Biomedical subjects

D Lin

Publications and source records attributed to D Lin.

At least 19 recordsLinked to original sources

PubMed2006

A novel T-77C polymorphism in DNA repair gene XRCC1 contributes to diminished promoter activity and increased risk of non-small cell lung cancer.

X-ray repair cross-complementing 1 (XRCC1) plays a key role in DNA base excision repair and cells lacking its activity are hypersensitive to DNA damage. Recently, we reported a SNP (rs3213245, -77T>C) in the XRCC1 gene 5' untranslated region (UTR) was significantly associated with the risk of developing esophageal squamous-cell carcinoma. Computer analysis predicted that this SNP was in the core of Sp1-binding motif, which suggested its functional significance. Gel shift and super shift assays confirmed that -77T>C polymorphic site in the XRCC1 promoter was within the Sp1-binding motif and the T>C substitution greatly enhanced the binding affinity of Sp1 to this region. Luciferase assays indicated that the Sp1-high-affinity C-allelic XRCC1 promoter was associated with a reduced transcriptional activity. The association between -77T>C and three other amino-acid substitution-causing polymorphisms in XRCC1 and risk of lung cancer was examined in 1024 patients and 1118 controls and the results showed that only the -77T>C polymorphism was significantly associated with an increased risk of developing lung cancer. Multivariate logistic regression analysis found that an increased risk of lung cancer was associated with the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR=1.46, 95% CI=1.18-1.82; P=0.001) and the increased risk was more pronounced in smokers (OR=1.63, 95% CI=1.20-2.21) than in non-smokers (OR=1.28, 95% CI=0.94-1.76). Taken together, these results showed that the functional SNP -77T>C in XRCC1 5'UTR was associated with cancer development owing to the decreased transcriptional activity of C-allele-containing promoter with higher affinity to Sp1 binding.

Adult↗

PubMed2006

Gain of 1q25-32, 12q23-24.3, and 17q12-22 facilitates tumorigenesis and progression of human squamous cell lung cancer.

To explore the genetic changes involved in the stepwise development of lung cancer, we have determined the genetic events associated with the histological progression from normal bronchial epithelium to squamous cell carcinoma. Comparative genomic hybridization was used to identify chromosomal imbalances in 54 microdissected samples, including squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumour derived from 23 patients with squamous cell carcinoma of the lung. Histopathological progression was accompanied by an increased number of chromosomal abnormalities. Gains of 1q25-32, 12q23-24.3, and 17q12-22, in particular, were detected at high frequencies in both carcinoma in situ and invasive tumours and were found more often in the cases with lymph node metastases than in those without. Our previous expression profiling of squamous cell carcinomas had identified overexpression of laminin5 gamma2, a gene located at 1q25-31. Therefore, this was investigated at the protein level by immunohistochemical analysis in 336 samples of squamous cell carcinoma of the lung. Consistent with the genomic data for this region, the expression level of laminin5 gamma2 was higher in the primary tumours with lymph node metastases than in tumours without metastases (p = 0.012). These data suggest that gains of genes from 1q25-32, 12q23-24.3, and 17q12-22 facilitate tumorigenesis and progression of squamous cell carcinoma of the lung, and may serve as potential predictors for this disease.

Aged↗

PubMed2006

HIV-related knowledge, stigma, and willingness to disclose: A mediation analysis.

Increasing HIV knowledge is a focus of many HIV education and prevention efforts. While the bivariate relationship of HIV serostatus disclosure with HIV-related knowledge and stigma has been reported in the literature, little is known about the mediation effect of stigma on the relationship of HIV knowledge with HIV serostatus disclosure. Data from 4,208 rural-to-urban migrants in China were analyzed to explore this issue. Overall, 70% of respondents reported willingness to disclose their HIV status if they were HIV-positive. Willingness to disclose was negatively associated with misconceptions about HIV transmission and stigma. Stigma mediated the relationship between misconceptions and willingness to disclose among women but not men. The mediation effect of stigma suggests that stigmatization reduction would be an important component of HIV prevention approaches. Gender inequality needs to be addressed in stigmatization reduction efforts.

Adolescent↗

PubMed2006

Genetic heterogeneity in acrokeratosis verruciformis of Hopf.

BACKGROUND: Acrokeratosis verruciformis of Hopf (AKV) is a rare genodermatosis characterized by multiple flat-topped, flesh-coloured papules on the dorsa of hands and feet, and punctuate keratoses on the palms and soles. A mutation in the ATP2A2 gene has been shown to be associated with AKV and with Darier's disease (DD). OBJECTIVES: To explore the molecular aetiology of AKV and DD. METHODS: We investigated the clinical and histological information in two families and a sporadic case with AKV and one family and a sporadic case with DD in China. Mutation analysis of ATP2A2 was performed by PCR and direct sequencing, and genotyping and linkage analysis performed using six polymorphic microsatellite markers spanning the locus at 12q23-12q24 containing ATP2A2. RESULTS: Mutational analysis showed no mutation in ATP2A2 among the AKV patients, but we found two novel mutations (p.C318F and p.M719fs) in the DD patients. The genotyping and linkage analysis results revealed no linkage evidence of the locus at 12q23-12q24 in a large AKV family. CONCLUSIONS: Our findings provide evidence for the genetic heterogeneity of AKV and demonstrate that mutations in genes other than ATP2A2 are responsible for AKV in a proportion of the Chinese population.

Acrodermatitis↗

PubMed2005

Risk factors for colonization with third-generation cephalosporin-resistant enterobacteriaceae.

BACKGROUND AND METHOD: Colonization and infections caused by Enterobacteriaceae resistant to third-generation cephalosporins (CRE) have been observed with increasing frequency in intensive care unit (ICU) patients. In contrast to outbreak investigations, information about risk factors for colonization in an endemic situation are rare. We studied risk factors for colonization with CRE in a case control study including 1,706 patients, admitted to any of the 15 ICUs of Heidelberg University Hospitals. RESULTS: 163 patients carried CRE with Enterobacter spp. representing the predominant species. Independent risk factors for CRE carriage in the multivariate logistic regression analysis were an age of under 2.5 years (OR 4.034), an indwelling central venous catheter (CVC) for more than 3 days (OR 2.640), treatment with second- or third generation cephalosporin for longer than 3 days (OR 2.260) and any antibiotic therapy before admission to the ICU. CONCLUSION: Apart from the well-recognized risk factor previous antibiotic treatment, the risk factors age and presence of a CVC might suggest that bacterial overgrowth of the gut either due to an increased susceptibility in younger age or as a consequence of parenteral nutrition is a relevant mechanism for acquiring carriage of CRE in a non-outbreak situation.

Adolescent↗

PubMed2005

A common polymorphism in the 3'UTR of cyclooxygenase 2/prostaglandin synthase 2 gene and risk of lung cancer in a Chinese population.

Cyclooxygenases (COXs) are key enzymes that convert arachidonic acid to prostaglandins. Overexpression of COX-2, one of the COX isozymes, has been shown to be an early event in lung carcinogenesis and may play an important role in lung cancer development. A common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'UTR of COX-2 gene was identified and we hypothesized that this COX-2 variant is associated with lung cancer risk. To test this hypothesis, we genotyped this variant in a case-control study of 322 histologically-confirmed lung cancer patients and 323 age and sex frequency-matched cancer-free controls in a Chinese population. The results showed that the frequencies of variant genotypes 8473CT/CC were significantly less common in the cases (27.3%) than in the controls (35.3%) (P=0.034), suggesting that the 8473C allele was protective against lung cancer. Multivariate logistic regression analyses revealed that the COX-2 variant genotypes (8473CT/CC) were associated with a significantly decreased risk of lung cancer compared with the 8473TT wild-type homozygotes (OR=0.64, 95% CI=0.45-0.92). When we defined the reference group as non-smokers having the 8473CT/CC variant genotypes, the smokers with the 8473TT wild-type genotype had the greatest risk (adjusted OR=5.28, 95% CI=3.10-9.00). These findings indicate that the COX-2 T8473C polymorphism may contribute to lung cancer susceptibility in the Chinese population. Further larger molecular epidemiological studies are warranted to confirm these findings.

3' Untranslated Regions↗

PubMed2005

Workplace and HIV-related sexual behaviours and perceptions among female migrant workers.

Data from 1,543 female migrants working in eight occupational clusters in Beijing and Nanjing, China were analysed to examine the association of workplace with HIV-related behaviours and perceptions. For sexually experienced women (n = 666, 43.2%), those working in entertainment establishments or personal service (e.g., nightclubs, dancing halls, barbershops, beauty salons, massage parlours, etc.) engaged in risky sexual practices twice as frequently as those working in non-entertainment establishments (e.g. restaurants, stalls, domestic service, factories, etc.). About 10% of women in the entertainment establishments reported having sold sex, 30% having multiple sexual partners and 40% having sex with men with multiple sexual partners. The rate of consistent condom use was less than 15%. They also tended to have a higher level of perceptions of both peer risk involvement and positive expectancy of risk behaviours, and lower perceptions of severity of STDs and HIV. For women who were not sexually experienced, those working in 'stalls' or 'domestic service' tended to perceive higher peer risk involvement, less severity of HIV infection, and less effectiveness of protective behaviour. The occupational pattern of sexual risk behaviours and perceptions observed in the current study indicates employment conditions are associated with HIV risk. Intervention strategies should be tailored to address occupational-related factors.

Adolescent↗

PubMed2005

Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer.

BACKGROUND: The FAS and FASL system plays a key role in regulating apoptotic cell death and corruption of this signalling pathway has been shown to participate in immune escape and tumorigenesis. There is reduced expression of FAS but elevated expression of FASL in many types of human cancers including lung cancer. We recently reported an association between functional polymorphisms in FAS (-1377G-->A) and FASL (-844T-->C) and risk of oesophageal cancer. OBJECTIVE: To examine the contribution of these polymorphisms to risk of developing lung cancer. METHODS: Genotypes of 1000 lung cancer patients and 1270 controls were analysed by PCR based restriction fragment length polymorphism. Associations with risk of lung cancer were estimated by logistic regression. RESULTS: Compared with non-carriers, there was a 1.6 fold excess risk of developing lung cancer for carriers of the FAS -1377AA genotype (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.21 to 2.10; p = 0.001), and 1.8 fold excess risk (OR 1.79, 95% CI 1.26 to 2.52; p = 0.001) for carriers of FASL -844CC. Gene-gene interaction of FAS and FASL polymorphisms increased risk of lung cancer in a multiplicative manner (OR for the carriers of both FAS -1377AA and FASL -844CC genotypes 4.18, 95% CI 2.83 to 6.18). Gene-environment interaction of FAS or FASL polymorphism and smoking associated with increased risk of lung cancer was also found. CONCLUSION: These results are consistent with our initial findings in oesophageal cancer and further support the hypothesis that the FAS and FASL triggered apoptosis pathway plays an important role in human carcinogenesis.

Aged↗

PubMed2005

Effects of maternal Campylobacter rectus infection on murine placenta, fetal and neonatal survival, and brain development.

BACKGROUND: Maternal periodontal infection has been associated with increased risk of prematurity and low birthweight. Infection and inflammatory pathways that mediate prematurity have also been implicated in neonatal developmental impairments. The objective of this study was to determine whether maternal Campylobacter rectus infection that induces fetal growth restriction in a mouse model also compromises neonatal pup survival, growth, and neurodevelopment. METHODS: Timed pregnant mice were challenged with C. rectus on gestation day 7.5. One group of animals was sacrificed on embryonic day 16.5 for placental histology and measurement of fetal brain mRNA expression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Another group of animals was allowed to deliver to follow pup survival, growth, and brain structure at day 9. RESULTS: C. rectus challenge resulted in abnormal placental architecture with inflammation and a 2.8-fold increase in fetal brain expression of IFN-gamma (P = 0.04). Pup birthweight was unaffected by C. rectus exposure, but lethality was 3.9-fold higher after 1 week. Ultrastructurally, the 9-day neonatal brain tissue displayed cellular and myelin alterations consistent with white matter damage. CONCLUSIONS: Maternal C. rectus infection induces placental inflammation and decidual hyperplasia as well as concomitant increase in fetal brain IFN-gamma. Maternal infection increased pup mortality, and preliminary findings demonstrate ultrastructural changes in the hippocampal region of the neonatal brain, in a manner analogous to the effects of maternal infection on white matter damage seen in humans. Thus, the threat of maternal oral infectious exposure during pregnancy may not be limited to the duration of gestation, but may also potentially affect perinatal neurological growth and development.

Animals↗

PubMed2004

The genetic epidemiology of alopecia areata in China.

BACKGROUND: Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease with genetic predisposition and an environmental trigger. There are few clinical data in Asians. OBJECTIVES: To describe the genetic epidemiological features of AA patients in China and to determine the possible genetic model for AA. METHODS: Data for 1032 patients with AA were obtained by questionnaire in the Institute of Dermatology of Anhui Medical University in China from 2001 to 2003. Complex segregation analysis and heritability analysis were performed using Falconer's method, EPI INFO 6.0 and SAGE-REGTL programs. RESULTS: In total, 1032 AA patients (male/female ratio 1.1 : 1) were enrolled, representing 0.94% of the total number of cases seen in our outpatient clinic during that time. The mean +/- SD age of onset was 28.98 +/- 13.43 years. The difference between the mean age of onset in males and females was not significant. Most patients (82.6%) experienced their first episode of AA within the first four decades of life. A positive family history of AA was obtained in 87 patients (8.4%). The prevalence of AA in first-, second- and third-degree relatives of the proband with AA was 1.6%, 0.19% and 0.03%, respectively. These figures were higher than those in controls. A greater severity and longer duration of AA were seen in the early onset group than in the late-onset group. The early onset group also had more affected first- and second-degree relatives. The heritability of AA in first-, second- and third-degree relatives was 47.16%, 42.53% and 22.29%, respectively. Based on the REGTL results, the best model was a polygenic additive model for AA. CONCLUSIONS: The effect of genetic factors is strong in AA, but environmental factors such as infection and psychological stress may still play an important role. Our findings on the genetics of AA are consistent with a polygenic additive mode of inheritance.

Adolescent↗

PubMed2004

Prevalence of colonisation with third-generation cephalosporin-resistant Enterobacteriaceae in ICU patients of Heidelberg University Hospitals.

The aim of this study was to assess colonisation and transmission of third-generation cephalosporin-resistant Enterobacteriaceae (CRE) from patients in 16 intensive care units. A prospective, repetitive point prevalence survey was performed over 6 months, involving samples from 1851 patients. CRE were isolated from 186 (10%) patients, with Enterobacter spp. being the most common. Mean point prevalence rates were significantly higher for paediatric wards (22.5%) compared to surgical (8.1%) and medical (5.5%) units. All CRE isolates were typed by pulsed-field gel electrophoresis. Non-outbreak nosocomial transmission rates of these pathogens were calculated as 12.8% for paediatric patients, compared to 6.8% for adult patients, which may reflect differences in sensitivity to overgrowth with resistant bacteria and contact with health care workers.

Adolescent↗

PubMed2004

Marker-based cloning of the region containing the UhAvr1 avirulence gene from the basidiomycete barley pathogen Ustilago hordei.

Race-cultivar specialization during the interaction of the basidiomycete smut pathogen Ustilago hordei with its barley host was described in the 1940s. Subsequent genetic analyses revealed the presence of dominant avirulence genes in the pathogen that conform to the gene-for-gene theory. This pathosystem therefore presents an opportunity for the molecular genetic characterization of fungal genes controlling avirulence. We performed a cross between U. hordei strains to obtain 54 progeny segregating for three dominant avirulence genes on three differential barley cultivars. Bulked segregant analysis was used to identify RAPD and AFLP markers tightly linked to the avirulence gene UhAvr1. The UhAvr1 gene is located in an area containing repetitive DNA and this region is undetectable in cosmid libraries prepared from the avirulent parental strain. PCR and hybridization probes developed from the linked markers were therefore used to identify cosmid clones from the virulent (Uhavr1) parent. By walking on Uhavr1-linked cosmid clones, a nonrepetitive, nearby probe was found that recognized five overlapping BAC clones spanning 170 kb from the UhAvr1 parent. A contig of the clones in the UhAvr1 region was constructed and selected probes were used for RFLP analysis of the segregating population. This approach genetically defined an approximately 80-kb region that carries the UhAvr1 gene and provided cloned sequences for subsequent genetic analysis. UhAvr1 represents the first avirulence gene cloned from a basidiomycete plant pathogen.

Base Sequence↗

PubMed2004

Ablation of atrial fibrillation: localizing triggers, mapping systems and ablation techniques.

Ablation to eliminate atrial fibrillation (AF) is a therapy in evolution. Approaches to the ablation appear to be currently divided into 2 major strategies anatomic versus electrically guided. In addition in using an electrically guided techniques debate remains whether a targeted approach should be used, whether exit block should be documented, and whether all non pulmonary vein triggers should be targeted. This review highlights the different ablation strategies and identifies a systematic approach to ablation of pulmonary and non pulmonary vein triggers that we have adapted at our institution. The role of intracardiac echo, trigger provocation and localization and the use of 3-D mapping systems in AF ablation are defined.

Adrenergic beta-Agonists↗

PubMed2002

Exposure to chronic mild stress alters thresholds for lateral hypothalamic stimulation reward and subsequent responsiveness to amphetamine.

Chronic mild stress in rodents has been proposed to model some of the environmental factors that contribute to the induction of depressive disorders in humans. This model is based on the hypothesis that chronic mild stress induces a change in brain reward function that resembles the symptomatology of major depression, namely, a decrease in responsiveness to rewarding stimuli. The purpose of the first experiment was to investigate whether chronic mild stress affects brain reward function as measured by alterations in lateral hypothalamic self-stimulation behavior in rats. Exposure to chronic mild stress induces a reduction in body weight which might affect brain reward function on its own. Therefore, the potential contribution of a reduction in body weight to the chronic mild stress-induced alterations in brain reward function was examined in a separate group of food-restricted rats. Thresholds for lateral hypothalamic self-stimulation were slightly but significantly lowered in animals exposed to chronic mild stress, indicating an enhancement of stimulation reward efficacy. Food restriction had no effect on brain reward function. The second experiment examined the interaction between prior exposure to chronic mild stress or food restriction and responsiveness to a pharmacological challenge, amphetamine, that enhances brain reward function. Acute administration of amphetamine produced a greater enhancement of lateral hypothalamic self-stimulation reward in animals exposed to chronic stress relative to non-stressed and food-restricted animals. Taken together, the present findings indicate that chronic mild stress sensitizes the neural substrates that mediate both lateral hypothalamic stimulation and psychostimulant drug reward. These findings support the hypothesis that prior exposure to stress affects the vulnerability for drug-taking behavior by increasing the positive reinforcing properties of drug of abuse.

Amphetamine↗

PubMed2001

Positional cloning of heart and soul reveals multiple roles for PKC lambda in zebrafish organogenesis.

BACKGROUND: The Par-3/Par-6/aPKC complex is a key regulator of cell polarity in a number of systems. In Drosophila, this complex acts at the zonula adherens (adherens junctions) to establish epithelial polarity and helps to orient the mitotic spindle during asymmetric neuroblast divisions. In MDCKII cells, this complex localizes to the zonula occludens (tight junctions) and appears to regulate epithelial polarity. However, the in vivo role of this complex during vertebrate embryogenesis is not known, due to the lack of relevant mutations. RESULTS: We have positionally cloned the zebrafish heart and soul (has) mutation, which affects the morphogenesis of several embryonic tissues, and show that it encodes atypical protein kinase C lambda (aPKC lambda). We find that loss of aPKC lambda affects the formation and maintenance of the zonula adherens in the polarized epithelia of the retina, neural tube, and digestive tract, leading to novel phenotypes, such as the formation of multiple lumens in the developing intestine. In addition, has mutants display defects in gut looping and endodermal organ morphogenesis that appear to be independent of the defects in epithelial polarity. Finally, we show that loss of aPKC lambda leads to defects in spindle orientation during progenitor cell divisions in the neural retina. CONCLUSIONS: Our results show that aPKC lambda is required for the formation and maintenance of the zonula adherens during early epithelial development in vertebrates and demonstrate a previously undescribed yet critical role for this protein in organ morphogenesis. Furthermore, our studies identify the first genetic locus regulating the orientation of cell division in vertebrates.

Adherens Junctions↗

PubMed2001

The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein.

The ubiquitin pathway is involved in the proteolytic turnover of many short-lived cellular regulatory proteins. Since selective degradation of substrates of this system requires the covalent attachment of a polyubiquitin chain to the substrates, degradation could be counteracted by de-ubiquitinating enzymes (or isopeptidases) which selectively remove the polyubiquitin chain. Unp is a human isopeptidase with still poorly understood biological functions. Here, we show that cellular Unp specifically interacts with the retinoblastoma gene product (pRb).

Amino Acid Motifs↗

PubMed2001

Body mass index and the risk of recurrent coronary events following acute myocardial infarction.

Although excess adiposity appears to increase the risk of coronary heart disease in the general population, its importance in patients with established coronary disease is less defined. We evaluated a population-based inception cohort of survivors to hospital discharge following first acute myocardial infarction (AMI) (n = 2,541) to assess the association between body mass index (BMI) and the risk of recurrent coronary events and to explore the mechanisms for this relation. Using Cox proportional-hazards regression, we assessed the risk of recurrent coronary events associated with levels of adiposity as defined by BMI and then investigated potential mechanisms through which adiposity conferred risk by examining how adjustment for diabetes mellitus, systemic hypertension, and dyslipidemia affected the association. Forty-one percent of the cohort were overweight (BMI 25 to 29.9), and 27.8% were obese (BMI > or =30). After adjustment for other risk factors, the risk of recurrent coronary events (n = 418) increased as BMI increased, especially among those who were obese. Using a BMI of 16 to 24.9 as the reference group, for mildly overweight patients (BMI 25 to 27.4), the relative risk (RR) was 0.93 (95% confidence interval [CI] 0.70 to 1.24); it was 1.16 for more severe overweight patients (BMI 27.5 to 29.9; 95% CI 0.87 to 1.55). For patients with class I obesity (BMI 30 to 34.9), the RR was 1.49 (95% CI 1.12 to 1.98), and for class II to III obesity (BMI > or =35), the RR was 1.80 (95% CI 1.30 to 2.48). We estimated that clinical measurements of diabetes, hypertension, and dyslipidemia explained approximately 43% of this risk. Thus, excess adiposity as measured by BMI was associated with an increased risk of recurrent coronary events following AMI, particularly among those who were obese.

Adult↗

PubMed2001

Dynamics of the Mrf-2 DNA-binding domain free and in complex with DNA.

Mrf-2 is a member of a new class of DNA-binding proteins known as the AT-rich interaction domain family or ARID. Chemical shift indices and characteristic NOE values indicate that the three-dimensional structure of the Mrf-2 ARID in complex with DNA is nearly identical to that of the free protein. The backbone dynamics of the Mrf-2 domain free and in complex with DNA have been characterized by (15)N NMR relaxation measurements and model-free analysis. Chemical shift perturbations and dynamic studies suggest that two flexible interhelical loops, the flexible C-terminal tail, and one alpha-helix are involved in DNA recognition, indicating the importance of protein dynamics in DNA binding. Some well-structured regions, in particular the putative DNA-contacting helix, in Mrf-2 show a decrease in the order parameters (S(2)) upon complex formation. The less well-structured loops and the unstructured C-terminus show reduced flexibility upon DNA binding. In addition, the model-free analysis indicates motions on the picosecond to nanosecond and micro- to millisecond time scales at the DNA-binding surface of the bound Mrf-2 ARID, suggesting a model where interactions between the protein and DNA are highly dynamic.

Anisotropy↗