Megalencephalic leukoencephalopathy with subcortical cysts protein-1: A new calcium-sensitive protein functionally activated by endoplasmic reticulum calcium release and calmodulin binding in astrocytes.

BACKGROUND: MLC1 is a membrane protein highly expressed in brain perivascular astrocytes and whose mutations account for the rare leukodystrophy (LD) megalencephalic leukoencephalopathy with subcortical cysts disease (MLC). MLC is characterized by macrocephaly, brain edema and cysts, myelin vacuolation and astrocyte swelling which cause cognitive and motor dysfunctions and epilepsy. In cultured astrocytes, lack of functional MLC1 disturbs cell volume regulation by affecting anion channel (VRAC) currents and the consequent regulatory volume decrease (RVD) occurring in response to osmotic changes. Moreover, MLC1 represses intracellular signaling molecules (EGFR, ERK1/2, NF-kB) inducing astrocyte activation and swelling following brain insults. Nevertheless, to date, MLC1 proper function and MLC molecular pathogenesis are still elusive. We recently reported that in astrocytes MLC1 phosphorylation by the Ca2+/Calmodulin-dependent kinase II (CaMKII) in response to intracellular Ca2+ release potentiates MLC1 activation of VRAC. These results highlighted the importance of Ca2+ signaling in the regulation of MLC1 functions, prompting us to further investigate the relationships between intracellular Ca2+ and MLC1 properties. METHODS: We used U251 astrocytoma cells stably expressing wild-type (WT) or mutated MLC1, primary mouse astrocytes and mouse brain tissue, and applied biochemistry, molecular biology, video imaging and electrophysiology techniques. RESULTS: We revealed that WT but not mutant MLC1 oligomerization and trafficking to the astrocyte plasma membrane is favored by Ca2+ release from endoplasmic reticulum (ER) but not by capacitive Ca2+ entry in response to ER depletion. We also clarified the molecular events underlining MLC1 response to cytoplasmic Ca2+ increase, demonstrating that, following Ca2+ release, MLC1 binds the Ca2+ effector protein calmodulin (CaM) at the carboxyl terminal where a CaM binding sequence was identified. Using a CaM inhibitor and generating U251 cells expressing MLC1 with CaM binding site mutations, we found that CaM regulates MLC1 assembly, trafficking and function, being RVD and MLC-linked signaling molecules abnormally regulated in these latter cells. CONCLUSION: Overall, we qualified MLC1 as a Ca2+ sensitive protein involved in the control of volume changes in response to ER Ca2+ release and astrocyte activation. These findings provide new insights for the comprehension of the molecular mechanisms responsible for the myelin degeneration occurring in MLC and other LD where astrocytes have a primary role in the pathological process.

Cost-utility evaluation of vortioxetine in patients with Major Depressive Disorder experiencing inadequate response to alternative antidepressants in the United Kingdom.

BACKGROUND: Patients frequently require several lines of therapy for treatment of major depressive episodes. This economic analysis details the management of patients who responded inadequately due to lack of efficacy or intolerability to two previous antidepressants in the UK. METHODS: The model included a decision tree and a Markov component. Health states considered in the decision tree were remission, response, no response, withdrawal due to adverse events, relapse, recovery, and recurrence. The time horizon was 24 months. Patients were on third-line treatment for up to a 3-month acute phase and a 6-month maintenance phase. As third-line efficacy data were not available, inputs were calculated by adjusting original second-line data to third-line based on proportionate reductions observed in STAR*D. Equivalent efficacy was assumed for all comparators. Healthcare resource use and utilities were based on UK estimates. RESULTS: Vortioxetine was a cost-effective treatment option at a threshold of £20,000/QALY vs. escitalopram, citalopram, sertraline, and was associated with more health benefits, less costs (was dominant) versus relevant third-line comparators venlafaxine and duloxetine. Agomelatine was found not to be a cost-effective option. The 22-month maintenance phase treatment scenario results were similar to the 6-month base case. LIMITATIONS: Third-line efficacy data were not available. This highlights the need for studies in patients receiving third-line treatment. CONCLUSION: This model provides an overview for the management of patients receiving third-line treatment where limited evidence currently exists. Vortioxetine, with its novel mechanism of action, is expected to be a dominant treatment option versus relevant comparators in the UK.

Pharmacotherapeutic strategies for patients treated for depression in UK primary care: a database analysis.

OBJECTIVE: To investigate long-term patterns of antidepressant treatment in patients in primary care in the UK, and to assess their healthcare resource use and disease outcomes. RESEARCH DESIGN AND METHODS: A retrospective longitudinal cohort study was conducted using the Clinical Practice Research Datalink. The study population comprised patients aged ≥18 years with depression receiving a prescription for antidepressant monotherapy between 1 January 2006 and 31 December 2011 with no antidepressants within the preceding 6 months. Recovery was defined by timing of antidepressant prescriptions (≥6 months without treatment). Treatment lines and strategies (switching, combining, augmenting and resuming medication) were analyzed. Healthcare resource use for the different treatment strategies and periods of no therapy was assessed. RESULTS: Data from 123,662 patients (287,564 treatment lines) were analyzed. Switching and resumption of treatment were more frequent than other strategies. Recovery was highest with first-line monotherapy (45% of patients), while as a second-line strategy switching was more successful (43%) than combination or augmentation. In subsequent lines of treatment, switching was associated with successively lower rates of recovery (31% in the third line and 24% from the fourth line onwards). Similar rates were observed for resumption. Healthcare resource use was greater during antidepressant use than treatment-free periods. Augmentation was associated with the highest proportions of patients with a psychiatrist referral, psychologist referral and psychiatric hospitalization. CONCLUSIONS: This study provides extensive real-world information on the prescribing patterns and treatment outcomes for a large cohort of patients treated for depression with antidepressants in primary care. Switching is more frequently used than augmentation or combination treatment, with decreasing effectiveness across successive lines. Key limitations of the study were: (i) risk of selection bias due to the use of inclusion criteria based on depression diagnoses recorded by the practitioner; and (ii) reliance on prescribing patterns as proxies for clinical outcomes, such as recovery.

[Evaluation of the impact of a training program on vitamin K antagonists (VKA) implemented by pharmacy students aiming at improving the knowledge of patients receiving vitamin K antagonists during their hospital clinical training course]. / Évaluation de l'impact d'un programme de formation aux antagonistes de la vitamine K (AVK) pour les étudiants en pharmacie sur l'amélioration des connaissances des patients traités par AVK pris en charge au cours de leur stage clinique hospitalier.

INTRODUCTION: We developed a training program for pharmacy students aiming at supporting patients receiving vitamin K antagonists (VKAs). The objective was to estimate how the program impacts VKA-treated patient knowledge acquisition and/or improvement on their anticoagulant treatment. METHOD: Using dedicated tools, pharmacy students received education on VKA treatment. Once appointed to clinical wards of Assistance publique-Hôpitaux de Paris, they were in charge of evaluating patient's knowledge on VKA treatment before and after training. Evaluation was conducted using a face-to-face standardized interview (14-item questionnaire). A global score was calculated for each patient. An univariate and multivariate analysis was performed to identify potential variables influencing score result. RESULTS: One hundred and seventy VKA-treated patients were recruited in seven hospitals for evaluation of their knowledge on VKA treatment and on clinical at risk situations. Before intervention, patients obtained an average score of 12.3±3.2 (maximum: 18). Factors significantly associated with the score were possession of a VKA information booklet, VKA treatment duration, treatment initiation and age. Fifty-two patients with a low score were further trained by the pharmacy student. After intervention, their initial score was improved significantly, from 9.9±3.3 to 13.5±2.3 (P<0.0001). DISCUSSION AND CONCLUSION: Increasing patient knowledge is a way to decrease the rate of adverse effects. This study demonstrates that patients with primary poor knowledge improved it significantly thanks to pharmacy students' intervention. This may contribute to lower the VKA-associated risk of adverse events and consequently to the improvement of patients quality of life and healthcare expenditures.

[Prescription guidebook for temozolomide usage in brain tumors]. / Guide de prescription et de bon usage du témozolomide dans les tumeurs cérébrales.

Malignant gliomas are the most frequent primary brain tumors in adults. Temozolomide is an oral alkylating cytotoxic agent of second generation, used in the treatment of high-grade gliomas. It is indicated in newly diagnosed glioblastoma multiform as well as in recurrent or progressive malignant gliomas, such as glioblastoma multiform or anaplastic astrocytoma. However, temozolomide is also used, off label, in other clinical situations and the main objective of this study was to establish recommendations and guidelines for relevant prescriptions of temozolomide in primary brain tumors and brain metastasis in adults. The literature review was analysed by experts who determined the evidence level (A to E) according to the scale of recommendations adopted by the "Haute Autorité de santé--HAS--(French National Authority for Health)". For high-grade and low-grade gliomas, based on the level of evidence from the literature, the use of temozolomide can be justified, with a B2 score attributed to these indications. In contrast, for the others indications, the use of temozolomide appeared to be more controversial or even not recommended (score C to E). Regarding the dosing schedule and administration scheme, as well as the co-administration with other anticancer drugs, a C score was attributed for the off label situations.

Protein S deficiency. Description of a case associated with chronic inflammatory bowel disease.

Thrombotic disease is one of the most relevant clinical problems for morbility and mortality. We can differentiate congenital and acquired forms. In this short communication we describe 1 case observed by us that seems interesting for the association of a congenital and acquired form [Protein S deficiency and inflammatory bowel disease (IBD)] and for the dramatic events suffered before receiving a complete diagnosis and therapy, indicating the importance of recollection of information from the patients, starting from anamnestic data.

[Eosinophilia and Strongyloides stercoralis infestation: case report] / Eosinofilia e infestazione da Strongyloides stercoralis: caso clinico.

Authors report about a case of Strongyloides stercoralis infestation. The patient, a 65-year old man, presented with a clinical history of eosinophilia but without symptomatology. Several stool specimen showed the presence of rhabditiform larvae of S. stercoralis and after therapy the patient had a normalization of the white blood ceIls count. The authors wish to point out the importance of the diagnosis because a change in immune status may convert a previously asymptomatic infection to hyperinfection.