[Advances in clinical studies of chronic cough].

Chronic cough is a common complaint in respiratory specialist clinics, with a significant impact on cough-specific quality of life and psychophysiological health. The diagnosis, treatment and management of chronic cough remains a major challenge. We summarized a series of recent advances from clinical studies in the epidemiology, diagnosis and management of chronic cough over the past year.

Patients with persistent symptoms after COVID-19 attending a multidisciplinary evaluation: Characteristics, medical conclusions, and satisfaction.

OBJECTIVE: Among patients attending a multidisciplinary day-hospital program for persistent symptoms after COVID-19, we aimed i) to describe their characteristics ii) to present the medical conclusions (diagnoses and recommendations) and iii) to assess the patients' satisfaction and its correlates. METHODS: For this retrospective chart review study, frequent symptoms were systematically assessed. Standardized questionnaires explored fatigue (Pichot scale), physical activity (Ricci & Gagnon scale), health-related quality of life (Short-Form Health Survey), anxiety and depressive symptoms (Hospital Anxiety and Depression scale) and associated psychological burden (Somatic-Symptom-Disorder B criteria Scale). Medical record conclusions were collected and a satisfaction survey was performed at 3-months follow-up. RESULTS: Among 286 consecutive patients (median age: 44 years; 70% women), the most frequent symptoms were fatigue (86%), breathlessness (65%), joint/muscular pain (61%) and cognitive dysfunction (58%), with a median duration of 429 days (Inter-quartile range (IqR): 216-624). Questionnaires revealed low levels of physical activity and quality of life, and high levels of fatigue, anxiety, depression, and psychological burden, with 32% and 23% meeting the diagnostic criteria for a depressive or anxiety disorder, respectively. Positive arguments for a functional somatic disorder were found in 76% of patients, including 96% with no abnormal clinical or test findings that may explain the symptoms. Physical activity rehabilitation was recommended for 91% of patients. Patients' median satisfaction was 8/10 (IqR: 6-9). CONCLUSION: Most patients attending this program presented with long-lasting symptoms and severe quality of life impairment, received a diagnosis of functional somatic disorder, and reported high levels of satisfaction regarding the program.

Development and validation of an individualized nomogram for predicting the high-volume (> 5) central lymph node metastasis in papillary thyroid microcarcinoma.

PURPOSE: Papillary thyroid microcarcinoma (PTMC) frequently presents a favorable clinical outcome, while aggressive invasiveness can also be found in some of this population. Identifying the risk clinical factors of high-volume (> 5) central lymph node metastasis (CLNM) in PTMC patients could help oncologists make a better-individualized clinical decision. METHODS: We retrospectively reviewed the clinical characteristics of adult patients with PTC in the Surveillance, Epidemiology, and End Results (SEER) database between Jan 2010 and Dec 2015 and in one medical center affiliated to Chongqing Medical University between Jan 2018 and Oct 2020. Univariate and multivariate logistic regression analyses were used to determine the risk factors for high volume of CLNM in PTMC patients. RESULTS: The male gender (OR = 2.02, 95% CI 1.46-2.81), larger tumor size (> 5 mm, OR = 1.64, 95% CI 1.13-2.38), multifocality (OR = 1.87, 95% CI 1.40-2.51), and extrathyroidal invasion (OR = 3.67; 95% CI 2.64-5.10) were independent risk factors in promoting high-volume of CLNM in PTMC patients. By contrast, elderly age (≥ 55 years) at diagnosis (OR = 0.57, 95% CI 0.40-0.81) and PTMC-follicular variate (OR = 0.60, 95% CI 0.42-0.87) were determined as the protective factors. Based on these indicators, a nomogram was further constructed with a good concordance index (C-index) of 0.702, supported by an external validating cohort with a promising C-index of 0.811. CONCLUSION: A nomogram was successfully established and validated with six clinical indicators. This model could help surgeons to make a better-individualized clinical decision on the management of PTMC patients, especially in terms of whether prophylactic central lymph node dissection and postoperative radiotherapy should be warranted.

Construction and validation of a nomogram for predicting cervical lymph node metastasis in classic papillary thyroid carcinoma.

PURPOSE: Patients with papillary thyroid carcinoma (PTC) frequently present a relatively poor prognosis when they coexist with cervical lymph node metastasis (LNM). Moreover, it remains controversial whether prophylactic lymph node dissection (LND) should be performed for patients without clinically lymph node metastasis. Thus, we hereby develop a nomogram for predicting the cervical LNM (including central and lateral LNM) in patients with PTC. METHODS: We retrospectively reviewed the clinical characteristics of adult patients with PTC in the surveillance, epidemiology, and end results (SEER) database between 2010 and 2015 and in our Department of Breast and Thyroid Surgery in the Second Affiliated Hospital of Chongqing Medical University between 2019 and 2020. RESULT: A total of 21,972 patients in the SEER database and 747 patients in our department who met the inclusion criteria were enrolled in this study. Ultimately, six clinical features including age, gender, race, extrathyroidal invasion, multifocality, and tumor size were identified to be associated with cervical LNM in patients with PTC, which were screened to develop a nomogram. This model had satisfied discrimination with a concordance index (C-index) of 0.733, supported by both internal and external validation with a C-index of 0.731 and 0.716, respectively. A decision curve analysis was subsequently made to evaluate the feasibility of this nomogram for predicting cervical LNM. Besides, a positive correlation between nomogram score and the average number of lymph node metastases was observed in all groups. CONCLUSION: This visualized multipopulational-based nomogram model was successfully established. We determined that various clinical characteristics were significantly associated with cervical LNM, which would be better helping clinicians make individualized clinical decisions for PTC patients.

[Molluscicidal effect of immersion with 50% wettable powder of niclosamide ethanolamine salt against Oncomelania hupensis on the soil surface and inside the soil layer in winter].

OBJECTIVE: To evaluate the molluscicidal effect of 50% wettable powder of niclosamide ethanolamine salt (WPNES) against Oncomelania hupensis on the soil surface and inside the soil layer by immersion method in winter. METHODS: O. hupensis snails were placed on the soil surface and 2, 5 cm and 10 cm under the soil layer outdoors in winter, and then immersed in 50% WPNES at concentrations of 1 mg/L and 2 mg/L for 1, 3 d and 7 d, while dechlorinated water served as controls. Snail mortality was observed following immersion with 50% WPNES on the soil surface and inside the soil layer. RESULTS: Following immersion with 50% WPNES at concentrations of 2 mg/L and 1 mg/L outdoors in winter, the 3-day corrected snail mortality rates were 98.0% and 76.0% on the soil surface, and the 7-day corrected snail mortality rate was both 100.0%. Following immersion with 50% WPNES at concentrations of 2 mg/L and 1 mg/L outdoors in winter, the 7-day corrected snail mortality rates were 95.5% and 85.6% 2 cm below the soil layer, 66.0% and 6.4% 5 cm below the soil layer. However, the 7-day snail mortality rate swere comparable between the 50% WPNES treatment group (at 2 mg/L and 1 mg/L) and controls 10 cm below the soil layer (both P > 0.05). CONCLUSIONS: Immersion of 50% WPNES at a concentration of 2 mg/L for 7 days presents a high molluscicidal efficacy against O. hupensis on the soil surface and 5 cm within the soil layers in winter.

Extended solid solutions and coherent transformations in nanoscale olivine cathodes.

Nanoparticle LiFePO4, the basis for an entire class of high power Li-ion batteries, has recently been shown to exist in binary lithiated/delithiated states at intermediate states of charge. The Mn-bearing version, LiMn(y)Fe(1-y)PO4, exhibits even higher rate capability as a lithium battery cathode than LiFePO4 of comparable particle size. To gain insight into the cause(s) of this desirable performance, the electrochemically driven phase transformation during battery charge and discharge of nanoscale LiMn0.4Fe0.6PO4 of three different average particle sizes, 52, 106, and 152 nm, is investigated by operando synchrotron radiation powder X-ray diffraction. In stark contrast to the binary lithiation states of pure LiFePO4 revealed in recent investigations, the formations of metastable solid solutions covering a remarkable wide compositional range, including while in two-phase coexistence, are observed. Detailed analysis correlates this behavior with small elastic misfits between phases compared to either pure LiFePO4 or LiMnPO4. On the basis of time- and state-of-charge dependence of the olivine structure parameters, we propose a coherent transformation mechanism. These findings illustrate a second, completely different phase transformation mode for pure well-ordered nanoscale olivines compared to the well-studied case of LiFePO4.

Usefulness of DWI in preoperative assessment of deep myometrial invasion in patients with endometrial carcinoma: a systematic review and meta-analysis.

BACKGROUND: The objective of this study was to perform a systematic review and a meta-analysis in order to estimate the diagnostic accuracy of diffusion weighted imaging (DWI) in the preoperative assessment of deep myometrial invasion in patients with endometrial carcinoma. METHODS: Studies evaluating DWI for the detection of deep myometrial invasion in patients with endometrial carcinoma were systematically searched for in the MEDLINE, EMBASE, and Cochrane Library from January 1995 to January 2014. Methodologic quality was assessed by using the Quality Assessment of Diagnostic Accuracy Studies tool. Bivariate random-effects meta-analytic methods were used to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and receiver operating characteristic (ROC) curves. The study also evaluated the clinical utility of DWI in preoperative assessment of deep myometrial invasion. RESULTS: Seven studies enrolling a total of 320 individuals met the study inclusion criteria. The summary area under the ROC curve was 0.91. There was no evidence of publication bias (P = 0.90, bias coefficient analysis). Sensitivity and specificity of DWI for detection of deep myometrial invasion across all studies were 0.90 and 0.89, respectively. Positive and negative likelihood ratios with DWI were 8 and 0.11 respectively. In patients with high pre-test probabilities, DWI enabled confirmation of deep myometrial invasion; in patients with low pre-test probabilities, DWI enabled exclusion of deep myometrial invasion. The worst case scenario (pre-test probability, 50%) post-test probabilities were 89% and 10% for positive and negative DWI results, respectively. CONCLUSION: DWI has high sensitivity and specificity for detecting deep myometrial invasion and more importantly can reliably rule out deep myometrial invasion. Therefore, it would be worthwhile to add a DWI sequence to the standard MRI protocols in preoperative evaluation of endometrial cancer in order to detect deep myometrial invasion, which along with other poor prognostic factors like age, tumor grade, and LVSI would be useful in stratifying high risk groups thereby helping in the tailoring of surgical approach in patient with low risk of endometrial carcinoma.

Association between KCNQ1 genetic variants and QT interval in a Chinese population.

AIM: There is a close link between electrocardiographic ventricular repolarization QT parameters and Type 2 diabetes. The aim of the present study was to assess the effects of QT-related and diabetes-related variants in KCNQ1 on QT interval in a Chinese population. METHODS: We recruited 2415 patients with Type 2 diabetes and 1163 subjects with normal glucose regulation in the present study. QT interval was obtained and the heart rate-corrected QT interval (QTc) was calculated using Bazett's formula. Four single nucleotide polymorphisms in KCNQ1 were selected (rs12296050, rs12576239, rs2237892 and rs2237895) and genotyped. RESULTS: In participants with normal glucose regulation, the minor allele T of rs12296050 was associated with a 3.46-ms QTc prolongation under an additive model (P = 0.0109, empirical P = 0.0498). In patients with Type 2 diabetes, we did not find any association for the single nucleotide polymorphisms. CONCLUSIONS: Our findings indicate that KCNQ1 is associated with QT interval in a Chinese population with normal glucose regulation.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Genetic variants of LPIN1 indicate an association with Type 2 diabetes mellitus in a Chinese population.

AIMS: Metabolic disorders are independent risk factors for the development of Type 2 diabetes. The aim of the study is to test the association of LPIN1 variants with Type 2 diabetes and clinical characteristics in large samples of the Chinese population. METHODS: In the first stage, 15 single nucleotide polymorphisms within the LPIN1 region were selected and genotyped in 3700 Chinese Han participants. In the second stage, the single nucleotide polymorphisms showing significant association or trends towards association were genotyped in an additional 3122 samples for replication. Meta-analyses and genotype-phenotype association studies were performed after combining the data from the two stages. RESULTS: In the first stage, we detected that rs16857876 was significantly associated with Type 2 diabetes with an odds ratio of 0.806 (95% CI 0.677-0.958, P = 0.015), while rs11695610 showed a trend with Type 2 diabetes (odds ratio 0.846, 95% CI 0.709-1.009, P = 0.062). In the second stage, a similar effect of rs11695610 on Type 2 diabetes was observed (odds ratio 0.849, 95% CI 0.700-1.030, P = 0.096). The meta-analyses combining the information from the two stages showed a significant effect of rs11695610 on Type 2 diabetes with an odds ratio of 0.847 (95% CI 0.744-0.965, P = 0.012). Finally, the phenotype-genotype association analyses showed that rs11695610 was associated with 2-h plasma glucose (P = 0.040) and triglyceride levels (P = 0.034). CONCLUSIONS: Our data implied that common single nucleotide polymorphisms within the LPIN1 region were associated with Type 2 diabetes and metabolic traits in the Chinese population.

Association between KCNQ1 genetic variants and obesity in Chinese patients with type 2 diabetes.

AIMS/HYPOTHESIS: There is evidence of overlap between susceptibility loci for type 2 diabetes and obesity. The aim of this study is to explore the association between the established type 2 diabetes locus KCNQ1 and obesity in Han Chinese. METHODS: We recruited 6,667 and 6,606 diabetic case-control samples from Shanghai and Hong Kong, respectively. Of the samples, 7.5% and 6.3% were excluded because of genotyping failure or data missing in the association analyses of rs2237892 and rs2237895 with obesity/BMI, respectively. RESULTS: We found that rs2237892 was associated with lower BMI and lower incidence of overweight/obesity in diabetic patients from Hong Kong (BMI, ß = -0.0060 per diabetes risk C allele for log(10)BMI [95% CI -0.0088, -0.0032; p = 2.83 × 10(-5)]; overweight/obesity, OR 0.880 for C allele [95% CI 0.807, 0.960; p = 0.004]) and in the meta-analysis of cases from the two regions (BMI, combined ß = -0.0048 per C allele for log(10)BMI [95% CI -0.0070, -0.0026; p = 2.20 × 10(-5)]; overweight/obesity, combined OR 0.890 for C allele [95% CI 0.830, 0.955; p = 0.001]). rs2237895 was also related to decreased BMI (combined ß = -0.0042 per diabetes risk C allele for log(10)BMI [95% CI -0.0062, -0.0022; p = 4.30 × 10(-5)]). A significant association with waist circumference was detected for rs2237892 in the pooled analyses (ß = -0.0026 per C allele for log(10)[waist circumference] [95% CI -0.0045, -0.0007; p = 0.007]). However, neither an association with the risk of being overweight or obese nor associations with quantitive traits were detected for rs2237892 or rs2237895 in controls. CONCLUSION: Our findings indicate that KCNQ1 is associated with obesity in Chinese patients with type 2 diabetes.

Functional analyses of the mutation nt-128 T→G in the hepatocyte nuclear factor-1α promoter region in Chinese diabetes pedigrees.

AIMS: Hepatocyte nuclear factor-1α (HNF-1α) regulates the expression of genes encoding proteins involved in glucose metabolism and insulin secretion. Mutations in the HNF-1α gene cause maturity-onset diabetes of the young Type 3. However, the mechanism leading to this disease has not been completely ascertained. Previously, we found a novel mutation in the regulatory element of the human HNF-1α gene in two Chinese diabetes pedigrees. The nucleotide at position -128 T was substituted by G (nt-128 T→G). In this study, we analysed the functional defect of nt-128 T→G in HNF-1α transcription activity. METHODS: Luciferase reporter gene assays were carried out to examine the functional characteristics of this mutant. Electrophoretic mobility shift assays and chromatin immunoprecipitation were performed to confirm the binding of nuclear proteins to oligonucleotides. RESULTS: The variant construct (nt-128 T→G) had a 1.65-fold increase in promoter activity compared with that of the wild-type construct in HepG2 cells and a 1.33-fold increase in MIN6 cells, respectively. The variant resided at a FOXA/HNF-3 binding site identified by a series of competitive electrophoretic mobility shift assays and antibody supershift analyses. The assays showed a differential binding affinity in the wild-type and the nt-128 T→G mutant fragments by FOXA/HNF-3. Chromatin immunoprecipitation indicated that FOXA/HNF-3 bound to this region in vivo. One nucleotide substitution in the FOXA/HNF-3 site in the human HNF-1α regulatory element caused an increase of HNF-1α transcriptional activity. CONCLUSIONS: Our data suggested that this substitution in the promoter region affects DNA-protein interaction and HNF-1α gene transcription. The mutant may contribute to the development of diabetes in these two nt-128 T→G pedigrees of Chinese.

Increment of 30-min post-challenge plasma glucose is associated with urine albumin excretion in men with normal glucose regulation.

AIMS: The overwhelming majority of subjects with normal glucose regulation have the highest plasma glucose concentration at 30 minutes during oral glucose tolerance. We aimed to examine the association between increment of 30-min post-challenge glucose and albuminuria in participants with normal glucose regulation. METHODS: A population-based cross-sectional study was conducted in six communities in Shanghai between 2007 and 2008. A total of 3508 subjects with normal glucose regulation had complete data and were enrolled into the analysis. Among the selected subjects, only 1525 individuals (581 men, 944 women) were examined for their serum insulin levels. We assessed post-challenge blood glucose and insulin at 0, 30 and 120 min, urinary albumin and creatinine. The 30-min post-challenge glucose increment (Δ) was calculated as 30-min post-challenge glucose minus fasting plasma glucose, and albumin/creatinine ratio was used to reflect urinary albumin excretion. RESULTS: Multivariable logistic regression analysis revealed that the Δ30-min post-challenge glucose was independently associated with increased albumin/creatinine ratio in men with normal glucose regulation (OR = 1.08, P = 0.025), but not in women. Furthermore, multivariable linear regression analysis revealed that early-phase glucose disposition index was the main factor responsible for Δ30-min post-challenge glucose and explained 14-20% of the variance of Δ30-min post-challenge glucose in the two subgroups (P < 0.05). Notably, men had higher Δ30-min post-challenge glucose and lower early-phase glucose disposition index than women (all P < 0.001). CONCLUSIONS: The 30-min post-challenge plasma glucose increment is associated with urine albumin excretion in men with normal glucose regulation.

Effects of KCNQ1 polymorphisms on the therapeutic efficacy of oral antidiabetic drugs in Chinese patients with type 2 diabetes.

The aim of this study was to explore the impact of KCNQ1 variants on the responses to oral antidiabetic drugs in a Chinese study population. A 48-week randomized pharmacogenetics study compared the effects of repaglinide and rosiglitazone in 209 newly diagnosed patients with type 2 diabetes. In the repaglinide cohort, individuals who were rs2237892 TT homozygotes exhibited lower 2-h glucose levels and significantly higher cumulative attainment rates of target 2-h glucose levels (P(log-rank) = 0.0383) than the C allele carriers; patients with a greater number of rs2237892 C alleles showed larger augmentations in both fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.0166 and 0.0026, respectively); moreover, the rs2237895 C allele was also associated with greater increments in both fasting insulin and HOMA-IR (P = 0.0274 and 0.0259, respectively). In contrast, only an association between rs2237897 and decrease in 2-h glucose levels was detected in the rosiglitazone cohort (P = 0.0321). Our results indicated that KCNQ1 polymorphisms are associated with repaglinide efficacy, and might also be associated with rosiglitazone response, in Chinese patients with type 2 diabetes.

A common variant of NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes.

AIMS: Electrocardiographic ventricular repolarization QT parameters are independent risk factors for cardiovascular events and sudden cardiac death in diabetic patients. The aim of the study was to investigate the association of polymorphisms of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene with QT interval in Chinese subjects with or without Type 2 diabetes. METHODS: Three single nucleotide polymorphisms (SNPs) (rs10494366, rs12143842 and rs12029454) were genotyped in 1240 Type 2 diabetic patients (631 men and 609 women) and 1196 normal controls (433 men and 763 women). Individuals with overt diseases other than diabetes were excluded. Heart-rate corrected QT interval (QTc) was determined by standard 12-lead ECG and Bazett formula. Sex-pooled analysis and sex-specific analysis for genotype-phenotype association were both conducted. RESULTS: In the diabetic group, the rs12143842 T allele was associated with a 3.87-ms (P = 0.014, empirical P = 0.039) increase in QTc duration for each additional allele copy, while rs10494366 and rs12029454 exhibited no significant association with QTc. We found no evidence of association for the three SNPs in subjects with normal glucose regulation. No significant SNP-gender and -diabetes affection interaction was observed. CONCLUSIONS: The genetic variant rs12143842 in NOS1AP is associated with QT interval duration in a Chinese population with Type 2 diabetes. Future studies in different populations are needed to validate this finding and to evaluate the impact of NOS1AP variants on cardiovascular events and sudden cardiac death in diabetic patients.

Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population.

AIMS/HYPOTHESIS: Chromosome 1q21-q24 has been shown to be linked to type 2 diabetes. The International Type 2 Diabetes 1q Consortium showed that one of the nominal associations was located in the NOS1AP gene. Although this association was not replicated in additional samples of European descent, it remains unknown whether NOS1AP plays a role in Chinese individuals. METHODS: In stage 1 analyses, 79 single nucleotide polymorphisms (SNPs) of the NOS1AP gene were successfully genotyped in a group of Shanghai Chinese individuals, comprising 1,691 type 2 diabetes patients and 1,720 control participants. In stage 2 analyses, the SNP showing the strongest association was genotyped in additional Chinese individuals, including 1,663 type 2 diabetes patients and 1,408 control participants. RESULTS: In stage 1 analyses, 20 SNPs were nominally associated with type 2 diabetes (p < 0.05), with SNP rs12742393 showing the strongest association (OR 1.24 [95% CI 1.11-1.38]; p = 0.0002, empirical p = 0.019). Haplotype analysis also confirmed the association between rs12742393 and type 2 diabetes. In stage 2 analyses, the difference in allele frequency distribution of rs12742393 did not reach statistical significance (p = 0.254). However, the meta-analysis showed a significant association between rs12742393 and type 2 diabetes with an OR of 1.17 (95% CI 1.07-1.26; p = 0.0005). CONCLUSIONS/INTERPRETATION: Our data suggest that NOS1AP variants may not play a dominant role in susceptibility to type 2 diabetes, but a minor effect cannot be excluded.

Identification of waist circumference cutoffs for abdominal obesity in the Chinese population: a 7.8-year follow-up study in the Shanghai urban area.

AIM: To identify the appropriate visceral adipose tissue (VAT) cutoff values for the diagnosis of abdominal obesity in predicting diabetes and the corresponding waist circumference in the Chinese population. METHODS: At baseline, 381 volunteers aged 35-75 years were enrolled without diabetes from the Shanghai urban area. Anthropometry and VAT area determined by magnetic resonance imaging were measured. During the average 7.8 years of follow-up, glucose tolerance was monitored. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cutoff points for abdominal obesity. RESULTS: At the end of the study, 290 participants were followed up, in which 63 participants developed diabetes. Using ROC curve analyses in participants with normal glucose regulation, the appropriate VAT cutoff was 90 cm(2) for both genders to predict diabetes development. In logistic regression models, the relative risks (95% confidence intervals) of VAT value over 90 cm(2) were 3.35 (1.10-10.18, P=0.033) in men and 4.57 (1.73-12.07, P=0.002) in women after adjusted for age, impaired glucose regulation, hypertension and dyslipidemia. The optimal waist circumference cutoffs were 88 cm for men and 82 cm for women to indicate VAT value over 90 cm(2) in ROC analyses. CONCLUSION: VAT cutoff of 90 cm(2) is useful for defining visceral obesity in Chinese individuals. The appropriate waist circumference cutoffs for abdominal obesity are 88 cm for men and 82 cm for women in the Chinese population.

Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population.

AIMS/HYPOTHESIS: Recent genome-wide association studies in East Asian populations reported that single nucleotide polymorphisms (SNPs) in KCNQ1 are associated with type 2 diabetes. The aim of this study was to validate this finding in a Chinese population. METHODS: We genotyped four SNPs, rs2074196, rs2237892, rs2237895 and rs2237897, in a group of 3,503 Shanghai Chinese individuals, comprising 1,769 type 2 diabetic patients and 1,734 normoglycaemic controls. Both the cases and the controls were extensively phenotyped for anthropometric and biochemical traits related to glucose metabolism. Arginine stimulation tests under fasting conditions were performed in a subgroup of 466 cases. RESULTS: All four of the SNPs were associated with type 2 diabetes, with rs2237892 showing strongest evidence for association (OR 1.532, 95% CI 1.381-1.698, p = 5.0 x 10(-16)). The SNP rs2237897 was associated with both acute insulin and C-peptide response after arginine stimulation in a subgroup of cases (p = 0.0471 and p = 0.0156, respectively). The SNP rs2237895 was associated with both first- and second-phase insulin secretion in the controls (p = 0.0334 and p = 0.0002, respectively). CONCLUSIONS/INTERPRETATION: In this study we found that KCNQ1 was associated with type 2 diabetes susceptibility in a Chinese population, possibly through its effect on beta cell function.

A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population.

AIMS/HYPOTHESIS: Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population. METHODS: We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r(2) >or= 0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls. RESULTS: Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p = 0.0009, empirical p = 0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p = 0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele. CONCLUSIONS/INTERPRETATION: In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration.

Chronic benzodiazepine-induced reduction in GABA(A) receptor-mediated synaptic currents in hippocampal CA1 pyramidal neurons prevented by prior nimodipine injection.

One week oral flurazepam (FZP) administration in rats results in reduced GABA(A) receptor-mediated synaptic transmission in CA1 pyramidal neurons associated with benzodiazepine tolerance in vivo and in vitro. Since voltage-gated calcium channel (VGCC) current density is enhanced twofold during chronic FZP treatment, the role of L-type VGCCs in regulating benzodiazepine-induced changes in CA1 neuron GABA(A) receptor-mediated function was evaluated. Nimodipine (10 mg/kg, i.p.) or vehicle (0.5% Tween 80, 2 ml/kg) was injected 1 day after ending FZP treatment and 24 h prior to hippocampal slice preparation for measurement of mIPSC characteristics and in vitro tolerance to zolpidem. The reduction in GABA(A) receptor-mediated mIPSC amplitude and estimated unitary channel conductance measured 2 days after drug removal was no longer observed following prior nimodipine injection. However, the single nimodipine injection failed to prevent in vitro tolerance to zolpidem's ability to prolong mIPSC decay in FZP-treated neurons, suggesting multiple mechanisms may be involved in regulating GABA(A) receptor-mediated synaptic transmission following chronic FZP administration. As reported previously in recombinant receptors, nimodipine inhibited synaptic GABA(A) receptor currents only at high concentrations (>30 muM), significantly greater than attained in vivo (1 muM) 45 min after a single antagonist injection. Thus, the effects of nimodipine were unlikely to be related to direct effects on GABA(A) receptors. As with nimodipine injection, buffering intracellular free [Ca(2+)] with BAPTA similarly prevented the effects on GABA(A) receptor-mediated synaptic transmission, suggesting intracellular Ca(2+) homeostasis is important to maintain GABA(A) receptor function. The findings further support a role for activation of L-type VGCCs, and perhaps other Ca(2+)-mediated signaling pathways, in the modulation of GABA(A) receptor synaptic function following chronic benzodiazepine administration, independent of modulation of the allosteric interactions between benzodiazepine and GABA binding sites.