A Zn2+-triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels.

The chloride intracellular channel (CLIC) protein family displays the unique feature of altering its structure from a soluble form to a membrane-bound chloride channel. CLIC1, a member of this family, is found in the cytoplasm or in internal and plasma membranes, with membrane relocalisation linked to endothelial disfunction, tumour proliferation and metastasis. The molecular switch promoting CLIC1 activation remains under investigation. Here, cellular Cl- efflux assays and immunofluorescence microscopy studies have identified intracellular Zn2+ release as the trigger for CLIC1 activation and membrane insertion. Biophysical assays confirmed specific binding to Zn2+, inducing membrane association and enhancing Cl- efflux in a pH-dependent manner. Together, our results identify a two-step mechanism with Zn2+ binding as the molecular switch promoting CLIC1 membrane insertion, followed by pH-mediated activation of Cl- efflux.

Common mental health disorders in children and adolescents in primary care: A survey of knowledge, skills and attitudes among general practitioners in a newly developed European country

Background and Objectives: General Practitioners (GPs) are generally the first point of contact for children and adolescents with mental health problems. This study investigates the confidence, beliefs, and knowledge of GPs regarding common mental health problems in youngsters. Methods: A self-designed questionnaire was distributed to nearly all registered GPs in a middle-income European country in order to address the aims of the study. Results: Response rate was 58%. Many GPs reported relatively low confidence on a number of issues, including diagnosis (70.0%), initiating management (86.6%), assessing the child-caregiver relationship (72.0%) and the ability to distinguish between normal and pathological behavioural problems (75.1%). However, GPs showed greater inclination to conduct follow-up care after assessment by specialist services (53.5%). Few GPs considered psychosocial interventions to play a role in the treatment of anxiety disorders (18.5%), hyperkinetic disorders (24.2%), depression (22.9%) and disruptive behaviour disorders (18.5%) and this largely came from younger GPs (p < 0.001). Conclusions: Confidence of GPs in the management of youngsters with mental health problems is generally low. They may require significant back-up from specialist services in the form of both training and clinical collaboration (AU)

[Methylphenidate augmentation of fluvoxamine for treatment-resistant depression: a case report and review literature]. / Tedaviye Dirençli Depresyonda Metilfenidat Ile Güçlendirme: Bir Olgu Bildirimi ve Literatürün Gözden Geçirmesi.

Methylphenidate and other psychostimulants have received substantial attention for the management of depression in patients with medical co-morbidities as well as for the symptomatic palliation of various neuropsychiatric disorders. Despite having been of little use in the first-line treatment of depressive disorders, some evidence does suggest that they may be of potential benefit as an antidepressant augmentation strategy in patients who fail to respond to stand-alone antidepressant regimens. However, such claims appear to be based entirely on case reports and to date, no appropriate placebo-controlled studies have been carried out on healthy young subjects. We report a case of a woman with refractory depression who successfully responded to methylphenidate augmentation of fluvoxamine. Her clinical picture was dominated by significant biological symptoms, which included apathy, anergia, increased appetite, and somnolence, with marked secondary functional impairment. Several antidepressant treatment modalities were attempted, including electroconvulsive therapy, with little improvement in her symptomatology. Augmentation of fluvoxamine with methylphenidate ultimately brought about a rapid and sustained complete remission of her depression. We will highlight how methylphenidate and other psychostimulants, when used with caution and an appreciation of their potential risk for abuse, may prove to be remarkably effective agents for antidepressant augmentation, including that of partially-effective or ineffective selective serotonin re-uptake inhibitors. Evidence for such use of methylphenidate unfortunately remains largely empirical and adequate placebo-controlled studies are therefore required to support or refute this claim.

Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).

OBJECTIVE: Mutations within the pituitary-specific paired-like homeobox gene PROP1 have been described in 50-100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1. DESIGN AND PATIENTS: Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly. RESULTS: The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent. CONCLUSIONS: PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.