Sibpair studies implicate chromosome 18 in essential hypertension

Interest in chromosome 18 in essential hypertension comes from comparative mapping of rat blood pressure quantitative trait loci (QTL), familial orthostatic hypotensive syndrome studies, and essential hypertension pedigree linkage analyses indicating that a locus or loci on human chromosome 18 may play a role in hypertension development. To further investigate involvement of chromosome 18 in human essential hypertension, the present study utilized a linkage scan approach to genotype twelve microsatellite markers spanning human chromosome 18 in 177 Australian Caucasian hypertensive (HT) sibling pairs. Linkage analysis showed significant excess allele sharing of the D18S61 marker when analyzed with SPLINK (P=0.00012), ANALYZE (Sibpair) (P=0.0081), and also with MAPMAKER SIBS (P=0.0001). Similarly, the D18S59 marker also showed evidence for excess allele sharing when analyzed with SPLINK (P=0.016), ANALYZE (Sibpair) (P=0.0095), and with MAPMAKER SIBS (P = 0.014). The adenylate cyclase activating polypeptide 1 gene (ADCYAP1) is involved in vasodilation and has been co-localized to the D18S59 marker. Results testing a microsatellite marker in the 3′ untranslated region of ADCYAP1 in age and gender matched HT and normotensive (NT) individuals showed possible association with hypertension (P = 0.038; Monte Carlo P = 0.02), but not with obesity. The present study shows a chromosome 18 role in essential hypertension and indicates that the genomic region near the ADCYAP1 gene or perhaps the gene itself may be implicated. Further investigation is required to conclusively determine the extent to which ADCYAP1 polymorphisms are involved in essential hypertension. © 2003 Wiley-Liss, Inc.

High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort

Copy number variations (CNVs) as described in the healthy population are purported to contribute significantly to genetic heterogeneity. Recent studies have described CNVs using lymphoblastoid cell lines or by application of specifically developed algorithms to interrogate previously described data. However, the full extent of CNVs remains unclear. Using high-density SNP array, we have undertaken a comprehensive investigation of chromosome 18 for CNV discovery and characterisation of distribution and association with chromosome architecture. We identified 399 CNVs, of which loss represents 98%, 58% are less than 2.5 kb in size and 71% are intergenic. Intronic deletions account for the majority of copy number changes with gene involvement. Furthermore, one-third of CNVs do not have putative breakpoints within repetitive sequences. We conclude that replicative processes, mediated either by repetitive elements or microhomology, account for the majority of CNVs in the healthy population. Genomic instability involving the formation of a non-B structure is demonstrated in one region.

Expression of high amounts of the CD117 molecule in a case of B-cell non-Hodgkin's lymphoma carrying the t(14:18) translocation.

The c-kit proto-oncogen (CD117) has been described to be present in normal and neoplastic hemopoietic cells including both myeloid and lymphoid lineages. Among the normal lymphoid cells CD117 expression would be restricted to a small subset of NK-cells, and to early T-cell precursors and it is not expressed by normal B-cells. Regarding chronic lymphoproliferative disorders the only data provided up to now suggests that CD117 expression is restricted to cases of Hodgkin's disease and anaplastic large-cell lymphoma. In the present paper we describe a case of a B-cell chronic lymphoproliferative disorder carrying the t(14:18) translocation as demonstrated by molecular studies, in which the flow cytometric immunophenotypic analysis of both peripheral blood and bone marrow samples revealed the expression of high amounts of the CD117 antigen in the surface of the clonal B-cell population. Further studies are necessary to explore both the functional role of c-kit expression in the neoplastic B-cells from this patient and its potential utility for the diagnosis and follow-up of patients with B-cell non-Hodgkin's lymphoma.

Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from Australia and the Netherlands

CONTEXT People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders. OBJECTIVES To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency. DESIGN Genome-wide linkage scan. SETTING Twin individuals and their family members from Australia and the Netherlands. PARTICIPANTS Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers. METHODS Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results. RESULTS Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice. CONCLUSIONS Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.

Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Keratosis pilaris and prevalence of acne vulgaris: a cross-sectional study

BACKGROUND: Acne vulgaris has an important genetic predisposition, as well as keratosis pilaris. Clinical observations suggest that patients with keratosis pilaris have less frequent or less severe acne breakouts; however, we found no studies on this regard OBJECTIVE: To determine if the presence of keratosis pilaris is associated with lower prevalence and severity of acne. METHODS: A cross-sectional study was conducted with dermatology outpatients aged between 14 and 35 years. We evaluated history and clinical grade of acne, demographic variables, history of atopy, smoking, and use of hormonal contraceptives. Two groups were defined by the presence or absence of moderate to severe keratosis pilaris on the arms and were compared by bivariate analysis and by conditional multiple logistic regression. RESULTS: We included 158 patients (66% women), with a median age of 23 +/- 11 years. Twenty-six percent of them had keratosis pilaris, which was associated with a history of atopy (odds ratio [OR]=2.80 [1.36 to 5.75]; p<0.01). Acne was present in 66% of subjects, and was related to family history of acne (OR=5.75 [2.47 to 13.37]; p<0.01). In bivariate and multivariate analysis, the group with keratosis pilaris had a less frequent history of acne (OR=0.32 [0.14 to 0.70]; p<0.01). CONCLUSION: The presence of moderate to severe keratosis pilaris on the arms was associated with lower prevalence of acne vulgaris and lower severity of facial lesions in adolescents and young adults.

Mapeamento físico dos genes ribosomais 18S e 5S em peixes do gênero Trichomycterus (Teleostei, Trichomycteridae)

The present study aimed to cytogenetic analysis and structural and molecular level of four fish species of the genus Trichomycterus: T. diabolus, T. iheringi, T. zonatus and T. cf. mimonha collected in different river basins in Brazil. Techniques were used for classical cytogenetic (Giemsa, Silver nitrate impregnation, C-banding) and molecular with the chromosomal location of genes for 18S and 5S rDNA. All individuals examined had a diploid number 54 chromosomes and karyotype consisting of types of metacentric, submetacentric and subtelocentric. The constitutive heterochromatin identified by C-banding was observed in two small blocks in the karyotype of T. diabolus and large blocks of centromeric several pairs in chromosomal karyotypes of T. iheringi, T. zonatus and T. cf. mimonha. The Silver nitrate impregnation and hybridization with 18S rDNA probe revealed the existence of only a couple carryng nucleolar organizing regions (NORs) on the species T. diabolus, T. iheringi and T. cf mimonha, and two pairs carrying 18S rDNA in T. zonatus. The 5S rDNA was observed in interstitial position 6 of the pair in T. iheringi, the synteny with the two pair in 18S rDNA of T.diabolus in pericentromeric position of and two pairs submetacentric, one being also a case of synteny with the 18S rDNA in T. zonatus and T. cf. mimonha, this rDNA was located in the pairs 3, 18 and 25, and synteny in the 18S rDNA pair 18. Although representatives of these four species Trichomycterus present diploid number and karyotypic formula preserved, three is specific about the distribuition patterns of heterochromatin and location of rDNA sequences, indicating that chromosomal differentiation events in this group of fish are acting directly on these genomic portions

Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescence in situ hybridisation and array-based comparative genomic hybridisation.

Deletion of the TP53 gene on chromosome 17p13.1 is the prognostic factor associated with the shortest survival in CLL. We used array-based comparative genomic hybridisation (arrayCGH) to identify additional DNA copy number changes in peripheral blood samples from 74 LRF CLL4 trial patients, 37 with >or=5% and 37 without TP53-deleted cells. ArrayCGH reliably detected deletions on 17p, including the TP53 locus, in cases with >or=50%TP53-deleted cells detected by fluorescence in situ hybridisation, plus seven additional cases with deleted regions on 17p excluding TP53. Losses on chromosomal regions 18p and/or 20p were found exclusively in cases with >or=5%TP53-deleted cells (por=5%TP53-deleted cases (p=0.02). In particular, amplification of 2p and deletion of 6q were both more frequent. Cases with >20%TP53-deleted cells had the worst prognosis in the LRF CLL4 trial.

Inward-Inclined Implant Platform for the Amplified Platform-Switching Concept: 18-Month Follow-up Report of a Prospective Randomized Matched-Pair Controlled Trial

Purpose: This prospective randomized matched-pair controlled trial aimed to evaluate marginal bone levels and soft tissue alterations at implants restored according to the platform-switching concept with a new inward-inclined platform and compare them with external-hexagon implants. Materials and Methods: Traditional external-hexagon (control group) implants and inward-inclined platform implants (test group), all with the same implant body geometry and 13 mm in length, were inserted in a standardized manner in the posterior maxillae of 40 patients. Radiographic bone levels were measured by two independent examiners after 6, 12, and 18 months of prosthetic loading. Buccal soft tissue height was measured at the time of abutment connection and 18 months later. Results: After 18 months of loading, all 80 implants were clinically osseointegrated in the 40 participating patients. Radiographic evaluation showed mean bone losses of 0.5 +/- 0.1 mm (range, 0.3 to 0.7 mm) and 1.6 +/- 0.3 mm (range, 1.1 to 2.2 mm) for test and control implants, respectively. Soft tissue height showed a significant mean decrease of 2.4 mm in the control group, compared to 0.6 mm around the test implants. Conclusions: After 18 months, significantly greater bone loss was observed at implants restored according to the conventional external-hexagon protocol compared to the platform-switching concept. In addition, decreased soft tissue height was associated with the external-hexagon implants versus the platform-switched implants. INT J ORAL MAXILLOFAC IMPLANTS 2012;27:927-934.

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes

Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a critical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the Salmonella typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence of ethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2Cl2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-transferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2′-deoxyguanosine to yield a major adduct, identified as S-[1-(N2-deoxyguanosinyl)methyl]GSH. Demonstration of the activation of dihalomethanes by this mammalian GSH S-transferase theta class enzyme should be of use in evaluating the risk of these chemicals, particularly in light of reports of the polymorphic expression of a similar activity in humans.

Self-assembly of a polymer pair through poly(lactide) stereocomplexation

A polymer pair composed of poly( N-isopropylacrylamide-co-2-hydroxyethyl methacrylate terminated oligo( L-lactide)) ( poly( NIPAAm-co-HEMAOLLA)) graft random copolymer and poly( D-lactide) ( PDLA) homopolymer was self-assembled into micelles with a diameter around 100 nm through the stereocomplexation between the OLLA branches of the graft copolymer and the PDLA homopolymer. The specific intermolecular stereocomplexation was considered as the powerful ordered aggregation force in the micelle cores. The shell's component of poly( NIPAAm-co-HEMA) and its thermosensitivity were proved by H-1 nuclear magnetic resonance ( NMR) and dynamic light scattering ( DLS), respectively. The incorporation of PDLA homopolymer into the graft copolymer affected the micelle size and the critical micelle concentration ( CMC). The incorporation of even a small quantity ( 11 wt%) of PDLA into the graft copolymer micelles resulted in a great decrease of the micelle size. For the graft copolymer with low per cent grafting of 18%, the size of the corresponding micelles decreased slightly even if the PDLA content increased up to 33 wt%. For the graft copolymer with high per cent grafting of 58%, with the further increase of PDLA content, the size of the corresponding micelles at first decreased further and then began to increase. The molecular weight of the PDLA did not significantly affect the micelle size.

Density functional and Monte Carlo studies of sulfur. I. Structure and bonding in S-n rings and chains (n=2-18) (vol 118, pg 9257, 2003)

Density functional calculations have been performed for ring isomers of sulfur with up to 18 atoms, and for chains with up to ten atoms. There are many isomers of both types, and the calculations predict the existence of new forms. Larger rings and chains are very flexible, with numerous local energy minima. Apart from a small, but consistent overestimate in the bond lengths, the results reproduce experimental structures where known. Calculations are also performed on the energy surfaces of S8 rings, on the interaction between a pair of such rings, and the reaction between one S8 ring and the triplet diradical S8 chain. The results for potential energies, vibrational frequencies, and reaction mechanisms in sulfur rings and chains provide essential ingredients for Monte Carlo simulations of the liquid–liquid phase transition. The results of these simulations will be presented in Part II.

‘Not like rose-tinted glasses… like taking a pair of dirty glasses off’: A pilot intervention using positive emotions in expressive writing

Studies conducted in various contexts and with varied populations have found expressive writing enhances physical and psychological wellbeing. This pilot intervention study countered the predominantly quantitative evidence by adopting a qualitative methodology, exploring the experience of using positive emotions in expressive writing. Participants (n = 10), who all had previous experience in expressive writing, were asked to select one of ten positive emotion cards (PECs) each day for three days. Participants were then asked to write expressively through the ‘lens’ of their chosen emotion. Semi-structured interviews were conducted and experiences were evaluated using Thematic Analysis. The results identified two main themes that compared the experience of expressive writing both with and without the PECs. The first theme, Processing (without the PECs) contained three sub-themes: sense of relief, habitual perspective and reactive to experience. The second main theme, Progressing (with the PECs) contained three different sub-themes: sense of direction, changed perspective and interactive with experience. This study found that, for expressive writers, positive emotions may function in three ways: to relate to others or self-expand, to move past challenges cognitively or change unconstructive perspectives, and finally as a way to interactively link or ‘bridge’ from the written subject matter to constructive action, thus breaking cycles of reactive writing and rumination. Implications of the study on the practice of expressive writing and its potential as a positive psychology intervention (PPI) are discussed.