Highly efficient direct visible-light-mediated oxidative esterification of aldehydes.

A very efficient one-pot procedure for the direct oxidation of aldehydes to esters mediated by visible-light is presented. Utilizing a combination of indium triflate and N-bromosuccinimide, NBS, with either ortho-esters or alcohols provided rapid access to a variety of esters. Certain substrates convert fully within a few seconds, other more challenging tert-butyl esters were formed in good yield after no more than 4 h.

Proteoforms in Peripheral Blood Mononuclear Cells as Novel Rejection Biomarkers in Liver Transplant Recipients.

Biomarker profiles of acute rejection in liver transplant recipients could enhance the diagnosis and management of recipients. Our aim was to identify diagnostic proteoform signatures of acute rejection in circulating immune cells, using an emergent "top-down" proteomics methodology. We prepared differentially processed and cryopreserved cell lysates from 26 nonviral liver transplant recipients by molecular weight-based fractionation and analyzed them by mass spectrometry of whole proteins in three steps: (i) Nanocapillary liquid chromatography coupled with high-resolution tandem mass spectrometry; (ii) database searching to identify and characterize intact proteoforms; (iii) data processing through a hierarchical linear model matching the study design to quantify proteoform fold changes in patients with rejection versus normal liver function versus acute dysfunction without rejection. Differentially expressed proteoforms were seen in patients with rejection versus normal and nonspecific controls, most evidently in the cell preparations stored in traditional serum-rich media. Mapping analysis of these proteins back to genes through gene ontology and pathway analysis tools revealed multiple signaling pathways, including inflammation mediated by cytokines and chemokines. Larger studies are needed to validate these novel rejection signatures and test their predictive value for use in clinical management.

Truly unentangled photon pairs without spectral filtering.

We demonstrate that an integrated silicon microring resonator is capable of efficiently producing photon pairs that are completely unentangled; such pairs are a key component of heralded single-photon sources. A dual-channel interferometric coupling scheme can be used to independently tune the quality factors associated with the pump and signal and idler modes, yielding a biphoton wavefunction with a Schmidt number arbitrarily close to unity. This will permit the generation of heralded single-photon states with unit purity.

Metabolomic Analysis of Plasma in Huntington's Disease Transgenic Sheep (Ovis aries) Reveals Progressive Circadian Rhythm Dysregulation.

BACKGROUND: Metabolic abnormalities have long been predicted in Huntington's disease (HD) but remain poorly characterized. Chronobiological dysregulation has been described in HD and may include abnormalities in circadian-driven metabolism. OBJECTIVE: Here we investigated metabolite profiles in the transgenic sheep model of HD (OVT73) at presymptomatic ages. Our goal was to understand changes to the metabolome as well as potential metabolite rhythm changes associated with HD. METHODS: We used targeted liquid chromatography mass spectrometry (LC-MS) metabolomics to analyze metabolites in plasma samples taken from female HD transgenic and normal (control) sheep aged 5 and 7 years. Samples were taken hourly across a 27-h period. The resulting dataset was investigated by machine learning and chronobiological analysis. RESULTS: The metabolic profiles of HD and control sheep were separable by machine learning at both ages. We found both absolute and rhythmic differences in metabolites in HD compared to control sheep at 5 years of age. An increase in both the number of disturbed metabolites and the magnitude of change of acrophase (the time at which the rhythms peak) was seen in samples from 7-year-old HD compared to control sheep. There were striking similarities between the dysregulated metabolites identified in HD sheep and human patients (notably of phosphatidylcholines, amino acids, urea, and threonine). CONCLUSION: This work provides the first integrated analysis of changes in metabolism and circadian rhythmicity of metabolites in a large animal model of presymptomatic HD.

Tick-Tock Consider the Clock: The Influence of Circadian and External Cycles on Time of Day Variation in the Human Metabolome-A Review.

The past decade has seen a large influx of work investigating time of day variation in different human biofluid and tissue metabolomes. The driver of this daily variation can be endogenous circadian rhythms driven by the central and/or peripheral clocks, or exogenous diurnal rhythms driven by behavioural and environmental cycles, which manifest as regular 24 h cycles of metabolite concentrations. This review, of all published studies to date, establishes the extent of daily variation with regard to the number and identity of 'rhythmic' metabolites observed in blood, saliva, urine, breath, and skeletal muscle. The probable sources driving such variation, in addition to what metabolite classes are most susceptible in adhering to or uncoupling from such cycles is described in addition to a compiled list of common rhythmic metabolites. The reviewed studies show that the metabolome undergoes significant time of day variation, primarily observed for amino acids and multiple lipid classes. Such 24 h rhythms, driven by various factors discussed herein, are an additional source of intra/inter-individual variation and are thus highly pertinent to all studies applying untargeted and targeted metabolomics platforms, particularly for the construction of biomarker panels. The potential implications are discussed alongside proposed minimum reporting criteria suggested to acknowledge time of day variation as a potential influence of results and to facilitate improved reproducibility.

Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion, is linked to chromosome 11p14-15.1. The newly cloned high-affinity sulfonylurea receptor (SUR) gene, a regulator of insulin secretion, was mapped to 11p15.1 by means of fluorescence in situ hybridization. Two separate SUR gene splice site mutations, which segregated with disease phenotype, were identified in affected individuals from nine different families. Both mutations resulted in aberrant processing of the RNA sequence and disruption of the putative second nucleotide binding domain of the SUR protein. Abnormal insulin secretion in PHHI appears to be caused by mutations in the SUR gene.

A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland.

Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.

Frequent occurrence of asplenism and cholelithiasis in patients with autoimmune polyglandular disease type I.

PURPOSE: This study assesses the occurrence of asplenism and gallstones in patients with autoimmune polyglandular disease type I (APG I). PATIENTS AND METHODS: Nine patients with APG I (ages 14 to 48) were studied at the National Institutes of Health. Each patient received endocrine testing, a careful examination of his or her peripheral blood smear, lymphocyte immunophenotyping, a liver-spleen scan, and either an upper abdominal ultrasound or a computer-assisted tomogram to evaluate the spleen and gallbladder. RESULTS: We documented asplenism in four patients and cholelithiasis in four patients, with two patients having both conditions. The patients with asplenism had Howell-Jolly bodies on peripheral blood smears, lack of splenic uptake by liver-spleen scan, and absent spleens by abdominal computed tomographic scan or ultrasound evaluation. The clinical presentation of the patients with cholelithiasis ranged from acute symptoms requiring surgery to asymptomatic gallstones. Lymphocyte immunophenotyping did not reveal consistent changes in either B- or T-cell subpopulations in the patients studied. CONCLUSION: Asplenism and gallstones occur frequently in patients with APG I. In addition to careful examination of the peripheral blood smear for Howell-Jolly bodies to screen for asplenism, we recommend an abdominal ultrasound to detect asplenism and/or gallstones in all patients with APG I. Appropriate immunizations and antibiotic coverage may be helpful in those patients with absent spleens.

Genetic mutations as a cause of hyperinsulinemic hypoglycemia in children.

Hyperinsulinemic hypoglycemia in children is associated with unregulated secretion of insulin and hypoglycemia, a condition that is now known to be genetically diverse. This article reviews recent progress that has elucidated several beta-cell molecular defects responsible for the pathogenesis of this disorder.

Maternal serum hexosaminidase A in pregnancy: effects of gestational age and fetal genotype.

The diagnostic usefulness of sulfated fluorogenic substrates in carrier detection of Tay-Sachs disease in serum during pregnancy was assessed by testing coded samples. Gradual increase in serum hexosaminidase activities toward these substrates was observed throughout pregnancy in both carrier and non-carriers of the Tay-Sachs gene, but absolute discrimination between the 2 genotypes could not be achieved even when values were compared within the same gestational age. Examination of isolated isozyme fractions with the sulfated substrates showed that the increased activities during pregnancy were due to a genuine increase in hexosaminidase A and not associated with the elevation of hexosaminidase I (or P), which was evident only with unsulfated substrates. The extent of the increase was influenced by the genotype of the fetus as indicated by higher values in pregnant carriers who carried non-carrier fetuses. We conclude that determination of serum hexosaminidase A during pregnancy by sulfated fluorogenic substrates may have a prenatal diagnostic value when used in obligate heterozygotes for Tay-Sachs disease, but is unreliable for screening purposes.

Elevated extracellular levels of glutamate, aspartate and gamma-aminobutyric acid within the intraoperative, spontaneously epileptiform human hippocampus.

We report preliminary results from four patients subjected to hippocampal electrocorticography and microdialysis during temporal lobe epilepsy surgery. In two cases, spontaneously vigorous hippocampal epileptiform activity (EA) was identified; basal dialysate levels for hippocampal glutamate, aspartate, and gamma-aminobutyric acid ranged from approximately 23- to 84-fold, 19- to 33-fold and 10- to 34-fold higher, respectively, compared to the two cases of minimal hippocampal EA. These findings represent the first intraoperative evidence of elevated extracellular levels of neuroactive amino acids within the spontaneously epileptiform human hippocampus.

Recovery of reproductive function in rats treated with the aromatase inhibitor fadrozole.

The aromatase inhibitor, fadrozole hydrochloride (CGS 16949A), was developed for the treatment of breast cancer, and has not been available for pediatric use because of the lack of information about potential reproductive toxicology. To determine the effect of fadrozole on subsequent fertility and reproductive performance in rats, peripubertal male and female Sprague-Dawley rats (10/group) were given fadrozole by oral gavage once a day for 60 consecutive days (age 21 through 80 d) at a dose of 0, 1200, or 6000 micrograms/kg/d (dose range in women with breast cancer: 60 to 240 micrograms/kg/d). Following a 30-d recovery period (days 81 through 111 of age), cohabitation with untreated rats of the opposite sex was accomplished for 30 d or until positive evidence of mating was obtained (daily vaginal smears). The nonfadrozole-treated males used for cohabitation were proven fertile breeders; the females were virgin with proven 4-d estrous cycles. The duration of pregnancy, number, sex, condition, and body weight of pups were determined. Pregnant rats were weighed on gestational days 7, 14, and 20. There was a profound decrease in the number of estrous cycles at both dose levels of fadrozole compared to the control (P < 0.001). During the 30-d recovery period, estrous cycles were reestablished within a few days in the treated rats and the number and length of estrous cycles were not statistically different between fadrozole-treated and control rats. The gestational body weights of fadrozole-treated and untreated females did not differ significantly. There were no statistically significant differences in the number of matings/number of pairings, gestational length, mean live pups/litter, % pups born alive/litter, and % male pups/litter in the three groups (vehicle-, low-, and high-dose fadrozole-treated females, cohabited with untreated males and fadrozole-treated males, cohabited with untreated females). Thus, young male and female rats treated for 60 d with large doses of fadrozole had no detectable adverse effect on subsequent reproductive function.

Reconstruction of real world head injury accidents resulting from falls using multibody dynamics.

OBJECTIVE: To reconstruct real life head injury accidents resulting from falls using multibody modelling software, with the aim of comparing simulation output to injuries sustained. BACKGROUND: Much previous research on head injury biomechanics has focussed on animals and cadavers. However, focus is increasingly turning towards the examination of real life head injury. Falls are a major cause of head injury and, in general, are simpler to model than other accident types. DESIGN AND METHODS: Five cases of simple falling accidents resulting in focal head injury were examined, and reconstructions were performed using a multibody model of the human body. Each case was reconstructed a number of times, varying the initial conditions and using two different sets of properties for head contact. RESULTS: Results obtained included velocities, accelerations and forces on the head during impact. This output appeared more sensitive to changes in head contact characteristics than to changes in initial conditions. Depending on the contact characteristics used, results were consistent with proposed tolerance limits from the literature for various lesion types. CONCLUSIONS: Provided it is used with caution, this method could prove a useful source of biomechanical data for the investigation of head injury biomechanics. RELEVANCE: Biomechanical investigation of real-life cases of head injury is very important, yet not as prevalent as work with animals and cadavers. Reconstruction of real life accidents is a good method of obtaining data that will aid in the investigation of mechanisms of head injury and human tolerance to head injury.

Structure of the mouse calcitonin/calcitonin gene-related peptide alpha and beta genes.

We report the cloning, genomic organization and sequence of the mouse alpha-CALC and beta-CALC genes. The two genes share extensive sequence homology. The transcription units of both genes contain 6 exons. Transcripts of the alpha-CALC gene were found to alternatively include exon 4 or exons 5 and 6. For the beta-CALC gene exon 4 was not detected in transcripts derived from this gene. The predicted mouse alpha-CGRP was found to be identical to rat alpha-CGRP, however, beta-CGRP predicted amino acid sequences revealed three amino acid differences suggesting these residues are not critical to CGRP function.

Complex orthodontic problems: the orthognathic patient with temporomandibular disorders.

The diagnosis and treatment of temporomandibular disorders (TMD) remain controversial despite considerable research and publication in this area. The relationship of these problems to dental and skeletal malocclusion is equally debatable. Recent studies suggest that although malocclusion may have a role, it is a small one. Accordingly, treatment of TMD with occlusion-altering therapy, such as orthodontics and orthognathic surgery, should be limited to specific situations. This report discusses the management of patients with coexisting TMD and skeletal malocclusion. Current concepts in clinical and radiographic diagnosis are discussed, as well as an overview of noninvasive therapy. A case report is used to illustrate an approach to diagnosis and treatment planning in an individual with active TMD and a skeletal malocclusion requiring orthognathic surgery for correction.

Orthodontic camouflage versus orthognathic surgery in the treatment of mandibular deficiency.

Clearly, there are postpubertal patients with Class II malocclusions for whom orthognathic surgery combined with orthodontics is the "best" option, but epidemiologic information suggests they are a relatively small percentage of the potential patient pool. The majority of patients fall into either an orthodontic treatment group or a borderline category. Many of these can be treated successfully with orthodontic camouflage. Research has shown psychosocial factors play a major role in determining the patient's selection of a treatment option. This emphasizes the need for careful attention to global psychologic factors, with special emphasis on patient concerns regarding body image. Morphometric criteria have been offered describing appropriate candidates for orthodontic camouflage. These are supported by a combination of research and clinical experience. Patients who do not fit these criteria should not automatically be considered candidates for surgery. Psychosocial research suggests a percentage of these individuals place less importance on facial change and are content to improve dental esthetics and function to the degree possible. To assist in the decision-making process, patients should be given the best information available regarding potential outcome. Currently this may involve treatment simulation using a combination of computer images and dental models. Caution has been suggested, given the variability associated with predicting soft tissue change. There are additional legal concerns regarding the implied guarantee of treatment outcome. Correspondingly, the influence of this technology must be kept in perspective. Recent research on the decision-making process found computer imaging to be an important factor in only 24% of the patients studied.(ABSTRACT TRUNCATED AT 250 WORDS)