bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma concentrations of Lp(a) lipoprotein and TGF‐β1 are altered in preeclampsia
Authors: Djurovic Srdjan , Schjetlein Rune , Wisløff Finn , Haugen Guttorm , Husby Henrik , Berg Kåre
Published: July 2010

This study was performed to investigate the possible association between preeclampsia and the plasma concentrations of Lp(a) lipoprotein and TGF‐β1 in a large series of patients. Additionally, correlation between the concentrations of these molecules and the severity of preeclampsia or fetal growth retardation was evaluated. Following clinical examination and biochemical analyses, both electroimmunoassay and RIA technique were used for quantitative determinations of plasma Lp(a) lipoprotein. ELISA technique was used to measure the active form of TGF‐β1 in plasma of pregnant normotensive and preeclamptic women. We examined 154 women with preeclampsia (preeclampsia group) and 76 healthy, pregnant normotensive women (control group). The preeclampsia group was further divided into the following subgroups: mild preeclampsia, severe preeclampsia and preeclampsia with fetal growth retardation. Plasma levels of Lp(a) lipoprotein were lower in the total preeclampsia group as well as in all preeclampsia subgroups (5.45 ± 7.41, 5.58 ± 8.02, 5.08 ± 5.38, and 4.32 ± 5.28 mg/dl in the total preeclampsia group, and in subgroups with mild preeclampsia, severe preeclampsia, and preeclampsia with fetal growth retardation, respectively) than in the control group (7.84 ± 9.26 mg/dl) as determined by quantitative electroimmunoassay. Corresponding results were obtained with a radioimmunoassay (166.03 ± 200.2 U/l in the total preeclampsia group vs. 229.18 ± 257.7 U/l in controls). There was good correlation between the two methods used for Lp(a) lipoprotein measurement. The differences between controls and the total preeclampsia group as well as each preeclampsia subgroup were statistically significant by a non‐parametric test (one‐way Kruskal‐Wallis test). Plasma concentrations of the active form of TGF‐β1 were increased in all preeclampsia subgroups as well as in the total group (5.63 ± 1.68 ng/ml) compared to controls (4.67 ± 1.33 ng/ml). This increase in TGF‐β1 was statistically highly significant. Plasma concentrations of Lp(a) lipoprotein and the active form of TGF‐β1 did not differ significantly between the preeclampsia subgroups. The outcome of this study may suggest involvement of both parameters in the pathophysiology of preeclampsia and may substantiate the notion of a multifactorial etiology of the disease.
High plasma levels of apo(a) fragments in Caucasians and African‐Americans with end‐stage renal disease: implications for plasma Lp(a) assay
Authors: Mooser Vincent , Marcovina Santica M. , Wang Jinping , Hobbs Helen H.
Published: July 2010

Apolipoprotein(a) [apo(a)] is a plasma glycoprotein that is highly polymorphic in size due to differences in the number of a tandemly arrayed cysteine‐rich repeat called kringle (K)4 at its N‐terminus. Most plasma apo(a) is covalently attached to apolipoprotein B‐100 and circulates as part of lipoprotein(a) [Lp(a)]. A fraction of apo(a) circulates free of lipoproteins. Almost all of the free apo(a) consists of fragments containing variable numbers of K4 repeats derived from the N‐terminal region. Previously we provided evidence suggesting that the apo(a) fragments present in human plasma are the source of the apo(a) fragments in human urine. If this were the case, it would be expected that plasma levels of fragments would be higher in subjects with end‐stage renal disease (ESRD). In this paper we quantified the levels of apo(a) fragments and plasma Lp(a) in 26 Caucasian and 26 African‐American subjects with ESRD and 52 healthy subjects matched for race, sex and the size of the apo(a) isoforms. The plasma levels of apo(a) fragments and Lp(a) were both higher in the ESRD subjects. In addition, the ratio of apo (a) fragments to total immunodetectable apo(a) was increased in ESRD. To determine how much the increase in the apo(a) fragments contributed to the increase in plasma Lp(a) in ESRD, the plasma Lp(a) levels were measured employing two different anti‐apo(a) enzyme‐linked immunoabsorption assays (ELISA). One assay detected both free and bound apo(a), whereas the other assay detected only bound apo(a). Although the plasma levels of apo(a) in the ESRD subjects tended to be higher using the assay that detected both fragments and full‐length apo(a), the increase was modest. Thus, although a greater proportion of the apo(a) in ESRD plasma circulates as fragments, most of the elevation in plasma levels of Lp(a) associated with renal insufficiency is due to an increase in intact Lp(a).
Standardization of Lp(a) measurements
Authors: Kostner Gert M. , Steinmetz Armin
Published: July 2010

The standardization of immunoassays for Lp(a) is a major challenge to clinical chemists. In order to establish a reference material acknowledged by the International Federation of Clinical Chemistry, the Center of Disease Control and possibly the World Health Organization, a working group with participants from four continents was put together. With the aid of 34 companies, eight proposed reference materials have been tested in the last 3 years and two of them have been selected for value assignment. A reference method based on dissociation‐enhanced, lanthanide fluorescence immunoassays was therefore developed which gives linear and parallel response curves by assaying freshly prepared primary reference standards, fresh plasma or serum as well as lyophilized or frozen proposed reference material. For value assignment, four laboratories simultaneously prepare primary reference standards with known isoforms and molecular weights. By assaying the amino acid composition of these primary reference standards, the molar concentration which is the basis of value transfer to the lyophilized proposed reference material can be calculated. In a final step, harmonization of all commercially available Lp(a) kits is to be tested by assaying 50 Lp(a) samples with increasing Lp(a) concentrations and varying isoforms. We hope to be able in the near future to create a basis for comparable results in epidemiological studies in different laboratories and also to help to improve future long‐term precision in clinical chemical laboratories.
22q11.2 deletions in a series of patients with non‐selective congenital heart defects: incidence, type of defects and parental origin
Authors: Fokstuen S. , Arbenz U. , Artan S. , Dutly F. , Bauersfeld U. , Brecevic L. , Fasnacht M. , Röthlisberger B. , Schinzel A.
Published: July 2010

Previous studies have indicated a wide spectrum of incidences of 22q11.2 deletions in isolated and syndromic (sporadic or familial) cases of conotruncal heart defects, whereby the detection rate of the deletion varied from 65% in one study to 0 in another. We analysed 110 patients with non‐selective syndromic or isolated non‐familial congenital heart malformations by fluorescence in situ hybridization (FISH) using the D22S75 DiGeorge chromosome (DGS) region probe. A 22q11.2 microdeletion has been detected in 9/51 (17.6%) syndromic patients. Five were of maternal origin and four of paternal origin. None of the 59 patients with isolated congenital cardiac defect had a 22q11.2 deletion. We compared the cardiac anomalies of our patients with a 22q11.2 deletion with those of previously published series and we describe types of congenital heart defects which appear to be often associated with a 22q11.2 deletion. The ability to detect such types of heart defects and to provide an early diagnosis of 22q11.2 deletion is particularly relevant in very young infants, who often show only very mild expression of the otherwise well‐characterized phenotypes of the DiGe‐orge/velo‐cardio‐facial syndrome (DG/VCFS).
Characterization of a novel mutation in exon 10 of the adrenoleukodystrophy gene
Authors: Holzinger Andreas , Maier Esther , Stöckler‐lpsiroglu Sylvia , Braun Andreas , Roscher Adelbert A.
Published: July 2010

We have detected a novel mutation in the adrenoleukodystrophy (ALD) gene in skin fibroblasts in primary culture derived from a patient suffering from the adrenocortical insufficiency‐only‐phenotype of ALD. This nonsense mutation (C2400T/Q672X) is the only mutation reported to date affecting exon 10. It leads to a translation product lacking the 74 C‐terminal amino acids. As a consequence of the loss of this region, which immediately follows the putative nucleotide binding domain, the ALD protein (ALDP) was not detectable at all by ALDP‐specific monoclonal antibodies. Since ALDP‐specific mRNA was readily detected in these fibroblasts, the loss of protein is probably not attributable to RNA instability but may be explained by protein instability. If the Q672X mutation leads in fact to an unstable translation product this would be consistent with the hypothesis that the C‐terminus is crucial for ALDP stability.
Holoprosencephaly: from Homer to Hedgehog
Authors: Ming Jeffrey E , Muenke Maximilian
Published: July 2010

Holoprosencephaly (HPE), a common developmental defect affecting the forebrain and face, is etiologically heterogeneous and exhibits wide phenotypic variation. Graded degrees of severity of the brain malformation are also reflected in the highly variable craniofacial malformations associated with HPE. In addition, individuals with microforms of HPE, who usually have normal cognition and normal brain imaging, are at risk for having children with HPE. Some obligate carriers for HPE may not have any phenotypic abnormalities. Recurrent chromosomal rearrangements in individuals with HPE suggest loci containing genes important for brain development, and abnormalities in these genes may result in HPE. Recently, Sonic Hedgehog (SHH) was the first gene identified as causing HPE in humans. Proper function of SHH depends on cholesterol modification. Other candidate genes that may be involved in HPE include components of the SHH pathway, elements involved in cholesterol metabolism, and genes expressed in the developing forebrain.
Kabuki (Niikawa‐Kuroki) syndrome associated with immunodeficiency
Authors: Chrzanowska Krystyna H , Krajewska‐Walasek M. , Kuś J. , Michalkdewicz J. , Maziarka D. , Wolski JK , Brecevic L. , Madaliński K.
Published: July 2010

We report a case of a 19‐year‐old male with the cardinal features of the Kabuki syndrome (KS) and, in addition, with severe immunodeficiency. Finding immune deficiency in a KS patient, prompted us to determine whether this association was related to a deletion within the DiGeorge chromosomal region. Fluorescence in situ hybridization (FISH) with the Oncor probe N25(D22S75) revealed no deletion of 22q11.2 in the patient.
Murine MPS I: insights into the pathogenesis of Hurler syndrome
Authors: Russell Christopher , Hendson Glenda , Jevon Gareth , Matlock Tina , Yu Jessica , Aklujkar Muktak , Ng Kwok‐Yu , Clarke Lome A
Published: July 2010

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme α‐L‐iduronidase. A murine model which shows complete deficiency in α‐L‐iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long‐term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.
Applicability of LDLR flanking microsatellite polymorphisms for prenatal diagnosis of homozygous state for familial hypercholesterolemia
Authors: Suva ER De Oliveirae , Haddad L. , Kwiterovich PO , Humphries SE , Day INM
Published: July 2010

Analysis of newly identified microsatellite polymorphisms flanking the low density lipoprotein receptor (LDLR) gene was undertaken in the kindred of a child with apparent homozygous LDLR deficiency. The applicability of these approaches to prenatal diagnosis is considered and compared with previous approaches applying functional studies of the LDLR in amniotic fibroblasts.
A ‘de novo’ point mutation of the low‐density lipoprotein receptor gene in an Italian subject with primary hypercholesterolemia
Authors: Cassanelli S. , Bertolini S. , Rolleri M. , Stefano F De , Casarino L. , Elicio N. , Naselli A. , Calandra S.
Published: July 2010

Severe hypercholesterolemia was found in an 11‐year‐old boy with no family history of familial hypercholesterolemia. The reduced LDL‐receptor activity in cultured skin fibroblasts (40%125I‐LDL degradation as compared with a control cell line) indicated the presence of an LDL‐receptor defect. The analysis of the promoter region and the exons of LDL‐receptor gene by single strand conformation polymorphism revealed an abnormal migration pattern in exon 1, which was due to a T A transversion at nucleotide 28 of the cDNA. This novel mutation causes an arginine for tryptophane substitution at position‐12 of the signal peptide (W‐12R) and introduces an AviII restriction site in exon 1. Screening of the mutation by polymerase chain reaction (PCR) amplification of exon 1 and AviII digestion revealed that none of the proband's family members carried the mutation. Non‐paternity was excluded after the analysis of a battery of 14 short tandem repeats located in 13 different chromosomes. These results are consistent with the hypothesis that the proband is heterozygous for a ‘de novo’ mutation of the LDL‐receptor gene producing a non‐conservative amino acid substitution. We suggest that the change in the net charge of the signal peptide, caused by the addition of a positively charged amino acid, impairs the co‐translational translocation of the nascent receptor protein across the endoplasmic reticulum membrane.
Deletion in chromosome region 22q11 in a child with CHARGE association
Authors: Devriendt Koen , Swillen Ann , Fryns Jean‐Pierre
Published: July 2010

We present a female child with features of the CHARGE association including iris coloboma, large ventricular septum defect (VSD), external ear abnormalities, severe growth retardation and moderate mental delay. A submicroscopic deletion in chromsome 22q11 was detected by means of fluorescence in situ hybridization (FISH) using probe D0832. The clinical features in this child compromise characteristics of both the velo‐cardio‐facial syndrome (VCFS) and the cat‐eye syndrome. This may suggest the presence of a more complex rearrangement of 22q, with a deletion‐duplication.
Phenotypic and genotypic variability in monozygotic triplets with Turner syndrome
Authors: Lespinasse J. , Gicquel C. , Robert M. , Bouc Y. Le
Published: July 2010

Turner syndrome (TS) is a common disorder (1/2500 and 1/5000 female births) which is diagnosed at birth in approximately 20% of patients and during childhood (usually due to growth retardation) or later, (due to lack of pubertal development) for the remaining patients. Here we present a cytogenetic and molecular analysis of three monozygotic sisters. The diagnosis of TS was done for one of them (patient 1) who presented with a typical Turner phenotype. A first karyotype was established as normal and a second karyotype (carried out on 200 cells) revealed a 45,X/46,XX mosaicism with 6% of cells with a 45,X karyotype. Lymphocyte karyotype analysis showed the same mosaicism pattern for the two other sisters, one of them exhibiting only a mild (patient 2) and the other no clinical features of Turner syndrome (patient 3). Karyotype analysis was this time conducted on fibroblasts and showed that the 45,X/46,XX mosaicism pattern correlated with the clinical phenotype with 99, 43 and 3% of 45,X cells in patients 1, 2, and 3, respectively.

These data suggest that different tissues other than lymphocytes should be subjected to a karyotype analysis when the observed genotype does not correlate with the clinical phenotype.
De novo direct duplication 2 (p12 p21) with paternally inherited pericentric inversion 2p11.2 2q12.2
Authors: Magee A. C. , Humphreys M. W. , McKee S. , Stewart M. , Nevin N. C.
Published: July 2010

We report a 4‐year‐old girl with a previously undescribed de novo duplication of 2p12 → 2p21 on the same homologue as a paternally inherited pericentric inversion of region 2p11.2 → 2q12.2, resulting in dysmorphic features, cardiac abnormality, cleft palate, respiratory problems, severe growth retardation and developmental delay. This case raises an important question ‐ did the paternal pericentric inversion influence the occurrence of the de novo duplication?
Autosomal dominant inheritance of adducted thumbs and other digital anomalies
Authors: Miranda A. , Zenteno J. C. , Santiago E. , Kofman‐Alfaro S.
Published: July 2010

Isolated adducted thumbs is an uncommon malformation that occurs sporadically in the majority of cases although some affected families have been reported. Previously, autosomal dominant inheritance was suggested in two familial cases, but this mode of inheritance has not been confirmed. Here we describe a family with adducted thumbs and other digital anomalies in which seven members (six females and one male) are affected in three consecutive generations. Additionally, the patients showed mild abnormalities of fingers 2nd–4th bilaterally and hypoplasia of the middle phalanx of the 5th fingers. This family represents an autosomal dominant condition that apparently has not been previously reported.
Marden—Walker syndrome versus isolated distal arthrogryposis: Evidence that both conditions may be variable manifestations of the same mutated gene
Authors: Fryns J. P. , Willekens D. , van Schoubroeck D. , Moerman Ph.
Published: July 2010

In this report we present evidence that Marden‐Walker syndrome and isolated distal arthrogryposis may be variable manifestations of the same entity.

We describe the clinical and pathological findings in two affected siblings, the first two children of normal, non‐consanguineous parents. The first child, a female, presented a typical Marden–Walker syndrome with Dandy–Walker type CNS malformation, corpus callosum hypoplasia and enlarged ventricles. In the second pregnancy, echographic examination revealed joint contractures of the hands and feet. Feto‐pathological examination revealed a normocephalic male fetus with severe distal arthrogryposis. There was no facial dysmorphism and pathological examination of the brain, the spinal cord and muscle was normal.
Infectious complications of propionic acidemia in Saudia Arabia
Authors: Essa M. Al. , Rahbeeni Z. , Jumaah S. , Joshi S. , Jishi E. Al. , Rashed M. S. , Amoudi M. Al. , Ozand P. T.
Published: July 2010

A retrospective study of 38 patients with propionic acidemia indicates a high frequency of infections; affecting 80% of such patients. The Saudi Arabian population studied is a product of consanguineous marriages, and presents with a severe phenotype. Most microorganisms implicated are unusual, which suggests an underlying immune deficiency. These frequent infections occur despite aggressive treatment with appropriate diets, carnitine and during acute episodes of the disease with metro‐nidazole, which suggests a global effect of the disease on T and B lymphocytes as well as on the bone marrow cells. Any patient with propionic acidemia should be closely followed up for an intercurrent infection in association with acute metabolic decompensation.
A gene‐dosage PCR method for the detection of elastin gene deletions in patients with Williams syndrome
Authors: del Rio Tony , Urbán Zsolt , Csiszár Katalin , Boyd Charles D
Published: July 2010

Williams syndrome (WS) is a multisystem developmental disorder associated with microdeletions at 7q11.23 that involve several genes, including the elastin gene. Using genomic DNA from a panel of normal individuals and WS patients with established hemizygosity of the elastin gene locus, we have developed a quantitative polymerase chain reaction (PCR)‐based gene‐dosage assay that rapidly detects the loss of one allele of the elastin gene. Using this procedure, we also studied a family in which the proband was previously diagnosed with WS and her mother with a balanced 7q translocation [t(7:11)(q34;q13)]. Using DNA isolated from buccal smears obtained from several individuals in this family we were able to establish normal disomy at 7q in all family members except for the proband, in which we established hemizygosity at the elastin gene locus. We were also able to successfully infer normal disomy in an unborn child in this family. The rapid diagnostic procedure described here may have a variety of applications, including fine mapping of deletion breakpoints at 7q11.23 associated with WS.
Neuropathological findings in Moebius syndrome
Authors: Lammens M. , Moerman Ph , Fryns JP , Schröder JM , Spinnewyn D. , Casaer P. , Dom R.
Published: July 2010

Pathological findings in two patients with Moebius syndrome and lethal fetal akinesia sequence are described. In both patients a congenital brain stem malformation with neuronal loss in the cranial nerve nuclei and tegmental microcalcifications was observed. In one patient, the association with splenogonadal fusion was observed, whilst in the second patient, the association with tetraperomelia was present. As the association of peromelia and splenogonadal fusion is a well‐known association, the different combination of splenogonadal fusion, peromelia and Moebius syndrome due to congenital brain stem anomalies with necrosis might be the result of a disruptive phenomenon during a prolonged vulnerable critical period in the 5th and 6th week of embryonic life. The finding of olivary dysplasia in one case, reminiscent of olivary dysplasia in Zellweger syndrome and in Miller–Dieker syndrome, might suggest a primary malformation underlying Moebius syndrome due to brain stem defects.
Predictive testing for Huntington's disease: II. Qualitative findings from a study of uptake in South Wales
Authors: Binedell Julia , Soldan Jo R , Harper Peter S
Published: July 2010

Semi‐structured interviews were conducted with a cohort of 22 test applicants who requested Huntington's disease (HD) predictive testing in South Wales, and a random sample of 32 non‐requesters, drawn from the South Wales HD register. Apart from identifying differences between the groups, the study afforded the opportunity to listen, at length, to at‐risk individuals' accounts of living at risk and their thoughts about predictive testing and genetic services. Emergent themes included difficulties in family communication and the uncertainties inherent in being at risk and undergoing testing. Important factors in decision making about testing were: moral imperatives to clarify one's genetic status; views about the controllability of the future; family attitudes and norms; and the impact of a test result on family members. At‐risk individuals' perceptions of the genetics service were that contact with the service would result in pressure to be tested and a need for test applicants to present a favourable view of coping capacities to secure testing. In addition, there was an expectation of ongoing contact with HD families at the initiative of the service providers. Implications of the findings for the way in which predictive testing services are structured and introduced to the at‐risk population are discussed.
Analysis of the transactivation domain of the androgen receptor in patients with male infertilitv
Authors: Wang Q. , Ghadessy FJ , Yong EL
Published: July 2010

Wang Q, Ghadessy FJ, Yong EL. Analysis of the transactivation domain of the androgen receptor in patients with male infertility. Clin Genet 1998: 54: 185–192. 0 Munksgaard, 1998

Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) in XY individuals ranging from phenotypic females, to defective spermatogenesis in otherwise normal males. We screened the non‐polymorphic regions of exon 1, transactivation domain (TAD), of the AR gene in 153 subjects with varying degrees of defective spermatogenesis of unknown aetiology, and compared them to 100 healthy fertile controls. Three different single‐strand conformation polymorphisms were detected and sequencing of the mutant fragments revealed three G+A transitions in codons 210, 211 and 214. The first two mutations were polymorphisms and the transition in codon 211 was related to ethnic origin occurring in 10–15% of Indian or Middle‐Eastern subjects, but not in the majority of Chinese. The third mutation resulted in a non‐conservative glycine to arginine substitution at codon 214 (G214R) and was associated with ˜ 20% lower transactivation capacity compared to the wild‐type (WT). This study, the first screening of the AR TAD for subtle mutations, in a large group of males with defective spermatogenesis, has uncovered novel polymorphisms which may be useful in ethnic studies. Although a possible pathogenic mutation was uncovered, mutations of the non‐polymorphic portions of the TAD of the AR do not appear to have a major role in the aetiology of idiopathic male infertility.
Identification of two novel mutations in the OCRLI gene in Japanese families with Lowe syndrome
Authors: Kubota Takeo , Sakurai Akihiro , Arakawa Kazuo , Shirnazu Mitsunobu , Wakui Keiko , Furihata Kenichi , Fukushirna Yoshimitsu
Published: July 2010

Kubota T, Sakurai A, Arakawa K, Shimazu M, Wakui K, Furihata K, Fukushima Y. Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. Clin Genet 1998: 54: 199–202. 0 Munksgaard, 1998

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X‐linked disorder with features of congenital cataracts. Fanconi syndrome of the renal tubule, and mental retardation. The OCRLI gene has been positionally cloned and shown to encode a phosphatidylinositol 4.5–biphos‐phate‐5–phosphatase. OCRL is thus thought to be an inborn error of inositol polyphosphate metabolism. We analyzed the gene in two Japanese OCRL patients and their families by DNA sequencing and mismatch polymerase chain reaction (PCR) followed by restriction digestion. A novel nonsense mutation (C1399T) replacing the glutamine of codon 391 (Gln 391 Stop) was identified in exon 12 in 1 patient and also in his mother. A novel missense mutation (C1743G) was identified in exon 15 in the second patient, his mother and maternal grandmother. The missense mutation predicts a substitution of serine for arginine (Ser 505 Arg) in a domain highly conserved among the inosi‐tol‐5–phosphatase family. Our observations expand the range of OCRLI mutations that cause Lowe syndrome. and will be useful for genetic counseling in these two Fdmilies.
Genetics of Noonan syndrome – a new gene, and the search is still on
Authors: Stein RA
Published: July 2010

Germline gain‐of‐function mutations in SOS1 cause Noonan syndrome Roberts et al. (2007) Nature Genetics 39: 70–74

Gain‐of‐function SOS1 mutations cause a distinctive form of Noonan syndrome Tartaglia et al. (2007) Nature Genetics 39: 75–79
Interstitial deletion of chromosome 4p associated with mild mental retardation, epilepsy and polymicrogyria of the left temporal lobe
Authors: Møller RS , Hansen CP , Jackson GD , Ullmann R , Ropers HH , Tommerup N , Tümer Z
Published: July 2010

In this study, we present a 38‐year‐old woman with an interstitial deletion of 4p15.1‐15.3, mild mental retardation, epilepsy and polymicrogyria adjacent to an arachnoid cyst of the left temporal lobe. The deletion was ascertained through array‐comparative genome hybridization screening of patients with epilepsy and brain malformations. To date, about 35 patients with cytogenetically visible deletions involving 4p15 and without Wolf‐Hirschhorn syndrome have been described, but the extent of the deletions has not been determined in the majority of these cases. The clinical manifestations of the patient described in this study were similar but not identical to the previously reported cases with 4p15 interstitial deletions. This finding indicates the presence of one or more genes involved in brain development and epilepsy in this chromosome region.
Germline hMSH2 promoter mutation in a Chinese HNPCC kindred: evidence for dual role of LOH
Authors: Yan H , Jin H , Xue G , Mei Q , Ding F , Hao L , Sun S‐H
Published: July 2010

Hereditary non‐polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer predisposition syndrome that is caused by germline mutations in mismatch repair genes. By screening the core promoters of hMSH2, hMLH1, and hMSH6 in 37 Chinese suspected HNPCC families, a novel germline mutation c.−78_−79delGT was found in the hMSH2 promoter. Its pathogenic effects were supported by the following findings: (a) it co‐segregated with HNPCC‐related cancers and was not present in the 220 control subjects, (b) tumors harboring the mutation lacked the expression of hMSH2 and showed high microsatellite instability, (c) it significantly decreased the promoter activity, and (d) it abolished the binding ability of the transcription factor E1A‐F. Loss of heterozygosity (LOH) was found in three of the tumors studied. Intriguingly, in the tumors from patients II:1 and III:1, LOH occurred in the wild‐type allele and agreed well with the traditional ‘two‐hit’ model. In contrast, in the tumor from patient III:3, LOH occurred in the mutant allele. A pathogenic somatic mutation (c.2210+1G>A) was also found in this tumor; therefore, we proposed that the ‘second hit’ was inactivated by somatic mutation, and the mutant allele was lost during tumor progression; this provided evidence for the new hypothesis for the dual role of LOH.
The use of genetic testing in hereditary colorectal cancer syndromes: genetic testing in HNPCC, (A)FAP and MAP
Authors: Ramsoekh D , van Leerdam ME , Tops CMJ , Dooijes D , Steyerberg EW , Kuipers EJ , Wagner A
Published: July 2010

This study evaluated the use of genetic testing and time trends in hereditary non‐polyposis colorectal cancer (HNPCC), (attenuated) familial adenomatous polyposis [(A)FAP] and human MutY homolog (MUTYH) associated polyposis (MAP) families. Eighty‐seven families, who were diagnosed with disease‐causing mutations between 1995 and 2006, were included in this study. The families consisted of 1547 individuals at risk. Data of these individuals were collected from medical records and family pedigrees. There was considerable interest in genetic testing with test rates of 41% in HNPCC families, 42% in (A)FAP families and 53% in MAP families. The use of genetic testing was associated with age and parenthood. Despite the interest in genetic testing, many risk carriers do not apply for testing. Moreover, time trend analysis showed a decline in test rate in HNPCC families. Studies evaluating the reasons for not testing are needed. Furthermore, a better implementation of genetic testing in clinical practice is desirable.
Random regression models on Legendre polynomials to estimate genetic parameters for weights from birth to adult age in Canchim cattle*
Authors: Baldi F. , Albuquerque L.G. , Alencar M.M.
Published: July 2010

The objective of this work was to estimate covariance functions for direct and maternal genetic effects, animal and maternal permanent environmental effects, and subsequently, to derive relevant genetic parameters for growth traits in Canchim cattle. Data comprised 49 011 weight records on 2435 females from birth to adult age. The model of analysis included fixed effects of contemporary groups (year and month of birth and at weighing) and age of dam as quadratic covariable. Mean trends were taken into account by a cubic regression on orthogonal polynomials of animal age. Residual variances were allowed to vary and were modelled by a step function with 1, 4 or 11 classes based on animal’s age. The model fitting four classes of residual variances was the best. A total of 12 random regression models from second to seventh order were used to model direct and maternal genetic effects, animal and maternal permanent environmental effects. The model with direct and maternal genetic effects, animal and maternal permanent environmental effects fitted by quadric, cubic, quintic and linear Legendre polynomials, respectively, was the most adequate to describe the covariance structure of the data. Estimates of direct and maternal heritability obtained by multi‐trait (seven traits) and random regression models were very similar. Selection for higher weight at any age, especially after weaning, will produce an increase in mature cow weight. The possibility to modify the growth curve in Canchim cattle to obtain animals with rapid growth at early ages and moderate to low mature cow weight is limited.
Antifungal action of the oxathiolone‐fused chalcone derivative
Authors: Łącka Izabela , Konieczny Marek T. , Bułakowska Anita , Rzymowski Tomasz , Milewski Sławomir
Published: July 2010

AMG‐148, an oxathiolone‐fused chalcone derivative, exhibited in vitro antifungal activity against several strains of human pathogenic yeast, with minimum inhibitory concentration values within the range of 1–16 μg ml−1 and a fungicidal effect was observed at higher concentrations. Presence of major drug‐effluxing membrane proteins Cdr1p, Cdr2p or Mdr1p, did not affect substantially the fungistatic activity of this compound against clinical Candida albicans strains. Studies on the mode of action revealed that AMG‐148 inhibited chitin and β(1→3)glucan biosynthesis and was in vitro an inhibitor of β(1→3)glucan synthase. Inhibition of chitin biosynthesis was responsible for fungistatic activity, while the fungicidal effect was a consequence of disturbance of β(1→3)glucan synthase function. The chalcone derivative may be a useful lead compound for the development of novel antifungal agents.
The Expression of FSH Receptor (FSHR) in the Neonatal Porcine Ovary and its Regulation by Flutamide
Authors: Durlej M , Knapczyk‐Stwora K , Duda M , Galas J , Slomczynska M
Published: July 2010

Contents

This study was designed to reveal the FSHR mRNA and protein expression in the neonatal porcine ovary and to determine whether maternal administration of antiandrogen flutamide may affect FSHR expression in the ovary of newborn piglets using real‐time PCR, immunohistochemistry and Western blot analysis. Pregnant sows were injected with flutamide at a dose of 50 mg/kg body weight, given five times, every second day, starting at day 20 post‐coitum (p.c.) or day 80 p.c., and ovaries were obtained from neonatal pigs. The FSHR mRNA expression was significantly decreased after flutamide administration. Furthermore, higher down‐regulation was observed following exposure to antiandrogen at day 20 than at day 80 p.c. Immunohistochemistry showed the positive immunostaining for FSHR in the oocytes, granulosa cells of primary follicles and the surface epithelium of the ovaries from both control and flutamide‐treated pigs. However, oocytes and granulosa cells of primary follicles in the ovaries exposed in utero to flutamide were weakly immunostained when compared to those in the control ones. The presence of FSHR protein in all investigated ovaries was confirmed by Western blot analysis. Based on our findings, we suggest that FSHR may be involved in the early follicle formation in pigs, which begins during prenatal life. Furthermore, the regulation of FSHR mRNA and protein expression in neonatal porcine ovaries after maternal exposure to flutamide confirms that androgens play a crucial role in porcine folliculogenesis at the early stages.
Expression of Thy 1.2 surface antigen increases significantly during the murine mesenchymal stem cells cultivation period
Authors: Eslaminejad Mohamadreza Baghaban , Nadri Samad , Hosseini Reza Hajji
Published: July 2010

This study sought to investigate the absence or expression of some surface antigens on murine mesenchymal stem cells (mMSCs) during the cultivation period of primary culture to passage 3 (equivalent to about 15 or 16 population doubling number). For this purpose, bone marrow cells from 6–8‐week‐old mice (either NMRI or Balb/c) were cultivated in 75‐cm2 culture flask for three successive passages, in each of which the culture was examined for the expression of CD135, CD44, CD31, Thy1.2, CD11b, CD45, CD34, Vcam1, Sca‐1, and c‐Kit antigens, using flow cytometry. Passage‐3 cells from each strain can easily be differentiated into bone and fat, which was indicative of their mesenchymal nature. Our results demonstrated that for each given antigen, the percentages of the cells expressing that antigen had been changed by subcultures. The statistical analysis showed that nearly all differences between the passages were statistically significant. In this term, the expressional changes of Thy 1.2 seemed to be very significant in such a way that the expression increased to about half of the whole population in passage 3. In conclusion, it seems that this antigen could be considered as an enriching antigen for mMSCs population from bone marrow adherent cell culture.
Difficult physician–patient encounters
Authors: Breen K. J. , Greenberg P. B.
Published: July 2010

Consultant physicians encounter patients, and families and carers of patients, who leave us feeling helpless, frustrated, irritated and even angry. There are limited opportunities for trainees and physicians to discuss how to recognize, manage, learn from and prevent these difficult physician–patient encounters. This paper addresses factors, including physician factors, that may contribute to making encounters difficult, categorizes the types of difficult encounters and provides generic and specific suggestions (based in part on published literature and in part on our personal experience) about prevention and management of many of them.
Dopamine and cognitive control: the prospect of monetary gains influences the balance between flexibility and stability in a set‐shifting paradigm
Authors: Müller Johannes , Dreisbach Gesine , Goschke Thomas , Hensch Tilman , Lesch Klaus‐Peter , Brocke Burkhard
Published: July 2010

Positive affect and the activity of the neurotransmitter dopamine seem to shift the balance between cognitive flexibility vs stability towards increased flexibility. Here we examined the impact of prospective monetary gains on this balance. Seventy healthy volunteers performed a set‐shifting task comprising a condition in which a bias towards new stimuli helped to overcome perseveration and increased flexibility, and a second condition in which directing attention towards new stimuli increased distractibility. From previous studies of executive functions, two contrasting predictions can be derived: the prospect of monetary gains might either increase cognitive flexibility due to a dopamine release in the prefrontal cortex or increase stability due to an assessment of high utility of action processed in the anterior cingulated cortex and orbitofrontal cortex. Overall, we observed increased cognitive stability in the face of prospective gains (η2 = 7%). However, this effect was modulated by the subjective evaluation of the reward cues: participants who reported increasing their effort in response to reward cues showed increased cognitive stability, whereas those who reported a positive and relaxed attitude towards the reward cues showed increased flexibility (η2 = 11%). The results thus suggest that the flexibility–stability balance is modulated by the perceived effort needed to receive the potential reward. On a neuropsychological level, an interaction of dopaminergic and noradrenergic processes might be involved in the allocation of control.
Contrasting effects of basic fibroblast growth factor and epidermal growth factor on mouse neonatal olfactory mucosa cells
Authors: Barraud Perrine , He Xiaoling , Zhao Chao , Ibanez Chrystelle , Raha‐Chowdhury Ruma , Caldwell Maeve A. , Franklin Robin J. M.
Published: July 2010

Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) affect proliferation and survival of many cell types, but their role in the maintenance of olfactory mucosa cells remains unclear. In the neonatal mouse olfactory mucosa, cell proliferation mainly occurs in the neuroepithelium and, to a lesser extent, in the lamina propria. To establish whether bFGF and EGF affect proliferation and/or survival of these cells, we isolated olfactory mucosa cells from the neonatal mouse and cultured them as free‐floating spheres under bFGF or EGF stimulation. Our data demonstrate that bFGF is a mitogen for the rapidly dividing cells (olfactory neuronal precursors and olfactory ensheathing cells), and also a survival factor for both slowly and rapidly dividing cells of the olfactory mucosa. In contrast, EGF appears to be primarily a survival factor for both the olfactory stem and precursor cells.
Basolateral amygdala inactivation by muscimol, but not ERK/MAPK inhibition, impairs the use of reward expectancies during working memory
Authors: Savage Lisa M. , Koch Andrew D. , Ramirez Donna R.
Published: July 2010

Rats were trained on a delayed matching to position (DMTP) task that embedded either a differential outcomes procedure (DOP) or a non‐differential outcomes procedure (NOP). The DOP, via Pavlovian conditioning (stimulus–outcome associations), results in the use of unique reward expectancies that facilitate learning and memory performance above subjects trained with a NOP that requires subjects to retain cue information for accurate choice behavior (stimulus–response associations). This enhancement in learning and/or memory produced by the DOP is called the differential outcomes effect (DOE). After being trained on the DMTP task, rats were implanted with two cannulae aimed at the basolateral amygdala (BLA) nuclei. Rats trained with the DOP, relative to those trained with the NOP, displayed enhanced short‐term memory (STM) performance under vehicle conditions (i.e. the DOE). However, injections of the γ‐aminobutyric acid (GABA)A agonist muscimol into the BLA dose‐dependently (0.0625 and 0.125 µg) impaired STM performance only in DOP‐trained rats. These results support the role of the BLA in the use of established reward expectancies during a short‐term working memory task. Despite the fact that extracellular signal‐regulated kinase/mitogen‐activated protein kinases (ERK/MAPK) have been shown to be necessary for amygdala‐dependent long‐term potentiation and some forms of long‐term and STM, inhibition of the ERK/MAPK signaling cascade by U0126 (2.0 or 4.0 µg) in the BLA was not critical for updating the STM of either spatial information or reward expectation.
Cholinergic modulation of visuospatial responding in central thalamus
Authors: Newman Lori A. , Mair Robert G.
Published: July 2010

Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory‐guided goal‐directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABAA agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 µmol/kg) and scopolamine (0.03, 0.09, 0.26 µmol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3‐s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention‐demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors.
Exercise normalizes levels of MAG and Nogo‐A growth inhibitors after brain trauma
Authors: Chytrova Gabriela , Ying Zhe , Gomez‐Pinilla Fernando
Published: July 2010

Myelin is a major obstacle for axonal growth after CNS injury, to the extent that it is crucial to develop interventions to counteract postinjury growth inhibition and foster neural repair. We have studied the effects of the fluid percussion injury (FPI) model of traumatic brain injury (TBI) on protein levels of two myelin‐associated molecules, myelin‐associated glycoprotein (MAG) and Nogo‐A, in the adult rat. We found that FPI elevated hippocampal levels of MAG and Nogo‐A. Given the beneficial effects of exercise on CNS function, we evaluated the capacity of exercise to reduce these myelin‐derived proteins after FPI. One week of voluntary running wheel exercise overcame the injury‐related increase in MAG and Nogo‐A. The action of brain‐derived neurotrophic factor (BDNF) has been associated with exercise as well as with the modulation of growth inhibition in vitro. We found that the selective blockade of BDNF using the immunoadhesive chimera TrkB‐IgG abolished the effects of exercise on MAG and Nogo‐A. FPI reduced levels of growth‐associated protein 43 (GAP‐43), a marker of axonal growth, and synaptophysin (SYP), an indicator of synaptic growth. Exercise counteracted the effects of FPI on GAP‐43 and SYP, while BDNF blockade abolished these effects of exercise. Protein kinase A (PKA) has been related to the ability of BDNF to overcome growth inhibition. In agreement, we found that exercise increased PKA levels and this effect was prevented by BDNF blockade. These results indicate that exercise promotes a permissive cellular environment for repair after TBI, in a process in which BDNF plays a central role.