bluuebunny/crossref_metadata_2025 huggingface dataset:
Preimplantation genetics: an explanation for poor human fertility?
Authors: DELHANTY J. D. A.
Published: March 2003

Compared with other mammals, humans as a species are relatively infertile. Various studies suggest that in young, unselected couples, who are trying to conceive, 20–25% of them should be successful each monthly cycle (Bonde et al. 1998; Edwards & Brody, 1995). This compares with an average of 70% in captive baboons for example (Stevens, 1997). Interestingly, the implantation rate after in vitro fertilisation (IVF) at best averages around 20% per embryo transferred (Edwards & Beard, 1999). Evidence is steadily accumulating to prove that the major cause of implantation failure in humans after both in vivo and in vitro fertilisation is the high incidence of chromosomal abnormality. Combining data from cytogenetic studies of spontaneous abortions with those obtained from preimplantation embryos suggests that meiotically derived aneuploidy occurs in 25% of conceptions, an order of magnitude higher than is found in other well studied species such as the mouse (Hassold & Jacobs, 1984; Jamieson, 1994). Additionally, interphase fluorescent in situ hybridisation (FISH) analysis of three day old human embryos has shown that up to 50% are chromosomally mosaic (Delhanty et al. 1997; Munnéet al. 1998), further increasing the chance of implantation failure. This review covers the evidence accumulating from a variety of sources that poor fertility in humans has a chromosomal basis.
An HLA Class‐II allele frequent in Eskimos and Amerindians is found in the Tyrolean Ice Man
Authors: FISCHER G. F. , FAE I. , MANN D. , KRIKS D. , JÄGER W. , PLATZER W. , MAYR W. R. , VOLC‐PLATZER B.
Published: March 2003

DNA was extracted from specimens derived from the calcaneus of the Tyrolean Ice Man under sterile conditions in a laboratory, where no DNA extractions and PCR experiments had been performed before. Agarose gel electrophoresis and ethidium bromide staining did not reveal any evidence of genomic DNA in the preparation obtained, indicating a high degree of DNA degradation. Nevertheless, we performed PCR amplifications with this sample using primer pairs specific for HLA class II alleles. HLA‐DRB and DQB1 alleles were amplified in a nested PCR approach. In one of the reactions, we observed a distinct amplification product, which we directly sequenced. By comparing the obtained nucleotide sequence with a database of HLA alleles we assigned the HLA‐DRB1*1402 type to the amplified sample. None of the investigators involved possesses this allele, indicating that no contamination with modern DNA had occured. The HLA‐DRB1*1402 allele is extremely rare in Europe, but is common in Inuits and South American Indians and has previously only once been identified in the laboratory.
Replication studies in longevity: puzzling findings in Danish centenarians at the 3′APOB–VNTR locus
Authors: VARCASIA O. , GARASTO S. , RIZZA T. , ANDERSEN‐RANBERG K. , JEUNE B. , BATHUM L. , ANDREEV K. , TAN Q. , YASHIN A. I. , BONAFÈ M. , FRANCESCHI C. , DE BENEDICTIS G.
Published: March 2003

In Danes we replicated the 3′APOB–VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20–64‐year‐old subjects. However, when Danish and Italian data were compared, a significant difference (p= 0.0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians (p= 0.290). Furthermore, the demographic‐genetic approach revealed in Danes a significant gene–sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene/longevity associations are population‐specific, and heavily affected by the population‐specific genetic and environmental history.
Coeliac disease: follow‐up linkage study provides further support for existence of a susceptibility locus on chromosome 11p11
Authors: KING A. L. , FRASER J. S. , MOODIE S. J. , CURTIS D. , DEARLOVE A. M. , ELLIS H. J. , ROSEN‐BRONSON S. , CICLITIRA P. J.
Published: March 2003

Susceptibility to coeliac disease has a strong genetic component. The HLA associations have been well described but it is clear that other genes outside this region must also be involved in disease development. Two previous genome‐wide linkage studies using the affected sib pair method produced conflicting results. Our own family based linkage study of 16 highly informative pedigrees identified 17 possibly linked regions, each of which produced a result significant at p < 0.05 or less.

We have now investigated these 17 regions in a larger set of pedigrees using more finely spaced markers. Fifty multiply affected families were studied, comprising the 16 pedigrees from the original genome screen plus 34 new highly informative pedigrees. A total of 128 microsatellite markers were genotyped with an average spacing between markers of 5 cM. Two‐point and three‐point linkage analysis using classical and model free methods identified five potential susceptibility loci with heterogeneity lod scores > 2.0, at 6p12, 11p11, 17q12, 18q23 and 22q13.3. The most significant was a heterogeneity lod of 2.6 at D11S914 on chromosome 11p11. This marker maps to a position implicated in one of the two previous genome scans and taken together these results provide strong support for the existence of a susceptibility locus in this region.
Prehistoric and historic traces in the mtDNA of Mozambique: insights into the Bantu expansions and the slave trade
Authors: PEREIRA L. , MACAULAY V. , TORRONI A. , SCOZZARI R. , PRATA M.‐J. , AMORIM A.
Published: March 2003

A sample of mitochondrial DNA (mtDNA) from the southeastern African population of Mozambique has been shown to have affinities with populations both to its north and south. From the north came sequences that may have been involved in the Bantu expansion (from western, through eastern, to southern Africa), such as members of haplogroups L3b, L3e1a and a subset of L1a. The dating of the major component of Mozambican mtDNAs, the subset L2a of haplogroup L2, displayed an age range compatible with the Bantu expansion. The southern influence was traced by the presence of sequence types from haplogroup L1d, a probable relict of Khoisan‐speaking populations that inhabited the region prior to their displacement by the Bantu‐speaking incomers. Within historical times, the forced displacement of Mozambicans as part of the slave trade, mainly documented as being to the Americas, generated a differential input of eastern African sequences into the mtDNA pools of the Americas and of Europe, as testified to by the greater number of sequence matches between Mozambique and the Americas, compared to those between Mozambique and Europe.
Exclusion of 5 functional candidate genes for distal hereditary motor neuropathy type II (distal HMN II) linked to 12q24.3
Authors: IROBI J. , NELIS E. , MEULEMAN J. , VENKEN K. , DE JONGHE P. , VAN BROECKHOVEN C. , TIMMERMAN V.
Published: March 2003

Distal hereditary motor neuropathies (distal HMNs) are characterised by degeneration of anterior horn cells of the spinal cord resulting in muscle weakness and atrophy. Distal HMN type II is genetically linked to chromosome 12q24.3 and located within a 13 cM region flanked by markers D12S86 and D12S340. We previously excluded the human phospholipase A2 group 1B gene (PLA2G1B) as the disease causing gene. Here, we report the mutation analysis of five other candidate genes localised within the distal HMN II region: the cytoskeletal proteins paxillin (PXN) and restin (RSN); the acidic ribosomal phosphoprotein, large P0 subunit (RPLP0); a nucleoside diphosphate kinase (NME2B); and the β 3 subunit of the voltage‐gated calcium channel (CACNB3). DNA sequencing of the coding regions was performed but no disease causing mutations could be identified, hence excluding these five genes for distal HMN type II.
Correcting for multiple analyses in genomewide linkage studies
Authors: CAMP N. J. , FARNHAM J. M.
Published: March 2003

The dissection of complex traits frequently calls for multiple analyses to be performed, including the use of both multiple phenotypes and genetic models. These multiple phenotypes and models are often not independent, and hence the necessary correction for the multiple testing is not straightforward. In this paper we offer a new approach to address the problem of how to correct for non‐independent multiple analyses in genomewide linkage studies. We describe one method of how to determine the number of ‘effectively independent’ tests performed in a linkage study using simple linear regression techniques. Further we describe how to use such information to establish genomewide significance thresholds for infinitely dense genomewide maps.
Volume 65 Part 4 July 2001 . Preimplantation genetics: an explanation for poor human fertility?
Authors: DELHANTY J. D. A.
Published: March 2003

The publishers would like to apologise to the author of this paper and their readers for the serious oversight which occurred. Figure 1 illustrating the results of CGH on a single cell from one embryo revealing chromosome breakage and reciprocal loss/gain of chromosome fragments should have been printed in full colour. Please refer to the reprinted colour version below.
Identification of human phosphoglucomutase 3 (PGM3) as N‐acetylglucosamine‐phosphate mutase (AGM1). PGM3 is equivalent to AGM1
Authors: PANG H. , KODA Y. , SOEJIMA M. , KIMURA H.
Published: March 2003

We performed phenotyping of human phosphoglucomutase 3 (PGM3) and screening for mutations in the human N‐acetylglucosamine‐phosphate mutase gene (AGM1) to identify PGM3 as AGM1. By sequencing the coding region of AGM1, two alleles containing a G or A base at nucleotide 1396, that can respectively encode aspartic acid or asparagine at codon 466, were identified. Cell extracts of COS7 cells after transfection with the pcDNA 3·1(+) plasmid containing an AGM1 allele with 1396G or 1396A showed similar electrophoretic patterns to the PGM3 1 or PGM3 2 protein, respectively, with the isozyme detection method used for PGM3 phenotyping. The genotypes determined by the two alleles of AGM1 coincided exactly with the PGM3 phenotypes in 20 individuals. We also investigated the allele frequency of the AGM1 nucleotide polymorphism in a Japanese population by DNA sequencing and found that the frequencies of alleles 1396G and 1396A were similar to previously reported PGM3*1 and PGM3*2 frequencies. Overall, the facts that the AGM1 gene product shows PGM activity, AGM1 is polymorphic, the electrophoretic mobility is similar between AGM1 allele‐specific products and PGM3 1 and 2 proteins, PGM3 phenotypes and AGM1 genotypes completely coincide in 20 individuals, and AGM1 allele frequencies are similar to those of PGM3*1 and PGM3*2 in Japanese populations, suggest that PGM3 is identical to AGM1.
A quick and simple method for detecting subjects with abnormal genetic background in case‐control samples
Authors: CURTIS D. , NORTH B. V. , GURLING H. M. D. , BLAVERI E. , SHAM P. C.
Published: March 2003

It is important that case‐control samples be drawn from a genetically homogeneous population in order to avoid artefactual false positive results and to enhance power to detect disease mutations and markers in linkage disequilibrium with them. Tests which simply compare overall marker allele frequencies between cases and controls will fail to identify a relatively small number of subjects drawn from a different genetic background who could usefully be discarded from the sample. Such subjects can be identified using multilocus tests, but previously described tests have been unnecessarily complex and cumbersome for this simple application. We describe a straightforward test, implemented in the CHECKHET program, which uses a measure of genetic difference and permutation procedures to rapidly identify such subjects using genotypes from multiple unlinked markers. It seems to perform reasonably well on simulated data, and with real data appears to identify two abnormal subjects within a case‐control sample. We recommend that such tests be routinely applied to case‐control samples once sufficient numbers of markers have been genotyped within them.
Determination of probability distribution of diplotype configuration (diplotype distribution) for each subject from genotypic data using the EM algorithm
Authors: KITAMURA Y. , MORIGUCHI M. , KANEKO H. , MORISAKI H. , MORISAKI T. , TOYAMA K. , KAMATANI N.
Published: March 2003

Haplotype analysis is important for mapping traits. Recently, methods for estimating haplotype frequencies from genotypes of unrelated individuals based on the expectation‐maximization (EM) algorithm have been developed. Our program estimates haplotype frequencies in the population and determines the posterior probability distribution of diplotype configuration (diplotype distribution) for each subject based on the estimated haplotype frequencies. Samples from three ethnic groups for the smoothelin gene (SMTN) and those from three Japanese groups for serum amyloid A genes (SAA@) were analyzed. The estimated diplotype distribution for each individual was concentrated, in most cases, in a single diplotype configuration. The diplotype configuration thus determined was the same as that determined in in vitro experiments, with one exception. Thus, the diplotype configurations determined using the estimated haplotype frequencies from unrelated individuals are reliable. Using this method, the risk of a subject developing a phenotype may be estimated from the diplotype distribution when the phenotype is associated with diplotype configurations.
Mitochondrial DNA variability in Poles and Russians
Authors: MALYARCHUK B. A. , GRZYBOWSKI T. , DERENKO M. V. , CZARNY J. , WOŹNIAK M. , MIŚCICKA‐ŚLIWKA D.
Published: March 2003

Mitochondrial DNA (mtDNA) sequence variation was examined in Poles (from the Pomerania‐Kujawy region; n = 436) and Russians (from three different regions of the European part of Russia; n = 201), for which the two hypervariable segments (HVS I and HVS II) and haplogroup‐specific coding region sites were analyzed. The use of mtDNA coding region RFLP analysis made it possible to distinguish parallel mutations that occurred at particular sites in the HVS I and II regions during mtDNA evolution. In total, parallel mutations were identified at 73 nucleotide sites in HVS I (17.8%) and 31 sites in HVS II (7.73%). The classification of mitochondrial haplotypes revealed the presence of all major European haplogroups, which were characterized by similar patterns of distribution in Poles and Russians. An analysis of the distribution of the control region haplotypes did not reveal any specific combinations of unique mtDNA haplotypes and their subclusters that clearly distinguish both Poles and Russians from the neighbouring European populations. The only exception is a novel subcluster U4a within subhaplogroup U4, defined by a diagnostic mutation at nucleotide position 310 in HVS II. This subcluster was found in common predominantly between Poles and Russians (at a frequency of 2.3% and 2.0%, respectively) and may therefore have a central‐eastern European origin.
On calculating the power of a TDT study – comparison of methods. Short communication
Authors: ILES M. M.
Published: March 2003

We show that the methods for calculating the power of the TDT of Risch & Merikangas (1996), McGinnis (1998, 2000), Tu & Whittemore (1999) and Knapp (1999) consist of three distinct approaches. The differences between the methods arise either by treating parental transmissions independently or not, and either conditioning on parental heterozygosity or not. Transmissions are only truly independent when the mode of inheritance of the disease is multiplicative, making this assumption invalid and the methods that assume them (Risch & Merikangas, 1996; McGinnis, 1998, 2000) inappropriate. We demonstrate a basic model that allows analytical comparisons of the methods, and suggest a new method that calculates power at least as accurately as any of the three previously published.
Accurate power approximations for χ2‐tests in case‐control association studies of complex disease genes
Authors: JACKSON M. R. , GENIN E. , KNAPP M. , ESCARY J. L.
Published: March 2003

A popular method for the analysis of case‐control association studies is to compare the frequencies of the alleles between cases and controls by means of Pearson's χ2‐statistic. Here, an approach for computing the power of this test is presented, which by computer simulation is shown to be more reliable than a previously published power approximation. Since the test based on Pearson's χ2‐statistic can be anti‐conservative if there is an excess of homozygotes for the susceptibility allele in the general population, it has been proposed to analyze case‐control association studies by means of a trend test based on genotypes instead of alleles. We present an accurate power approximation for the trend test. The power approximations are implemented in an available computer program ‘GenOdyPower’, which in addition has an option to determine the empirical power of these tests by simulations.
Multifunctional zinc finger proteins in development and disease
Authors: LADOMERY M. , DELLAIRE G.
Published: March 2003

Post‐transcriptional processes contribute significantly towards the generation of proteomic diversity. An increasing number of mutations have been described that affect genes encoding components of the post‐transcriptional machinery. In particular, multifunctional proteins that link transcription with post‐transcriptional processes have been implicated in several human diseases including cancer. A predominant feature of these proteins is the zinc finger, an ancient structural motif that mediates protein : protein interactions and is capable of interacting with both DNA and RNA. Zinc finger proteins are the most abundant class of proteins in the human proteome, yet the majority remain uncharacterised. Here we describe multifunctional zinc finger proteins linked to human development and disease. The examples discussed are WT1, ZNF74, EWS, TLS, TAFII68, YY1, CTCF and the GLI proteins. The study of these and other zinc finger proteins provides insights into the functional versatility of the zinc finger motif and suggests that both alternative splicing and sub‐cellular compartmentalisation may modulate their multifunctionality.
Genetic Heterogeneity of Icelanders
Authors: Árnason E.
Published: March 2003

Recently statements have been made about a special ‘genetic homogeneity’ of the Icelanders that are at variance with earlier work on blood groups and allozymes. To validate these claims an extensive reanalysis was undertaken of mtDNA variation by examining primary data from original sources on 26 European populations. The results show that Icelanders are among the most genetically heterogeneous Europeans by the mean number of nucleotide differences as well as by estimates of θ parameters of the neutral theory. The distribution of pairwise differences in general has the same shape as European populations and shows no evidence of bottlenecks of numbers in Iceland. The allelic frequency distribution of Iceland is relatively even with a large number of haplotypes at polymorphic frequencies contrasting with other countries. This is a signature of admixture during the founding or history of Iceland. Assumptions of models used to simulate number of haplotypes at sampling saturation for comparing populations are violated to different degrees by various countries. Anomalies identified in data in previous reports on Icelandic mtDNA variation appear to be due to errors in publicly accessible databases. This study demonstrates the importance of basing analyses on primary data so that errors are not propagated. Claims about special genetic homogeneity of Icelanders are not supported by evidence.
Genetic Polymorphisms in the Renin‐Angiotensin System in High‐Altitude and Low‐Altitude Native American Populations
Authors: Rupert J. L. , Kidd K. K. , Norman L. E. , Monsalve M. V. , Hochachka P. W. , Devine D. V.
Published: March 2003

Cardiovascular disease (CVD) is reportedly less common in high‐altitude native populations than in lowlanders. To some extent, this is due to cultural and demographic factors; however, increased cardiovascular efficiency contributing to hypoxia adaptation may also be involved. Numerous genetic variants have been associated with cardiovascular health. If the decreased incidence of CVD in modern high‐altitude populations reflects selective pressures having favoured the transmission of these alleles in their antecedents, it would be expected that these alleles would be more common in highlanders than in lowlanders. We tested this hypothesis by determining the allele frequencies of five polymorphic loci in genes encoding components of the renin‐angiotensin system (RAS) that have alleles associated with hypertension and cardiovascular disease in a high‐altitude native Andean population, Quechua from the Peruvian altiplano, and in a lowland Amerindian population, Maya from the Yucatan peninsula. The polymorphisms examined were 1) the insertion/deletion polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene; 2) the A/G2350 transition (ACE‐8) in intron 17 of the ACE gene; 3) the A/C1166 transversion in the 3′ untranslated region of the angiotensin II receptor (type 1) gene (AGTR1); 4) the G/AI9–83 transition in intron 8 of the renin gene (REN); and 5) the T/C704 (Met235Thr) transition mutation in angiotensinogen (AGT).

There was no evidence for an over‐representation of the RAS alleles associated with cardiovascular fitness in the high‐altitude Amerindian population when compared to the lowland Amerindian population.
Seven Novel Acid Sphingomyelinase Gene Mutations in Niemann‐Pick Type A and B Patients
Authors: Sikora J. , Pavlu‐Pereira H. , Elleder M. , Roelofs H. , Wevers R. A.
Published: March 2003

We have analyzed acid sphingomyelinase (SMPD1; E.C. 3.1.4.12) gene mutations in four Niemann‐Pick disease (NPD) type A and B patients of Turkish ancestry and in three patients of Dutch origin.

Among four NPD type A patients we found two homozygotes for the g.1421C > T (H319Y) and g.3714T > C (Y537H) mutations and two compound heterozygotes, one for the g.3337T > C (F463S) and g.3373C > T (P475L) mutations and the other for the g.84delC (G29fsX74) and g.1208A > C (S248R) mutations.

One of the type B patients was homozygous for the g.2629C>T (P371S) mutation. The last two type B patients were homozygotes for the common g.3927_3929delCGC (R608del) mutation.

The G29fsX74, S248R, H319Y, P371S, F463S, P475L and Y537H SMPD1 mutations are all novel and were verified by PCR/RFLP and/or ARMS. All of the identified mutations are likely to be rare or private, with the exception of R608del which is prevalent among NPD type B patients from the North‐African Maghreb region. Geographical and/or social isolation of the affected families are likely contributing factors for the high number of homozygotes in our group.
Gene Admixture in the Costa Rican Population
Authors: Morera B. , Barrantes R. , Marin‐Rojas R.
Published: March 2003

The general population of Costa Rica has sometimes been considered to be the product of an amalgamation of groups of diverse origin. To determine the magnitude of accumulated admixture since Spanish colonization, 11 classic genetic markers were analyzed in a total of 2196 individuals originating from five distinct regions of the country. A maximum likelihood approach was used. The proportions of genes of European, Amerindian and African ancestry were found to be 61%, 30% and 9% of the total population, respectively. Variation was observed at a regional level, with an increased European influence in the North (66%) and Central (65%) regions. Meanwhile an increase in Amerindian ancestry was found in the South (38%), and a higher incidence in the contribution of African genes was detected in the coastal regions (13% in the Atlantic and 14% in the North Pacific). A principal component (PC) analysis showed that 76% of the existing variability can be explained by the first two PCs, which is in agreement with the variations observed in the admixture process by geographic area. It has been concluded that the Costa Rican population is truly trihybrid, similar to populations in other Latin American countries; however, it differs from them fundamentally by the proportion of gene flow from ancestral populations.
Using Affected Sibling Pairs to Distinguish the Direct Effect of a Susceptibility Gene and the Indirect Effect of Linkage Disequilibrium
Authors: Lee W.‐C.
Published: March 2003

A positive result for a transmission/disequilibrium test (TDT) can occur for two reasons: a) the allele itself is a cause of disease predisposition (direct effect); or b) the allele is in linkage disequilibrium with a disease‐causing gene (indirect effect). A test was proposed based on affected sibling pairs (ASPs) to distinguish between the two. Simulation showed that the test has the correct type I error rate and favourable power (power >50% for 50 ASPs; >75% for 100 ASPs; >85% for 150 ASPs). Making this distinction is important for setting the direction for subsequent studies following a positive TDT result.
Allowing for Genotyping Error in Analysis of Unmatched Case‐Control Studies
Authors: Rice K. M. , Holmans P.
Published: March 2003

A commonly‐used method for testing for association between disease and a single‐nucleotide polymorphism (SNP) is to compare the frequencies of the SNP genotypes in a sample of unrelated cases to those in a sample of unrelated controls drawn from the same population (an unmatched case‐control study). A drawback of such a study is that it is impossible to detect genotyping errors, and few methods have been developed to allow for the presence of undetected genotyping errors. In this paper, we obtain analytic formulae for estimates of genotypic relative risks in terms of error probability (e). In general, e will be unknown. We investigate the effect of assuming both correct and incorrect values of e on power and type I error, and also on the genotypic relative risk estimates. The choice of e was found to have no effect on power or Type I error probability (provided a 2df test was used, allowing relative risks of homozygotes and heterozygotes to differ). However, overestimating e in the presence of a true association was found in general to bias relative risk estimates away from the null, with underestimates of e having the opposite effect. Although e is unknown, it may be estimated from an external “validation” study, such as genotyping a sample of unrelated individuals twice and counting the discrepancies. Simulation results suggest that, for such a study, 25 individuals would be sufficient to give approximately unbiased estimates of relative risks.
Segregation Analysis of Prostate Cancer in France: Evidence for Autosomal Dominant Inheritance and Residual Brother‐brother Dependence
Authors: Valeri A. , Briollais L. , Azzouzi R. , Fournier G. , Mangin P. , Berthon P. , Cussenot O. , Demenais F.
Published: March 2003

Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two‐locus model than single‐locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X‐linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneity.

To assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 CaP patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts.

Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother‐brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at‐risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.
A Note on the Optimal Measure of Allelic Association
Authors: Shete S.
Published: March 2003

Association of pairs of loci due to departure of gamete frequencies from expected frequencies is called allelic association. This measure is useful for fine‐scale mapping. There are several measures of allelic association in the literature. With the availability of a SNP map, the use of linkage disequilibrium to map genes is one of the central issues in the human genome project. The size of linkage disequilibrium blocks is of considerable interest. In this note, we investigate the statistical properties of a measure which is known to have the strongest theoretical population basis and be least sensitive to the marker allele frequencies. In particular, we have shown that this measure has intuitive appeal and the estimator for this measure has several statistically optimal properties such as consistency, asymptotic unbiasedness and asymptotic efficiency.
Biological characteristics and life tables of Neoseiulus umbraticusChant (Acari, Phytoseiidae) at three constant temperatures
Authors: Kazak C. , Yildiz S. , Sekeroglu E.
Published: March 2003

The development time, survival and fecundity of the generalist predatory mite, Neoseiulus umbraticusChant, were determined at 20, 25, and 30 °C and 65 ± 10 % RH. N. umbraticus females completed development in 9.7, 8.0 and 5.9 days, respectively, using a diet of all life stages of Tetranychus cinnabarinus Boisduval. Total developmental times of males were relatively shorter at 25 and 30 °C than at 20 °C. In general, preoviposition, oviposition, and postoviposition periods of N. umbraticus shortened as temperature increased. The longest survival rate of N. umbraticus of 80.5 days occurred at 20 °C, followed by 67.0 and 57.6 days at 25 and 30 °C, respectively.

 Mated females laid an average 0.9, 1.3 and 1.4 eggs per female per day and 33.1, 44.0 and 43.6 eggs over their entire lives at 20, 25 and 30 °C, respectively. The sex ratios of this species were 0.57, 0.57 and 0.54 female (female+male) at 20, 25 and 30 °C, respectively. The intrinsic rate of increase (rm) became greater with rising temperatures from 0.123 at 20 °C to 0.180 at 30 °C. The net reproduction rate (Ro) was highest at 25 °C (25.0 females/female) and lowest at 20 °C (18.8 females/female), while To decreased with increasing temperatures, from 23.8 days at 20 °C to 17.5 days at 30 °C.
Neurochemical regulation of cough response to capsaicin in guinea‐pigs
Authors: Li J. Q. , Jia Y. X. , Yamaya M. , Arai H. , Ohrui T. , Sekizawa K. , Sasaki H.
Published: March 2003

1 Although monumental efforts have been made to define the action sites of cough, the importance of neurotransmitter systems in the cough reflex has received limited attention. We studied the roles for four major neurotransmitters [acetylcholine, histamine, serotonin (5‐hydroxytryptamine, 5‐HT) and dopamine] in the modulation of the cough reflex.

2 Atropine (muscarinic cholinergic blocking agent), pyrilamine maleate (PM, histamine H1 blocker), cimetidine (histamine H2 blocker), 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT, specific 5‐HT1A receptor agonist) and SCH‐23390 (selective dopamine D1 receptor antagonist) were examined on the cough response to inhaled capsaicin in conscious guinea‐pigs.

3 All the drugs significantly decreased the number of capsaicin‐induced coughs in a dose‐dependent manner. To compare the sensitivity of these drugs on cough response, we calculated the effective doses for 50% inhibition of cough (ED50) when the animals were exposed to 3 × 10−4 m capsaicin. The ED50 values were 0.03 μm kg−1 for atropine, 0.2 μm kg−1 for 8‐OH‐DPAT, 6.2 μm kg−1 for SCH‐23390, 8.5 μm kg−1 for PM and 13.9 μm kg−1 for cimetidine.

4 These findings indicated that all these four neurotransmitters may be involved in the regulation of the cough reflex. Multiple changes of these neurotransmitters in disorders of the central nervous system might synergically affect the cough reflex.
Salivary glands and noradrenergic transmission in diabetic rats
Authors: Vatta M. S. , Hope S. I. , Prendes G. M. , Bianciotti L. G. , Elverdin J. C. , Fernandez B. E.
Published: March 2003

1 Type 2 diabetes is associated with diverse oral pathologies in which salivary flow reduction is one of the causes of these oral abnormalities. Scarce literature exists regarding noradrenergic transmission and adrenergic‐induced salivary flow in submaxillary and parotid glands of type 2 diabetic rats.

2 We studied noradrenergic transmission as well as the secretory response to α1‐ and β‐adrenoceptor stimulation in the parotid and submaxillary glands of type 2 diabetic rats.

3 Diabetic rats exhibited diminished neuronal uptake, release and endogenous content of noradrenaline (NE) in both salivary glands. Further, NE synthesis was also diminished accompanied by decreased tyrosine hydroxylase activity. Salivary flow responses to α1‐(methoxamine) and β‐(isoprenaline) adrenoceptor stimulation were reduced in the submaxillary as well as the parotid glands of diabetic rats.

4 Our results suggest that the reduction of noradrenergic transmission in the salivary glands of type 2 diabetic rats is in part responsible for the diminished salivary flow evoked by α1‐ and β‐adrenergic stimulation. Reduced noradrenergic activity may contribute to the pathophysiology of oral abnormalities in diabetic patients.
The enhanced plasma levels of soluble tumor necrosis factor receptors (sTNF‐R1; sTNF‐R2) and interleukin‐10 (IL‐10) in patients suffering from chronic heart failure are reversed in patients treated with β‐adrenoceptor antagonist
Authors: Loppnow Harald , Werdan Karl , Werner Claudia
Published: March 2003

1 Cytokines may parallel or regulate the beneficial effects of β‐adrenoceptor antagonist treatment observed in chronic heart failure (CHF) patients. Therefore, this study was performed in order to investigate alterations of cytokine levels in β‐blocker‐treated patients suffering from CHF.

2 We investigated plasma cytokine levels in eight healthy controls and 12 CHF patients. The patients were treated with standard medication (CHFstd) or with standard medication and additional β1‐blocker metoprolol (CHFmet). Interleukin‐(IL)‐1α, IL‐1β, IL‐1 receptor antagonist (IL‐1ra), IL‐2, IL‐6, IL‐8, IL‐10, tumor necrosis factor‐α (TNF), soluble TNF receptor type 1 (sTNF‐R1), sTNF‐R2, and sCD14 were measured by ELISA.

3 IL‐1α and IL‐1β were not detectable in any of the tested groups. IL‐2, TNF, or sCD14 were not altered as compared with healthy control subjects. CHFstd patients expressed enhanced IL‐1ra, IL‐6, IL‐8, IL‐10, sTNF‐R1 and sTNF‐R2. In CHFmet patients IL‐1ra, IL‐6 and IL‐8 remained at the same level. In contrast, sTNF‐R1 levels were significantly reduced, although not to control, whereas the sTNF‐R2 and IL‐10 were reduced to control levels.

4 The cAMP levels of mononuclear cells – recalculated for the patients included in this study from previous work [Werner et al. (2001). Basic Res. Cardiol., 96, 290]– correlated inversely with the sTNF‐R2 data (Pearson, r=−0.46; P=0.041; Spearman, r=−0.64, P=0.002).

5 The present data indicate an interaction of the neurohumoral and the cytokine system in CHF patients at the cAMP level. Thus, measurement and correlation of sTNF‐R2 and cAMP may provide a tool useful during investigation of β‐blocker therapy.
The effect of nitric oxide synthase blockade on responses to morphine in rat aortic rings
Authors: Ahin N. , Özdem S. , Adan G.
Published: March 2003

1 It has been suggested that opioids may play an indirect role in the regulation of the peripheral circulation through the control of nitric oxide (NO) release in vascular tissue. The current study was undertaken to investigate the effect of nitric oxide synthase (NOS) blockade on responses to morphine in phenylephrine (PE)‐ or KCl‐precontracted rat aortic rings.

2 Morphine (3 × 10−8−3 × 10−5 m) administration did not cause any significant effect on basal tonus of endothelium‐intact or endothelium‐denuded preparations. Morphine produced concentration‐dependent relaxation responses in endothelium‐intact as well as in endothelium‐denuded rat aortic rings precontracted by PE or KCl. Removal of endothelium did not significantly alter the relaxation responses to morphine.

3 The relaxant responses to morphine were significantly and partially inhibited by pretreatment of tissues with naloxone (NAL, 3 × 10−5 m) for 5 min. The inhibitory effect of NAL on relaxant responses to morphine in PE‐ or KCl‐precontracted rings did not differ significantly between endothelium‐intact and endothelium‐denuded preparations.

4 Incubation of endothelium‐intact or endothelium‐denuded rat aortic rings with NOS inhibitor, Nω‐nitro‐l‐arginine methyl ester (l‐NAME, 10−4 m) for 20 min did not cause a significant inhibition on relaxation responses to morphine.

5 These findings confirmed the presence of opiate receptors in rat thoracic aorta, but suggested that mechanisms other than NO release play a role in the relaxant effect of morphine on rat aortic rings.
Neuropeptide Y inhibits double peaked vasoconstrictor responses to periarterial nerve stimulation primarily through prejunctional Y2 receptor subtype in canine splenic arteries
Authors: Yang X.‐P. , Chiba S.
Published: March 2003

1 The effects of BIIE 0246, a novel and non‐peptide neuropeptide Y (NPY) Y2 receptor antagonist on sympathetic vasoconstriction of the canine splenic artery were investigated.

2 The vasoconstrictor response to periarterial electrical nerve stimulation was described to be a double peaked vasoconstriction consisting of an initial transient, dominantly P2X purinoceptor‐mediated constriction followed by a prolonged, mainly α1 adrenoceptor‐induced response.

3 BIIE 0246 at a concentration of 0.1–1 μm dose‐dependently potentiated double peaked constrictions at low frequencies (1 and 4 Hz), whereas at high frequency (10 Hz), it failed to affect these responses. BIIE 0246 (1 μm) also enhanced double peaked responses even in the presence of rauwolscine (0.1 μm). NPY (13–36) (1–100 nm), a selective Y2 receptor agonist reduced these two peaked responses in a dose‐related manner. The vasoconstriction to noradrenaline (0.1–10 nmol) or adenosine triphosphate (0.01–1 μmol) was not significantly influenced by either 1 μm BIIE 0246 or 100 nm NPY (13–36). Exposure of tissues to 1 μm BIIE 0246 almost completely prevented the suppression of double peaked constrictions by NPY (13–36) (10 nm) or by NPY (10 nm).

4 We conclude that NPY inhibits sympathetic purinergic and adrenergic vasoconstrictions through an activation of prejunctional Y2 receptor subtype in the neurovascular junction of the canine splenic artery.
GABAB receptor function in the ileum and urinary bladder of wildtype and GABAB1 subunit null mice
Authors: Sanger G. J. , Munonyara M. L. , Dass N. , Prosser H. , Pangalos M. N. , Parsons M. E.
Published: March 2003

Summary 1 GABAB1 receptor subunit knockout mice were generated and the effects of the GABAB receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/–) and knockout (–/–) animals. For this purpose, neuronally‐mediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS).

2 In ileum resected from 4–8‐week‐old‐mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 μM and reduced by baclofen (33.4 ± 5.6%, 100 μm). The latter effect was antagonized by the GABAB receptor antagonist CGP54626 0.2 μm. Baclofen 100 μm did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABAB receptors.

3 To avoid the development of grand mal seizure by GABAB1 (–/–) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1–3‐week‐old‐animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/–) mice, of both 1–3 weeks and 4–8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n=6 (+/+) and n=5 (+/–), IC50 19.2 ± 4.8 μm) and this effect was greatly reduced in the presence of CGP54626 0.2 μm.

4 In urinary bladder from 1–3‐week‐old‐mice, using higher frequencies of EFS to evoke clear, nerve‐mediated contractions (10 Hz), baclofen 10–300 μm concentration‐dependently inhibited contractions in (+/+) mice (IC50 9.6 ± 3.8 μm). This effect was inhibited by CGP54626 (0.2 μm, 46.2 ± 13.6% inhibition, 300 μm baclofen n=7) a concentration which, by itself, had no effect on the EFS‐evoked contractions.

5 The effects of baclofen in both ileum and urinary bladder were absent in the GABAB1 receptor subunit (–/–) mice; however, responses to EFS were unaffected in (–/–) when compared to the (+/+) mice.

6 Our data suggest that, as in the central nervous system (CNS), the GABAB1 receptor subunit is an essential requirement for GABAB receptor function in the enteric and PNS. As such, these data do not provide a structural explanation for the existence of putative subtypes of GABAB receptor, suggested by studies such as those in which different rank‐orders of GABAB agonist affinity have been reported in different tissues.
Pharmacological analysis of functional neurovascular transmission in canine splenic arteries: role of neuropeptide Y
Authors: Chiba S. , Yang X.‐P.
Published: March 2003

1 The effects of neuropeptide Y (NPY) upon the isolated vasculature are reviewed.

2 The vasconstrictor responses to periarterial nerve stimulation (PNS) and neurotransmission by noradrenaline (NA) and ATP are discussed and illustrated using canine isolated perfused splenic artery.

3 Modulation of the vascular responses to PNS by NPY via pre‐ and post‐junctional NPY Y2and Y1receptors is discussed.

4 Evidence is presented for different α1‐adrenoceptor subtypes mediating vasoconstriction to exogenous and endogenously released NA and their different locations in the neurovascular junction and extrajunctional regions.

5 Activation of NPY Y1‐receptors potentiates sympathetic nerve activated α1‐adrenoceptor vasoconstriction. The proposal that the postjunctional α1Badrenoceptor may be linked to the NPY Y1‐receptor and is responsible for co‐operation between sympathetic and NPYergic interactions in the vasculature is discussed.
The demography of slow aging in male and female Drosophila mutant for the insulin‐receptor substrate homologue chico
Authors: Tu Meng‐Ping , Epstein Diane , Tatar Marc
Published: March 2003

Hypomorphic mutants affecting the Drosophila insulin/IGF signal pathway are reported to increase longevity in females but not in males. To understand this sex‐difference, we conducted a large‐scale demographic study with three new isogenic strains of alleles at chico, the insulin‐receptor substrate homologue. We verify that female dwarf homozygotes (ch1/ch1) and normal‐sized heterozygotes (ch1/+) are long‐lived, as originally reported. We find for the first time that male heterozygotes are long‐lived relative to wildtype, by about 50%. The life span of male ch1/ch1 is similar to that of wildtype but these dwarf males age at a slow demographic rate. The levels of demographic frailty and of age‐independent mortality are elevated in ch1/ch1 males, counteracting the effect of slow aging upon life expectancy. Mortality deceleration occurs amongst the oldest‐old wildtype adults, as seen in many organisms. Remarkably, in similarly sized cohorts of male and female ch1/ch1 and of male ch1/+ mortality deceleration is absent. Mortality deceleration is a phenotype of chico.
The shortened replicative life span of prohibitin mutants of yeast appears to be due to defective mitochondrial segregation in old mother cells
Authors: Piper Peter W. , Jones Gary W. , Bringloe David , Harris Nicholas , MacLean Morag , Mollapour Mehdi
Published: March 2003

Prohibitin proteins have been implicated in cell proliferation, aging, respiratory chain assembly and the maintenance of mitochondrial integrity. The prohibitins of Saccharomyces cerevisiae, Phb1 and Phb2, have strong sequence similarity with their human counterparts prohibitin and BAP37, making yeast a good model organism in which to study prohibitin function. Both yeast and mammalian prohibitins form high‐molecular‐weight complexes (Phb1/2 or prohibitin/BAP37, respectively) in the inner mitochondrial membrane. Expression of prohibitins declines with senescence, both in mammalian fibroblasts and in yeast. With a total loss of prohibitins, the replicative (budding) life span of yeast is reduced, whilst the chronological life span (the survival of stationary cells over time) is relatively unaffected. This effect of prohibitin loss on the replicative life span is still apparent in the absence of an assembled respiratory chain. It also does not reflect the production of extrachromosomal ribosomal DNA circles (ERCs), a genetic instability thought to be a major cause of replicative senescence in yeast. Examination of cells containing a mitochondrially targeted green fluorescent protein indicates this shortened life span is a reflection of defective mitochondrial segregation from the mother to the daughter in the old mother cells of phb mutant strains. Old mother phb mutant cells display highly aberrant mitochondrial morphology and, frequently, a delayed segregation of mitochondria to the daughter. They often arrest growth with their last bud strongly attached and with the mitochondria adjacent to the septum between the mother and the daughter cell.
Life history response of Mediterranean fruit flies to dietary restriction
Authors: Carey James R. , Liedo Pablo , Harshman Lawrence , Zhang Ying , Müller Hans‐Georg , Partridge Linda , Wang Jane‐Ling
Published: March 2003

The purpose of this study was to investigate medfly longevity and reproduction across a broad spectrum of diet restriction using a protocol similar to those applied in most rodent studies. Age‐specific reproduction and age of death were monitored for 1200 adult males and 1200 females, each individually maintained on one of 12 diets fromad libitumto 30% ofad libitum. Diet was provided in a fixed volume of solution that was fully consumed each day, ensuring control of total nutrient consumption for every fly. Contrary to expectation and precedence, increased longevity was not observed at any level of diet restriction. Among females, reproduction continued across all diet levels despite the cost in terms of increased mortality. Among males, life expectancy exceeded that of females at most diet levels. However, in both sexes, mortality increased more sharply and the pattern of survival changed abruptly once the diet level fell to 50% ofad libitumor below, even though the energetic demands of egg production has no obvious counterpart in males. We believe that a more complete picture of the life table response to dietary restriction will emerge when studies are conducted on a wider range of species and include both sexes, more levels of diet, and the opportunity for mating and reproduction.