bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia
Authors: Brakensiek K , Frye‐Boukhriss H , Mälzer M , Abramowicz M , Bahr MJ , Von Beckerath N , Bergmann C , Caselitz M , Holinski‐Feder E , Muschke P , Oexle K , Strobl‐Wildemann G , Wolff G , El‐Harith EA , Stuhrmann M
Published: January 2009

Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II‐like 1 gene (ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT (ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease.
Increased release and activity of matrix metalloproteinase‐9 in patients with mandibuloacral dysplasia type A, a rare premature ageing syndrome
Authors: Lombardi F , Fasciglione GF , D’Apice MR , Vielle A , D’Adamo M , Sbraccia P , Marini S , Borgiani P , Coletta M , Novelli G
Published: January 2009

Mandibuloacral dysplasia type A (MADA; OMIM 248370), a rare disorder caused by mutation in theLMNAgene, is characterized by post‐natal growth retardation, craniofacial and skeletal anomalies (mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, low bone mass and joint contractures), cutaneous changes and partial lipodystrophy. Little is known about the molecular mechanisms by whichLMNAmutations produce bone alterations. An altered bone extracellular matrix (ECM) remodelling could play a pivotal role in this disorder and influence part of the typical bone phenotype observed in patients. Therefore, we have focused our investigation on matrix metalloproteinases (MMPs), which are degradative enzymes involved in ECM degradation and ECM remodelling, thus likely contributing to the altered bone mineral density and bone metabolism values seen in five MADA patients. We evaluated the serum levels of several MMPs involved in bone development, remodelling and homeostasis, such as MMP‐9, ‐2, ‐3, ‐8 and ‐13, and found that only the 82 kDa active enzyme forms of MMP‐9 are significantly higher in MADA sera compared with healthy controls (n = 16). The serum level of MMP‐3 was instead lower in all patients. No significant differences were observed between controls and MADA patients for the serum levels of MMP‐2, ‐8 and ‐13 and of tissue inhibitor of metalloproteinase 2, a natural inhibitor of MMP‐9. Similarly, normal serum levels of tumour necrosis factor alpha (TNF‐α), interleukin (IL)‐6 and IL‐1β were detected. These data suggest a possible involvement of MMP‐9 in MADA disease, underlying the potential use in diagnosis and therapy.
USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22‐23
Authors: Ahmed ZM , Riazuddin S , Khan SN , Friedman PL , Riazuddin S , Friedman TB
Published: January 2009

Usher syndrome (USH) is a hereditary disorder associated with sensorineural hearing impairment, progressive loss of vision attributable to retinitis pigmentosa (RP) and variable vestibular function. Three clinical types have been described with type I (USH1) being the most severe. To date, six USH1 loci have been reported. We ascertained two large Pakistani consanguineous families segregating profound hearing loss, vestibular dysfunction, and RP, the defining features of USH1. In these families, we excluded linkage of USH to the 11 known USH loci and subsequently performed a genome‐wide linkage screen. We found a novel USH1 locus designated USH1H that mapped to chromosome 15q22‐23 in a 4.92‐cM interval. This locus overlaps the non‐syndromic deafness locus DFNB48 raising the possibility that the two disorders may be caused by allelic mutations.
Laminopathies in Russian families
Authors: Rudenskaya GE , Polyakov AV , Tverskaya SM , Zaklyazminskaya EV , Chukhrova AL , Groznova OE , Ginter EK
Published: January 2009

Mutations in LMNA gene produce a wide spectrum of disorders called laminopathies. In this article, the first cases of laminopathies from Russia are reported. In 10 unrelated families, 9 different mutations were identified: Asp47His, Gly232Arg, c.[781_783delAAG, 781insGTGGAGCAGTATAAGAAA], Arg249Gln (in two families), Arg377His, Arg541His, Ala350Pro, Leu52Pro, and Gly635Asp. Mutations Arg249Gln, Arg377His, and Arg541His were reported previously, others are novel. Four cases present de novo mutations, among them two cases with Arg249Gln are found. Because this mutation occurred de novo also in other reported cases, a mutational ‘hot spot’ was supposed. Three phenotypes were observed: autosomal dominant (AD) Emery–Dreifuss muscular dystrophy (EDMD), limb‐girdle MD type 1B, and AD dilated cardiomyopathy with conduction defect type 1A (DCM1A). Atypical clinical presentations were a very severe EDMD and an infantile DCM1A.
Triangular tibia with fibular aplasia associated with a microdeletion on 2q11.2 encompassing LAF4
Authors: Steichen‐Gersdorf E , Gaßner I , Superti‐Furga A , Ullmann R , Stricker S , Klopocki E , Mundlos S
Published: January 2009

Nievergelt syndrome (NS) is an autosomal dominant mesomelic dysplasia characterized by specific deformities of the radius, ulna, fibula and a rhomboid shape of the tibia. Phenotypically overlapping conditions such as mesomelic dysplasia, Savarirayan‐type (MIM 605274), have been described, but their pathogenesis also remains unknown. We report on a girl with fibular agenesis, severely abnormal, triangular tibiae, urogenital tract malformations, failure to thrive, convulsions and recurrent apnoeas leading to respiratory arrest at the age of 4 months. Her skeletal findings correspond to those of the mesomelic dysplasia, Savarirayan‐type recently described in two patients. In addition to the skeletal findings, our patient had central nervous system manifestations and developmental anomalies of the urogenital tract. In the patient described in this study, array comparative genomic hybridization (CGH) analysis revealed a de novo interstitial microdeletion of 500 kb on chromosome 2q11.1 containing the LAF4/AFF3 (lymphoid‐nuclear‐protein‐related AF4) gene. In situ hybridization analysis of Laf4 in mouse embryos revealed expression in the developing brain, in the limb buds and in the zeugopod corresponding to the limb phenotype. Haploinsufficiency for LAF4/AFF3 is associated with limb, brain and urogenital malformations and specific changes of the tibia that are part of the NS spectrum.
MLPA and cDNA analysis improves COL4A5 mutation detection in X‐linked Alport syndrome
Authors: Hertz JM , Juncker I , Marcussen N
Published: January 2009

The X‐linked form of Alport syndrome (AS) is caused by mutations in the COL4A5 gene encoding the α5 chain of type IV collagen. Most COL4A5 mutations are individual, and mutation analysis is complicated by the size of the gene and the number of exons. Larger structural rearrangements account for 10–15% of mutations. We have established a method for mutation analysis of COL4A5 based on reverse transcriptase‐polymerase chain reaction analysis of mRNA from cultured skin fibroblasts and multiplex ligation‐dependent probe amplification (MLPA) on genomic DNA. One advantage of using skin biopsies for the mRNA analysis is the possibility of immunohistochemical staining for the α5(IV) chain on skin sections to support a diagnosis of X‐linked AS. A mutation was detected in all five cases included. One patient presenting with AS and diffuse leiomyomatosis was found to have a COL4A5 deletion extending into and comprising COL4A6 exons 1, 1′, and 2. We have evaluated the MLPA assay on samples from 67 previously tested AS patients (45 males and 22 females) and 20 controls. We found that the combination of cDNA and MLPA analysis improves the mutation detection rate in COL4A5 and that MLPA should be the first step in genetic testing for X‐linked AS.
The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland
Authors: Moore SJ , Buckley DJ , MacMillan A , Marshall HD , Steele L , Ray PN , Nawaz Z , Baskin B , Frecker M , Carr SM , Ives E , Parfrey PS
Published: January 2009

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty‐two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world.
Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology
Authors: Menon SC , Michels VV , Pellikka PA , Ballew JD , Karst ML , Herron KJ , Nelson SM , Rodeheffer RJ , Olson TM
Published: January 2009

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non‐obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non‐specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.
LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients
Authors: Oliveira J , Santos R , Soares‐Silva I , Jorge P , Vieira E , Oliveira ME , Moreira A , Coelho T , Ferreira JC , Fonseca MJ , Barbosa C , Prats J , Aríztegui ML , Martins ML , Moreno T , Heinimann K , Barbot C , Pascual‐Pascual SI , Cabral A , Fineza I , Santos M , Bronze‐da‐Rocha E
Published: January 2009

Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin‐α2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin‐α2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750‐1713_7899‐2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin‐α2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.
Confirmation of RAX gene involvement in human anophthalmia
Authors: Lequeux L , Rio M , Vigouroux A , Titeux M , Etchevers H , Malecaze F , Chassaing N , Calvas P
Published: January 2009

Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. Mutations in several genes have been involved in syndromic and non‐syndromic anophthalmia. Previously, RAX recessive mutations were implicated in a single patient with right anophthalmia, left microphthalmia and sclerocornea. In this study, we report the findings of novel compound heterozygous RAX mutations in a child with bilateral anophthalmia. Both mutations are located in exon 3. c.664delT is a frameshifting deletion predicted to introduce a premature stop codon (p.Ser222ArgfsX62), and c.909C>G is a nonsense mutation with similar consequences (p.Tyr303X). This is the second report of a patient with anophthalmia caused by RAX mutations. These findings confirm that RAX plays a major role in the early stages of eye development and is involved in human anophthalmia.
Spectrum of novel mutations in the human PKLR gene in pyruvate kinase‐deficient Indian patients with heterogeneous clinical phenotypes
Authors: Kedar P , Hamada T , Warang P , Nadkarni A , Shimizu K , Fujji H , Ghosh K , Kanno H , Colah R
Published: January 2009

Eighteen unrelated pyruvate kinase (PK)‐deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion‐dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G>A, 499C>A, 1072G>A, 1180G>T, 1216G>A, 1220A>G, 644delG, IVS5 (+20) C>A, IVS9 (+44) C>T, and IVS9 (+93) A>C. A severe syndrome was commonly associated with some mutations, 992A>G, 1436G>A, 1220A>G, 644delG and IVS9 (+93) A>C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6‐diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G>A and 1219G>A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G>A (19.44%), followed by 1456C>T (16.66%) and 992A>G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non‐spherocytic haemolytic anaemia were identified.
Ghosal syndrome – genetics unveiled
Authors: Stein RA
Published: January 2009

Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome) Geneviève et al. (2008) Nature Genetics 40(3):284–286
The genetic basis of uric acid variance
Authors: Stein RA
Published: January 2009

SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout Vitart et al. (2008) Nature Genetics 40(4): 437–442

SLC2A9 influences uric acid concentrations with pronounced sex‐specific effects Döring et al. (2008) Nature Genetics 40(4): 430–436
Promoting ectopic pancreatic fates: pancreas development and future diabetes therapies
Authors: Pearl EJ , Horb ME
Published: January 2009

Diabetes is a disease that could be treated more effectively with a better understanding of pancreas development. This review examines the role of master regulator genes driving crucial steps in pancreas development, from foregut specification to differentiation of the five endocrine cell types. The roles of Pdx1, Ptf1a, and Ngn3 are particularly examined as they are both necessary and sufficient for promoting pancreatic cell fates (Pdx1, Ptf1a) and endocrine cell development (Ngn3). The roles of Arx and Pax4 are studied as they compose part of the regulatory mechanism balancing development of different types of endocrine cells within the iselts and promote the development of α/PP and β/δ cell progenitors, respectively. The roles of the aforementioned genes, and the consequences of misexpression of them for functionality of the pancreas, are examined through recent studies in model organisms, particularly Xenopus and zebrafish. Recent developments in cell replacement therapy research are also covered, concentrating on stem cell research (coaxing both adult and embryonic stem cells toward a β cell fate) and transdifferentiation (generating β cells from other differentiated cell types).
Search for genomic imbalances in a cohort of 24 Cornelia de Lange patients negative for mutations in the NIPBL and SMC1L1 genes
Authors: Gervasini C , Pfundt R , Castronovo P , Russo S , Roversi G , Masciadri M , Milani D , Zampino G , Selicorni A , Schoenmakers EFPM , Larizza L
Published: January 2009

Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by varied clinical signs including facial dysmorphism, pre‐ and post‐natal growth defects, small hands and malformations of the upper limbs. Established genetic causes include mutations in the NIPBL (50–60%), SMC1L1 and SMC3 (5%) genes. To detect chromosomal rearrangements pointing to novel positional candidate CdLS genes, we used array‐CGH to analyze a subgroup of 24 CdLS patients negative for mutations in the NIPBL and SMC1L1 genes. We identified three carriers of DNA copy number alterations, including a de novo 15q26.2‐qter 8‐Mb deletion, and two inherited 13q14.2‐q14.3 1‐Mb deletion and 13q21.32‐q21.33 1.5‐Mb duplication, not reported among copy number variants. The clinical presentation of all three patients matched the diagnostic criteria for CdLS, and the phenotype of the patient with the 15qter deletion is compared to that of both CdLS and 15qter microdeletion patients.
Adaptation to living with a genetic condition or risk: a mini‐review
Authors: Biesecker BB , Erby L
Published: January 2009

One goal of genetic counseling is to facilitate client adaptation to a genetic condition or risk. Adaptation refers to both the process of coming to terms with the implications of the condition or risk and the observable outcomes of that process. This review summarizes existing studies on how well clients adapt to living with a common chronic disease, and more specifically, a genetic condition. Overall, it appears that about one‐third of clients do not adjust well to the stress of living with a genetic condition or at risk. However, the data are limited by inconsistencies in the conceptualization of adaptation, a paucity of theoretical models, poor study design and inadequate outcome measures. Well‐designed studies based upon multidimensional models are needed that focus on familial as well as individual adaptation. We conclude with a summary of studies that have explored the use of interventions to enhance adaptation and suggest improved client outcomes. Further research should result in evidence‐based interventions to facilitate client adaptation that can be used effectively by genetic providers within the confines of their clinical work.
Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway
Authors: Do R , Kiss RS , Gaudet D , Engert JC
Published: January 2009

High levels of plasma low‐density lipoprotein cholesterol (LDL‐C) are a significant risk factor for heart disease. Statins (3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase inhibitors) have been extensively used to treat high‐plasma LDL‐C levels and are effective in preventing heart disease. However, statins can be associated with adverse side effects in some patients and do not work effectively in others. As an alternative to statins, the development of cholesterol‐lowering agents that directly inhibit squalene synthase have shown promise. Clinical studies have shown that squalene synthase inhibitors are effective in lowering plasma levels of total cholesterol and LDL‐C. Squalene synthase plays an important role in the cholesterol biosynthesis pathway as it is responsible for the flow of metabolites into either the sterol or the non‐sterol branches of the pathway. In addition, variants of the squalene synthase gene appear to modulate plasma cholesterol levels in human populations and therefore may be linked to cardiovascular disease. In this review, we examine squalene synthase and the gene that codes for it (farnesyldiphosphate farnesyltransferase 1). In particular, we investigate their role in the regulation of cellular and plasma cholesterol levels, including data that suggest that squalene synthase may be involved in the etiology of hypercholesterolemia.
A diagnostic tattoo
Authors: Whittaker RG , Turnbull DM
Published: January 2009

The hallmarks of the myoclonic epilepsy with ragged red fibers (MERRF) syndrome are myoclonic epilepsy, ataxia and ragged red fibres detected on muscle biopsy. We present a case of a 25‐year‐old male who first presented to his general practitioner at the age of 22 years with myoclonic jerks affecting the arms and legs, fatigue and mild ataxia. He was found to carry an A>G transition at nucleotide 8344 in mitochondrial DNA. This mutation is the most common cause of the MERRF syndrome, found in more than 80% of affected patients. Our patient had the diagnosis tattooed on his arm, both out of frustration at how few people had heard of it, and as a way of accepting that his condition was a part of who he was. Although the MERRF syndrome is one of the more common forms of mitochondrial encephalomyopathy, with a prevalence estimated at between 0.25 and 0.39 per 100,000, it is still a rare disorder. We are always striving to increase the public’s understanding of these important conditions. Our patient has perhaps helped more than most towards this aspiration.
The genetics of antiplatelet drug resistance
Authors: Feher G , Feher A , Pusch G , Lupkovics G , Szapary L , Papp E
Published: January 2009

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets’ response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)‐1, COX‐2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y1, P2Y12, CYP2C9, CYP3A4 and CYP3A5 genotypes.
Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects
Authors: Freeman SB , Torfs CP , Romitti PA , Royle MH , Druschel C , Hobbs CA , Sherman SL
Published: January 2009

We report Down syndrome (DS)‐associated congenital gastrointestinal (GI) defects identified during a 15 year, population‐based study of the etiology and phenotypic consequences of trisomy 21. Between 1989 and 2004, six sites collected DNA, clinical and epidemiological information on live‐born infants with standard trisomy 21 and their parents. We used chi‐squared test and logistic regression to explore relationships between congenital GI defects and infant sex, race, maternal age, origin of the extra chromosome 21, and presence of a congenital heart defect. Congenital GI defects were present in 6.7% of 1892 eligible infants in this large, ethnically diverse, population‐based study of DS. Defects included esophageal atresia/tracheoesophageal fistula (0.4%), pyloric stenosis (0.3%), duodenal stenosis/atresia (3.9%), Hirschsprung disease (0.8%), and anal stenosis/atresia (1.0%). We found no statistically significant associations between these defects and the factors examined. Although not significant, esophageal atresia was observed more often in infants of younger mothers and Hispanics, Hirschsprung disease was more frequent in males and in infants of younger mothers and blacks, and anal stenosis/atresia was found more often among females and Asians.
Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy
Authors: Bisgaard A‐M , Kirchhoff M , Nielsen JE , Kibæk M , Lund A , Schwartz M , Christensen E
Published: January 2009

A deletion on one chromosome and a mutant allele on the other may cause an autosomal recessive disease. We report on two patients with mental retardation, dysmorphic features and low catalytic activity of arylsulfatase A. One patient had a pathogenic mutation in the arylsulfatase A gene (ARSA) and succumbed to metachromatic leukodystrophy (MLD). The other patient had a pseudoallele, which does not lead to MLD. The presenting clinical features and low arylsulfatase A activity were explained, in each patients, by a deletion of 22q13 and, thereby, of one allele of ARSA.
LeaPIN’ toward the cause of myoglobinuria in childhood
Authors: Brunham LR
Published: January 2009

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood Zeharia et al. (2008) The American Journal of Human Genetics 83: 1–6
Digital clubbing: finally, a gene
Authors: Stein RA
Published: January 2009

Mutations in 15‐hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy Uppal et al. (2008) Nature Genetics 40 (6): 789–793
A short‐lived mRNA linked to blindness
Authors: Stein RA
Published: January 2009

Age‐related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA Fritsche et al. (2008) Nature Genetics 40 (7): 892–896
Impact of a regional anesthesia rotation on ultrasonographic identification of anatomic structures by anesthesiology residents
Authors: OREBAUGH S. L. , BIGELEISEN P. E. , KENTOR M. L.
Published: January 2009

Objective: The specific aim of this study was to determine the ability of anesthesiology residents to independently identify a series of anatomic structures in a live model using ultrasound, both before and after a 4‐week regional anesthesia rotation that incorporates a standardized ultrasound training curriculum for peripheral nerve blockade.

Methods: Ten CA2 and CA3 anesthesiology residents volunteered to participate in this study. Each resident was subjected to a pre‐rotation practical exam, in which he attempted to identify 15 structures at four sites of peripheral nerve blockade, in a test subject. Each resident then received specific training for ultrasound‐guided nerve blocks during a 4‐week regional anesthesia rotation, and then completed a post‐rotation exam. The mean number of structures correctly identified on the exams was compared for significant differences utilizing a paired t‐test.

Results: Residents were able to identify significantly more anatomic structures on the post‐rotation exam as compared with the pre‐rotation exam (mean 14.1 vs. 9.9, P<.001), as well as more peripheral nerve targets. The most frequently misidentified structures on the pre‐rotation exam were the subclavian vein, the sciatic nerve in the popliteal fossa, and the femur.

Conclusions: Ultrasound‐naïve anesthesiology residents, who received instruction and experience with ultrasound‐guided peripheral nerve blocks on a 4‐week regional anesthesia rotation, significantly improved their ability to independently identify relevant anatomic structures with ultrasonography.
Equal effects of gelatin and hydroxyethyl starch (6% HES 130/0.42) on modified thrombelastography in children
Authors: OSTHAUS W. A. , WITT L. , JOHANNING K. , BOETHIG D. , WINTERHALTER M. , HUBER D. , HEIMBUCHER C. , SUEMPELMANN R.
Published: January 2009

Background: Artificial colloids are frequently used to prevent or treat circulatory failure due to hypovolaemia. Whereas gelatin has been shown not to affect coagulation besides its haemodilutional effect, hydroxyethyl starches (HES) have additional negative effects on haemostasis. The third‐generation HES solutions have been developed to minimise these effects. We therefore conducted a prospective, randomised study, to verify the hypothesis that a 6% HES 130/0.42/6 : 1 and a 4% gelatin infusion influences modified thrombelastography (TEM) parameters in children in the same manner and to the same extent.

Methods: A total of 50 paediatric patients aged 0–12 years scheduled for surgery were assigned to receive either 10 ml/kg HES 130/0.42 or gelatin. Blood gas analysis, haemodynamic parameters and TEM measurements were performed before and after colloid administration.

Results: Patient characteristics, indications/surgical procedures and the main results obtained from blood gas analysis were comparable between the two groups. After administration of either gelatin or HES, all TEM parameters, except for clotting time, indicated impaired coagulation whereas the mean values of all TEM parameters remained within the normal ranges. Comparing the gelatin and HES 130/0.42/6 : 1 groups, none of the measured TEM parameters was found to show between‐group differences at baseline or after colloid infusion.

Conclusion: In conclusion, we could demonstrate that the investigational product, HES 130/0.42/6 : 1 solution, administered at a dosage of 10 ml/kg to children, had comparable effects on coagulation monitored with TEM as a gelatin solution. Perioperative administration of HES 130/0.42/6 : 1 does not alter coagulation to an extent above and beyond the effect of haemodilution.
Living without aprotinin: the results of a 5‐year blood saving program in cardiac surgery
Authors: RANUCCI M. , CASTELVECCHIO S. , ROMITTI F. , ISGRÒ G. , BALLOTTA A. , CONTI D.
Published: January 2009

Background: After 20 years of regular use in cardiac surgery patients, aprotinin has recently been withdrawn from the market due to many concerns about its safety. For a number of reasons aprotinin has not been available in Italy since 1998. The present study presents an aprotinin‐free treatment protocol applied at our institution during the last 5 years, and aims to verify the results of this protocol in terms of allogeneic blood product transfusions, postoperative blood loss and surgical re‐exploration rate.

Methods: Retrospective study on 7988 consecutive patients who underwent cardiac surgery during the years 2003–2007. All the patients received specific hemostasis/coagulation management based on (a) routine use of tranexamic acid, (b) heparin dose–response monitoring, thromboelastography, platelet (PLT) function analysis in a select population of patients, and (c) use of fresh frozen plasma (FFP), PLTs, and desmopressin according to the hemostasis/coagulation profile. Data retrieved from the institutional database were quantity of packed red cells (PRCs), FFP, PLT transfusion rate, blood loss in the first 12 postoperative hours, and surgical re‐exploration rate.

Results: PRCs were transfused in 40.4% of patients (with higher rates for selected high‐risk subpopulations), FFP in 12.9% and PLTs in 2.6%. Surgical re‐exploration rate was 3.7%. With respect to historical controls, a significant reduction of PRCs and FFP transfusions was obtained using closed circuits, point of care coagulation tests, and combination of the two.

Conclusion: This aprotinin‐free blood saving program is an effective strategy for allogeneic blood products transfusion containment.
Glycomolecule Modifications in the Seminiferous Epithelial Cells and in the Acrosome of Post‐testicular Spermatozoa in the Alpaca
Authors: Parillo F , Verini Supplizi A , Mancuso R , Catone G
Published: January 2009

Contents

A lectin histochemical investigation of the seminiferous epithelium and acrosomes of spermatozoa present in the efferent ductules and epididymal regions was carried out in the alpaca. The histochemical characterization was performed using a battery of different lectins: Con‐A, UEA‐I, LTA, WGA, GSA‐IB4, SBA, PNA, ECA, DBA, MAL‐II and SNA. Sialidase digestion and deglycosilation pre‐treatments were also employed. The cytoplasm of the Sertoli cells contained N‐linked oligosaccharides with α‐d‐Man/α‐d‐Glc and GlcNAc and O‐linked glycans with α‐l‐Fuc, β‐GalNAc, β‐d‐Gal‐(1‐4)‐d‐GlcNAc, α–Gal and Neu5Acα2,6α‐GalNAc moieties whereas β‐d‐Gal‐(1‐3)‐d‐GalNAc residues were included in both O‐ and N‐glycoproteins. Spermatogonia expressed α‐d‐Man/α‐d‐Glc residues included in N‐glycoproteins and α‐Fuc in O‐glycoproteins. Spermatocytes contained the N‐glycoproteins residues α‐d‐Man/α‐d‐Glc and GlcNAc and the O‐glycoproteins residues α‐l‐Fuc, β‐d‐Gal‐(1‐4)‐d‐GlcNAc, α–Gal, β‐GalNAc, Neu5Acα2,6α‐GalNAc and Neu5Acα2,6β‐d‐Gal‐(1‐3)‐d‐GalNAc. The results of the present study show differences in the presence and distribution of lectin reactive sites throughout the acrosomal development in the alpaca. In particular, Fuc moieties were found only during the Golgi‐phase of spermatids, α‐Gal were found in the acrosome of Golgi‐ and cap‐phase spermatids, sialic‐acid/α‐GalNAc sequence was revealed during the cap‐phase and elongated spermatids, and α‐d‐Man/α‐d‐Glc and GlcNAc were detected only in the acrosomes of elongated spermatids. Finally, β‐GalNAc, β‐d‐Gal‐(1‐3)‐d‐GalNAc and β‐d‐Gal‐(1‐4)‐d‐GlcNAc were added to acrosomal glycoproteins in the early stages of spermatogenesis and remained unchanged during the later phases. Differences in the carbohydrate expression were also demonstrated on the sperm acrosomes during passage through the post‐testicular ducts.
Impact of rurality on environmental determinants and hazards
Authors: Veitch Craig
Published: January 2009

The original of this paper was prepared as invited pre‐reading for the Inaugural Rural Health Symposium held in Brisbane in July 2008 under the theme ‘The impact of “rurality” ’, sub‐theme (a) Environmental determinants. The natural environment shapes human activity, both economically and socially. It also directly and indirectly influences health and well‐being. People in rural and remote areas are more directly exposed to the natural environment than their urban counterparts. The built environment is largely a product of economic activity; thus, the built environment in rural areas tends to reflect the predominant primary industry/ies. The rural built environment presents many potential hazards and risks to health and well‐being, particularly for those involved in the primary industries, which are either not present in urban areas, or are present on smaller or more contained scales. The natural and built environments also influence individuals' attitudes and behaviours, both positively and negatively.

The environmental determinants of rural health, therefore, can be considered in terms of the natural environment, the built environment and individuals' responses to environmental influences. This paper raises some of the common environmental determinants of rural health and well‐being and briefly touches on what these mean for rural health service delivery.
Integration and coordination of care
Authors: Dunbar James , Reddy Prasuna
Published: January 2009

The health care systems in Australia are under pressure from workforce shortages, increasing costs and an ageing population with a high prevalence of chronic disease. There is a well‐established description of inequity in health outcomes among rural and remote populations. Most of the inequity appears to be due to poorer access to services than higher levels of health risk factors, such as cholesterol, blood pressure or obesity. Over the last 15 years, the science of improvement has led to quality improvement techniques, such as collaboratives, managed clinical networks and collaborative care, all of which have been tried successfully in Australia. Each of these offers ways to reduce the inequity in health outcomes attributed to rurality or remoteness.
Relationship of hypersensitivity to anxiety and depression in children with high‐functioning pervasive developmental disorders
Authors: Tsuji Hisashi , Miyawaki Dai , Kawaguchi Takeshi , Matsushima Noriaki , Horino Akemi , Takahashi Kazuhiro , Suzuki Futoshi , Kiriike Nobuo
Published: January 2009

Aims:  Sensory–perceptual abnormalities, which include hyper‐ and hyposensitivity, have been identified by numerous researchers as prevalent in individuals with pervasive developmental disorders (PDD). Hypersensitivity has a greater impact on PDD patients' daily lives than hyposensitivity. The purpose of the present study was to clarify the relationship of hypersensitivity to anxiety, depression and other psychopathology in children with PDD.

Methods:  Sixty‐four children were divided into a hypersensitivity group (HG; n = 43) and a non‐hypersensitivity group (non‐HG; n = 21), and compared for anxiety, depression and other psychopathology on the Child Behavior Checklist (CBCL), State–Trait Anxiety Inventory for Children (STAIC) and Children's Depression Inventory (CDI).

Results:  The HG group had significantly higher scores than the non‐HG group in Total, Internalizing, and Somatic complaints on the CBCL. On STAIC, the mean sore of Total Score, State Score and Trait Score in the HG group tended to be higher than in the non‐HG group, but the difference was not significant. The score on the CDI in the HG group was significantly higher than that in the non‐HG group.

Conclusion:  PDD children with hypersensitivity have more serious psychopathologies, especially internalizing symptoms including depression.
Increased soluble tumor necrosis factor‐α receptors in patients with major depressive disorder
Authors: Grassi‐Oliveira Rodrigo , Brietzke Elisa , Pezzi Júlio C. , Lopes Rodrigo P. , Teixeira Antonio L. , Bauer Moisés E.
Published: January 2009

Aim:  Several lines of evidence suggest that major depressive disorder is associated with an inflammatory status. Tumor necrosis factor‐α has been investigated as a potential molecular target in mood disorders. Tumor necrosis factor‐α exerts its activity through binding to specific cell membrane receptors named as TNFR1 and TNFR2. The aim of the present study was to investigate soluble plasma TNFR1 (sTNFR1) and TNFR2 levels (sTNFR2) in major depressive disorder patients.

Methods:  Female outpatients with major depressive disorder (n = 30) were compared with a healthy control group (n = 19). Severity of depressive symptoms was evaluated on Beck Depression Inventory; post‐traumatic stress disorder (PTSD) symptoms were evaluated on PTSD Checklist–Civilian Version; and childhood abuse and neglect on the Childhood Trauma Questionnaire. Plasma tumor necrosis factor‐α and its soluble receptors were measured by ELISA.

Results:  Patients had no changes in tumor necrosis factor‐α concentrations but did have increased sTNFR1 (P < 0.001) and sTNFR2 (P < 0.001) levels compared to controls. Plasma level of sTNFR1 was positively predicted by age (B = 0.25, P = 0.05) and PTSD‐like symptoms (B = 0.41, P = 0.002) and plasma levels of sTNFR2 by depression severity (B = 0.67, P < 0.001).

Conclusions:  Soluble tumor necrosis factor‐α receptors could be reliable markers of inflammatory activity in major depression.
Outcomes of robotic assisted radical prostatectomy
Authors: Dasgupta Prokar , Kirby Roger S
Published: January 2009

Robot‐assisted radical prostatectomy (RARP) is a rapidly evolving technique for the treatment of localized prostate cancer. However, cynics point to the increasing role of market forces in the robotic revolution. As yet, Europe has not taken up RARP in large numbers and this may in part relate to the high level of expertise in laparoscopy previously gained. Furthermore, setting up a robotic program is a major undertaking for many surgical units. This article reviews the current literature on RARP with regard to oncologic, continence and potency outcomes – the so called ‘trifecta’. Preliminary data appears to show an advantage of RARP over open prostatectomy with reduced blood loss, decreased pain, early mobilization, shorter hospital stay and lower margin rates. Most intra‐institutional studies demonstrate good postoperative continence and potency with RARP; however this needs to be viewed in the context of a paucity of randomized data available in the literature. There is no definitive data to show an advantage over standard laparoscopy, but the fact that this technique has reached parity with laparoscopy within 5 years is encouraging.
Gerontology in the developing Brazil: Achievements and challenges in public policies
Authors: Nóbrega Otávio T , Faleiros Vicente P , Telles José L
Published: January 2009

Aim:  In the last three decades, the segment of population aged 60 years and older has more than doubled in Brazil. People aged 80 years and older are expected to be the fastest‐growing segment in the near future. This aim of this study was to analyze the legal structures currently in place in Brazil and to provide a framework for care policies and practices towards older‐adults.

Methods:  This article focuses on past and present major socioeconomic burdens on this segment of the Brazilian population as well as on public achievements to overcome inequities.

Results:  Both the public health and the social security systems have been directed to provide preferential assistance to the aged. Nonetheless, the elderly remain the most impoverished segment of Brazil and carry the burden of an overall lack of specialized services. Moreover, socioeconomic inequalities and population diversity in Brazil affects elderly care, adding complexity to this unique scenario.

Conclusion:  Brazil has adopted legal hallmarks that substantially shifted public practices towards the elderly segment from a philanthropic status to a legitimate right for care and assistance. The demographic transition that took place provides an opportunity for innovative solutions in public policies for older adults in a developing economic environment.
Parental aging synergistically decreases offspring sex ratio
Authors: Matsuo Koji , Ushioda Norichika , Udoff Laurence C.
Published: January 2009

Objective:  The aim of this study was to investigate the effect of parental age as a factor in the observed decline in the male to female birth ratio expressed as the offspring sex ratio (OSR).

Study Design:  A prospective multicenter study was conducted from August 2005 to February 2007 at five community‐based hospitals in Osaka, Japan. Pregnant women in the first trimester were recruited at their first prenatal care visit and followed until delivery. Multiple pregnancies and assisted conceptions were excluded. Periconceptional parental ages were recorded. Neonatal information was obtained at the time of delivery. Proportional distribution of categorical variables was studied using the χ2 or Fisher's exact tests (two‐tailed).

Results:  Data on 3,049 deliveries were available for review. OSR for the largest paternal and maternal subgroup (both, age 30–34) were male dominant (1.17 and 1.12, respectively). Paternal age ≥40 showed a smaller OSR (0.75 vs 1.17, P = 0.001). Advanced maternal age was associated with smaller OSR: age 35–39, 0.87 versus 1.12, P = 0.02; and age ≥40, 0.63 versus 1.12, P = 0.047. Synergistic effects of increasing paternal and maternal age on the OSR were observed. OSR for parental ages ≥40 were significantly smaller than ages 30–34 (0.52 vs 1.17, P = 0.029).

Conclusions:  Increasing paternal ages synergistically decrease the male to female birth ratio.
Utero‐relaxant effect of PDE4‐selective inhibitor alone and in simultaneous administration with β2‐mimetic on oxytocin‐induced contractions in pregnant myometrium
Authors: Franova Sona , Janicek Frantisek , Visnovsky Jozef , Dokus Karol , Zubor Pavol , Sutovska Martina , Nosalova Gabriela
Published: January 2009

Background: The objective of the study was to observe the effect of rolipram, the prototype phosphodiesterase 4 selective inhibitor, on oxytocin‐induced contractions of human term myometrial strips, and compare the effect with salbutamol, β2‐adrenergic agonist, in single and the simultaneous application.

Methods: Human myometrium was obtained from pregnant women in term that had a term delivery by the caesarian section. Myometrial strips were excised from the lower uterine segment and placed into an organ‐bath with Krebs‐Henseleit buffer. The mean peak amplitude of contraction (mN) of the myometrial smooth muscle to the doses of oxytocin (10−6 mmol/L−1) with subsequent single administration of rolipram (10−4 mmol/L−1), salbutamol (10−4 mmol/L1) and simultaneous administration of rolipram and salbutamol (both 10−4 mmol/L−1), was used as a parameter of myometrial reactivity.

Results: Rolipram alone decreased the oxytocin‐induced contractile amplitude to 47.98%, single salbutamol application resulted in amplitudinal decrease to 56.07%, and the combination of both compounds in their simultaneous administration resulted in the decrease of oxytocin‐induced contractile amplitude to 29.1%.

Conclusion: Our data are consistent with previous studies of the enhanced efficiency of the β2‐adrenergic agonist, when administered together with the phosphodiesterase 4‐inhibitor. Moreover we have shown that rolipram alone has a more profound effect on oxytocin‐induced contractions than salbutamol alone.