Enzymic degradation of a beta-lactam antibiotic,ampicillin, in the gut: a novel treatment modality

Antibiotics can cause severe alterations in the gut microflora and promote diarrhoea and overgrowth of pathogenic bacteria. The present study investigated the potency of targeted recombinant beta-lactamase (TRBL) to degrade a beta-lactam antibiotic in the jejunum of fistula-operated beagles. We used different peroral doses of purified beta-lactamase (PenP) of Bacillus licheniformis in enteric-coated pellets together with intravenous ampicillin. Serum and jejunal samples were collected for ampicillin and beta-lactamase analysis. A dose-response effect of TRBL on ampicillin concentrations in the jejunal samples could be observed. The highest doses applied decreased the jejunal ampicillin concentrations to undetectable levels. In the serum samples, the ampicillin concentrations were not affected by the beta-lactamase dose used. Our results indicate that it may be possible to evolve a targeted treatment to degrade beta-lactam antibiotics intestinally and, thus, decrease antibiotic-induced adverse effects on the gut microflora.     

Leisure Time Physical Activity Instrument and Physical Activity at Home and Work Instrument. Development, face validity, construct validity and test-retest reliability for subjects with fibromyalgia

Purpose. A new instrument measuring leisure time physical activity (LTPAI) in populations predominately engaging in low intensity activities and a new instrument measuring the Physical Activity at Home and Work (PAHWI) were designed.

Methods. Patients with long-lasting pain and expert physiotherapists participated in the development of the two instruments. Test-retest reliability was evaluated for the LTPAI and the PAHWI. Construct validity was evaluated for the LTPAI by comparing it with an instrument measuring physical activities for older people, six-minute walk test and aerobic capacity.

Population. 37 women with FM, with the mean age of 46 years (SD 8.4) and mean symptom duration of 11 years (SD 5.9) were recruited to the study.

Results. The mean time that the study population spent in physical activities during leisure time was 5.2 hours (SD 4.0) a week. Satisfactory test-retest reliability was found for the total score of LTPAI (ICC 0.86, CI 0.79 - 0.93) and for the PAHWI (ICC 0.91, CI 0.82 - 9.96). A significant association between the LTPAI and the six-minute walk test (r_s 0.40, p = 0.02) and another physical activity instrument (r_s 0.39, p = 0.02) was found. As expected, LTPAI did not have any association with aerobic capacity.

Conclusions. Face validity of the instruments was ensured during the development process. Satisfactory test-retest reliability was found for the LTPAI and the PAHWI. Significant but low associations were found between the LTPAI and the six-minute walk test and an instrument designed for older people, respectively, while no association was found between the LTPAI and aerobic capacity.     

Outcome of patients with dual diagnosis in secondary psychiatric care

Background: Dual diagnosis (DD) is a common co-morbidity of mental illness and substance use disorder (SUD) and patients with DD are prone to complications. Better knowledge on the outcome, mortality and management of patients with DD in usual secondary psychiatric care would help to inform improved treatment strategies in the future. Aims: To explore the functional outcome and mortality of patients with DD receiving psychiatric treatment. To assess the recognition of substance use disorders (SUDs) in terms of diagnosis, and the associations of clinically diagnosed SUDs with treatment-related variables. Methods: The sample of 330 patients was collected by screening all currently treated patients with the Alcohol Use Disorders Identification Test (AUDIT) and a question about other substances used. The inclusion criteria were AUDIT?>7 and/or reported use of other substances during the preceding 12 months. The Global Assessment of Functioning scale was used to assess functional outcomes during a 2-year follow-up. Information concerning treatment and patient characteristics was collected retrospectively. Results: Level of functioning remained stable among all study patients during follow-up. The mortality rate was not increased. Effective medication use was associated with improved functional outcomes. SUDs were underdiagnosed. A clinically diagnosed SUD seemed to have an impact on the regularity of appointments and the doses of prescribed medications. Conclusions: Given our results suggesting a stable level of functioning, patients with DD appear to be well managed within secondary psychiatric care. Attention should be paid to more precise diagnostics of SUDs and to effective use of medication.     

Growth differentiation factor-9 induces Smad2 activation and inhibin B production in cultured human granulosa-luteal cells

The TGF beta family member growth differentiation factor-9 (GDF-9) is an oocyte-derived factor that is essential for mammalian ovarian folliculogenesis. GDF-9 mRNAs have been shown to be expressed in the human ovarian follicle from the primary follicle stage onward, and recombinant GDF-9 has been shown to promote human ovarian follicle growth in vitro. In this study with primary cultures of human granulosa-luteal (hGL) cells, we investigated whether recombinant GDF-9 activates components of the Smad signaling pathways known to be differentially activated by TGF beta and the bone morphogenetic proteins (BMPs). As with TGF beta, GDF-9 treatment caused the phosphorylation of endogenous 53-kDa proteins detected in Western blots with antiphospho-Smad2 antibodies (alpha PS2). However, unlike BMP-2, GDF-9 did not activate the phosphorylation of antiphospho-Smad1 antibody (alphaPS1)-immunoreactive proteins in hGL cells. Infection of hGL cells with an adenovirus expressing Smad2 (Ad-Smad2) confirmed that GDF-9 activates specifically phosphorylation of the Smad2 protein. Infection of hGL cells with Ad-Smad7, which expresses the inhibitory Smad7 protein, suppressed the levels of both GDF-9-induced endogenous and adenoviral alpha PS2-reactive proteins. Furthermore, GDF-9 increased the steady state levels of inhibin beta(B)-subunit mRNAs in hGL cells and strongly stimulated the secretion of dimeric inhibin B. Again, Ad-Smad7 blocked GDF-9-stimulated inhibin B production in a concentration-dependent manner. We identify here for the first time distinct molecular components of the GDF-9 signaling pathway in the human ovary. Our data suggest that GDF-9 mediates its effect through the pathway commonly activated by TGF beta and activin, but not that activated by many BMPs. The results are also consistent with the suggestion that in addition to endocrine control of inhibin production by gonadotropins, a local paracrine control of inhibin production is likely to occur via oocyte-derived factors in the human ovary.     

Intravenous oxycodone for pain relief in the first stage of labour--maternal pharmacokinetics and neonatal exposure

Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open‐labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1 mg i.v., up to a cumulative dose of 5 mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half‐life of 2.6 hr (range, 1.8–2.8). Oxycodone concentrations in the umbilical plasma 2.7 μg/l (0.3–14.5) were similar as in maternal plasma 2.4 (0.1–14.8) μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half‐life of i.v. oxycodone was significantly shorter than that reported in non‐pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure.     

Psychotic boys performing well in school are at increased risk of suicidal ideation

Aim:  This study investigated how the level of school performance is associated with suicidal behavior and psychiatric disorders among adolescent psychiatric inpatients aged 12–17 years.
Methods:  Data were collected from 508 adolescents (300 girls, 208 boys; age 12–17 years) admitted to inpatient psychiatric hospitalization between April 2001 and March 2006. Information on the adolescents' school performance, suicidal ideation, suicide attempts and self-mutilation as well as psychiatric DSM-IV diagnoses was obtained using the Schedule for Affective Disorder and Schizophrenia for School-Age Children.
Results:  An elevated risk of suicidal ideation (OR = 3.6, 95% CI 1.3–10.2, P  = 0.017) and of psychotic disorders (OR = 3.2, 95% CI 1.0–10.0, P  = 0.048) was observed among male adolescents performing well in school. In addition, adolescents with poor school performance had an increased likelihood of substance-related disorder both in boys (OR = 2.6, 95% CI 1.1–6.1, P  = 0.027) and girls (OR = 2.5, 95% CI 1.2–5.1, P  = 0.011).
Conclusions:  Our findings indicate that psychotic inpatient male adolescents performing well in school are at an elevated risk of suicidal ideation. Although good school performance is often considered a marker of high intelligence and good general ability, symptoms of major psychiatric disorders and suicidality need to be taken very seriously among adolescents performing well in school.     

The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland

Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population.     

Increasing process understanding by analyzing complex interactions in experimental data

There is a recognized need for new approaches to understand unit operations with pharmaceutical relevance. A method for analyzing complex interactions in experimental data is introduced. Higher-order interactions do exist between process parameters, which complicate the interpretation of experimental results. In this study, experiments based on mixed factorial design of coating process were performed. Drug release was analyzed by traditional analysis of variance (ANOVA) and generalized multiplicative ANOVA (GEMANOVA). GEMANOVA modeling is introduced in this study as a new tool for increased understanding of a coating process. It was possible to model the response, that is, the amount of drug released, using both mentioned techniques. However, the ANOVA model was difficult to interpret as several interactions between process parameters existed. In contrast to ANOVA, GEMANOVA is especially suited for modeling complex interactions and making easily understandable models of these. GEMANOVA modeling allowed a simple visualization of the entire experimental space. Furthermore, information was obtained on how relative changes in the settings of process parameters influence the film quality and thereby drug release.