bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemochromatosis: genetics helps to define a multifactorial disease
Authors: Burke Wylie , Press Nancy , McDonnell Sharon M
Published: July 2010

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified; the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene–gene and gene–environment interactions.
Recent progress in the molecular genetics of congenital heart defects
Authors: Belmont John W.
Published: July 2010

Congenital heart defects (CHD) constitute the single most common anatomic class of birth defects and are a major cause of infant mortality. Correlation of normal and pathological embryology/anatomy has led to the formulation of mechanistic models, but there is limited understanding of the genetic basis for the inferred embryological processes. Most evidence points to extensive etiologic heterogeneity and a re‐evaluation of simple multifactorial models is required. The recent identification of several genes responsible for congenital heart defects in the context of more complex clinical disorders provides significant entry points for the genetic analysis of human heart development. The association of aneusomies (particularly microdeletion syndromes) with specific cardiac lesions provides further strong support for mechanistic classification. Studies in the mouse are laying the groundwork for a comprehensive genetic model of cardiac organogenesis. Nevertheless, the basis for the large majority of CHD, especially isolated defects, remains obscure. Dissection of the genetic components of CHD is one of the greatest challenges in medical genetics for the coming decades.
Functional mosaic trisomy of 1q12 1q21 resulting from X‐autosome insertion translocation with random inactivation
Authors: Vust A. , Riordan D. , Wickstrom D. , Chudley A. E. , Dawson A. J.
Published: July 2010

Cytogenetic studies of a 16‐year‐old female with behaviour and learning problems revealed that one X chromosome had additional material inserted at Xq21. Fluoroescence in situ hybridization (FISH) analysis showed that the inserted segment contained heterochromatin and adjacent euchromatin of chromosome 1 origin. The karyotype of this patient was established as: 46,X,der(X)ins(X;?)(q21;?).ish der(X) ins(X;1)(q21;q12q21)(wcpl +). Chromosome replication studies demonstrated a random pattern of X inactivation, suggesting that the inserted material may be too ‘small.’ to skew lyonization. The consequences of this abnormal X chromosome in relation to the clinical phenotype are discussed.
Life expectancy in British Marfan syndrome populations
Authors: Gray JR , Bridges AB , West RR , McLeish L. , Stuart AG , Dean JCS , Porteous MEM , Boxer M. , Davies SJ
Published: July 2010

A total of 206 patients with Marfan syndrome were ascertained throughout genetic clinics in Wales and Scotland during the period 1970–1990. There were 45 deaths representing 22% of the cohort. Mean age at death was 45.3 ± 16.5 years. 50% median cumulative survival in the total cohort (n = 206) was 53 years for males and 72 years for females. Multivariate analysis confirmed severity as the best independent indicator of survival. These findings and survival curves will assist in the counselling of British families and individuals with Marfan syndrome.
Spinal and bulbar muscular atrophy (SBMA): Somatic stability of an expanded CAG repeat in fetal tissues
Authors: Jedele Kerry Baldwin , Wahl Dagmar , Chahrokh‐Zadeh Soheyla , Wirtz Antje , Murken Jan , Holinski‐Feder Elke
Published: July 2010

Spinal and bulbar muscular atrophy (SBMA) is a rare X‐linked motor neuron degenerative disease caused by an expanded trinucleotide repeat. Unlike most other trinucleotide repeat diseases, SBMA shows limited meiotic instability, and evidence thus far indicates absence of somatic instability in adults. Data regarding the presence of fetal tissue somatic mosaicism is unavailable. We present a family in which a woman whose father had SBMA requested prenatal testing. After informed consent, molecular genetic evaluation showed the male fetus to carry the SBMA repeat elongation. Testing of fetal tissues after elective pregnancy termination showed no somatic mosaicism in the CAG repeat length. This is the first report of molecular genetic analysis of multiple tissues in an affected fetus, and only the second report of prenatal diagnosis in SBMA.
Genetic variants of the human obesity (OB) gene in subjects with and without Prader—Willi syndrome: comparison with body mass index and weight
Authors: Butler Merlin G , Hedges Lora , Hovis Christopher L , Feurer Irene D
Published: July 2010

We investigated whether an association exists between genetic variants of the human obesity (OB or leptin) gene and body mass index (BMI) or weight in subjects with Prader‐Willi syndrome (PWS) and in age‐and gender‐matched lean and obese subjects without PWS. The study included 51 subjects with PWS (mean age = 17.7 ± 9.5 years, BMI = 29.7 ± 8.3 kg/m2); 50 non‐PWS obese subjects (mean age = 18.2 ± 10.8 years, BMI = 33.3 ± 9.5 kg/m2); and 53 non‐PWS lean subjects (mean age = 17.8 ± 9.5 years, BMI = 19.5 ± 2.9 kg/m2). Allele sizes were determined via standard polymerase chain reaction of the D7S1875 locus, a dinucleotide repeat polymorphism close to the OB gene and classified as trichotomous (homozygous < 208 bp, heterozygous < 208/≥ 208 bp, homozygous < 208 bp) or dichotomous (homozygous < 208 bp or not). Non‐PWS males showed a marked decrease in weight with larger alleles while females did not (interaction effect, p < 0.05). Comparable effects were not observed among the PWS subjects. Associations between BMI and genotype were statistically significant (r = 0.22, one‐tailed p < 0.05) and comparable to previous research among the non‐PWS subjects < 18 years, but not the adults (r = 0.05, one‐tailed p = 0.38). Correlations were not statistically significant among either the adult or non‐adult PWS subjects.
Genetic variation in paraoxonase‐2 is associated with variation in plasma lipoproteins in Canadian Oji‐Cree
Authors: Hegele Robert A , Harris Stewart B , Connelly Philip W , Hanley Anthony JG , Tsui Lap‐Chee , Zinman Bernard , Scherer Stephen W
Published: July 2010

We report studies of the association between genetic variation in PON2 and variation in plasma quantitative traits in a sample of 334 non‐diabetic Oji‐Cree. We detected associations between PON2 variation in codon 148 (Ala → Gly) and variation in fasting plasma concentrations of total and low‐density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. In particular, homozygotes for a PON2 allele that encoded A148 had significantly higher plasma total, LDL cholesterol and apo B than subjects having the other two genotypes (p <0.01). Taken together, our results suggest that common genetic variation on chromosome 7q21.3–22.1 in PON2 is associated with significant variation of intermediate traits in plasma lipoprotein metabolism.
Severe malformations in males from families with osteopathia striata with cranial sclerosis
Authors: Bueno AL , Ramos FJ , Bueno O. , Olivares JL , Bello ML , Bueno M.
Published: July 2010

Osteopathia striata with cranial sclerosis (OS‐CS) is a bone dysplasia characterized by longitudinal striations of the long bones and sclerosis of the craniofacial bones. Affected patients show macrocephaly, ocular hypertelorism, frontal bossing, broad nasal bridge and abnormalities of the palate. Anomalies such as hearing loss, congenital heart defect, vertebral anomalies and mental impairment have also been reported. Pedigree analysis has suggested an autosomal dominant inheritance, but a recent report of a family with significantly more affected males than females suggested the possibility of X‐linked inheritance. Here we describe a new family with OS‐CS (the twelfth in the literature) with four affected individuals (two males and two females) spanning three generations. The affected male in the third generation was stillborn with multiple congenital anomalies, whereas the other three affected individuals had mild features. This family may represent another example of X‐linked OS‐CS where the mutated gene(s) is more severe in males.
Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association
Authors: Angle Brad , Hersh Joseph H , Christensen Katherine M
Published: July 2010

We report on a case of cloverleaf skull deformity in a patient with hypochondroplasia, a disorder which has not been previously associated with this anomaly. Hypochondroplasia is a bone dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Cloverleaf skull is a trilobar skull deformity which is etiologically and genetically heterogeneous and occurs in association with a number of disorders which result from mutations in the fibroblast growth factor receptor genes.

Our patient demonstrated one of the common FGFR3 mutations identified in hypochondroplasia, a C‐to‐A change at nucleotide 1620 (C1620A) in the tyrosine kinase domain. The occurrence of a cloverleaf skull deformity appears to represent an example of variable expressivity in hypochondroplasia and suggests that additional factors other than a specific mutation can modify the phenotype in this disorder. In addition, identification of another FGFR mutation associated with cloverleaf skull further illustrates the genetic heterogeneity of this anomaly.
Predictive testing for Huntington's disease: I. Predictors of uptake in South Wales
Authors: Binedell Julia , Soldan Jo R , Harper Peter S
Published: July 2010

In Wales, predictive testing for Huntington's disease (HD) has not been offered proactively to families and uptake of testing is low in comparison to other centres. Little is known of those not requesting testing, particularly those not in direct contact with the genetics service. This study examined differences between a cohort of 22 test applicants and a random group of 32 ‘non‐requesters’, drawn from the South Wales HD register. Respondents were interviewed by means of a semi‐structured schedule in their own homes. The study groups differed significantly on a number of variables including: knowledge of the availability of testing; perceived attitudes of family members and significant others to testing; length of knowledge and perceived stressfulness of being at risk; and perceived ability to cope with an unfavourable result. Overall, knowledge of testing procedures was poor and at‐risk individuals' understanding of genetic terminology was at odds with scientific distinctions. Discussion focuses on the organisational and psychological factors associated with lack of knowledge of the availability of testing and the interpretation of reported coping capacities.
Corneal arcus, case finding and definition of individual clinical risk in heterozygous familial hypercholesterolaemia
Authors: Winder Anthony F , Jolleys John CW , Day Lorna B , Butowski Paul F
Published: July 2010

Premature corneal arcus may identify individuals with hyperlipidaemia and increased cardiovascular risk. We have attempted to quantitate relationships through determination of graded prevalence of corneal arcus with age for 81 males and 73 females suffering from heterozygous familial hypercholesterolaemia (HFH) at presentation, and for 280 male and 353 female unselected patients (age range 16–76 years) attending a country general practice. Some degree of arcus affected 50% of HFH patients by age 31–35 years, and 50% of practice patients by age 41–45 years. Complete full ring arcus affected 50% of the familial hypercholesterolaemia (FH) group by age 50 years, with only 5% similarly affected in the non‐FH group. Arcus grade with age was advanced by some 5 years in males versus females. Premature arcus potentially alerting to HFH can be broadly defined for males and females combined, as heavy full ring by age 50 years, or any degree of arcus by age 30–35 years. Arcus grade was not related to the presence of coronary disease. Accelerated development of corneal arcus with age is an indicator of HFH, but premature arcus is not an additional marker of premature coronary disease for individual cases of HFH.
Cell proliferation rate and nuclear morphometry in Roberts syndrome
Authors: Pavlopoulos Petros M , Konstantinidou Anastasia E , Agapitos Emmanuel , Davaris Panagiotis
Published: July 2010

Roberts syndrome (RS) is a rare autosomal recessive disorder characterized primarily by symmetric reduction anomalies of all limbs, growth retardation and craniofacial abnormalities. Most RS patients are reported to present a typical abnormality of their constitutive heterochromatin, accompanied by abnormal cytological growth characteristics. We present an extremely severe case of an RS fetus, karyotypically documented, with a clinical presentation including growth deficiency, tetraphocomelia, frontal meningocele, craniofacial abnormalities and penile enlargement with hypospadias. Nuclear morphometrical analysis in tissues of various organs revealed a reduced nuclear size in RS as compared to normal controls, and statistically significant differences in morphometric parameters related to the nuclear shape. Immunohistochemical study of the same organs showed a reduced expression of proliferating cell nuclear antigen in the presented case, thus indicating a decreased cell proliferation rate in RS. Our results reconfirm previously reported findings in cultured fibroblasts of RS cases, thereby reinforcing on a histologic level, the hypothesis that reduced cell proliferation may be involved in the growth retardation and the reduction abnormalities observed in RS.
A genetic diagnostic survey in a population of 202 mentally retarded institutionalized patients in the south of Brazil
Authors: Félix Têmis Maria , Leite Júlio César Loguercio , Maluf Sharbel Weidner , Coelho Janice Carneiro
Published: July 2010

Filix TM, Leite JCL, Maluf SW, Coelho JC. A genetic diagnostic survey in a population of 202 mentally retarded institutionalized patients in the south of Brazil. Clin Genet 1998: 54: 219–223. 0 Munksgaard, 1998

The Associaciio dos Pais e Amigos dos Excepciondis (APAE) is an institution for mentally retarded patients located at Caxias do Sul in the south of Brazil. A genetic diagnostic survey of 202 individuals from this institution is presented. The patients had a male:female ratio of 1.3:l and their ages vaned from 1 month to 47 years with a mean of 5.5 years. Using personal and family data, careful clinical examination and laboratory investigation, the authors established a definitive diagnosis in 132 patients (65.34%). A constitutional disorder was present in 111 patients (54.95%). Down's syndrome patients represented 32.15%, while I.98% had other chromosomal anomalies. In 15 patients (12.37%) a disorder of Mendelian inheritance was diagnosed. In 8 patients (3.96%) a multiple congenital anomalies/mental retardation (MCA/MR) syndrome was recorded. Eight patients (3.960/0) had a central nervous system (CNS) malformation. An acquired condition was observed in 21 patients (10.39%), including pre‐ or post‐natal infections. In the remaining 70 patients (34.65%) a conclusive diagnosis was not possible.
Severe mental retardation ‐ distal arthrogryposis in the upper limbs and complex chromosomal rearrangements resulting from a lOq25→qter deletion
Authors: Lukusa T. , Devriendt K. , Holvoet M. , Fryns JP
Published: July 2010

Lukusa T, Devriendt K, Holvoet M, Fryns JP. Severe mental retardation ‐ distal arthrogryposis in the upper limbs and complex chromosomal rearrangements resulting from a 10q25→qter deletion. CIin Genet 1998: 54: 224–230. 8 Munksgaard, 1998

We present the first report of chromosomal rearrangement involving chromosomes 4, 10 and 12. The proband was a 42–year‐old woman with severe mental retardation and multiple congenital anomalies. The most striking physical anomalies were upper limb contractures resulting in distal arthrogryposis. As upper limb flexion contrdctures have been previously reported in individuals with partial distal 1Oq deletion, this sign should be considered as part of the clinical manifestations of 10q25→qter monosomy.
Assessment of the genetic causes of recessive childhood non‐syndromic deafness in the UK – implications for genetic testing
Authors: Hutchin T , Coy NN , Conlon H , Telford E , Bromelow K , Blaydon D , Taylor G , Coghill E , Brown S , Trembath R , Liu XZ , Bitner‐Glindzicz M , Mueller R
Published: July 2010

Approximately one in 2000 children is born with a genetic hearing impairment, mostly inherited as a non‐syndromic, autosomal recessive trait, for which more than 30 different genes have been identified. Previous studies have shown that one of these genes, connexin 26 (GJB2), accounts for 30–60% of such deafness, but the relative contribution of the many other genes is not known, especially in the outbred UK population. This lack of knowledge hampers the development of diagnostic genetic services for deafness. In an effort to determine the molecular aetiology of deafness in the population, 142 sib pairs with early‐onset, non‐syndromic hearing impairment were recruited. Those in whom deafness could not be attributed to GJB2 mutations were investigated further for other mapped genes. The genetic basis of 55 cases (38.7%) was established, 33.1% being due to mutations in the GJB2 gene and 3.5% due to mutations in SLC26A4. None of the remaining 26 loci investigated made a significant contribution to deafness in a Caucasian population. We suggest that screening the GJB2 and SLC26A4 genes should form the basis of any genetic testing programme for childhood deafness and highlight a number of important issues for consideration and future work.
Amino acid changes in the amino terminus of the Na,K‐adenosine triphosphatase alpha‐2 subunit associated to familial and sporadic hemiplegic migraine
Authors: Tonelli A , Gallanti A , Bersano A , Cardin V , Ballabio E , Airoldi G , Redaelli F , Candelise L , Bresolin N , Bassi MT
Published: July 2010

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura inherited with an autosomal dominant pattern. Here, we report the genetic analysis of four families and one sporadic case with hemiplegic migraine (HM) in whom we searched for mutations in the three genes associated with the disease CACNA1A, ATP1A2 and SCN1A. Two novel amino acid changes p.Arg65Trp and p.Tyr9Asn, in the Na,K‐adenosine triphosphatase (ATPase) alpha‐2 subunit encoded by the ATP1A2 gene, were found in one FHM family and in the sporadic case, respectively. These mutations are peculiar for their location in the extreme N‐terminus, an uncommon mutation target in this protein. Low frequency of migraine attacks in all our mutant patients with low complexity of the associated aura symptoms in the sporadic case is also observed. Besides the two novel mutations, the data here reported confirm the involvement of ATP1A2 gene in the sporadic form of HM, while the negative results on the other families tested for all genes known in HM strengthen the hypothesis of the existence of at least another locus involved in FHM.
β‐Globin gene cluster polymorphisms are strongly associated with severity of HbE/β0‐thalassemia
Authors: Ma Q , Abel K , Sripichai O , Whitacre J , Angkachatchai V , Makarasara W , Winichagoon P , Fucharoen S , Braun A , Farrer LA
Published: July 2010

We evaluated the contribution of 67 single nucleotide polymorphisms (SNPs) within the β‐globin gene cluster to disease severity in groups of 207 mild‐ and 305 severe unrelated patients from Thailand with Hemoglobin E (HbE)/β0‐thalassemia and normal α‐globin genes. Our analysis showed that these SNPs comprise two distinct linkage disequilibrium blocks, one containing the β‐globin gene and the other extending from the locus control region (LCR) to the δ gene, which are separated by a recombination hotspot in the narrow region of the β‐globin gene promoter. Forty‐five SNPs within the interval including the LCR region and the δ gene showed strong association with disease severity. The strongest association was observed with the XmnI polymorphism located 158‐bp upstream to the Gγ gene (p = 4.6E−12). Carriers of the T allele of XmnI were more likely to have a milder disease course and higher level of fetal hemoglobin (HbF) in both the mild (p = 0.005) and severe (p = 8.7E−06) patient groups. Haplotype analysis revealed that the T allele of XmnI was nearly always in cis with the HbE allele. The high frequency of this haplotype may be favored by positive selection against malarial infection. Further studies are needed to validate this hypothesis and determine whether XmnI or another closely linked variant modulates severity and HbF levels in patients with β0‐thalassemia/HbE disease.
Association of the estrogen receptor α gene polymorphisms with osteoporosis in the Mexican population
Authors: Gómez R , Magaña JJ , Cisneros B , Pérez‐Salazar E , Faugeron S , Véliz D , Castro C , Rubio J , Casas L , Valdés‐Flores M
Published: July 2010

The estrogen receptor gene (ERα) has been implicated in the development of osteoporosis. In this study, the association of two ERα gene polymorphic markers (a TA dinucleotide repeat and a single nucleotide polymorphism, G2014A) with osteoporosis was tested in 70 osteoporotic women, 70 non‐osteoporotic women and 500 subjects from the Mexican population. According to the genetic analysis of the Mexican population using eight unlinked polymorphic markers, we found that our population is structured into three subpopulations; therefore, the allele–phenotype relationship was analyzed with a statistical method that considered population stratification. We found that the G2014A polymorphism is associated with the presence of osteoporosis while the TA dinucleotide repeat is not. The G allele and the GG genotype frequencies of the G2014A marker were significantly higher in osteoporotic than in non‐osteoporotic women. Likewise, subjects bearing the G allele in heterozygous or homozygous displayed lower values for lumbar bone mineral density and T score than those who did not present any G allele. The effect of confounders for osteoporosis on the association of G allele–osteoporosis was ruled out. In summary, we conclude that the G2014 polymorphism may become a useful marker for genetic studies of osteoporosis in the Mexican population.
Post‐transplant lymphoproliferative disorder in children: Recent outcomes and response to dual rituximab/low‐dose chemotherapy combination
Authors: Gupta Sushil , Fricker Frederick J. , González‐Peralta Regino P. , Slayton William B. , Schuler Pamela M. , Dharnidharka Vikas R.
Published: July 2010

Gupta S, Fricker FJ, González‐Peralta RP, Slayton WB, Schuler PM, Dharnidharka VR. Post‐transplant lymphoproliferative disorder in children: Recent outcomes and response to dual rituximab/low‐dose chemotherapy combination. Pediatr Transplantation 2010: 14:896–902. © 2010 John Wiley & Sons A/S.

Abstract:  PTLD is a major complication after transplantation. Treatment options for PTLD are not standardized, usually sequential, starting with reduction in immunosuppression. Recently, we have used a dual combination of rituximab and reduced dose chemotherapy (R/C) directly after failed RI. We retrospectively identified 30 pediatric PTLD cases across four organ systems at our center from 1995 to 2008. We assessed recent outcomes of PTLD in children, comparing the responses to different regimens. Two‐yr failure‐free survival was best in renal and heart recipients (80–88%), followed by liver (57%) and lung (0%). Of note, two patients were Epstein–Barr peripheral blood viral load low positive but tumor EBER negative. Three patients had no detectable viral load but were EBER positive. The R/C regimen (n = 8) had the highest CR rate (100%), low recurrence (12%) and lowest mortality (12%). Interferon (n = 4) had 75% CR, 33% recurrence and 25% mortality. Rituximab/prednisone (n = 5) had 80% CR, 50% recurrence and 20% mortality. Other chemotherapy (n = 7, including all 4 T‐cell PTLDs) had 57% CR, 0% recurrence and 14% mortality. Direct dual R/C combination therapy after failed RI is effective and offers another treatment option for B‐cell PTLD.
Fast‐track surgery for bariatric laparoscopic gastric bypass with focus on anaesthesia and peri‐operative care. Experience with 500 cases
Authors: BERGLAND A. , GISLASON H. , RAEDER J.
Published: July 2010

Background: Bariatric surgery for morbid obesity implies challenges in anaesthesiological handling. We report our experience from 500 consecutive patients during 3 years.

Methods: The patients were due for laparoscopic Roux–en–Y gastric bypass and enteral bypass. Sleep was induced after pre‐oxygenation with target control infusions (TCI) of remifentanil and propofol; vecuronium was supplied for facilitating endotracheal intubation. The propofol infusion was stopped and desflurane 3–6% was given for BIS‐titrated anaesthetic maintenance together with remifentanil TCI. Antiemetic prophylaxis was supplied with intravenous (IV) droperidol, ondansetron and dexamethasone; post‐operative pain prophylaxis was IV paracetamol, parecoxib and bupivacaine infiltration. The patients were extubated in the operating room and kept in the post‐operative care unit for 3–4 h, being tested for a 20 m walk before discharge to the ward.

Results: The procedure was uncomplicated peri‐operatively in all 500 cases and in 497 patients (99.4%) post‐operatively. Three patients had one complication, which resolved without sequelae: oesophageal rupture from gastric tubing, reoperation for anastomosis leakage and pneumonia. The mean duration of surgery was 57 min (range 37–91). The mean time from the start of anaesthesia until the start of surgery and time from the end of surgery until the end of anaesthesia were both significantly reduced throughout the study period, from 23 to 7.8 and 5.8 to 1.9 min, respectively (P<0.001). The mean total hospital stay was reduced from 3 days at start to 2 days in the end of the series (P<0.05).

Conclusion: Safe bariatric short‐stay surgery is feasible with a dedicated anaesthesiological concept in an expert surgical team.
An association study of 20 candidate genes with cryptorchidism in Siberian Husky dogs
Authors: Zhao X. , Du Z.‐Q. , Rothschild M.F.
Published: July 2010

Cryptorchidism (CO) as a common developmental defect in purebred dogs causes health concerns of reduced fertility and increases risk of testicular malignancies. A total of 49 single nucleotide polymorphisms (SNPs) discovered from 20 candidate genes was investigated to analyse their associations with CO in Siberian Huskies. The sibling‐transmission disequilibrium test on 38 discordant full‐sibs revealed seven SNPs in the collagen type II α 1 (COL2A1) gene were significantly (p < 0.05) or suggestively (p < 0.10) associated with CO. Further analyses showed that only one SNP (rs23358342) in this gene remained suggestively significant (p < 0.1) on a data set of full‐sibs with additional related dogs, but not significant on all 156 Siberian Huskies. Based on the statistical results and the involvement of COL2A1 in the testicle development and descent, we could not exclude COL2A1 as a potential candidate gene for CO in Siberian Huskies. Further studies are necessary to clarify these results from our relatively small sample size.
Proteomic analysis of human umbilical vein endothelial cells incubated with Cryptococcus neoformans var. neoformans
Authors: Wang Xiao‐Jun , Zhu Yuan‐Jie , Cui Jian‐Guo , Huang Xin , Gu Julin , Xu Hong , Wen Hai
Published: July 2010

Cryptococcus neoformans is a medically important fungus and can infect all the organs of the body. As vascular endothelial cell is an important target for C. neoformans to penetrate any organs, the differential protein expression of human umbilical vascular endothelial cell (HUVEC) after incubating with C. neoformans may be the key to penetration. The proteins of HUVECs incubated with C. neoformans and normal HUVECs were collected and purified. After two‐dimensional electrophoresis, the differential protein expression was identified by matrix‐assisted laser desorption/ionisation mass spectrometry. The mRNA levels of some proteins were measured by real‐time PCR. Three proteins were found significantly overexpressed in HUVECs incubated with C. neoformans, and nine other proteins were downregulated. The mRNA levels of S100A10 and peroxiredoxin I fluctuated with the protein levels. These results suggested that the expressions of peroxiredoxin I and S100A10 were regulated during the process of invasion of HUVECs by C. neoformans. We hypothesise that these proteins take part in the modifications of HUVEC cytoskeleton and the tolerance to oxidative stress, which may affect the process of invasion by C. neoformans.
Axonal projections of single auditory neurons in the thalamic reticular nucleus: implications for tonotopy‐related gating function and cross‐modal modulation
Authors: Kimura A. , Imbe H. , Donishi T. , Tamai Y.
Published: July 2010

Tonotopically comparable subfields of the primary auditory area (AI) and nonprimary auditory areas (non‐AI), i.e. posterodorsal area (PD) and ventral auditory area (VA), in the rat cortex have similar topographies in the projection to the ventral division of the medial geniculate nucleus (MGV), but reverse topographies in the projection to the thalamic reticular nucleus (TRN). In this study, we examined axonal projections of single auditory TRN cells, using juxtacellular recording and labeling techniques, to determine features of TRN projections and estimate how the TRN mediates corticofugal inhibition along with the reverse topographies of cortical projections to the TRN. Auditory TRN cells sent topographic projections to limited parts of the MGV in a manner that relays cortical inputs from tonotopically comparable subfields of the AI and non‐AI (PD and VA) to different parts of the MGV. The results suggest that corticofugal excitations from the AI and non‐AI modulate thalamic cell activity in the same part of the MGV, whereas corticofugal inhibitions via the TRN modulate cell activity in different parts of the MGV with regard to tonotopic organization. The AI and non‐AI could serve distinctive gating functions for auditory attention through the differential topography of inhibitory modulation. In addition, we obtained an intriguing finding that a subset of auditory TRN cells projected to the somatosensory but not to the auditory thalamic nuclei. There was also a cell projecting to the MGV and somatosensory nuclei. These findings extend the previously suggested possibility that TRN has a cross‐modal as well as an intramodal gating function in the thalamus.
Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine
Authors: Svenningsson Per , Bateup Helen , Qi Hongshi , Takamiya Kogo , Huganir Richard L. , Spedding Michael , Roth Bryan L. , McEwen Bruce S. , Greengard Paul
Published: July 2010

Depression is associated with abnormal neuronal plasticity. AMPA receptors mediate transmission and plasticity at excitatory synapses in a manner which is positively regulated by phosphorylation at Ser831‐GluR1, a CaMKII/PKC site, and Ser845‐GluR1, a PKA site. Treatment with the selective serotonin (5‐hydroxytryptamine; 5‐HT) reuptake inhibitor fluoxetine increases P‐Ser845‐GluR1 but not P‐Ser831‐GluR1. Here, it was found that treatment with another antidepressant, tianeptine, increased P‐Ser831‐GluR1 in the frontal cortex and the CA3 region of hippocampus and P‐Ser845‐GluR1 in the CA3 region of hippocampus. A receptorome profile detected no affinity for tianeptine at any monaminergic receptors or transporters, confirming an atypical profile for this compound. Behavioural analyses showed that mice bearing point mutations at both Ser831‐ and Ser845‐GluR1, treated with saline, exhibited increased latency to enter the centre of an open field and increased immobility in the tail‐suspension test compared to their wild‐type counterparts. Chronic tianeptine treatment increased open‐field locomotion and reduced immobility in wild‐type mice but not in phosphomutant GluR1 mice. P‐Ser133‐CREB was reduced in the CA3 region of hippocampus in phosphomutant mice, and tianeptine decreased P‐Ser133‐CREB in this region in wild‐type, but not in phosphomutant, mice. Tianeptine increased P‐Ser133‐CREB in the CA1 region in wild‐type mice but not in phosphomutant GluR1 mice. There were higher basal P‐Ser133‐CREB and c‐fos levels in frontal and cingulate cortex in phosphomutant GluR1 mice; these changes in level were counteracted by tianeptine in a GluR1‐independent manner. Using phosphorylation assays and phosphomutant GluR1 mice, this study provides evidence that AMPA receptor phosphorylation mediates certain explorative and antidepressant‐like actions under basal conditions and following tianeptine treatment.
Adenosine A1receptor‐mediated inhibition of dopamine release from rat striatal slices is modulated by D1dopamine receptors
Authors: O'Neill C. , Nolan B. J. , Macari A. , O'Boyle K. M. , O'Connor J. J.
Published: July 2010

Dopamine release is regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented. In the present study, dopamine release from isolated striatal slices from Wistar rats was measured using fast cyclic voltammetry. Single‐pulse stimulation (0.1 ms, 10 V) was applied every 5 min over a 2‐h period. Superfusion with the adenosine (A)1receptor agonist N6‐cyclopentyladenosine (CPA), but not the A2receptor agonist 3‐[4‐[2‐[[6‐amino‐9‐[(2R,3R,4S,5S)‐5‐(ethylcarbamoyl)‐3,4‐dihydroxy‐oxolan‐2‐yl]purin‐2‐yl]amino]ethyl] phenyl]propanoic acid (CGS 21680), inhibited dopamine release in a concentration‐dependent manner (IC503.80 × 10−7 m;n = 10). The dose–response curve to CPA was shifted to the right (IC506.57 × 10−6 m;n = 6,P < 0.05 vs. control) by the A1receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX). Neither the D1agonist 6‐chloro‐APB nor the D1antagonist R‐(+)‐8‐chloro‐2,3,4,5‐tetrahydro‐3‐methyl‐5‐phenyl‐1H‐3‐ benzazepine‐7‐ol (SCH 23390) altered dopamine release on their own. However, SCH 23390 (3 µm) significantly attenuated the response to CPA (IC501.44 × 10−5 m;n = 6,P < 0.01 vs. control). Furthermore, the inhibitory effect of CPA was significantly increased in the presence of 6‐chloro‐APB (1 µm). In radioligand binding experiments, CPA interacted with high‐ and low‐affinity states of [3H]DPCPX‐lableled A1receptors. The high‐affinity agonist binding to A1receptors was inhibited by the stable guanosine triphosphate analogue Gpp(NH)p. In contrast, neither the proportion nor the affinity of high‐affinity A1receptors was altered by dopamine or SCH 23390. These results provide evidence that the inihibition of dopamine release by adenosine A1receptors is dependent, at least in part, on the simultaneous activation of D1dopamine receptors. While the mechanism underlying this interaction remains to be determined, it does not appear to involve an intramembrane interaction between A1and D1receptors.
Target regulation of V2R expression and functional maturation in vomeronasal sensory neurons in vitro
Authors: Muramoto Kazuyo , Hashimoto Mitsuhiro , Kaba Hideto
Published: July 2010

Vomeronasal receptors from the V1R and V2R gene families mediate the detection of chemical stimuli such as pheromones via the vomeronasal organ (VNO). The differential expression of vomeronasal receptors might contribute in part to a variety of pheromonal effects, which are different sexually, developmentally and even individually. However, little is known about the mechanisms controlling vomeronasal receptor expression. Cultured vomeronasal sensory neurons (VSNs) bear phenotypic resemblance to the intact VNO but they remain immature. Because indices of VSN maturation are increased by coculture with the target cells for VSNs, accessory olfactory bulb (AOB) neurons, AOB neurons may regulate vomeronasal receptor expression and functional maturation in VSNs. To test this hypothesis, we examined the expression of V2R‐type vomeronasal receptors (VR1 and VR4) and chemosensory responsiveness in VNOs cocultured with AOB neurons. Immunoblot and immunocytochemical analysis revealed that the coculture of VNOs with AOB neurons resulted in a greater expression of VR1 and VR4 after 10 days than VNOs cultured alone. Moreover, calcium imaging analysis showed that cocultured VNOs responded to urine components applied iontophoretically into their cavities with a time course similar to the V2R expression, in contrast to singly cultured VNOs that displayed no response. These results demonstrate that AOB neurons induce the expression of vomeronasal receptors in VSNs, allowing them to function.
A potential role for calcium / calmodulin‐dependent protein kinase‐related peptide in neuronal apoptosis: in vivo and in vitro evidence
Authors: Schenk Geert J. , Engels Bart , Zhang Yan‐Ping , Fitzsimons Carlos P. , Schouten Theo , Kruidering Marieke , Ron de Kloet E. , Vreugdenhil Erno
Published: July 2010

Previously, we have established that a product of the doublecortin‐like kinase (DCLK) gene, DCLK‐short, is cleaved by caspases during serum deprivation. Subsequently, the N‐terminal cleavage product of DCLK‐short facilitates apoptosis in the neuroblastoma cell line NG108. As this N‐terminal cleavage product is highly homologous to calcium/calmodulin‐dependent protein kinase‐related peptide (CARP), another DCLK gene splice variant, we aimed to determine the possible apoptotic properties of CARP in vivo and in vitro. We report highly specific CARP expression in apoptotic granule cells in the rat dentate gyrus after adrenalectomy relative to healthy granule cells. CARP is significantly upregulated in the suprapyramidal blade of the dentate gyrus, with varying levels of upregulation, depending on the extent of adrenalectomy‐induced apoptosis. Similar to the caspase‐cleaved N‐terminus of DCLK‐short, CARP overexpression itself facilitated apoptosis in serum‐deprived NG108 cells. Furthermore, CARP facilitated polymerization of tubulin in vitro and was capable of interacting with growth factor receptor‐bound protein 2, an intracellular protein involved in vesicle trafficking. Together, our data demonstrate a facilitating role for CARP in the apoptotic process in granule cell populations sensitive to adrenalectomy, and suggest that this proapoptotic effect is mediated by increasing the stability of the microtubule cytoskeleton.
Influence of macrophages and lymphocytes on the survival and axon regeneration of injured retinal ganglion cells in rats from different autoimmune backgrounds
Authors: Luo Jian‐Min , Zhi Ye , Chen Qing , Cen Ling‐Ping , Zhang Cheng‐Wu , Lam Dennis S. C. , Harvey Alan R. , Cui Qi
Published: July 2010

The immune response after neural injury influences the survival and regenerative capacity of neurons. In the primary visual pathway, previous studies have described beneficial effects of macrophages and T‐cells in promoting neural survival and axonal regeneration in some rat strains. However, the contributions of specific cell populations to these responses have been unclear. In adult Fischer (F344) rats, we confirm prior reports that intravitreal macrophage activation promotes the survival of retinal ganglion cells (RGCs) and greatly enhances axonal regeneration through a peripheral nerve graft. Neonatal thymectomy that results in elimination of T‐cell production enhanced RGC survival after axotomy, but diminished the effect of intravitreal macrophage activation on axon regeneration. Thus, in F344 rats, lymphocytes appear to suppress RGC survival but augment the pro‐regenerative effects of macrophages. The cytotoxic effect of lymphocytes on RGCs was confirmed in in vitro studies; coculture of retinal explants with lymphocytes led to a 60% reduction in viable RGCs. Similar in vivo results were obtained in Sprague Dawley rats. By comparison, in adult Lewis rats, neither RGC survival nor axonal regeneration was increased after intravitreal macrophage activation. Neonatal thymectomy had only a small beneficial effect on RGC survival, and although Lewis lymphocytes reduced RGC viability in culture, they did so to a lesser extent. Thus, in addition to a complex role of lymphocytes, particularly T‐cells, after central nervous system injury, the present results demonstrate that the impact of macrophages is also influenced by genetic background.
Epileptiform synchronization in the rat insular and perirhinal cortices in vitro
Authors: Sudbury Jessica R. , Avoli Massimo
Published: July 2010

The hippocampus plays a primary role in temporal lobe epilepsy, a common form of partial epilepsy in adults. Recent studies, however, indicate that extrahippocampal areas such as the perirhinal and insular cortices represent important participants in this epileptic disorder. By employing field potential recordings in the in vitro 4‐aminopyridine model of temporal lobe epilepsy, we have investigated here the contribution of glutamatergic and GABAergic signaling to epileptiform activity in these structures. First, we provide evidence of epileptiform synchronicity between the perirhinal and insular cortices, and resolve some pharmacological and network mechanisms involved in sustaining the interictal‐ and ictal‐like discharges recorded there. Second, we report that in the absence of ionotropic glutamatergic transmission, GABAergic networks produce synchronous potentials that spread between the perirhinal and insular cortices. Finally, we have established that such activity is modulated by activating µ‐opioid receptors. Our findings support clinical and experimental evidence concerning the involvement of the perirhinal and insular cortex networks in temporal lobe epilepsy, and provide observations that may impact research focussing on the role of the insular cortex in nociception.
Cognitive impairment and transmitter‐specific pre‐ and postsynaptic changes in the rat cerebral cortex during ageing
Authors: Majdi Maryam , Ribeiro‐da‐Silva Alfredo , Cuello A. Claudio
Published: July 2010

Recent studies suggest that age‐related cognitive decline is correlated with an excitatory–inhibitory imbalance in synaptic discharges on pyramidal neurons. This study focuses on whether ageing and cognitive status correlates with relative numbers of excitatory and inhibitory presynaptic boutons. We investigated the density of excitatory and inhibitory presynaptic inputs across several areas of the rat cerebral cortex in young and aged male Fischer 344 rats. Aged animals were segregated into aged cognitively impaired (AI) and aged cognitively unimpaired (AU) groups using the Morris water maze. We applied immunohistochemistry to reveal the majority of excitatory and inhibitory presynaptic boutons captured with confocal microscopy and quantitative image analysis. A gradual decline in the density of excitatory and inhibitory presynaptic boutons occurred from young to AU to AI animals; however, the ratios of excitatory to inhibitory presynaptic bouton densities were not significantly altered. We further investigated the density of receptor scaffolding proteins representing key excitatory and inhibitory receptor postsynaptic sites, using antibodies against specific markers of excitatory and inhibitory postsynaptic densities, respectively. Significant changes in the ratios of excitatory to inhibitory postsynaptic densities were observed only in AI compared to young rats.
Regulated recycling and plasma membrane recruitment of the high‐affinity choline transporter
Authors: Ribeiro Fabiola M. , Pinthong Metta , Black Stefanie A. G. , Gordon Alexis C. , Prado Vania F. , Prado Marco A. M. , Rylett R. Jane , Ferguson Stephen S. G.
Published: July 2010

The high‐affinity choline transporter (CHT1) is responsible for uptake of choline from the synaptic cleft and supplying choline for acetylcholine synthesis. CHT1 internalization by clathrin‐coated vesicles is proposed to represent a mechanism by which high‐affinity choline uptake can be modulated. We show here that internalized CHT1 is rapidly recycled back to the cell surface in both human embryonic kidney cells (HEK 293 cells) and SH‐SY5Y neuroblastoma cells. This rapidly recycling pool of CHT1 comprises about 10% of total CHT1 protein. In the SH‐SY5Y neuroblastoma cell line K+‐depolarization promotes Ca2+‐dependent increase in the rate of CHT1 recycling to the plasma membrane without affecting the rate of CHT1 internalization. K+‐depolarization also increases the size of the pool of CHT1 protein that can be mobilized to the plasma membrane. Thus, the activity‐dependent increase in plasma membrane CHT1 localization appears to be regulated by two mechanisms: (i) an increase in the rate of externalization of the intracellular CHT1 pool; and (ii) the recruitment of additional intracellular transporters to the recycling pool.
Isolating endogenous visuo‐spatial attentional effects using the novel visual‐evoked spread spectrum analysis (VESPA) technique
Authors: Lalor Edmund C. , Kelly Simon P. , Pearlmutter Barak A. , Reilly Richard B. , Foxe John J.
Published: July 2010

In natural visual environments, we use attention to select between relevant and irrelevant stimuli that are presented simultaneously. Our attention to objects in our visual field is largely controlled endogenously, but is also affected exogenously through the influence of novel stimuli and events. The study of endogenous and exogenous attention as separate mechanisms has been possible in behavioral and functional imaging studies, where multiple stimuli can be presented continuously and simultaneously. It has also been possible in electroencephalogram studies using the steady‐state visual‐evoked potential (SSVEP); however, it has not been possible in conventional event‐related potential (ERP) studies, which are hampered by the need to present suddenly onsetting stimuli in isolation. This is unfortunate as the ERP technique allows for the analysis of human physiology with much greater temporal resolution than functional magnetic resonance imaging or the SSVEP. While ERP studies of endogenous attention have been widely reported, these experiments have a serious limitation in that the suddenly onsetting stimuli, used to elicit the ERP, inevitably have an exogenous, attention‐grabbing effect. Recently we have shown that it is possible to derive separate event‐related responses to concurrent, continuously presented stimuli using the VESPA (visual‐evoked spread spectrum analysis) technique. In this study we employed an experimental paradigm based on this method, in which two pairs of diagonally opposite, non‐contiguous disc‐segment stimuli were presented, one pair to be ignored and the other to be attended. VESPA responses derived for each pair showed a strong modulation at 90–100 ms (during the visual P1 component), demonstrating the utility of the method for isolating endogenous visuo‐spatial attention effects.