bluuebunny/crossref_metadata_2025 huggingface dataset:
The application of an indirect electromagnetic geothermometer to temperature extrapolation in depth
Authors: Spichak Viacheslav V. , Zakharova Olga K.
Published: January 2009

We study the feasibility of the application of an indirect EM geothermometer, developed recently, to the temperature extrapolation in depth using magnetotelluric data collected in the seismically active northern Tien Shan faulted area (Bishkek Geodynamic Test Site, Kyrgyzstan) and Hengill geothermal zone (Iceland). The approach used is based on the artificial neural network technique, which does not imply the prior knowledge of the electrical conductivity mechanisms on the one hand and provides temperature estimates based on the analysis of the implicit conductivity‐temperature relations, on the other.

The samples for neuronet teaching consisted in the well temperature records and electrical conductivity values determined for the same depths from the magnetotelluric data measured in the vicinities of eight boreholes in each testing area. The testing of the taught neuronets was carried out using the temperature records not involved in the teaching process. The results indicate that the temperature extrapolation accuracy essentially depends on the ratio between the well length and the extrapolation depth. In particular, in extrapolation to a depth twice as large as the well depth the relative error is 5–6% and in case of threefold excess, the error is around 20%. This result makes it possible to increase significantly the depth of indirect temperature estimation in the Earth's interior (in particular, for geothermal exploration) based on the available temperature logs.

The practical application of an indirect electromagnetic geothermometer could provide the following facilities: 1) more exact temperature estimation in the extrapolation mode; 2) remote temperature estimates in the boreholes in areas characterized by extreme conditions for conventional geothermometers.
Influence of temperature and spawning effort on Haliotis tuberculata mortalities caused by Vibrio harveyi: an example of emerging vibriosis linked to global warming
Authors: TRAVERS MARIE‐AGNÈS , BASUYAUX OLIVIER , LE GOÏC NELLY , HUCHETTE SYLVAIN , NICOLAS JEAN‐LOUIS , KOKEN MARCEL , PAILLARD CHRISTINE
Published: January 2009

Since 1998, Haliotis tuberculata mass mortalities have been occurring regularly in wild abalone populations in France during their reproductive period and in conjunction with seawater summer temperature maxima and Vibrio harveyi presence. To confirm the importance of bacterial exposure, temperature and reproductive status on abalone susceptibility, experimental infections via bath exposure were performed using abalone ranging from immature to reproductively mature. Ripe abalone were more susceptible to the bacterium than immature specimens (P<0.001), and a difference of only 1 °C in temperature had a highly significant impact on the mortalities (P<0.001). The natural mortalities that were surveyed during summer 2007 confirmed that recent epidemic losses of European abalone appeared in conjunction with host reproductive stress, elevated temperatures and presence of the pathogen V. harveyi. In view of the elevation of the mean summer temperatures observed in Brittany and Normandy over the last 25 years, this temperature‐dependent vibriosis represents a new case of emerging disease associated with global warming.
Hippuric acid and benzoic acid inhibition of urine derived N2O emissions from soil
Authors: BERTRAM JANET E. , CLOUGH TIM J. , SHERLOCK ROBERT R. , CONDRON LEO M. , O'CALLAGHAN MAUREEN , WELLS NAOMI S. , RAY JESSICA L.
Published: January 2009

Atmospheric concentrations of the greenhouse gas nitrous oxide (N2O) have continued to rise since the advent of the industrial era, largely because of the increase in agricultural land use. The urine deposited by grazing ruminant animals is a major global source of agricultural N2O. With the first commitment period for reducing greenhouse gas emissions under the Kyoto Protocol now underway, mitigation options for ruminant urine N2O emissions are urgently needed. Recent studies showed that increasing the urinary concentration of the minor urine constituent hippuric acid resulted in reduced emissions of N2O from a sandy soil treated with synthetic bovine urine, due to a reduction in denitrification. A similar effect was seen when benzoic acid, a product of hippuric acid hydrolysis, was used. This current laboratory experiment aimed to investigate these effects using real cow urine for the first time. Increased concentrations of hippuric acid or benzoic acid in the urine led to reduction of N2O emissions by 65% (from 17% to <6% N applied), with no difference between the two acid treatments. Ammonia volatilization did not increase significantly with increased hippuric acid or benzoic acid concentrations in the urine applied. Therefore, there was a net reduction in gaseous N loss from the soil with higher urinary concentrations of both hippuric acid and benzoic acid. The results show that elevating hippuric acid in the urine had a marked negative effect on both nitrification and denitrification rates and on subsequent N2O fluxes. This study indicates the potential for developing a novel mitigation strategy based on manipulation of urine composition through ruminant diet.
Roles of phosphatidylinositol 3‐kinase and p38 mitogen‐activated protein kinase in the regulation of protein kinase C‐α activation in interferon‐γ‐stimulated macrophages
Authors: Hardy Pierre‐Olivier , Diallo Tamsir O. , Matte Christine , Descoteaux Albert
Published: January 2009

Members of the protein kinase C (PKC) family are activated by interferon‐γ (IFN‐γ) and modulate IFN‐γ‐induced cellular responses by regulating the activity of transcription factors. We previously reported that PKC‐α enhances the ability of IFN regulatory factor‐1 to transactivate the class II transactivator (CIITA) promoter IV in IFN‐γ‐stimulated macrophages. In addition, we showed that IFN‐γ induces the nuclear translocation of PKC‐α but the mechanisms for this remain to be elucidated. In this study, we sought to identify signalling pathways involved in IFN‐γ‐induced activation of PKC‐α and to characterize their potential roles in modulating IFN‐γ‐induced responses in macrophages. IFN‐γ‐mediated nuclear translocation of PKC‐α was a Janus activated kinase 2 (JAK2)‐independent process, which required phosphatidylinositol 3‐kinase (PI3K) and p38 mitogen‐activated protein kinase (MAPK). However, PKC‐α phosphorylation was independent of PI3K and p38 MAPK, indicating that IFN‐γ‐induced phosphorylation and nuclear translocation of PKC‐α are mediated by distinct mechanisms. In addition, inhibition of PI3K, but not of p38 MAPK, strongly impaired IFN‐γ‐induced CIITA and MHC II gene expression. Finally, PKC‐α associated with signal transducer and activator of transcription 1 (STAT1) and was required for the phosphorylation of STAT1 on serine 727 in IFN‐γ‐stimulated macrophages. Taken together, our data indicate that PI3K and p38 MAPK modulate IFN‐γ‐stimulated PKC‐α nuclear translocation independently of JAK2 activity and that both PI3K and PKC‐α are required for type IV CIITA and MHC II gene expression in IFN‐γ‐stimulated macrophages.
Induction of allogeneic mixed chimerism by immature dendritic cells and bone marrow transplantation leads to prolonged tolerance to major histocompatibility complex disparate allografts
Authors: Yu Ping , Xiong Sidong , He Qiuzao , Chu Yiwei , Lu Chi , Ramlogan Charmaine A. , Steel Jason C.
Published: January 2009

Mixed chimerism has been shown to lead to prolonged major histocompatibility complex (MHC) disparate allograft survival and immune‐specific tolerance; however, traditional conditioning regimes often involve myeloablation, which may pose a significant safety risk. In this study we examined the use of donor C57BL/6 (H‐2b) immature dendritic cells (imDCs) to tolerize the BALB/c (H‐2d) recipient to bone marrow transplantation (BMT), allowing the induction of mixed chimerism without immunosuppression or myeloablation. We showed that successful mismatched bone marrow engraftment can be achieved using imDCs given up to 3 days prior to BMT and that mixed chimerism can be established and detected in excess of 100 days post‐BMT without evidence of graft‐versus‐host disease. Furthermore, we showed that imDCs can suppress lymphocyte proliferation in response to mismatched MHC stimulation, leading to increased expression of interleukin (IL)‐4 and IL‐10 and decreased expression of IL‐2 and interferon‐γ (IFN‐γ). The induction of stable chimeras through pre‐conditioning of mice with donor imDCs followed by BMT led to tolerance, allowing the long‐term survival (> 110 days) of mismatched cardiac allografts and the prolonged survival of mismatched skin allografts without the need for immunosuppression or myeloablation. Transplantation with third‐party C3H allografts were rapidly rejected in this model, suggesting that immune‐specific tolerance was achieved. The induction of immune‐specific tolerance without the need for immunosuppression or myeloablation represents a significant advance in transplant immunology and may provide clinicians with a plausible alternative in combating organ rejection following transplantation.
Following TRAIL’s path in the immune system
Authors: Falschlehner Christina , Schaefer Uta , Walczak Henning
Published: January 2009

The members of the tumour necrosis factor (TNF) superfamily of cytokines play important roles in the regulation of various immune‐cell functions. Likewise, induction of cell death by apoptosis is indispensable for the normal functioning of the immune system. There are two major pathways of apoptosis induction. The intrinsic, or mitochondrial, pathway is regulated by the activation and interaction of members of the Bcl‐2 family. The extrinsic, or death receptor, pathway is triggered by certain TNF family members when they engage their respective cognate receptors on the surface of the target cell. Hence, cell‐to‐cell‐mediated death signals are induced by activation of these death receptor–ligand systems. Besides TNF itself and the CD95 (Fas/APO‐1) ligand (FasL/Apo1L), the TNF‐related apoptosis‐inducing ligand (TRAIL/Apo2L) belongs to the subfamily of ligands that is responsible for extrinsic induction of cell death. Depending on their status of stimulation, TRAIL can be expressed by various cells of the immune system, amongst them natural killer (NK) cells, T cells, natural killer T cells (NKT cells), dendritic cells and macrophages. TRAIL has been implicated in immunosuppressive, immunoregulatory and immune‐effector functions. With respect to pathological challenges, TRAIL and its receptors have been shown to play important roles in the immune response to viral infections and in immune surveillance of tumours and metastases. In this review we summarize the current knowledge on the role of TRAIL and its receptors in the immune system and, based on this, we discuss future directions of research into the diverse functions of this fascinating receptor–ligand system.
Separating the influences of environment and species interactions on patterns of distribution and abundance: competition between large herbivores
Authors: Ritchie Euan G. , Martin Jennifer K. , Johnson Christopher N. , Fox Barry J.
Published: January 2009

Much recent research has focused on the use of species distribution models to explore the influence(s) of environment (predominantly climate) on species’ distributions. A weakness of this approach is that it typically does not consider effects of biotic interactions, including competition, on species’ distributions.

Here we identify and quantify the contribution of environmental factors relative to biotic factors (interspecific competition) to the distribution and abundance of three large, wide‐ranging herbivores, the antilopine wallaroo (Macropus antilopinus), common wallaroo (Macropus robustus) and eastern grey kangaroo (Macropus giganteus), across an extensive zone of sympatry in tropical northern Australia.

To assess the importance of competition relative to habitat features, we constructed models of abundance for each species incorporating habitat only and habitat + the abundance of the other species, and compared their respective likelihoods using Akaike's information criterion. We further assessed the importance of variables predicting abundance across models for each species.

The best‐supported models of antilopine wallaroo and eastern grey kangaroo abundance included both habitat and the abundance of the other species, providing evidence of interspecific competition. Contrastingly, models of common wallaroo abundance were largely influenced by climate and not the abundance of other species. The abundance of antilopine wallaroos was most influenced by water availability, eastern grey kangaroo abundance and the frequency of late season fires. The abundance of eastern grey kangaroos was most influenced by aspects of climate, antilopine wallaroo abundance and a measure of cattle abundance.

Our study demonstrates that where census and habitat data are available, it is possible to reveal species’ interactions (and measure their relative strength and direction) between large, mobile and/or widely‐distributed species for which competition is difficult to demonstrate experimentally. This allows discrimination of the influences of environmental factors and species interactions on species’ distributions, and should therefore improve the predictive power of species distribution models.
A novel statistical model for mandibular helical axis analysis
Authors: HAYASHI K. , REICH B. , DeLONG R. , LEE S.‐P. , MIZOGUCHI I.
Published: January 2009

Summary  The purpose of this study was to establish a new statistical method for the analysis of noisy mandibular helical axis parameters, especially the position vector of the finite helical axis (FHA). The subjects were children with anterior cross‐bite who had received orthodontic treatment. Maximum mouth‐opening was measured by means of an opto‐electronic motion analysis system. These movements were compared with similar movement in the same group after treatment of their anterior cross‐bite. Each curve of FHA position vectors was modelled as a spline function with random coefficients. To determine the optimal number of knots, two criteria were used: deviance information criteria (DIC) and mean squared prediction error (MSE). We were interested in estimating a typical curve for a population. Self‐modelling regression (SEMOR) was extended to three dimensions to model groups of three‐dimensional curves. Each curve was modelled as a spline function using nine knots. Population average curves were created using SEMOR. This study provided detailed information about jaw movement for comparing cross‐bite to normal occlusion by calculating the population mean curves of the position vector of the FHA. Our results suggested that the two population mean curves for the position vector of the FHA were significantly different in the closing phase. The combination of a spline function with random coefficients and SEMOR extended to three dimensions can be used not only for FHA analysis but also for the analysis of other jaw movements.
Evaluation of different occlusal splints and counselling in the management of myofascial pain dysfunction
Authors: ALENCAR JR F. , BECKER A.
Published: January 2009

Summary  The aim of this study was to compare the effectiveness of different occlusal splints associated with counselling and self‐care in the management of signs and symptoms of myofascial pain. In a double‐blind controlled clinical trial, 42 myofascial pain patients with chief complaint of pain in the masseter muscle area were randomly assigned to 1 of the 3 experimental groups: hard (HS), soft (SS) or non‐occluding (NS) occlusal splints. The Modified Symptom Severity Index (Mod‐SSI) and tenderness to palpation were used as outcome measures during a 90‐day follow‐up. All patients improved over time and all splints offered the benefit. The results showed that all the three different appliances (HS, SS, and NS) associated with counselling were able to equally reduce the Mod‐SSI (symptoms‐Tukey test) and digital palpation (signed Kruskal–Wallis) test between baseline and 90 days.
The CHAP domain of Cse functions as an endopeptidase that acts at mature septa to promote Streptococcus thermophilus cell separation
Authors: Layec Séverine , Gérard Joëlle , Legué Valérie , Chapot‐Chartier Marie‐Pierre , Courtin Pascal , Borges Frédéric , Decaris Bernard , Leblond‐Bourget Nathalie
Published: January 2009

Cell separation is dependent on cell wall hydrolases that cleave the peptidoglycan shared between daughter cells. In Streptococcus thermophilus, this step is performed by the Cse protein whose depletion resulted in the formation of extremely long chains of cells. Cse, a natural chimeric enzyme created by domain shuffling, carries at least two important domains for its activity: the LysM expected to be responsible for the cell wall‐binding and the CHAP domain predicted to contain the active centre. Accordingly, the localization of Cse on S. thermophilus cell surface has been undertaken by immunogold electron and immunofluorescence microscopies using of antibodies raised against the N‐terminal end of this protein. Immunolocalization shows the presence of the Cse protein at mature septa. Moreover, the CHAP domain of Cse exhibits a cell wall lytic activity in zymograms performed with cell walls of Micrococcus lysodeikticus, Bacillus subtilis and S. thermophilus. Additionally, RP‐HPLC analysis of muropeptides released from B. subtilis and S. thermophilus cell wall after digestion with the CHAP domain shows that Cse is an endopeptidase. Altogether, these results suggest that Cse is a cell wall hydrolase involved in daughter cell separation of S. thermophilus.
Strain measurement during antral contractions by ultrasound strain rate imaging: influence of erythromycin
Authors: Ahmed A. B. , Gilja O. H. , Hausken T. , Gregersen H. , Matre K.
Published: January 2009

Abstract  Strain rate imaging (SRI) is a non‐invasive ultrasound (US) modality that enables the study of mechanical deformation (strain) with high spatial and temporal resolution. A total of 244 contractions in seven healthy volunteers were studied by SRI on two separate days to characterize radial strain of antral contractions in the fasting and fed states and to assess the influence of intravenous erythromycin. Gastric accommodation and emptying were assessed by 2D ultrasonography. The perception of hunger was registered by the participants. The strain increased from early to late phase II and phase III activity by (median) 18%, 58% and 82%, respectively, P < 0.05. Erythromycin infusion in phase I induced contractions with median strain of 35%, but did not increase postprandial strain. Both fasting and postprandially, lumen‐occlusive contractions with erythromycin were more frequent than in naturally occurring contractions, 69%vs 48%, P = 0.036 and 40%vs 5%, P < 0.001 respectively. All subjects had rumbling in their abdomens when intraluminal air was detected sonographically (85% of all phase III contractions) and that rumbling was perceived by the participant as maximal awareness of hunger. SRI enabled detailed strain measurement of individual antral contractions. Erythromycin initiated fasting antral contractions and increased the number of lumen‐occlusive contractions.
Interstitial cells of Cajal contain signalling molecules for transduction of nitrergic stimulation in guinea pig caecum
Authors: Iino S. , Horiguchi K. , Nojyo Y. , Ward S. M. , Sanders K. M.
Published: January 2009

Abstract  Nitric oxide (NO) is an inhibitory signalling molecule in the gastrointestinal (GI) tract that is released from neurons and from leucocytes during inflammation. NO stimulates soluble guanylate cyclase (sGC), elevates cyclic guanosine 3′,5′‐monophospate (cGMP), and subsequently activates cGMP‐dependent protein kinase (PKG). Targets for NO in the guinea pig caecum were investigated by characterizing the cellular distribution of sGC, cGMP and PKG. Immunoreactivity for both isoforms of sGC, sGCα1 and sGCβ1, was observed in the interstitial cells of Cajal (ICC) and enteric neurons in the tunica muscularis. Double labelling with anti‐Kit and anti‐sGC antibodies showed sGCα1 and sGCβ1‐like immunoreactivity (LI) in almost all intramuscular (IM) and myenteric ICC. Neuronal processes with neuronal NO synthase were closely apposed to ICC expressing sGC‐LI. Cells with sGC‐LI possessed ultrastructural features of ICC‐IM: caveolae, close association with nerve bundles and contacts with smooth muscle cells (SMC). Sodium nitroprusside, added with the phosphodiesterase inhibitors (3‐isobutyl‐1‐methylxanthine and zaprinast), enhanced cGMP‐LI in almost all ICC and in some enteric neurons. Nerve stimulation also increased cGMP‐LI in ICC and enteric neurons. In contrast, no resolvable increase in cGMP‐LI was observed in any cells when the sGC inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one was present. ICC and SMC also expressed PKG type I‐LI. These data show that ICC express the downstream signalling molecules necessary to transduce nitrergic signals and activate inhibitory pathways and thus are primary targets for NO released from neurons and other cells in the GI tract.
Genetic model system studies of the development of the enteric nervous system, gut motility and Hirschsprung’s disease
Authors: Burzynski G. , Shepherd I. T. , Enomoto H.
Published: January 2009

Abstract  The enteric nervous system (ENS) is the largest and most complicated subdivision of the peripheral nervous system. Its action is necessary to regulate many of the functions of the gastrointestinal tract including its motility. Whilst the ENS has been studied extensively by developmental biologists, neuroscientists and physiologists for several decades it has only been since the early 1990s that the molecular and genetic basis of ENS development has begun to emerge. Central to this understanding has been the use of genetic model organisms. In this article, we will discuss recent advances that have been achieved using both mouse and zebrafish model genetic systems that have led to new insights into ENS development and the genetic basis of Hirschsprung’s disease.
Neural stem cell transplantation in the enteric nervous system: roadmaps and roadblocks
Authors: Schäfer K.‐h. , Micci M.‐a. , Pasricha P. J.
Published: January 2009

Abstract  The enteric nervous system (ENS) is vulnerable to a variety of genetic, metabolic or environmental threats, resulting in clinical disorders characterized by loss or malfunction of neuronal elements. These disorders have been difficult to treat and there is much enthusiasm for novel therapies such as neural stem cell (NSC) transplantation to restore ENS function in diseased segments of the gut. Recent research has indicated the potential for a variety of innovative approaches to this effect using NSC obtained from the central nervous system (CNS) as well as gut derived enteric neuronal progenitors. The main goal of this review is to summarize the current status of NSC research as it applies to the ENS, delineate a roadmap for effective therapeutic strategies using NSC transplantation and point out the numerous challenges that lie ahead.
Choosing the types of biological sample to collect in longitudinal birth cohort studies
Authors: Jones Richard , Golding Jean
Published: January 2009

There are a variety of biological samples that can be collected from participants in longitudinal studies. Here we outline those that are particularly useful in longitudinal birth cohort studies starting in pregnancy, and discuss their advantages and disadvantages.
Challenge and co‐operation: civil society activism for access to HIV treatment in Thailand
Authors: Ford Nathan , Wilson David , Cawthorne Paul , Kumphitak Aree , Kasi‐Sedapan Siriras , Kaetkaew Suntharaporn , Teemanka Saengsri , Donmon Boripat , Preuanbuapan Chalerm
Published: January 2009

Civil society has been a driving force behind efforts to increase access to treatment in Thailand. A focus on HIV medicines brought civil society and non‐governmental and government actors together to fight for a single cause, creating a platform for joint action on practical issues to improve care for people with HIV/AIDS (PHA) within the public health system. The Thai Network of People with HIV/AIDS, in partnership with other actors, has provided concrete support for patients and for the health system as a whole; its efforts have contributed significantly to the availability of affordable generic medicines, early treatment for opportunistic infections, and an informed and responsible approach towards antiretroviral treatment that is critical to good adherence and treatment success. This change in perception of PHA from ‘passive receiver’ to ‘co‐provider’ of health care has led to improved acceptance and support within the healthcare system. Today, most PHA in Thailand can access treatment, and efforts have shifted to supporting care for excluded populations.
Sex‐linked deafness
Authors: Petersen MB , Wang Q , Willems PJ
Published: January 2009

Many human syndromes associated with hearing loss are caused by disease genes located on the X chromosome, but few X‐linked loci for non‐syndromic hearing loss have been reported. Surprisingly, a Y‐linked locus has been identified, representing one of the only disease loci on the Y chromosome. This study reviews the different sex‐linked genes and loci on the X‐ and Y chromosome leading to syndromic and especially non‐syndromic hearing loss.
Haplogroup analysis supports a pathogenic role for the 7510T>C mutation of mitochondrial tRNASer(UCN) in sensorineural hearing loss
Authors: Labay V , Garrido G , Madeo AC , Nance WE , Friedman TB , Friedman PL , Del Castillo I , Griffith AJ
Published: January 2009

We ascertained a large North American family, LMG309, with matrilineal transmission of non‐syndromic, progressive sensorineural hearing loss (SNHL). There was no history of aminoglycoside exposure, and penetrance was complete. We sequenced the entire mitochondrial genome and identified the previously reported 7510T>C transition in the tRNASer(UCN) gene. The 7510T>C was homoplasmic in all affected members. The LMG309 mitochondrial sequence belongs to an unnamed subgroup of mitochondrial haplogroup H. We demonstrate that the previously reported Spanish family S258 carries 7510T>C on a different mitochondrial sub‐haplogroup, H1. We did not detect 7510T>C among 79 Caucasian haplogroup H control samples, including 11 from sub‐haplogroup H1 and one from the same sub‐haplogroup as LMG309. Our results provide strong genetic evidence that 7510T>C is a pathogenic mutation that causes non‐syndromic SNHL.
Pediatric restrictive cardiomyopathy associated with a mutation in β‐myosin heavy chain
Authors: Ware SM , Quinn ME , Ballard ET , Miller E , Uzark K , Spicer RL
Published: January 2009

Most children do not have a known cause of cardiomyopathy which limits the potential for disease‐specific therapies. Of the different phenotypic presentations of cardiomyopathy, the restrictive form carries the poorest prognosis and has the lowest rate of identification of etiology. We present the first description of a β‐myosin heavy chain gene mutation in an infant with restrictive cardiomyopathy requiring cardiac transplantation. As demonstrated by three‐dimensional protein structure modeling, the missense mutation is in a highly conserved amino acid at the critical binding region for the essential light chain. This case emphasizes that mutations in sarcomeric proteins, which are known to cause hypertrophic cardiomyopathy in adults, may be associated with the development of restrictive physiology in childhood. Identification of the genetic basis of pediatric cardiomyopathy has important implications for management and genetic counseling.
Genetic polymorphisms of matrix metalloproteinases in lung, breast and colorectal cancer
Authors: Decock J , Paridaens R , Ye S
Published: January 2009

The matrix metalloproteinases (MMPs) can degrade various components of the extracellular matrix and are implicated in the development and progression of cancer. There is evidence suggesting an association of MMP gene polymorphisms with cancer susceptibility and/or metastasis. This paper reviews the findings on several single nucleotide polymorphisms in the collagenase, stromelysin and gelatinase genes in lung cancer, breast cancer and colorectal cancer.
Predictors of psychological distress among individuals with a strong family history of malignant melanoma
Authors: Kasparian NA , Meiser B , Butow PN , Simpson JM , Mann GJ
Published: January 2009

Despite rapid advancements in molecular genetics research, little is known about the psychological experiences of individuals with a family history of melanoma. The present study aimed to identify factors contributing to psychological distress among affected and unaffected individuals with a strong family history of melanoma. A total of 121 adults who had recently been informed of the identification of a family‐specific mutation in the CDKN2A melanoma susceptibility gene, completed a self‐report questionnaire assessing cancer‐specific and generalized distress, and a variety of potential predictors. Having a personal history of melanoma (OR = 3.37, p = 0.033), perceiving greater family implications of melanoma (OR = 2.52, p < 0.0001), and the tendency to monitor for threatening information (OR = 3.12, p = 0.008) were associated with melanoma‐specific distress. Being childless (β = 2.09, p = 0.007), perceiving sun exposure as an important cause of melanoma (β = 1.15, p = 0.015), and perceiving greater family implications of melanoma (β = 1.02, p = 0.002) were associated with greater generalized anxiety, while monitoring moderated the relationship between endorsement of a genetic model of melanoma and generalized anxiety (p = 0.005). As in other common familial cancers, distress was relatively uncommon in this familial melanoma cohort, even after notification of the presence of a family mutation. Participants do not contemplate their melanoma risk in isolation, but evaluate their risk vis‐à‐vis the experiences of their relatives.
Novel mutations of the ferroportin gene (SLC40A1): analysis of 56 consecutive patients with unexplained iron overload
Authors: Pelucchi S , Mariani R , Salvioni A , Bonfadini S , Riva A , Bertola F , Trombini P , Piperno A
Published: January 2009

The aim of this study was to search for SLC40A1 mutations in iron overloaded patients, which tested negative for HFE mutations and other iron‐related genes. After a careful differential diagnosis, we selected 56 patients with unexplained iron overload whose phenotype could suggest the ferroportin disease. Iron overload was assessed by liver biopsy or by superconducting quantum interference device. SLC40A1 exons and intron–exon boundaries were amplified by polymerase chain reaction and sequenced. We also evaluated the presence of the insulin‐resistance hepatic iron overload and of non‐alcoholic fatty liver disease. Iron status was assessed in 44 families. We identified two novel mutations (D157N and V72F) at the heterozygous state in two probands. Phenotype heterogeneity was observed in both families, suggesting variable penetrance and expression. Including the two affected ones, 25 of the 44 families (57%) available for the iron study had one or more relatives with increased serum iron indices. Our findings not only suggest that the presence of major alterations of serum iron parameters in probands’ relatives is a main criteria to improve the power of the genetic testing for ferroportin disease but also indicate that a number of patients exists in which the etiology of iron overload remains still undefined.
Molecular analysis of mucopolysaccharidosis type IIIB in Portugal: evidence of a single origin for a common mutation (R234C) in the Iberian Peninsula
Authors: Mangas M , Nogueira C , Prata MJ , Lacerda L , Coll MJ , Soares G , Ribeiro G , Amaral O , Ferreira C , Alves C , Coutinho MF , Alves S
Published: January 2009

Mucopolysaccharidosis type IIIB (Sanfilippo B disease) is a rare autosomal recessive disorder caused by defective α‐N‐acetylglucosaminidase (NAGLU). We examined the NAGLU gene in 11 MPS IIIB Portuguese patients, having identified five novel (M1K, W147X, G304V, S522P, and R533X) and four previously reported mutations (W168X, R234C, R565W and R643C). R234C attained the high prevalence of 32% of the mutated alleles. Because R234C had already been reported to be common in Spanish patients, a haplotypic analysis was conducted to address the question of its origin in the Iberian Peninsula. Three neutral markers were studied that allowed for the identification of the probable founder haplotype (174‐234‐G) on which R234C arose. The sharing of the ancestral haplotype by Portuguese and Spanish patients clearly implied a common origin of the mutation in Iberia, through an event that was inferred to have been rather recent. Therefore, the reconstructed history of R234C explains the high incidence of the mutation in Iberian patients with Sanfilippo B disease.
ATM, an unexpected new target in metabolic syndrome
Authors: Kruit JK
Published: January 2009

ATM‐dependent suppression of stress signaling reduces vascular disease in metabolic syndrome Schneider et al. (2006) Cell Metabolism: 4 (5): 377–389
Genotype–phenotype correlation in five Pelizaeus–Merzbacher disease patients with PLP1 gene duplications
Authors: Regis S , Biancheri R , Bertini E , Burlina A , Lualdi S , Bianco MG , Devescovi R , Rossi A , Uziel G , Filocamo M
Published: January 2009

Pelizaeus–Merzbacher disease (PMD) is an X‐linked myelination disorder most frequently caused by duplication of a genomic segment of variable length containing the PLP1 gene. We studied five PMD male patients affected by the classic PMD form carrying a PLP1 gene duplication. On the basis of clinical and neuroradiological features, two of the five patients appeared to be the most severely affected. In order to establish a possible genotype–phenotype correlation, the extent of the duplication was determined in each patient and in the respective mother by quantifying the copy number of genomic markers surrounding the PLP1 gene by a real‐time PCR‐based approach. Duplications, ranging in size from 167–195 to 580–700 kb, were in the same genomic interval of the majority of the reported duplications. The extent of the duplicated genomic segments does not correlate with the clinical severity. Interestingly enough, each duplication had one of the two breakpoints in or near to low copy repeats (LCRs), supporting recent evidence concerning a possible role of LCRs in the generation of the duplications in PMD.
Genetic modifiers of ataxin‐3‐mediated neurodegeneration: approaching protein misfolding from different angles
Authors: Ehrnhoefer DE
Published: January 2009

Genome‐wide screen for modifiers of ataxin‐3 neurodegeneration in Drosophila Bilen et al. (2007) PLoS Genetics 3: 1950–1963
A new function of TFIIH explains the neurological symptoms in trichothiodystrophy
Authors: Ehrnhoefer DE
Published: January 2009

Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH Compe et al. (2007) Nature Neuroscience 10: 1414–1422
Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies
Authors: Bernal S , Solans T , Gamundi MJ , Hernan I , De Jorge L , Carballo M , Navarro R , Tizzano E , Ayuso C , Baiget M
Published: January 2009

The nuclear receptor protein NR2E3 is postulated to play an important role in rod and cone photoreceptor development. NR2E3 gene mutational analyses were carried out in 103 unrelated subjects with different retinal diseases. A total of 14 different sequence variants were identified, including 3 mutations, 6 rare sequence variants and five polymorphisms. One of three mutations is novel (a frameshift mutation: c.1034_1038del5bp). Five of the six rare sequence variants and one of the polymorphisms identified are novel. Splice prediction programs and functional splicing assays were performed to study three of these variants. The c.119‐2 A>C mutant allele construction produces, in addition to the normal one, an abnormal transcript of 180 bp resulting from an aberrant splicing with skipping of exon 2 and the generation of a premature stop codon in exon 3. These experimental data confirm the splice predictions made by the computer programs. The obtained results reinforce the idea that NR2E3 gene is involved in several retinal diseases without a clear genotype–phenotype correlation.
A locus for autosomal dominant progressive non‐syndromic hearing loss, DFNA27, is on chromosome 4q12‐13.1
Authors: Peters LM , Fridell RA , Boger ET , San Agustin TB , Madeo AC , Griffith AJ , Friedman TB , Morell RJ
Published: January 2009

We ascertained a large North American family, LMG2, segregating progressive, non‐syndromic, sensorineural hearing loss. A genome‐wide scan identified significant evidence for linkage (maximum logarithm of the odds (LOD) score = 4.67 at θ = 0 for D4S398) to markers in a 5.7‐cM interval on chromosome 4q12‐13.1. The DFNA27 interval spans 8.85 Mb and includes at least 61 predicted and 8 known genes. We sequenced eight genes and excluded them as candidates for the DFNA27 gene.
Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia
Authors: Shoukier M , Teske U , Weise A , Engel W , Argyriou L
Published: January 2009

Using quantitative real‐time polymerase chain reaction (QRT‐PCR), molecular genetic analysis was carried out for endoglin (ENG) and activin A receptor type II‐like kinase 1 (ACVRL1/ALK1) gene rearrangements in a group of 45 clinically confirmed hereditary haemorrhagic telangiectasia (HHT) families with negative direct sequencing results. We detected five large novel deletions, four in the ALK1 gene and one in the ENG gene. In two families, the whole ALK1 gene was deleted. One of these two deletions spanned at least 216 kb and included five neighbouring genes (LOC728503, ANKRD33, ACVR1B, GRASP, and NR4A1). The lack of additional symptoms in the patient carrying this large deletion indicates that heterozygous loss of these five genes has no obvious phenotypical effect. To our knowledge, this is the first report on whole ALK1 gene deletions in HHT patients. We rescreened our 45 families for large rearrangements using the multiplex ligation‐dependent probe amplification (MLPA) method. No discrepancies between the results of QRT‐PCR and MLPA were found. Our present work proves QRT‐PCR as a reliable and sensitive method. Thus, our study supports that screening for large rearrangements should be considered to improve the genetic analysis in HHT patients with no apparent mutations in ALK1 and ENG using direct sequencing.
FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus
Authors: Amorosi S , D’Armiento M , Calcagno G , Russo I , Adriani M , Christiano AM , Weiner L , Brissette JL , Pignata C
Published: January 2009

The forkhead, Fox, gene family comprises a diverse group of ‘winged‐helix’ transcription factors that play important roles in development, metabolism, cancer and aging. Recently, several forkhead genes have been demonstrated to play critical roles in lymphocyte development and effector functions. Alterations of the FOXN1 gene in both mice and humans result in a severe combined immunodeficiency caused by an intrinsic defect of the thymus associated with congenital alopecia (Nude/severe combined immunodeficiency phenotype). FOXN1 is a member of the class of proteins involved in the development and differentiation of the central nervous system. We identified a human fetus homozygous for a mutation in FOXN1 gene who lacked the thymus and also had abnormal skin, anencephaly and spina bifida. Moreover, we found that FOXN1 gene is expressed in mouse developing choroid plexus. These observations suggest that FOXN1 may be involved in neurulation in humans.
DNA methylation and mental retardation
Authors: Grant ME
Published: January 2009

Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation Nan et al. (2007) Proc Natl Acad Sci U S A 104: 2709–2714

Structural consequences of disease‐causing mutations in the ATRX‐DNMT3‐DNMTL (ADD) domain of the chromatin‐associated protein ATRX Argentaro et al. (2007) Proc Natl Acad Sci U S A 104: 11939–11944
Gene dosage imbalances in patients with 46,XY gonadal DSD detected by an in‐house‐designed synthetic probe set for multiplex ligation‐dependent probe amplification analysis
Authors: Barbaro M , Cicognani A , Balsamo A , Löfgren Å , Baldazzi L , Wedell A , Oscarson M
Published: January 2009

The development of a testis requires the proper spatiotemporal expression of the SRY gene and other genes that act in a dosage‐sensitive manner. Mutations in the SRY gene account for only 10–15% of patients with 46,XY gonadal disorder of sex development (DSD). To enable the diagnostics of deletions and duplications of genes known to be involved in different forms of DSD, we developed a synthetic probe set for multiplex ligation‐dependent probe amplification (MLPA) analysis. Here, we report the results from the analysis of 22 patients with 46,XY gonadal DSD. The analysis with the DSD probe set has led to the identification of two copy number variations, an 800‐kb NR0B1 (DAX1) locus duplication on Xp21 in a patient with isolated partial gonadal dysgenesis and a duplication of the SRD5A2 gene that represents a rare normal variant. The described MLPA kit represents an optimal complement to DNA sequence analysis in patients with DSD, enabling screening for deletions and duplications of several genes simultaneously. Furthermore, the second identification of an NR0B1 locus duplication in a patient with isolated gonadal dysgenesis, without dysmorphic features and/or mental retardation, highlights the importance of evaluating NR0B1 duplication in patients with gonadal dysgenesis.
Inclusion body myopathy, Paget’s disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling
Authors: Viassolo V , Previtali SC , Schiatti E , Magnani G , Minetti C , Zara F , Grasso M , Dagna‐Bricarelli F , Di Maria E
Published: January 2009

The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget’s disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult‐onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline.
Family history as a predictor of uptake of cancer preventive procedures by women with a BRCA1 or BRCA2 mutation
Authors: Metcalfe KA , Foulkes WD , Kim‐Sing C , Ainsworth P , Rosen B , Armel S , Poll A , Eisen A , Gilchrist D , Chudley A , Ghadirian P , Maugard C , Lemire EG , Sun P , Narod SA
Published: January 2009

Women with a BRCA1 or BRCA2 mutation are at an elevated risk of developing breast and ovarian cancer; however, it is unclear to what extent family history influences the uptake of cancer prevention options.Women with a BRCA1/2 mutation completed a follow‐up questionnaire that assessed uptake of cancer preventive options. The pedigree of each woman was reviewed, and information was recorded on cancers diagnosed in relatives. Five hundred and seventeen women were included in the study. Women with a sister with breast cancer were more likely to have a prophylactic mastectomy than those without a sister with breast cancer [odds ratios (OR) = 2.4, p = 0.003]. Uptake of prophylactic mastectomy was significantly lower in women with a mother with ovarian cancer compared with those whose mother did not have ovarian cancer (OR = 0.4, p = 0.01). Having a mother or sister with ovarian cancer significantly predicted the uptake of prophylactic oophorectomy (OR = 1.6, p = 0.04). Women with a BRCA2 mutation were less likely to have a prophylactic oophorectomy than those with a BRCA1 mutation (OR = 0.49, p = 0.0004). Among women with a BRCA1 or BRCA2 mutation, family history predicts the uptake of prophylactic mastectomy and prophylactic oophorectomy.
Sugar coats on proteins, not always as sweet as they sound!
Authors: Kremer PHC
Published: January 2009

Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+‐ATPase subunit ATP6V0A2 Kornak et al. (2008) Nature Genetics 40: 32–34
Cytogenetic and molecular characterization of a three‐generation family with chromosome 5p terminal deletion
Authors: Fang J‐S , Lee K‐F , Huang C‐T , Syu C‐L , Yang K‐J , Wang L‐H , Liao D‐L , Chen C‐H
Published: January 2009

Terminal or interstitial deletion on the short arm of chromosome 5 is associated with a genetic disorder, cri‐du‐chat syndrome (cat cry syndrome), which is characterized by a cat‐like cry in infancy, facial dysmorphism, microcephaly, and mental retardation. There is a high degree of variation in clinical presentations of patients with cri‐du‐chat syndrome, which is usually associated with different sizes and locations of deletions in chromosome 5p. Most patients with a 5p deletion havede novomutations; familial 5p deletion is rare in literature. Here, we report a three‐generation family with a 5p terminal deletion. The terminal 5p deletion (5p15.2‐pter) in this family was confirmed and characterized by karyotyping analysis, fluorescentin situhybridization, array comparative genome hybridization, and quantitative polymerase chain reaction. Although the affected family members apparently share deletions of the same size, there are some variations in mental symptoms within this family. Two affected females manifest moderate mental retardation and psychotic symptoms such as delusion of persecution, auditory hallucination, self‐talking, and self‐laughing, which are rare in cri‐du‐chat syndrome. In contrast, the other three affected males express mild‐to‐moderate mental retardation but no psychotic symptoms. Our study suggests that other factors besides the size and location of 5p deletions may modify the mental presentations of patients with 5p deletions.
Genetic factors in congenital heart malformation
Authors: Andelfinger G
Published: January 2009

Congenital heart disease is the commonest malformation in humans and contributes greatly to the burden of disease in infancy. Increasingly, developmental origins are also implicated in heart disease in adults. Significant advances have been made over the past decade in elucidating morphogenetic events of heart formation and their underlying molecular cascades, mostly in animal models. Clinical studies are increasingly successful in quantifying and unraveling genetic factors. This review focuses on recent progress made in understanding the genetic underpinnings of normal and abnormal heart formation and highlights the importance of understanding these mechanisms to improve patient management.