A history of childhood attention‐deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD

Objective: The occurrence of comorbid attention‐deficit hyperactivity disorder (ADHD) might have an impact of the course of the bipolar disorder. Method: Patients with bipolar disorder (n = 159) underwent a comprehensive evaluation with respect to affective symptoms. Independent psychiatrists assessed childhood and current ADHD, and an interview with a parent was undertaken. Results: The prevalence of adult ADHD was 16%. An additional 12% met the criteria for childhood ADHD without meeting criteria for adult ADHD. Both these groups had significantly earlier onset of their first affective episode, more frequent affective episodes (except manic episodes), and more interpersonal violence than the bipolar patients without a history of ADHD. Conclusion: The fact that bipolar patients with a history of childhood ADHD have a different clinical outcome than the pure bipolar group, regardless of whether the ADHD symptoms remained in adulthood or not, suggests that it represent a distinct early‐onset phenotype of bipolar disorder.     

Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

Background

In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.

Findings

Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.

Conclusions

When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.

Trial registration

ClinicalTrials.gov: NCT00455351     

Understanding the dynamics emerging from the interplay among poor mental wellbeing,energy balance-related behaviors,and obesity prevalence in adolescents: A simulation-based study

Both obesity and poor mental wellbeing have a high prevalence in European youth. Adolescents in six countries identified mental wellbeing factors as main drivers of youth obesity through systems mapping. This study sought to (1) explore the dynamics of the interplay between poor mental wellbeing, energy balance-related behaviors, and adolescent overweight and obesity prevalence and (2) test the effect of intervention point scenarios to reduce adolescent obesity. Drawing on the youth-generated systems maps and a literature synthesis, we built a simulation model that represents the links from major feedback pathways for poor mental wellbeing to changes in dietary, physical activity, and sleep behaviors. The model was calibrated using survey data from Norway, expert input, and literature and shows a good fit between simulated behavior and available statistical data. The simulations indicate that adolescent mental wellbeing is harmed by socio-cultural pressures and stressors, which trigger reinforcing feedback mechanisms related to emotional/binge eating, lack of motivation to engage in physical activity, and sleep difficulty. Targeting a combination of intervention points that support a 25% reduction of pressure on body image and psychosocial stress showed potentially favorable effects on mental wellbeing—doubling on average for boys and girls and decreasing obesity prevalence by over 4%.     

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I,dose-finding study

Aim

To investigate whether mesna—sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%.

Methods

C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine.

Results

Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; P_overall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC_0-12h decreased (P_trend < .001), and urine tCys excretion increased (P_trend = .004).

Conclusions

Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.     

Rheumatoid arthritis, gold therapy, contact allergy and blood cytokines

Background

During the last decade, medium-dose UVA1 phototherapy (50 J/cm²) has achieved great value within the treatment of severe atopic dermatitis (AD). The purpose of our study was to investigate to what extent UVA1 irradiation is able to modulate the status of protease activity by the use of a monoclonal antibody labeling cathepsin G.

Methods

In order to further elucidate the mechanisms by which medium-dose UVA1 irradiation leads to an improvement of skin status in patients with AD, biopsy specimens from 15 patients before and after treatment were analyzed immunohistochemically for proteolytic activation.

Results

Compared to lesional skin of patients with AD before UVA1 irradiation, the number of cells positive for cathepsin G within the dermal infiltrate decreased significantly after treatment. The decrease of cathepsin G⁺ cells was closely linked to a substantial clinical improvement in skin condition.

Conclusions

In summary, our findings demonstrated that medium-dose UVA1 irradiation leads to a modulation of the expression of cathepsin G in the dermal inflammatory infiltrate in patients with severe AD. Cathepsin G may attack laminin, proteoglycans, collagen I and insoluble fibronectin, to provoke proinflammatory events, to degrade the basement membrane, to destroy the tissue inhibitor of metalloproteinases and to increase the endothelial permeability. Therefore, its down-regulation by UVA1 phototherapy may induce the reduction of skin inflammation as well as improvement of the skin condition.     

Cost effectiveness of local collagen-gentamicin as prophylaxis for sternal wound infections in different risk groups

Objective : The use of protein S100B as a marker of brain cell injury in conjunction with cardiopulmonary bypass (CPB) has recently been questioned. The present study investigates functional brain injury based on the relation between S100B and memory disturbances. Methods : Four hundred and fifteen low-risk coronary artery bypass patients exposed to CPB were examined. The protein S100B was sampled during and after surgery. Explicit and implicit memory function was assessed preoperatively and at discharge from hospital. Possible associations between the release of the protein S100B and memory function were studied. Results : Serum concentration of S100B peaked at termination of CPB (0.895 &#45 0.84 µ g/l) and decreased gradually; 7 h post CPB (0.436 &#45 0.59 µ g/l), day 1 (0.149 &#45 0.27 µ g/l) and day 2 (0.043 &#45 0.15 µ g/l). High levels of S100B (>1.5 µ g/l) 7 h post CPB were associated with a significant (-1 SD) decline of explicit memory function ( p = 0.006); this was not seen at termination of CPB ( p = 0.834). Predictors of memory decline were S100B 7 h post CPB, length of stay in hospital and concomitant neurological disorders. Postoperative S100B concentration was higher among patients with atrial fibrillation ( p = 0.022). Conclusion : Only high levels of protein S100B found 7 h post CPB were associated with decline of explicit memory function, not the release seen during CPB. Thus, when using protein S100B, only values several hours remote from surgery should be used as a brain cell injury marker.     

Regulatory T cell phenotype and function 4 years after GAD–alum treatment in children with type 1 diabetes

Glutamic acid decarboxylase (GAD)₆₅ formulated with aluminium hydroxide (GAD‐alum) was effective in preserving insulin secretion in a Phase II clinical trial in children and adolescents with recent‐onset type 1 diabetes. In addition, GAD‐alum treated patients increased CD4⁺CD25^hi forkhead box protein 3⁺ (FoxP3⁺) cell numbers in response to in‐vitro GAD₆₅ stimulation. We have carried out a 4‐year follow‐up study of 59 of the original 70 patients to investigate long‐term effects on the frequency and function of regulatory T cells after GAD‐alum treatment. Peripheral blood mononuclear cells were stimulated in vitro with GAD₆₅ for 7 days and expression of regulatory T cell markers was measured by flow cytometry. Regulatory T cells (CD4⁺CD25^hiCD127^lo) and effector T cells (CD4⁺CD25^–CD127⁺) were further sorted, expanded and used in suppression assays to assess regulatory T cell function after GAD‐alum treatment. GAD‐alum‐treated patients displayed higher frequencies of in‐vitro GAD₆₅‐induced CD4⁺CD25⁺CD127⁺ as well as CD4⁺CD25^hiCD127^lo and CD4⁺FoxP3⁺ cells compared to placebo. Moreover, GAD₆₅ stimulation induced a population of CD4^hi cells consisting mainly of CD25⁺CD127⁺, which was specific of GAD‐alum‐treated patients (16 of 25 versus one of 25 in placebo). Assessment of suppressive function in expanded regulatory T cells revealed no difference between GAD‐alum‐ and placebo‐treated individuals. Regulatory T cell frequency did not correlate with C‐peptide secretion throughout the study. In conclusion, GAD‐alum treatment induced both GAD₆₅‐reactive CD25⁺CD127⁺ and CD25^hiCD127^lo cells, but no difference in regulatory T cell function 4 years after GAD‐alum treatment.     

Unfavourable working conditions for female GPs. A comparison between Swedish general practitioners and district nurses

Objective - The aim was to analyse gender and occupational differences in the psychosocial working conditions of general practitioners (GPs) and district nurses (DNs) in Sweden. Design - A stratified random sample of GPs (n = 566) and DNs (n =554) from four county councils in Sweden. The overall participation rate was 83%. Setting - Primary health care. Main outcome measures - A mailed questionnaire comprising 10 items providing demographic data and 36 items on psychosocial working conditions was used. The questionnaire had been tested for validity and reliability. A factor analysis included five items: strains and symptoms, professional content, social support at work, workload and job control. Results - Professional content was the most positively rated aspect, whereas workload was the most negatively rated. GPs perceived a higher workload and lower social support than did the DNs. Female GPs scored significantly more negatively than both male GPs and female DNs did in four out of the five factors. Female GPs reported a high workload, low job control and low social support at work. Female DNs, too, reported a high workload, relatively low job control but fairly strong social support. Conclusion - Female GPs perceived more unfavourable psychosocial working conditions than both male GPs and female DNs did in the same organisational setting.