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PubMed2006

The evolution of condition-dependent sexual dimorphism.

Theory suggests that the net benefit of allocating resources to a sexual trait depends both on the strength of sexual selection on that trait and on individual condition. This predicts a tight coevolution between sexual dimorphism and condition dependence and suggests that these patterns of within-sex and between-sex variation may share a common genetic and developmental basis. Although condition-dependent expression of sexual traits is widely documented, the extent of covariation between condition dependence and sexual dimorphism remains poorly known. I investigated the effects of condition (larval diet quality) on multivariate sexual dimorphism in the fly Telostylinus angusticollis (Neriidae). Condition determined the direction of sexual size dimorphism and modulated sexual shape dimorphism by affecting allometric slopes and/or intercepts of sexually homologous traits in both sexes. Although the greatest responses to condition manipulation were observed in male sexual traits, both sexual and nonsexual traits exhibited substantial variation in the nature and magnitude of condition effects. Nonetheless, condition dependence and sexual dimorphism were remarkably congruent: variation in the strength of condition effects on male traits explained more than 90% of the variation in the magnitude of sexual dimorphism, whether quantified in terms of trait size or allometric slope. The genetic mechanisms that give rise to multivariate sexual dimorphism in body shape thus function in a strongly condition-dependent manner in this species, suggesting a common genetic basis for body shape variation within and between sexes.

Animals↗
PubMed2026

Long-read Sequences Mapped to a Complete Reference Genome Uncover Uncaptured Structural Variants across the Beta-globin Cluster in Africans with Sickle Cell Disease.

African genomes are marked by extensive complexity in the number and distribution of variants, yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD) - one of the most common monogenic diseases - has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the beta-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes presents a challenge to translating these advances to Africa. Here, we align long-read single molecule sequences (LRS) targeted to the beta-globin region to the hg38 and T2T-CHM13v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13v2 reference sequence at this locus reduces Structural Variant (SV) calls by 70% and uncovers uncaptured single nucleotide variants (SNVs). Across the cluster we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

SNV↗
PubMed1998

Fusion variations of pancreatic ducts in patients with anomalous arrangement of pancreaticobiliary ductal system.

Fusion variations of the pancreatic ducts were studied to elucidate the significance of such variations. We classified structural fusion anomalies of the main and accessory pancreatic ducts on endoscopic retrograde cholangio-pancreatography (ERCP) in 37 patients with anomalous arrangement of the pancreaticobiliary ductal system (AAPB). The fusion variations of the pancreatic ducts were classified into five types: common, ansa pancreatica, branch fusion, looped, and separated. These fusion variations, except for common type, were found in 68% of the 37 patients with AAPB on ERCP. Fusion variations of the pancreatic ducts were very frequent (93%) in the 30 patients with congenital cystic dilatation of the common bile duct (CCD). The branch confluence fashion, in which the terminal bile duct communicated with a pancreatic duct branch, was found only in patients with cystic dilatation cyst of the CCD, and it appeared that cystic dilatation cyst of CCD might differ from spindle or cylindrical cyst originating from embryonic formation of an anomalous confluence. It was also suggested that in patients with fusion variations of the pancreatic ducts, the flow of pancreatic juice might be disordered, leading to the development of acute pancreatitis or pancreatic dysfunction. Consequently, it appears to be necessary to carefully examine patients with AAPB for the presence or absence of any fusion variations of the pancreatic ducts and to observe such patients with long-term monitoring by ERCP, and computed temography, and with pancreatic function tests.

Adult↗
PubMed1980

Cerebrovascular disease in the community: results of a WHO collaborative study.

In a cooperative study coordinated by WHO, stroke was registered between 1971 and 1974 in 17 centres both in developing and developed countries. A common operating protocol was used to obtain comparable data. Age-adjusted incidence of stroke shows moderate geographical variations, cerebrovascular accidents being common in all the contrasting populations studied in various parts of the world. Data were also obtained on the types of management of stroke patients, their survival rates, and functional prognosis. Control of hypertension, although known to be effective in the prevention of stroke, seemed to be insufficient in most countries. It is concluded that stroke registers may be used as a source of information for the planning and implementation of stroke control programmes in the community.

Age Factors↗
PubMed2003

Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population.

CD94 and NKG2 are members of the NK cell receptor families, and are encoded in the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the candidate chromosomal regions for rheumatic diseases. To examine a possible association between variations in CD94 and NKG2 genes and genetic susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), we carried out a systematic polymorphism screening of NKG2-A (KLRC1), NKG2-C (KLRC2) and CD94 (KLRD1) genes on a population basis. In NKG2-A, previously considered to be highly conserved, 10 polymorphisms in the noncoding region and introns, as well as one rare variation leading to an amino acid substitution within the transmembrane region, c.238T>A (Cys80Ser), were detected. In NKG2-C, in addition to the previously described two nonsynonymous substitutions, c.5G>A (Ser2Asn) and c.305C>T (Ser102Phe), two polymorphisms were newly detected in the noncoding region. In CD94, only one single nucleotide substitution was identified in the 5' untranslated region. When the patients and healthy individuals were genotyped for these variations, no significant association was observed. However, although statistically not significant, NKG2-A c.238T>A (Cys80Ser) was observed in three patients with RA, but in none of the healthy individuals and the patients with SLE. Unexpectedly, in the process of polymorphism screening, we identified homozygous deletion of NKG2-C in approximately 4.3% of healthy donors; under the assumption of Hardy-Weinberg equilibrium, the allele frequency of NKG2-C deletion was estimated to be 20.7%. These results demonstrated that, although human NKG2-A, -C and CD94 are generally conserved with respect to amino acid sequences, NKG2-A is polymorphic in the noncoding region, and that the number of genes encoded in the human NKC is variable among individuals, as previously shown for the leukocyte receptor complex (LRC), HLA and Fcgamma receptor (FCGR) regions.

Adult↗
PubMed2006

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

Adolescent↗
PubMed2006

Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins: role of heredity.

The Rho/Rho kinase (ROCK) pathway is implicated in experimental hypertension. We, therefore, explored the role of ROCK2 genetic variation in human blood pressure (BP) regulation, exploiting the advantages of a human twin sample to probe heritability. The focus of this work is the common nonsynonymous variant at ROCK2: Thr431Asn. Cardiovascular and autonomic traits displayed substantial heritability (from approximately 33% to 71%; P<0.05). The Asn/Asn genotype (compared with Asn/Thr or Thr/Thr) was associated with greater resting systolic (P<0.001), diastolic (P<0.0001), and mean BP (P<0.0001); allelic variation at ROCK2 accounted for up to approximately 5% of BP variation (P<0.0001). Systemic vascular resistance was higher in Asn/Asn individuals (P=0.049), whereas cardiac output, large artery compliance, and vasoactive hormone secretion were not different. Coupling of the renin-angiotensin system to systemic resistance and BP was diminished in Asn/Asn homozygotes, suggesting genetic pleiotropy of Thr431Asn, confirmed by bivariate genetic analyses. The Asn/Asn genotype also predicted higher BP after environmental (cold) stress. The rise in heart rate after cold was less pronounced in Asn/Asn individuals, consistent with intact baroreceptor function, and baroreceptor slope was not influenced by genotype. Common genetic variation (Thr431Asn) at ROCK2 predicts increased BP, systemic vascular resistance (although not large artery compliance), and resistance in response to the endogenous renin-angiotensin system, indicating a resistance vessel-based effect on elevated BP. The results suggest that common variation in ROCK2 exerts systemic resistance-mediated changes in BP, documenting a novel mechanism for human circulatory control, and suggesting new possibilities for diagnostic profiling and treatment of subjects at risk of developing hypertension.

Adult↗
PubMed2001

Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite.

Microsatellites are common repeated sequences, which are useful as genetic markers and lack any clearly established function. In a previous study we suggested that an intronic polymorphic TCAT repeat in the tyrosine hydroxylase (TH) gene, the microsatellite HUMTH01, may regulate transcription. The TH gene encodes the rate-limiting enzyme in the synthesis of catecholamines, and the microsatellite HUMTH01 has been used in genetic studies of neuropsychiatric and cardiovascular diseases, in which disturbances of catecholaminergic neurotransmission have been implicated. HUMTH01 alleles associated with these diseases act as transcriptional enhancers when linked to a minimal promoter and are recognized by specific nuclear factors. Here we show that allelic variations of HUMTH01 commonly found in humans have a quantitative silencing effect on TH gene expression. Two specific proteins, ZNF191, a zinc finger protein, and HBP1, an HMG box transcription factor, which bind the TCAT motif, were then cloned. Finally, allelic variations of HUMTH01 correlate with quantitative and qualitative changes in the binding by ZNF191. Thus, this repeated sequence may contribute to the control of expression of quantitative genetic traits. As the HUMTH01 core motif is ubiquitous in the genome, this phenomenon may be relevant to the quantitative expression of many genes in addition to TH.

Alleles↗
PubMed2001

Chromosome 21: from sequence to applications.

Last year we celebrated the sequencing of the entire long arm of human chromosome 21. This achievement now provides unprecedented opportunities to understand the molecular pathophysiology of trisomy 21, elucidate the mechanisms of all monogenic disorders of chromosome 21, and discover genes and functional sequence variations that predispose to common complex disorders. All these steps require the functional analysis of gene products and the determination of the sequence variation of this chromosome.

Animals↗
PubMed2004

Analysis of inadequate cervical smears using Shewhart control charts.

BACKGROUND: Inadequate cervical smears cannot be analysed, can cause distress to women, are a financial burden to the NHS and may lead to further unnecessary procedures being undertaken. Furthermore, the proportion of inadequate smears is known to vary widely amongst providers. This study investigates this variation using Shewhart's theory of variation and control charts, and suggests strategies for addressing this. METHODS: Cervical cytology data, from six laboratories, serving 100 general practices in a former UK Health Authority area were obtained for the years 2000 and 2001. Control charts of the proportion of inadequate smears were plotted for all general practices, for the six laboratories and for the practices stratified by laboratory. The relationship between proportion of inadequate smears and the proportion of negative, borderline, mild, moderate or severe dyskaryosis as well as the positive predictive value of a smear in each laboratory was also investigated. RESULTS: There was wide variation in the proportion of inadequate smears with 23% of practices showing evidence of special cause variation and four of the six laboratories showing evidence of special cause variation.There was no evidence of a clinically important association between high rates of inadequate smears and better detection of dyskaryosis (R2 = 0.082). CONCLUSIONS: The proportion of inadequate smears is influenced by two distinct sources of variation - general practices and cytology laboratories, which are classified by the control chart methodology as either being consistent with common or special cause variation. This guidance from the control chart methodology appears to be useful in delivering the aim of continual improvement.

Cytological Techniques↗
PubMed1975

Non-compliance and errors of drug administration in patients discharged from acute medical wards.

Three hundred and fifteen patients discharged from acute general medical wards over an 18-month period were studied prospectively to determine deficiencies in medication ingestion from that expected by the hospital clinicians. Thirteen percent did not receive an entirely correct written prescription at the time of discharge from hospital. In 4.5 percent this was the sole reason for treatment failure. Excluding these patients, 40.5 percent of the remainder admitted to medication variations over a 1-6 week period. Non-compliance proved to be a cause of drug default by patients three times as frequently as simple error. Where all errors were considered the ratio was 2 : 1. Whereas non-compliance (indicating volitional intent) was a more common basis for medication variation in Europeans, simple error was a more common cause in Polynesians. Two out of every five of the latter group took incorrect or incomplete therapy because of misinterpretation of instructions, either provided by hospital clinical staff, or printed upon their medication containers. The reasons for non-compliance and simple error are elucidated and the problem of non-delivery of expected medication is discussed. In devising methods for improving accuracy of drug self-administration after discharge from hospital the entities of simple error and non-compliance warrant individual attention.

Drug Prescriptions↗
PubMed1980

Synthesis of the contingent negative variation brain potential from noncontingent stimulus and motor elements.

Slow shifts in brain potential (commonly called the contingent negative variation), obtained during a warned reaction-time task with a foreperiod of 1 second, were compared with waveforms synthesized by the addition of separately obtained potentials associated with individual (nonpaired) sensory stimuli and self-initiated motor movements. The synthesized waveforms match closely the actual contingent negative variation, suggesting that it is constituted largely of separate, noncontingent elements related to sensory and motor processes.

Auditory Perception↗
PubMedDate not supplied

Assessment of methods to identify sources of interindividual pharmacokinetic variations.

The advantages and limitations of the 2 most commonly used methods to investigate interindividual pharmacokinetic variations are reviewed. The first method is based on pharmacokinetic comparisons made after repeated administration of a model drug such as antipyrine, before, during and after imposition of a carefully controlled environmental perturbation. A principal virtue of the test is the use of each subject as a control. Subjects are usually under near basal conditions with respect to factors capable of altering hepatic drug-metabolising capacity. Exceedingly sensitive, the test yields highly reproducible results. It has been useful as a research tool in identifying environmental factors for which dose-response curves can be generated and compared. However, the test requires careful selection and control of subjects, and it may be hazardous to extrapolate results to subjects under different, non-basal, environmental conditions. This method most frequently involves antipyrine as the test compound, but other drugs can and have been used. The results disclose that many host factors that influence antipyrine disposition also affect the disposition of other drugs metabolised by hepatic mixed-function oxidases. Recent refinement of the antipyrine test involves measurement of the rate constant for formation of each of the 3 main metabolites of antipyrine. Sensitivity and specificity of the test are increased through examination of the effect of each factor on a separate hepatic cytochrome P-450. Due to the labouriousness of this procedure and its requirement for several days of urine collection from each subject, metabolite analysis will probably remain an experimental method not applicable for screening populations. The second method involves a particular model based on multiple regression analysis. Relying on correlations with historical data of a qualitative nature, previous applications of this method have been retrospective, rather than prospective. Several such correlations could not be confirmed in normal subjects under the conditions of a controlled prospective experiment. Thus, prospective studies need to be performed to check results obtained with this method. The model used appears to enjoy certain advantages, including speed, simplicity, and ease of execution.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylation↗
PubMed2002

Surface antigenic variation in Giardia lamblia.

Giardia lamblia, a common intestinal dwelling protozoan and a cause of diarrhoea in humans and animals world-wide, undergoes surface antigenic variation. The variant-specific surface proteins (VSPs) are a family of related, highly unusual proteins that cover the entire surface of the parasite. VSPs are cysteine-rich proteins containing many CXXC motifs, one or two GGCY motifs, a conserved hydrophobic tail and a Zn finger motif. The biological role(s) of VSPs is unclear. As VSPs are resistant to the effects of intestinal proteases, they likely allow the organism to survive in the protease-rich small intestine. Although immune escape is commonly mentioned as the reason antigenic variation occurs, VSP expression changes in vivo even in the absence of an adaptive immune system suggesting the biological role of antigenic variation is more complex. The molecular mechanisms involved in antigenic variation are not known but appear to differ from those known to occur in other protozoa.

Animals↗
PubMed2002

Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases.

BACKGROUND: Anatomical variations in right liver lobe are common. However, clinical implications and surgical management of these variations in living donor liver transplantation have not been analyzed systematically. METHODS: Surgical anatomy of vascular and biliary structures in 120 right lobe grafts were reevaluated by reviewing the results of preoperative (computerized tomography and Doppler ultrasonography) and intraoperative (cholangiography) imaging as well as surgical findings. The data were analyzed in relation to surgical management of anatomical variations. RESULTS: The incidence of variants leading to multiple portal vein anastomoses was 7.5%. The incidence of dual right hepatic veins was 0.8%; 30% of the grafts had significant accessory hepatic veins (>5 mm) and 13.9% of these were multiple. All of them were successfully reconstructed with technical modifications including venoplasty and venous grafts, except for two cases with multiple intraparenchymal portal vein branches to the anterior segment. The incidence of dual hepatic arteries was 1.7%, but only one of them was reconstructed without negative sequelae. The incidence of variants potentially leading to multiple bile duct anastomoses was 35.0%, and eventually 39.2% of the grafts had multiple orifices. With a variety of techniques including ductoplasty, hepaticohepaticostomy, and biliary stent, total incidence of leakage and stenosis was 10.8% and 9.2%, respectively. Although ductoplasty, internal stent or no stenting, seemed to be associated with increased risk of complications, anatomical variants, multiple bile ducts, and duct-to-duct reconstruction did not bear a significant risk. CONCLUSIONS: Anatomical variations of vascular and biliary structures in right lobe grafts are common. However, most can be managed safely with technical modifications. Only cases with intraparenchymal origin of the anterior portal vein(s) may form a relative contraindication, especially when combined with similar biliary variants. Otherwise, intraoperative assessment of biliary anatomy was enough for successful management. Detailed and precise assessment of vascular and biliary anatomy is vital for appropriate surgical management.

Adult↗
PubMed2000

Oral steroids for cystic fibrosis.

BACKGROUND: In cystic fibrosis, airway obstruction and recurrent respiratory infection leads to inflammation and eventually long term lung damage, (bronchiectasis), respiratory failure and death. Inflammation occurs early in the disease process, hence the rationale for the use of anti-inflammatory agents such as oral steroids. OBJECTIVES: To assess the effectiveness of oral steroids in management of respiratory complications cystic fibrosis with particular regard to lung function and occurrence of adverse events. We aimed to to examine short term use for a respiratory exacerbation separately (up to 30 days) from long term anti-inflammatory use (greater than 30 days). SEARCH STRATEGY: We searched The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised trials comparing oral corticosteroids given for a period of five to 30 days for treatment of an exacerbation or for more than 30 days used long term, with placebo or no additional therapy in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality. MAIN RESULTS: Three trials were identified studying a total of 354 patients. Two of these were long term trials with four year follow up whilst one had follow up to 12 weeks only. There was a lack of data on our predefined outcomes with common outcomes examined at different time-points and also variations in the presentation of common outcomes. A meta-analysis was not possible. Oral corticosteroids at a prednisolone equivalent dose of 1 mg/kg alternate days appear to slow the progression of lung disease in cystic fibrosis. At 24 months from commencement, 70.4% patients treated with 1mg/kg prednisolone on alternate days had an increase in per cent predicted forced vital capacity (FVC) compared to 41.6% patients treated with placebo. The mean absolute change in per cent predicted forced expiratory volume at one second (FEV1) 48 months from commencement was -2% in the 1 mg/kg alternate days prednisolone group but -6% in the placebo group. In the long term, this benefit needs to be weighed against the occurrence of adverse events. Linear growth retardation was observed as early as six months from start of treatment in the 2 mg/kg alternate days prednisolone group and from 24 months of treatment in the 1 mg/kg alternate days prednisolone group. Occurrence of adverse events, particularly glucose abnormalities, cataracts and growth retardation resulted in early termination of one of the four year studies ( approximately approximately Eigen 1995 approximately approximately ), with the group taking 2 mg/kg prednisolone on alternate days being stopped first but followed by the 1 mg/kg alternate days. REVIEWER'S CONCLUSIONS: Oral corticosteroids at a prednisolone equivalent dose of 1-2 mg/kg alternate days appear to slow the progression of lung disease in CF but this benefit needs to be weighed against the occurrence of adverse events, in particular, development of cataracts and effect on linear growth. A risk/benefit analysis of low-dose alternate days corticosteroids would be important and the role of short term use of oral steroids should be more fully evaluated.

Anti-Inflammatory Agents↗
PubMed1981

Dorsolumbosacral phlebography.

Two variations on the currently most commonly used technical method for phlebography are described. The first variation involves an original method for visualizing the dorsolumbosacral epidural plexus via the retrograde route from the azygos vein. If necessary this can be associated with catheterization and simultaneous injection into an ascending lumbar vein or into a lateral sacral vein. This method permits exploration from T7 to S1 and provides phlebograms of excellent quality, owing to the reduction in the flow caused by countercurrent injection. The second variation involves visualizing the epidural venous plexus by means of double percutaneous transfemoral catheterization of the hypogastric veins, using balloon catheters. This method is performed easily and rapidly. Preferential flow is obtained via the epidural plexus, and there is less diversion of the contrast medium through anastomoses and less filling of the vena cava. The specific indications for these methods are described. The availability of alternative methods beyond the traditional one renders epidural phlebography more reliable and more manageable, and it ensures certainty of diagnosis.

Azygos Vein↗
PubMed2001

Anatomical variations in the human testicular blood vessels.

The testis is an important organ upon which the survival of the human species depends. The testicular arteries and veins play major roles in the thermo-regulation that is essential for the efficient functioning of this organ. However, very little is found in the literature about the veins and their anatomical variations. Therefore the testicular veins and arteries in 150 dissection room cadavers at the University of the Witwatersrand, Johannesburg and University of Zimbabwe, Harare were examined for anatomical variations from the usual descriptions in textbooks of Anatomy. Variations were found more frequently in the testicular veins than in the accompanying arteries. The variations, which were more common on the left side, were seen in 32 (21.3%) of the cadavers. In 6 (18.8%) of these cases, the variations were present bilaterally. The veins were either completely or partially duplicated, with or without beading. The duplicated veins terminated in the corresponding renal veins either separately or after combining into one vein. In two cases, the right testicular vein terminated in the right renal vein, rather than in the inferior vena cava. Anatomical variations of the testicular artery were present in 4.7% of cases and were associated with their origin, which were either from unusually high levels of the abdominal aorta or from the renal artery.

Arteries↗