Clinical presentation of young people (10–24 years old) with brain tumors: results from the international MOBI-Kids study

Journal of Neuro-Oncology - We used data from MOBI-Kids, a 14-country international collaborative case–control study of brain tumors (BTs), to study clinical characteristics of the tumors in...     

Efficacy and safety of secukinumab in the treatment of moderate‐to‐severe plaque psoriasis: a randomized,double‐blind,placebo‐controlled phase II dose‐ranging study

Background Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long‐term safety. Interleukin (IL)‐17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. Objectives To assess the efficacy and safety of different doses of secukinumab, a fully human anti‐IL‐17A IgG1κ monoclonal antibody, in patients with moderate‐to‐severe plaque psoriasis. Methods Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12‐week treatment period, patients entered a follow‐up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates. Results After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow‐up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow‐up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort. Conclusions Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate‐to‐severe psoriasis.     

Mechanisms of increased brain glucose and glycogen after hydrocortisone: possible clinical significance

We reported previously that chronic administration of hydrocortisone to normal developing mice increases the brain glucose content and cerebral energy reserve. The present report concerns possible mechanisms of this action. Increases in brain glucose (and glycogen) levels were not due to reduction of cerebral metabolic rate, and the effect of hydrocortisone in facilitating transport of hexose from blood to brain was not impressive. Chronic hydrocortisone treatment induced increases in the activities of brain glycerophosphate dehydrogenase and pyruvate carboxylase in vivo; there was no effect on eleven other enzymes of brain glucose and glycogen metabolism. In normal nursing mice, hydrocortisone produced consistent elevations in plasma beta-hydroxybutyrate (and glycerol) levels. Brain beta-hydroxybutyrate levels were also increased. Therefore, the brain glucose concentration may be elevated in these animals because of the availability of an increased supply of ketone bodies as alternative substrates for cerebral oxidative metabolism and biosynthesis. Ketonemia, elevated cerebral glucose and beta-hydroxybutyrate concentrations, and increased glycerophosphate dehydrogenase activity in brain suggest possible explanations for the beneficial action of adrenocorticotropic hormone and glucocorticoids in the treatment of infantile myoclonic epilepsy and other neurological disorders.     

Basic features of the ancestral chordate brain: a protochordate perspective

Basic features of the anterior nerve cord in amphioxus larvae are summarized to highlight its essential similarity with the vertebrate brain. Except for a pineal homolog, the amphioxus brain consists of a much simplified version of the ventral brainstem, including a region probably homologous with the hypothalamus, and a locomotory control center roughly comparable to the vertebrate tegmentum and reticulospinal system. Amphioxus has direct pathways for activating its locomotory circuits in response to mechanical stimuli via epithelial sensory cells, but this response is evidently modulated by inputs from diverse sensory-type cells located in the putative hypothalamic homolog, and from the lamellar body, the pineal homolog. This implies that a basic function of the amphioxus brain is to switch between locomotory activities, of which there are several, and the principal non-locomotory one, namely feeding. A similar involvement in switching between behavioral modes may thus have been a core brain function in ancestral chordates. Currently, however, incomplete knowledge of the physiology and behavior of amphioxus limits how effectively it can be used as an evolutionary model. Eye evolution is briefly discussed to illustrate how a better understanding of living forms can inform the evolutionary debate. An account of recent data on dorsoventral inversion is also included, as this bears directly on the question of where the chordate brain originated in relation to other structures. It now appears likely that key components of the ancestral brain were originally located around the mouth. A secondary repositioning of the latter would therefore have been required before a unitary brain could be assembled and internalized. This association between the mouth and the evolving brain reinforces the idea of a fundamental early connection between core brain structures and the control of feeding activity.     

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

How nonclinical are community samples?

Mental health services are underutilized in our society by both adults and children. This finding presents a potential problem for researchers conducting community‐based research. Previous studies have demonstrated that community‐based researchers frequently do not screen participants for the presence of psychopathology nor do they ascertain whether therapeutic services are currently utilized. The present study explored the prevalence of psychopathology and treatment involvement in a sample of families recruited from the community. Results indicated that a fifth of the participants in this community‐based sample met diagnostic criteria for a psychiatric disorder or were in treatment for psychological difficulties at the time of recruitment for this study. Furthermore, mothers, fathers, and adolescents who met the criteria according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV; American Psychiatric Association, 1994 ) for a psychological disorder had higher symptomatology than those who did not meet criteria. Methodological suggestions are provided. © 2008 Wiley Periodicals, Inc.     

The role of air pollution in asthma and other pediatric morbidities

A growing body of research supports the role of outdoor air pollutants in acutely aggravating chronic diseases in children, and suggests that the pollutants may have a role in the development of these diseases. This article reviews the biologic basis of children's unique vulnerability to highly prevalent outdoor air pollutants, with a special focus on ozone, respirable particulate matter (PM 2.5 [<2.5 microm in diameter] and PM 10 [<10 microm in diameter]), lead, sulfur dioxide, carbon monoxide, and nitrogen oxides. We also summarize understanding regarding health effects and molecular mechanisms of action. Practitioners can significantly reduce morbidity in children and other vulnerable populations by advising families to minimize pollutant exposures to children with asthma, or at a broader level by educating policymakers about the need to act to reduce pollutant emissions. Management of children with asthma must expand beyond preventing exposures to agents that directly cause allergic reactions (and therefore can be diagnosed by means of skin tests) and must focus more attention on agents that cause a broad spectrum of nonspecific, generalized inflammation, such as air pollution.