Stress and hippocampal abnormalities in psychiatric disorders.

The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.     

A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).     

Mandibulofacial dysostosis, acral anomalies and frontonasal dysplasia: a new form of acrofacial dysostosis

We describe a stillborn female with acrofacial dysostosis and frontonasal dysplasia. She had protrusion of the forehead, with marked hypertelorism and absence of the nose but with the rhinencephalon present. Autopsy showed wide cranial sutures, severe hydrocephalus with separation of the right and left hemispheres of the brain, preservation of the olfactory bulb and first and second cranial nerves. The child also had small kidneys bilaterally, rectal atresia and an absent anus with rectovaginal fistula. These clinical findings suggest a new form of acrofacial dysostosis.     

Development of a job exposure matrix for the epidemiological follow-up of workers in the French nuclear industry

BACKGROUND: A pilot study was carried out in the AREVA NC Pierrelatte nuclear facility in order to investigate a possible carcinogenic effect of internal radiation exposure among nuclear workers in France. The objective of this study was to develop a method for retrospective reconstruction of the occupational exposure to internal radiation from uranium and associated chemical exposures. METHODS: A plant- and period-specific job exposure matrix (JEM) was designed. Job groups and exposure agents groups including uranium compounds and other chemical agents known as being carcinogenic, mutagenic or toxic were defined by an expert committee. Exposure was evaluated by active and retired workers included in the evaluator committee. A quantitative assignment of quantity and frequency of handling (both coded from 0 to 3) was performed for each agent groups using a method derived from the Delphi technique. RESULTS: In all, 23 experts and 353 evaluators participated to the JEM elaboration. A final JEM involved 232 "job-periods" presenting throughout the plant period 1960-2006 and 22 exposure agents groups in use at the plant. Six of them involved uranium compounds classified by their blood-transferability and toxicity characteristics. A first validation of the JEM by experts in radiological protection and industrial hygiene showed an acceptable internal consistency. CONCLUSION: In the context of missing past exposure measurement data, the plant- and period-specific job exposure matrices may be considered as a valid alternative for exposure estimation. This method may be applied to other nuclear plants and offers allowance to investigate a possible carcinogenic effect of internal radiation exposure among nuclear workers.     

Isolation of antihemorrhagic factors in opossum (Didelphis virginiana) serum using a monoclonal antibody immunoadsorbent

The antihemorrhagic factor in opossum (Didelphis virginiana) serum isolated by Sephadex G-200 gel filtration and DEAE A-50 ion exchange chromatography was used as antigen to immunize BALB/c mice. Hybrid cell lines secreting monoclonal antibodies against antihemorrhagic factor were produced by fusion of Sp2/0 myeloma cells with spleen cells of the immunized mice. The ascites fluid was produced in BALB/c mice. The monoclonal antibody in the ascites fluid was partially purified by DEAE A-50 ion exchange and coupled to CNBr-activated isolation of isolation of antihemorrhagic factor. The neutralization capacity of the conventionally isolated antihemorrhagic factor was 14.6 times and the affinity isolated antihemorrhagic factor was 16.8 times that of crude opossum serum. Both antihemorrhagic factors were homogeneous, with one fast migrating band in the area of albumin shown by polyacrylamide gel electrophoresis. However, the antihemorrhagic factor showed one heavy band and one faint band in SDS-polyacrylamide electrophoresis, as well as in isoelectric focusing. The molecular weight of the heavy band was estimated to be 65,000 with a value of p1 4.8 and the faint band was 57,000 with a value of pI 4.1.     

Appendicolith revealed on CT in children with suspected appendicitis: how specific is it in the diagnosis of appendicitis?

OBJECTIVE. The purpose of this study was to determine the sensitivity, specificity, and positive and negative predictive values of a diagnosis of appendicitis when CT without enteric contrast material reveals an appendicolith in children with suspected appendicitis. MATERIALS AND METHODS. A retrospective review of children who underwent abdominal CT for suspected appendicitis over a 25-month period was performed to identify patients with an appendicolith. An age-matched group of patients examined for trauma served as controls. RESULTS. CT was performed in 104 children. Appendicitis was present in 60 (58%) of 104 children; 39 (65%) of 60 had an appendicolith. Appendicitis was not present in 44 (42%) of 104; six (14%) of 44 had an appendicolith. An appendicolith detected on CT had a sensitivity of 65% and a specificity of 86% for the radiologist diagnosing appendicitis. An appendicolith had a positive predictive value of 74% and a negative predictive value of 26%. Among the control population, two (3%) of 74 children had an appendicolith. This number was statistically significant compared with children in the study group with an appendicolith and abdominal pain, but without appendicitis (p = 0.02). CONCLUSION. Although an appendicolith is significantly associated with appendicitis, the detection of an isolated appendicolith on CT is not sufficiently specific to be the sole basis for the diagnosis of acute appendicitis.     

Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance)

BackgroundAnthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC.MethodsIntravenous pixantrone was administered at 180 mg/m² every 3 weeks (group A) versus 85 mg/m² on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population.ResultsForty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%).ConclusionPixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT01086605","term_id":"NCT01086605"}}NCT01086605).