Genome rearrangements detected by SNP microarrays in individuals with intellectual disability referred with possible Williams syndrome.

Background: Intellectual disability (ID) affects 2-3% of the population and may occur with or without multiple congenital anomalies (MCA) or other medical conditions. Established genetic syndromes and visible chromosome abnormalities account for a substantial percentage of ID diagnoses, although for approximately 50% the molecular etiology is unknown. Individuals with features suggestive of various syndromes but lacking their associated genetic anomalies pose a formidable clinical challenge.

Alpha 1 antitrypsin deficiency alleles are associated with joint dislocation and scoliosis in Williams syndrome.

Elastin haploinsufficiency is responsible for a significant portion of the Williams syndrome (WS) phenotype including hoarse voice, supravalvar aortic stenosis (SVAS), hernias, diverticuli of bowel and bladder, soft skin, and joint abnormalities. All of the connective tissue signs and symptoms are variable in the WS population, but few factors other than age and gender are known to influence the phenotype. We examined a cohort of 205 individuals with WS for mutations in SERPINA1, the gene that encodes alpha-1-antitrypsin (AAT), the inhibitor of elastase.

Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome.

Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure.

Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice.

Generalized vitiligo is thought to have an autoimmune etiology and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation Ag. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase.

A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer.

Objectives: Lapatinib (GW572016) is a selective and potent dual tyrosine kinase inhibitor of the epidermal growth factor 1 (EGFR) and 2 (HER2), approved in the treatment of HER2 positive breast cancer. Since EGFR and HER2 overexpression has also been seen in prostate cancer and appears to correlate with a worse clinical outcome, Lapatinib may represent a novel therapeutic strategy in prostate cancer. This Phase II multicenter clinical trial is the first to evaluate Lapatinib in early stage, hormonally untreated recurrent or metastatic prostate cancer.

Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD).

In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis.

Mutations in TRPM1 are a common cause of complete congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity. We report here that six out of eight female probands with autosomal-recessive complete CSNB (cCSNB) had mutations in TRPM1, a retinal transient receptor potential (TRP) cation channel gene. These data suggest that TRMP1 mutations are a major cause of autosomal-recessive CSNB in individuals of European ancestry.

Muscle contractions guide rohon-beard peripheral sensory axons.

Multiple molecular cues guide neuronal axons to their targets during development. Previous studies in vitro have shown that mechanical stimulation also can affect axon growth; however, whether mechanical force contributes to axon guidance in vivo is unknown. We investigated the role of muscle contractions in the guidance of zebrafish peripheral Rohon-Beard (RB) sensory axons in vivo.

The Ca2+ channel subunit beta2 regulates Ca2+ channel abundance and function in inner hair cells and is required for hearing.

Hearing relies on Ca(2+) influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca(2+) channel subunit Ca(V)beta(2) in hearing. Of the Ca(V)beta(1-4) mRNAs, IHCs predominantly contained Ca(V)beta(2).

Improvements in atrial fibrillation detection for real-time monitoring.

Electrocardiographic (ECG) monitoring plays an important role in the management of patients with atrial fibrillation (AF). Automated real-time AF detection algorithm is an integral part of ECG monitoring during AF therapy. Before and after antiarrhythmic drug therapy and surgical procedures require ECG monitoring to ensure the success of AF therapy.

Genetic variations associated with red hair color and fear of dental pain, anxiety regarding dental care and avoidance of dental care.

Background: Red hair color is caused by variants of the melanocortin-1 receptor (MC1R) gene. People with naturally red hair are resistant to subcutaneous local anesthetics and, therefore, may experience increased anxiety regarding dental care. The authors tested the hypothesis that having natural red hair color, a MC1R gene variant or both could predict a patient's experiencing dental care-related anxiety and dental care avoidance.

The management of thymoma: a systematic review and practice guideline.

Introduction: Thymoma is a rare tumor for which there is little randomized evidence to guide treatment. Because of the lack of high-quality evidence, a formal consensus-based approach was used to develop recommendations on treatment.

Methods: A systematic refview of the literature was performed.

A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells.

On bipolar cells are connected to photoreceptors via a sign-inverting synapse. At this synapse, glutamate binds to a metabotropic receptor which couples to the closure of a cation-selective transduction channel. The molecular identity of both the receptor and the G protein are known, but the identity of the transduction channel has remained elusive.

Philips QT interval measurement algorithms for diagnostic, ambulatory, and patient monitoring ECG applications.

Background: Commonly used techniques for QT measurement that identify T wave end using amplitude thresholds or the tangent method are sensitive to baseline drift and to variations of terminal T wave shape. Such QT measurement techniques commonly underestimate or overestimate the "true" QT interval.

Methods: To find the end of the T wave, the new Philips QT interval measurement algorithms use the distance from an ancillary line drawn from the peak of the T wave to a point beyond the expected inflection point at the end of the T wave.

Evolutionary shifts in courtship pheromone composition revealed by EST analysis of plethodontid salamander mental glands.

Courtship behavior in salamanders of the family Plethodontidae can last more than an hour. During courtship, males use stereotyped behaviors to repeatedly deliver a variety of proteinaceous pheromones to the female. These pheromones are produced and released from a specialized gland on the male's chin (the mental gland).

Technical challenges and future directions in lead reconstruction for reduced-lead systems.

Reduced-lead electrocardiographic systems are currently a widely accepted medical technology used in a number of applications. They provide increased patient comfort and superior performance in arrhythmia and ST monitoring. These systems have unique and compelling advantages over the traditional multichannel monitoring lead systems.

Where do derived precordial leads fail?

A 12-lead electrocardiogram (ECG) reconstructed from a reduced subset of leads is desired in continued arrhythmia and ST monitoring for less tangled wires and increased patient comfort. However, the impact of reconstructed 12-lead lead ECG on clinical ECG diagnosis has not been studied thoroughly. This study compares the differences between recorded and reconstructed 12-lead diagnostic ECG interpretation with 2 commonly used configurations: reconstruct precordial leads V(2), V(3), V(5), and V(6) from V(1),V(4), or reconstruct V(1), V(3), V(4), and V(6) from V(2),V(5).

Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses.

An electroretinogram (ERG) screen identified a mouse with a normal a-wave but lacking a b-wave, and as such it was designated no b-wave3 (nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene (Grm6). Sequence analyses of cDNA identified a splicing error in Grm6, introducing an insertion and an early stop codon into the mRNA of affected mice (designated Grm6(nob3)).

Comparisons of structural and functional abnormalities in mouse b-wave mutants.

In the most simplistic view, the retinal circuit can be divided into vertical excitatory pathways that use glutamate as their neurotransmitter and lateral inhibitory pathways in the outer and inner synaptic layers that modulate excitation via glycine and GABA. Within the vertical excitatory pathways, the visual signal is initiated in the rod, cone or both photoreceptors, depending on the adaptation state of the retina. This signal is transmitted to the rest of the retina through the bipolar cells, which can be subdivided based on: the photoreceptor that provides their input, their dendritic and axonal morphology, and the polarity of their response evoked by a luminance increment, e.

Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.

Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.

Zebrafish blowout provides genetic evidence for Patched1-mediated negative regulation of Hedgehog signaling within the proximal optic vesicle of the vertebrate eye.

In this study, we have characterized the ocular defects in the recessive zebrafish mutant blowout that presents with a variably penetrant coloboma phenotype. blowout mutants develop unilateral or bilateral colobomas and as a result, the retina and retinal pigmented epithelium are not contained within the optic cup. Colobomas result from defects in optic stalk morphogenesis whereby the optic stalk extends into the retina and impedes the lateral edges of the choroid fissure from meeting and fusing.

Innocuous IFNgamma induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production.

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206-220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon gamma (IFNgamma) protect against passive TID. Because IFNgamma is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages.

What is inside the electrocardiograph?

The details of digital recording and computer processing of a 12-lead electrocardiogram (ECG) remain a source of confusion for many health care professionals. A better understanding of the design and performance tradeoffs inherent in the electrocardiograph design might lead to better quality in ECG recording and better interpretation in ECG reading. This paper serves as a tutorial from an engineering point of view to those who are new to the field of ECG and to those clinicians who want to gain a better understanding of the engineering tradeoffs involved.

Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.

Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.