CTM, Amplicor, and Bayer Versant HIV-1 bDNA 3.0 (Versant) assays using a commercially available panel. Versant averaged 0.829 log₁₀ copies/ml lower than CAP/CTM and Amplicor averaged 0.427 log₁₀ copies/ml lower than CAP/CTM for the subtype panel. Correlation with samples previously tested by Amplicor was excellent (R² = 0.884; average difference [Amplicor value minus CAP/CTM value], 0.008 log₁₀ copies/ml). Of the 305 HIV samples tested, 7 samples generated CAP/CTM titers between 1.0 and 2.75 log₁₀ copies/ml lower than those for Amplicor. Three of these samples revealed primer and probe mismatches that could account for the discrepancies. Otherwise, the CAP/CTM assay exhibits excellent sensitivity, dynamic range, reproducibility, and correlation with Amplicor in an automated format.Measurement of HIV-1 RNA in the plasma of infected patients is critical for guiding treatment. Over the past decade, several commercial quantitative HIV-1 RNA assays have become available that utilize endpoint PCR, isothermal amplification, or signal amplification techniques. Most recently, Abbott Molecular (Des Plaines, IL) and Roche Molecular Systems (Branchburg, NJ) received FDA approval for their real-time PCR-based systems, the RealTime HIV-1 assay and Cobas AmpliPrep/Cobas TaqMan HIV-1 Test (CAP/CTM), respectively. Each assay has its own advantages and disadvantages in terms of sensitivity, equipment requirements, throughput, dynamic range, subtype detection, and cost (1a, 4, 6, 7, 8, 11, 13, 15, 16).The CAP/CTM test includes a “docked” version that permits automated “sample in—results out” analysis of specimens without user intervention. We evaluated this configuration and compared its performance to those of the Roche Amplicor HIV-1 monitor test, version 1.5 (Amplicor), and the Bayer Versant HIV-1 bDNA 3.0 assay (Versant). Seven samples which gave discrepant Amplicor versus CAP/CTM results were further evaluated by sequencing analysis.     

Longitudinal association of preference-weighted health-related quality of life measures and substance use disorder outcomes

Aim To examine the construct validity of generic preference‐weighted health‐related quality of life measures in a sample of patients with a substance use disorder (SUD). Design Longitudinal (baseline and 6‐month follow‐up) data from a research study that evaluated interventions to improve linkage and engagement with SUD treatment. Setting A central intake unit that referred patients to seven SUD treatment centers in a Midwestern US metropolitan area. Participants A total of 495 individuals with a SUD. Measurements Participants completed two preference‐weighted measures: the self‐administered Quality of Well‐Being scale (QWB‐SA) and the standard gamble weighted Medical Outcomes Study SF‐12 (SF‐6D). They were also administered two clinical assessments: all seven domains of the Addiction Severity Index (ASI) and a symptom checklist based on the DSM‐IV. Construct validity was determined via the relationships between disease‐specific SUD and generic measures. Findings In unadjusted analyses, the QWB‐SA and SF‐6D change scores were correlated significantly with six ASI subscale change scores, but not with employment status. In adjusted repeated‐measures analyses, three of seven ASI subscale scores were significant predictors of QWB‐SA and 5/7 ASI subscale scores were significant predictors of SF‐6D. Abstinence and problematic use at follow‐up were significant predictors of QWB‐SA and SF‐6D. Effect sizes ranged from 0.352 to 0.400 for abstinence and ?0.484 to ?0.585 for problematic use. Conclusions Generic preference‐weighted health‐related quality of life measures show moderate to good associations with substance‐use specific measures and in certain circumstances can be used in their stead. This study provides further support for the use of the Quality of Well‐Being scale and Medical Outcomes Study SF‐12 in clinical and economic evaluations of substance use disorder interventions.