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PubMed2001

Variation in diagnosis and management of common foot problems by GPs.

BACKGROUND: There are indications that the diagnosis and management of common foot problems vary widely in general practice. OBJECTIVES: Our aim was to explore the variation of GPs' diagnosis and management of common foot problems and the possible correlation between GPs' characteristics and their competence to diagnose correctly. METHODS: In a cross-sectional design, 90 GPs in The Netherlands were invited to complete a questionnaire regarding seven vignettes with common foot problems (hallux valgus, hallux rigidus, fasciitis plantaris, tarsal tunnel syndrome, metatarsalgia, corns and calluses, and rheumatoid arthritis), combined with questions covering diagnoses, management options and some GP characteristics. RESULTS: A total of 72 GPs responded (80%). They most often diagnosed hallux valgus (79%) and rheumatoid arthritis (86%) correctly, and most often hallux rigidus (37%) and tarsal tunnel syndrome (74%) incorrectly. GP characteristics did not correlate with their competence in diagnosing. The most frequently suggested management was referral to a podiatrist. The referral rate to medical specialists was low, except in the case of rheumatoid arthritis (79%). CONCLUSIONS: More than half of the GPs were competent in diagnosing vignettes of common foot problems. This diagnostic competence showed great variation and was not associated independently with GP characteristics. Educational programmes are recommended. Management showed less variation and often included referral to podiatrists. Further research into the effectiveness of specific treatments for different foot problems is recommended.

Adult↗
PubMed2003

The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk.

Transforming growth factor-beta 1 (TGF-beta1) is a potent inhibitor of proliferation of epithelial, endothelial and hematopoietic cells and acts as a tumor suppressor. The gene for TGF-beta1, TGFB1, carries a common T/C variation of nucleotide 29, resulting in a leucine (L) to proline (P) polymorphism at codon 10 (TGFB1 L10P). The less common 10P allele has repeatedly been linked to higher TGF-beta1 levels and in at least one study to a lower incidence of breast cancer. To further analyze the role of this polymorphism for breast cancer risk, 500 patients with histologically confirmed breast cancer and 500 sex-and age-matched healthy control subjects were genotyped for the TGFB1 L10P polymorphism by an allele-specific polymerase chain reaction assay. TGFB1 LL, LP and PP genotype frequencies were not significantly different for patients (39.6, 44.2, 16.2%) and controls (36.5, 45.9, 17.6%). We conclude that the TGFB1 L10P polymorphism is not associated with breast cancer risk.

Adult↗
PubMed1996

Peroperative cholangiography through the gallbladder (cholecystocholangiography) during laparoscopic cholecystectomy.

The indications and best technique for peroperative cholangiography during laparoscopic cholecystectomy remain unclear, but the operation has been associated with an increased use of preoperative endoscopic retrograde cholangiography. Cystic duct cholangiography, particularly in the hands of the trainee, can be time consuming, and bile duct injury may be caused by attempts to cannulate the cystic duct. This study analyses 113 consecutive patients undergoing peroperative cholangiography through the gallbladder, or cholecystocholangiography. It was successful in 92 (81.4%) patients, the procedure adding less than 10 min to the operating time. There were no cholangiogram-related complications. Common anatomical variations included both short and particularly wide cystic ducts. This information helps to minimize the risk of damage to the common bile duct. This study demonstrates that cholecystocholangiography is a safe, simple, and effective alternative to cystic duct cholangiography with virtually no "learning curve." It provides a "road-map" of biliary anatomy and identifies common bile duct stones prior to the commencement of dissection. Unsuccessful cholecystocholangiography does not preclude the use of cystic duct cholangiography later in the operation. Difficult anatomy is demonstrated prior to dissection. When unsuspected bile duct calculi necessitate open exploration, further laparoscopic dissection is avoided.

Adult↗
PubMed1998

Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus.

Uncoupling protein-1 (UCP-1) activity in brown adipose tissue increases thermogenesis, contributes to facultative energy expenditure in humans, and has been implicated in the pathogenesis of rodent obesity. To determine genetic factors controlling UCP-1 expression in humans, we measured intra- and extraperitoneal UCP-1 mRNA abundance levels by a competitive RT-PCR method and compared expression levels with common sequence variations in the beta3-adrenergic receptor gene and the distal UCP-1 gene promoter in obese human subjects. While median and average UCP-1 mRNA levels in both the intra- and extraperitoneal tissue were lower in subjects heterozygous for the Trp64Arg mutation in the beta3-adrenergic receptor gene, this difference was not statistically significant. However, a strong association of intraperitoneal UCP-1 mRNA abundance with the UCP-1 gene polymorphism at -3826 relative to the transcription start site was observed that explained 19.3% of the interindividual variability. The minor allele imparted a dose-dependent reduction on UCP gene expression. The importance of sequence variations at the UCP-1 gene locus as a common source of UCP-1 mRNA abundance variability was supported by allele-specific expression studies utilizing a newly identified polymorphism in exon 2 of the UCP-1 gene that predicts a substitution of alanine by threonine. In four subjects heterozygous for the -3826 polymorphism, the mRNA species transcribed from the wild-type allele accounted for 63+/-6% percent of total intraperitoneal mRNA abundance. In one subject homozygous for the minor promoter allele, wild-type mRNA was also more abundant than variant mRNA. Thus, the UCP-1 polymorphism at -3826 is probably only a marker for a frequent mutation causing reduced mRNA expression.

Adipose Tissue↗
PubMed2005

Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population.

Cytochrome P450 2C9 (CYP2C9) shows genetic polymorphism with high interethnic variation, but no report has addressed the genetic polymorphism in the Vietnamese population. In the present study, the distribution of 2 common allelic variations of CYP2C9 was investigated in Vietnamese Kinh population, a major ethnic group in Vietnam. Genomic DNA from 157 Vietnamese subjects was amplified by polymerase chain reaction, and the presence of CYP2C9*2 and CYP2C9*3 allelic variants was determined by pyrosequencing. Among 157 Vietnamese subjects, no subject with the CYP2C9*2 allele was detected, but 7 subjects were heterozygous for the CYP2C9*3 allele. The allele frequency of CYP2C9*3 was 2.2% in the Vietnamese Kinh population. This genotype distribution was well correlated with previous reports suggesting no occurrence of CYP2C9*2 in Asians. These results suggest that CYP2C9*2 may be absent in Vietnamese Kinh population and that CYP2C9*3 is major allelic variant that causes interindividual variation of drug responses to CYP2C9 substrate drugs in the Vietnamese Kinh population.

Alleles↗
PubMed2005

Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases.

BACKGROUND: Several studies have identified rare genetic variations responsible for many cases of familial breast cancer but their contribution to total breast cancer incidence is relatively small. More common genetic variations with low penetrance have been postulated to account for a higher proportion of the population risk of breast cancer. METHODS AND RESULTS: In an effort to identify genes that influence non-familial breast cancer risk, we tested over 25,000 single nucleotide polymorphisms (SNPs) located within approximately 14,000 genes in a large-scale case-control study in 254 German women with breast cancer and 268 age-matched women without malignant disease. We identified a marker on chromosome 14q24.3-q31.1 that was marginally associated with breast cancer status (OR = 1.5, P = 0.07). Genotypes for this SNP were also significantly associated with indicators of breast cancer severity, including presence of lymph node metastases (P = 0.006) and earlier age of onset (P = 0.01). The association with breast cancer status was replicated in two independent samples (OR = 1.35, P = 0.05). High-density association fine mapping showed that the association spanned about 80 kb of the zinc-finger gene DPF3 (also known as CERD4). One SNP in intron 1 was found to be more strongly associated with breast cancer status in all three sample collections (OR = 1.6, P = 0.003) as well as with increased lymph node metastases (P = 0.01) and tumor size (P = 0.01). CONCLUSION: Polymorphisms in the 5' region of DPF3 were associated with increased risk of breast cancer development, lymph node metastases, age of onset, and tumor size in women of European ancestry. This large-scale association study suggests that genetic variation in DPF3 contributes to breast cancer susceptibility and severity.

Journal Article↗
PubMed1993

Surgical common trunk training in Europe.

There are wide variations of surgical common trunk training programmes among European countries. Variations are also found in entry criteria to training programmes, in training evaluation methods and final certification, and also in accreditation of training institutions. Finally manpower control should be applied to secure production of an adequate number of competent surgeons and consequently high quality of health care.

Education, Medical, Graduate↗
PubMed2006

Genetic variation in the nucleotide excision repair pathway and bladder cancer risk.

Nucleotide excision repair (NER) is critical for protecting against damage from carcinogens in tobacco smoke. We evaluated the influence of common genetic variation in the NER pathway on bladder cancer risk by analyzing 22 single nucleotide polymorphisms (SNP) in seven NER genes (XPC, RAD23B, ERCC1, ERCC2, ERCC4, ERCC5, and ERCC6). Our study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from Spain. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, and smoking status. Subjects with the variant genotypes for SNPs in four of the seven genes evaluated had small increases in bladder cancer risk compared to subjects with the homozygous wild-type genotypes: RAD23B IVS5-15A>G (OR, 1.3; 95% CI, 1.1-1.5; P = 0.01), ERCC2 R156R (OR, 1.3; 95% CI, 1.1-1.6; P = 0.006), ERCC1 IVS5+33A>C (OR, 1.2; 95% CI, 1.0-1.5; P = 0.06; P(trend) = 0.04), and ERCC5 M254V (OR, 1.4; 95% CI, 1.0-2.0; P = 0.04). A global test for pathway effects indicated that genetic variation in NER characterized by the 22 SNPs analyzed in this study significantly predicts bladder cancer risk (P = 0.04). Pairwise comparisons suggested that carrying variants in two genes could result in substantial increases in risk. Classification tree analyses suggested the presence of subgroups of individuals defined by smoking and NER genotypes that could have substantial increases in risk. In conclusion, these findings provide support for the influence of genetic variation in NER on bladder cancer risk. A detailed characterization of genetic variation in key NER genes is warranted and might ultimately help identify multiple susceptibility variants that could be responsible for substantial joint increases in risk.

Adult↗
PubMed2004

Mechanisms of genetic susceptibility to type I diabetes: beyond HLA.

An individual's predisposition to Type I diabetes (T1D) is largely determined by complex interactions between several genetic loci and other, nonheritable factors. In T1D, the HLA locus has been known for decades to contribute 50% of the inherited risk. Outside the HLA are many proposed candidate loci with smaller effects, but only two confirmed candidate genes, the INS-VNTR and the CTLA-4 genes, which together do not contribute more than 15% of the risk. Because of the high frequency of the disease-associated DNA variants of these genes, understanding the biological mechanisms of such DNA variation in the context of T1D can have tremendous impact on the development of preventive therapeutics. However, establishing a causal relationship between common DNA variations and disease-predisposing functional effects is not trivial and remains difficult, as the effects are expected to be subtle. The variable-number tandem-repeat (VNTR) region upstream of the insulin gene is known to mediate expression in the thymus and pancreas, whereas various polymorphisms in the 5' and 3' regulatory regions of CTLA-4 are thought to alter gene expression and a coding A49G polymorphism exerts effects on post-translational processing. This review details the latest efforts in elucidating the functional mechanisms that explain the genetic association of the INS-VNTR and CTLA-4 genes with T1D.

Antigens, CD↗
PubMedDate not supplied

Fine needle aspiration cytology of pleomorphic adenoma. An analysis of 212 cases.

OBJECTIVE: To assess the value of fine needle aspiration cytology (FNAC) in the diagnosis of pleomorphic adenoma and to determine the cytologic variations responsible for diagnostic errors. STUDY DESIGN: We retrospectively studied 212 cases cytologically diagnosed as pleomorphic adenoma. In 184 a histologic diagnosis was available. Fourteen cases of histologically proven pleomorphic adenomas with a previously erroneous cytologic diagnosis were also reviewed. This study was based on those cases with a histologic diagnosis. RESULTS: The sensitivity and specificity of the cytologic diagnosis of pleomorphic adenoma in our series were 92.6% and 98.4%, respectively. In relation to malignancy, the series showed six false negative and three false positive diagnoses. In those cases correctly diagnosed on aspiration (175), a typical cytologic appearance, with no diagnostic difficulties, was observed in 118 cases (67.4%); the remainder showed cytologic variations. Cellular atypia (20.6%), cystic transformation (7%) and the presence of a cylindromatous pattern (5%) resembling adenoid cystic carcinoma were the most common cytologic variations observed and responsible for the majority of the errors. CONCLUSION: The cytologic variations in FNAC of pleomorphic adenoma must be considered in order to avoid important errors in the preoperative management of and surgical approach to salivary gland lesions.

Adenoma, Pleomorphic↗
PubMed1998

A simulation study comparing tests for the equality of coefficients of variation.

The coefficient of variation is commonly used in medical and biological sciences. In this paper, several parametric and non-parametric tests for the equality of coefficients of variation in kappa populations are reviewed. Simulation studies are conducted to compare the sizes and power of these tests. It is found that the parametric tests perform well if the data are normally distributed, but perform poorly if otherwise. The non-parametric test, however, is rather robust against the underlying distribution. An example using data of the Quality Assurance Program from the Hong Kong Medical Technology Association in Haematology and Serology is provided. The insensitivity of the non-parametric test to outliers is demonstrated.

Analysis of Variance↗
PubMed1990

Ethylene glycol monopropyl ether: a developmental toxicity study in rabbits.

To determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), groups of pregnant New Zealand white rabbits were exposed to target concentrations of 0, 125, 250, or 500 ppm EGPE vapors for 6 hr a day on Days 6-18 of gestation. Maternal effects included a slight reduction in feed consumption during the first week of treatment at the 250- and 500-ppm exposure levels and slightly reduced body weight gain at the 500-ppm level compared to those of the controls, but the differences were not statistically significant. One doe exposed to 500 ppm had red-colored urine during the 24-hr period following the second exposure. Hematologic determinations, absolute and relative organ weights, and observations at necropsy revealed no treatment-related maternal effects. Reproductive indices, i.e., pregnancy rate, number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal body weights, fetal sex ratio, and the gravid uterine and corrected body weights, were not affected by exposures to EGPE. The occurrences of external and internal soft tissue malformations and variations and the incidences of skeletal malformations in the EGPE-exposed groups were not significantly different from those in the control group. Common skeletal variations, in many instances, were seen less frequently in EGPE-exposed fetuses than in control fetuses. In those cases where the incidence of fetuses with a skeletal variation was greater for EGPE-exposed fetuses than that for control fetuses, the number of litters involved was not significantly different from that of the control group. Thus, EGPE vapor concentrations as high as 500 ppm did not produce teratogenicity or other developmental toxicity in the rabbit conceptus.

Abnormalities, Drug-Induced↗
PubMed2005

Genetic variation, nucleotide diversity, and linkage disequilibrium in seven telomere stability genes suggest that these genes may be under constraint.

To maintain chromosomal integrity and to protect the ends of chromosomes against recognition as damaged DNA, end-to-end fusion, or recombination, a coordinated set of genes is required to stabilize the telomere. We surveyed common genetic variation in seven genes that are vital to telomere stability (TERT, POT1, TNKS, TERF1, TINF2, TERF2, and TERF2IP) and validated single nucleotide polymorphisms (SNPs) in four different ethnic groups (n=118 total). Overall, our data show limited degrees of nucleotide diversity in comparison with data from other gene families. We observed that these genes are highly conserved in sequence between species, and that for nearly all of the coding SNPs the most common allele is ancestral (i.e., it is observed in primate sequences). Our findings support the hypothesis that genetic variation in a pathway that is critical for telomere stability may be under constraint. These data establish a foundation for further investigation of these genes in population-genetics, evolution, and disease-association studies.

Animals↗
PubMed2004

Variation in the SHC1 gene and longevity in humans.

Mice in which the p66(SHC) specific region of the SHC gene is deleted live 30% longer without apparent disease. These mice have lower levels of oxidative stress and apoptosis, both of which have been linked to old age survival in man. This makes SHC1 an important candidate gene for longevity in humans. We found no variations in the p66 specific region of the SHC1 gene in 30 young and 30 extreme long-lived subjects. Thus in man, no common sequence variations occur in p66 specific region of the SHC1 gene. In two independent cohorts of respectively 730 and 563 subjects aged 85 and over, we tested the only known non-synonymous polymorphism, Met(410)Val, for association with longevity using a prospective follow-up design. In the first cohort, we found increasing valine allele frequency in three strata of increasing age at death (2.8-5.2%). Moreover, compared to Met/Met carriers, mortality rate was a factor of 0.71 (95% CI 0.45-1.13) reduced for Met/Val carriers in the combined cohorts, with similar risk estimates in both cohorts. Low valine allele frequency resulted, however, in low power to detect statistical significance. These data suggest that an association between the Met(410)Val polymorphism and longevity in humans may exist.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Identification of genetic variation in the human hormone-sensitive lipase gene and 5' sequences: homology of 5' sequences with mouse promoter and identification of potential regulatory elements.

Hormone-sensitive lipase (HSL) plays a crucial role in triglyceride hydrolysis in adipose tissue and exhibits cholesterol hydrolase activity in steroidogenic tissue and macrophages. Thus, common genetic variation in the HSL gene could affect both energy metabolism and atherogenesis. Using overlapping single-strand conformational polymorphism analysis (SSCP), a common single base change (T/C) in intron 4 [allele frequency 0.012 (95% CI 0.007-0. 018)] and a variable CA repeat in intron 6 with 9 alleles (heterozygosity index = 0.66) were identified. Sequence of 1.123 kb upstream from the reported 5'UTR (1) which includes intron B, exon B, and 159 bp of the promoter (2) was obtained and a single common nucleotide change, -60C/G [allele frequency 0.052 (95% CI 0.039-0. 064)], identified. Preliminary in vitro studies show that the -60G construct has 38.5% lower luciferase activity compared to the -60C construct (P = 0.035), suggesting a functional change affecting HSL gene expression. The 5' sequence shows 57-59% homology with the mouse promoter with higher homology at potential regulatory motifs. Thus, the 1.7 kb of 5' sequences is well conserved and may play a part in the regulation of HSL gene expression.

Adipocytes↗
PubMed2002

Evidence of diversifying selection in human papillomavirus type 16 E6 but not E7 oncogenes.

Human papillomavirus type 16 is a common sexually transmitted pathogen capable of giving rise to cervical intraepithelial neoplasia and invasive carcinoma through the expression and activity of two adjacent oncogenes: E6 and E7. Naturally occurring amino acid variation is commonly observed in the E6 protein but to a much lesser extent in E7. In order to investigate the evolutionary mechanisms involved in the generation and maintenance of this variation, we examine 42 distinct E6-E7 haplotypes using codon-based genealogical techniques. These techniques involve estimation of the ratio of nonsynonymous to synonymous substitutions (dn/ds) and allow testing for directional (positive) natural selection. Positive selection was detected for four codon sites within the E6 oncogene but not in any E7 codons. The amino acid compositions and locations of selected sites are described. Possible sources of natural selection including antiviral immune pressure and polymorphism of host cellular proteins are discussed.

Amino Acid Sequence↗