Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.

The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.

Phenocopy syndrome of behavioral variant frontotemporal dementia: a systematic review.

BACKGROUND: The phenocopy syndrome of behavioral variant of frontotemporal dementia (phFTD) refers to patients presenting with neuropsychiatric symptoms mimicking the behavioral variant frontotemporal dementia (bvFTD), but lacking frontotemporal atrophy/hypometabolism on neuroimaging and not evolving to dementia during the follow-up. It is important to recognize phFTD for clinical and research purposes. OBJECTIVE: The aim of this study was to perform a systematic review of the available literature on phFTD taking into account its clinical, cognitive, imaging, genetic, and pathological features. METHODS AND RESULTS: We searched for the following terms in two electronic databases (PubMed and Scopus): "frontotemporal dementia and slowly progressive," "frontotemporal dementia and phenocopy," "frontotemporal dementia and non-progressive," "frontotemporal dementia and benign progression," and "frontotemporal dementia and benign." We did not include review articles. Papers had to be written in English, French, Portuguese, or Spanish. Overall, 235 studies were retrieved in the initial search. A total of 31 studies composed the final selection, comprising 292 patients. Patients with phFTD are predominantly male and have no major cognitive deficits, with globally preserved executive functions and episodic memory. Some cases (n = 7) of slowly progressive FTD have been associated with C9orf72 genetic expansion. There are only four reports of phFTD neuropathological data, with two patients with no neurodegenerative findings and two with frontotemporal lobar degeneration with ubiquitin-positive inclusions. CONCLUSION: The neurobiological underpinnings of phFTD remain unknown. It is controversial whether phFTD belongs to the FTD spectrum. Studies with biomarkers and pathological data are needed to solve the phFTD conundrum.

Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development.

Volumetric MRI scans from 26 women with repeated episodes of childhood sexual abuse and 17 healthy female comparison subjects (ages 18-22 years) were analyzed for sensitive period effects on hippocampal and amygdala volume, frontal cortex gray matter volume and corpus callosum area. Hippocampal volume was reduced in association with childhood sexual abuse at ages 3-5 years and ages 11-13 years. Corpus callosum was reduced with childhood sexual abuse at ages 9-10 years, and frontal cortex was attenuated in subjects with childhood sexual abuse at ages 14-16 years. Brain regions have unique windows of vulnerability to the effects of traumatic stress.

Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder: I. Effects of different dosing regimens.

BACKGROUND AND PURPOSE: Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. METHOD: Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. RESULTS: The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Lateral visual field stimulation reveals extrastriate cortical activation in the contralateral hemisphere: an fMRI study.

We examined whether lateral visual field stimulation (LSTM) could activate contralateral extrastriate cortical areas as predicted by a large experimental literature. We asked seven unscreened, control subjects to wear glasses designed to allow vision out of either the left (LVF) or right lateral visual field (RVF) depending upon which side the subject looked toward. Each subject participated in a block design functional magnetic resonance imaging (fMRI) study with alternating 30-s epochs in which he was asked to look to one side and then the other for a total of five epochs. On each side of the bore of the scanner, we taped a photograph for the subject to view in the LVF and RVF. The data were analyzed with SPM99 using a fixed effect, box-car design with contrasts for the LVF and the RVF conditions. Both LVF and RVF conditions produced the strongest fMRI activation in the contralateral occipitotemporal and posterior parietal areas as well as the contralateral dorsolateral prefrontal cortex. LSTM appears to increase contralateral fMRI activation in striate and extrastriate cortical areas as predicted by earlier studies reporting differential cognitive and/or emotional effects from unilateral sensory or motor stimulation.

The effect of the addition of resistance training to a dietary education intervention on apolipoproteins and diet quality in overweight and obese older adults.

OBJECTIVES: The aim of the study was to examine the additive effect of resistance training (RT) to a dietary education (DE) intervention on emerging coronary heart disease (CHD) risk factors, concentration of apolipoproteins B (apoB) and A-I (apoA-I), and Dietary Approaches to Stop Hypertension (DASH) Diet Index scores in overweight and obese older adults. PATIENTS AND METHODS: This was an ancillary study of a randomized clinical trial held in the Fall of 2008 at the University of Rhode Island. Participants were overweight or obese subjects (mean body mass index [BMI] of 31.7 kg/m(2)) randomized into two groups, one participating in DE only (n = 12) and the other participating in DE plus RT (DERT) (n = 15). The intervention involved all subjects participating in 30 minutes of DE per week for 10 weeks. Subjects in the DERT group participated in an additional 40 minutes of RT three times per week for 10 weeks. Measurements taken were anthropometric (height, weight, waist circumference, and body composition using the BOD POD(®) [Body Composition System, v 2.14; Life Measurement Instruments, Concord, CA]), clinical (blood pressure), and biochemical (lipid profile and apoB and apoA-I concentrations), and the DASH Diet Index was used to measure diet quality. RESULTS: 27 subjects (11 males, 16 females), with a mean age of 66.6 ± 4.3 years, were included in analyses. The DERT subjects had significantly better triacylglycerol and apoB concentrations and DASH Diet Index scores than the DE subjects post-intervention. Improvements were seen within the DE group in energy intake, fat-free mass, and systolic blood pressure and within the DERT group in body weight, percentage of body fat, BMI, diastolic blood pressure, and oxidized low-density lipoprotein (all P < 0.05). CONCLUSION: The addition of RT effectively reduced CHD risk factors, body composition, and diet quality in overweight and obese older adults; DERT was more effective than DE alone in improving DASH Diet Index scores and lowering apoB concentrations but was not more effective in increasing apoA-I concentrations. Future research is needed to determine if apolipoproteins are superior to lipoprotein cholesterol concentrations in predicting CHD risk.