Direct detection of dark matter-APPEC committee report.

This report provides an extensive review of the experimental programme of direct detection searches of particle dark matter. It focuses mostly on European efforts, both current and planned, but does it within a broader context of a worldwide activity in the field. It aims at identifying the virtues, opportunities and challenges associated with the different experimental approaches and search techniques.

The First Treatment for PKU: The Pioneers-Birmingham 1951.

Prior to the introduction of newborn screening, Phenylketonuria (PKU) was a devastating disorder with affected individuals usually committed to a life in care in large institutions (asylums). Newborn screening only began after it was shown that those with PKU could be treated with a modified diet and could subsequently lead normal lives. The first production of a diet and the demonstration of its effectiveness was thus a key milestone in the history of both PKU and newborn screening, and took place in Birmingham, UK, in 1951.

Atypical ductal hyperplasia on core needle biopsy: Surgical outcomes of 200 consecutive cases from a high-volume breast program.

Atypical ductal hyperplasia (ADH) is an indication for excisional biopsy to rule out occult breast cancer. We analyzed pathological findings on excisional biopsy for ADH diagnosed in a high volume breast center equipped with digital tomosynthesis. Two hundred consecutive patients were diagnosed with ADH on core biopsy with radiographic concordance followed by excisional biopsy.

Atypical lobular hyperplasia on core needle biopsy: contemporary results from a large community hospital breast program.

Purpose: The management of biopsy proven atypical lobular hyperplasia (ALH) is controversial. Although upgrade rates are low, excisional biopsy is often performed to rule out occult breast cancer.

Methods: In this study, we analyzed our experience with excisional biopsy for ALH diagnosed in the digital tomosynthesis era with radiographic concordance in the community hospital setting.

Model independent determination of the dark matter mass from direct detection experiments.

Determining the dark matter (DM) mass is of paramount importance for understanding dark matter. We present a novel parametrization of the DM speed distribution which will allow the DM mass to be accurately measured using data from weakly interacting massive particle (WIMP) direct detection experiments. Specifically, we parametrize the natural logarithm of the speed distribution as a polynomial in the speed v.

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: prevalence, predictive value and test validity based on 1.5 million screened babies.

Background: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain.

Objective: To estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance.

17Beta-estradiol elevates cGMP and, via plasma membrane recruitment of protein kinase GIalpha, stimulates Ca2+ efflux from rat hepatocytes.

Rapid non-genomic effects of 17beta-estradiol, the principal circulating estrogen, have been observed in a wide variety of cell types. Here we investigate rapid signaling effects of 17beta-estradiol in rat hepatocytes. We show that, above a threshold concentration of 1 nm, 17beta-estradiol, but not 17alpha-estradiol, stimulates particulate guanylyl cyclase to elevate cGMP, which through activation and plasma membrane recruitment of protein kinase G isoform Ialpha, stimulates plasma membrane Ca(2+)-ATPase-mediated Ca(2+) efflux from rat hepatocytes.

Relationship of octanoylcarnitine concentrations to age at sampling in unaffected newborns screened for medium-chain acyl-CoA dehydrogenase deficiency.

Background: Although octanoylcarnitine (C8) concentrations measured from newborn screening dried blood spots are used to identify those at high risk of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), age-related reference values are currently not available for unaffected newborn populations. Because age at sampling may vary within and between screening programs, variations in C8 concentrations by age may affect screening program performance. We determined whether C8 concentrations vary by age at sampling, sex, birth weight, or gestational age in unaffected newborns.

Information transfer in signaling pathways: a study using coupled simulated and experimental data.

Background: The topology of signaling cascades has been studied in quite some detail. However, how information is processed exactly is still relatively unknown. Since quite diverse information has to be transported by one and the same signaling cascade (e.

ANP stimulates hepatocyte Ca2+ efflux via plasma membrane recruitment of PKGIalpha.

In rat hepatocytes, atrial natriuretic peptide (ANP) elevates cGMP through activation of particulate guanylyl cyclase and attenuates Ca(2+) signals by stimulating net plasma membrane Ca(2+) efflux. We show here that ANP-stimulated hepatocyte Ca(2+) efflux is mediated by protein kinase G (PKG) isotype I. Furthermore, we show that ANP recruits endogenous PKGIalpha, but not PKGIbeta, to the plasma membrane.

Spatio-temporal modelling explains the effect of reduced plasma membrane Ca2+ efflux on intracellular Ca2+ oscillations in hepatocytes.

In many non-excitable eukaryotic cells, including hepatocytes, Ca(2+) oscillations play a key role in intra- and intercellular signalling, thus regulating many cellular processes from fertilisation to death. Therefore, understanding the mechanisms underlying these oscillations, and consequently understanding how they may be regulated, is of great interest. In this paper, we study the influence of reduced Ca(2+) plasma membrane efflux on Ca(2+) oscillations in hepatocytes.

Establishing the stochastic nature of intracellular calcium oscillations from experimental data.

Calcium has been established as a key messenger in both intra- and intercellular signaling. Experimentally observed intracellular calcium responses to different agonists show a variety of behaviors from simple spiking to complex oscillatory regimes. Here we study typical experimental traces of calcium oscillations in hepatocytes obtained in response to phenylephrine and ATP.

Atrial natriuretic peptide attenuates elevations in Ca2+ and protects hepatocytes by stimulating net plasma membrane Ca2+ efflux.

Elevations in intracellular Ca(2+) concentration and calpain activity are common early events in cellular injury, including that of hepatocytes. Atrial natriuretic peptide is a circulating hormone that has been shown to be hepatoprotective. The aim of this study was to examine the effects of atrial natriuretic peptide on potentially harmful elevations in cytosolic free Ca(2+) and calpain activity induced by extracellular ATP in rat hepatocytes.

Quantitation of urinary glycosaminoglycans using dimethylene blue as a screening technique for the diagnosis of mucopolysaccharidoses: an evaluation.

Background: The mucopolysaccharidoses (MPSs) are a group of inherited disorders due to defects in lysosomal enzymes catalysing the breakdown of glycosaminoglycans (GAGs). Usually they are detected using techniques to separate the accumulating GAGs in urine. However more recently an improved dye-based method measuring total urine GAG concentrations has become available.

Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis.

A multidisciplinary group (representing various professional bodies and supported by the Cystic Fibrosis Trust) has developed evidence-based guidelines for the performance of the sweat test in the UK. The guidelines cover patient information, subject suitability, sweat collection, sweat analysis, quality, interpretation of results, and responsibility for testing and training. The guidelines were produced following a detailed literature search by the process described by the Royal College of Paediatrics and Child Health (RCPCH), using the Scottish Intercollegiate Guidelines Network 1 (SIGN 1) criteria to grade the evidence.

The sweat test for the diagnosis of cystic fibrosis--a personal experience of guideline production.

The need for evidence-based guidelines as to how to conduct the sweat test in the UK was highlighted in 2000 by the National External Quality Assessment Scheme Specialist Advisory Committee. A Guideline Group supported by several professional bodies was subsequently convened and formal evidence-based guidelines were produced and published in 2003. The process of undertaking guideline production is summarized here, together with the author's personal opinions about the experience and highlights of the shortcomings and lessons learnt from the project.

Transition from stochastic to deterministic behavior in calcium oscillations.

Simulation and modeling is becoming more and more important when studying complex biochemical systems. Most often, ordinary differential equations are employed for this purpose. However, these are only applicable when the numbers of participating molecules in the biochemical systems are large enough to be treated as concentrations.

Bile acids induce a cationic current, depolarizing pancreatic acinar cells and increasing the intracellular Na+ concentration.

Biliary disease is a major cause of acute pancreatitis. In this study we investigated the electrophysiological effects of bile acids on pancreatic acinar cells. In perforated patch clamp experiments we found that taurolithocholic acid 3-sulfate depolarized pancreatic acinar cells.

Atrial natriuretic peptide attenuates Ca2+ oscillations and modulates plasma membrane Ca2+ fluxes in rat hepatocytes.

Background & Aims: Oscillations in cytosolic free Ca2+ concentration are a fundamental mechanism of intracellular signaling in hepatocytes. The aim of this study was to examine the effects of atrial natriuretic peptide (ANP) on cytosolic Ca2+ oscillations in rat hepatocytes.

Methods: Cyclic guanosine monophosphate (cGMP) was measured by enzyme immunoassay.

Pregnancy and inherited metabolic disorders: maternal and fetal complications.

Some inherited metabolic disorders (IMDs) can cause significant complications during pregnancy, affecting the mother and/or the fetus. Although it appears that only a minority of IMDs have these effects, experience is still being acquired. For some disorders, patients will not have reached child-bearing age.

The impact of phenylketonuria on folate metabolism.

Several reports indicate that biopterin and folate pathways may interact. We examined folate metabolism in PKU patients where hyperphenylalaninaemia leads to a likely excess of THB. We found an increase in total HPLC determined red cell folate in PKU (p=0.

Organization of the human liver carnitine palmitoyltransferase 1 gene ( CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation. CPT1 controls the import of long-chain fatty acids into the mitochondria, where they are oxidized. Two CPT1 isoforms, the so-called "liver" and "muscle" CPT1s encoded by the CPT1Aand CPT1Bgenes, respectively, have been identified so far.

Gamma-glutamyltransferase: value of its measurement in paediatrics.

Gamma-glutamyltransferase (GGT) is a microsomal enzyme that is widely distributed in human tissues involved in secretory and absorptive processes, particularly the bile canaliculi. Serum GGT is elevated in liver diseases affecting the biliary system, such as extrahepatic biliary atresia, sclerosing cholangitis and progressive familial intrahepatic cholestasis (PFIC) type 3. Conversely, two other subtypes of PFIC have normal or low serum GGT activity, discordant with the degree of cholestasis.