Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct

To investigate the role of inner medullary collecting duct (IMCD) urea transporters in the renal concentrating mechanism, we deleted 3 kb of the UT-A urea transporter gene containing a single 140-bp exon (exon 10). Deletion of this segment selectively disrupted expression of the two known IMCD isoforms of UT-A, namely UT-A1 and UT-A3, producing UT-A1/3(-/-) mice. In isolated perfused IMCDs from UT-A1/3(-/-) mice, there was a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. On a normal protein intake (20% protein diet), UT-A1/3(-/-) mice had significantly greater fluid consumption and urine flow and a reduced maximal urinary osmolality relative to wild-type controls. These differences in urinary concentrating capacity were nearly eliminated when urea excretion was decreased by dietary protein restriction (4% by weight), consistent with the 1958 Berliner hypothesis stating that the chief role of IMCD urea transport in the concentrating mechanism is the prevention of urea-induced osmotic diuresis. Analysis of inner medullary tissue after water restriction revealed marked depletion of urea in UT-A1/3(-/-) mice, confirming the concept that phloretin-sensitive IMCD urea transporters play a central role in medullary urea accumulation. However, there were no significant differences in mean inner medullary Na(+) or Cl(-) concentrations between UT-A1/3(-/-) mice and wild-type controls, indicating that the processes that concentrate NaCl were intact. Thus, these results do not corroborate the predictions of passive medullary concentrating models stating that NaCl accumulation in the inner medulla depends on rapid vasopressin-regulated urea transport across the IMCD epithelium.     

Association between angiotensin I-converting enzyme gene insertion/deletion polymorphism and risk of rheumatic heart disease

Scarring and collagen deposition in the valves and destruction of myocytes may result from the combined effects of a smoldering rheumatic process and a constant trauma to the mitral valve or aortic valve by the turbulent flow in rheumatic heart disease (RHD). It has been suggested that angiotensin I-converting enzyme (ACE) may be responsible for the increased valvular fibrosis and calcification in the pathogenesis of RHD. However, the role of ACE genetic variant in RHD has not been studied among the Chinese population in Taiwan. Hence, a case-controlled study was carried out to investigate the possible relationship between the ACE gene insertion/deletion (I/D) and G2350A polymorphisms and RHD. A group of 115 patients with RHD documented by echocardiography and 100 age- and sex-matched normal control subjects were studied. ACE gene I/D and G2350A polymorphisms were identified by polymerase chain reaction-based restriction analysis. There was a significant difference in the distribution of ACE I/D genotypes (P = 0.02) and allelic frequencies (P = 0.04) between RHD cases and normal controls. An odds ratio for the risk of RHD associated with the ACE I/D II genotype was 2.12 (95% CI, 1.21-3.71). An odds ratio for the risk of RHD associated with the ACE I allele was 1.50 (95% CI, 1.02-2.21). The ACE G2350A polymorphism showed no association with RHD (P = 0.90). Further categorization of RHD patients into mitral valve disease and combined valve disease subgroups revealed no statistical difference in these gene polymorphisms when compared between the two subgroups. This study shows that patients with RHD have a higher frequency of ACE II genotype and I allele, which supports a role for ACE I/D gene polymorphisms in determining the risk of RHD in Taiwan Chinese.     

Identification of 7,12-dimethylbenz[a]anthracene metabolites that lead to mutagenesis in mammalian cells

The mutagenicity of 7,12-dimethylbenz[a]-anthracene (DMBA) and 11 of its enzymatically derived metabolites was tested with Chinese hamster V79 cells for identification of mutagenic metabolites. The metabolites consisted of 7-hydroxymethyl-12-methylbenz[a]anthracene, 7-methyl-12-hydroxymethylbenz[a]anthracene, 7,12-dihydroxymethylbenz[a]anthracene, three trans-3,4-diols, two trans-5,6-diols, and three trans-8,9-diols, all of which derived from DMBA or from the hydroxymethyl derivatives. Mutations were characterized by resistance to ouabain and 6-thioguanine. None of the tested metabolites were mutagenic in V79 cells, which do not metabolize polycyclic aromatic hydrocarbons. Therefore, mutagenesis in the V79 cells was tested in the presence of golden hamster cells capable of metabolizing polycyclic aromatic hydrocarbons (cell-mediated assay). In this assay, DMBA, 7-hydroxymethyl-12-methylbenz[a]anthracene, 7-methyl-12-hydroxymethylbenz[a]anthracene, and their trans3,4-diols were mutagenic for both genetic markers, and the mutagenic response increased as a function of the hydrocarbon dose. All other metabolites were either inactive or showed up to a 4-fold higher mutation frequency than the untreated V79 cells for ouabain and 6-thioguanine resistance. The DMBA-trans-3,4-diol was the only metabolite that was more active than DMBA itself; at 0.05 muM it was 6-8 times more active than DMBA itself; at 0.05 muM it was 6-8 times more active than DMBA in inducing both ouabain and 6-thioguanine resistance. This diol was mutagenic at a dose as low as 0.01 muM. Mutagenesis by DMBA and the trans-3,4-diols was inhibited by 7,8-benzoflavone, an inhibitor of mixed-function oxidases. Analysis of DMBA metabolism in intact golden hamster cells indicated that DMBA-trans-3,4-diol is one of the major metabolites produced. Our results therefore suggest that DMBA-trans-3,4-diol may be metabolized to a diol-epoxide, presumably the trans-3,4-diol-1,2-epoxide, which may be a major reactive metabolite responsible for DMBA mutagenicity in mammalian cells.     

Estimating medical costs of gastroenterological diseases

AIM: To estimate the direct medical costs of gastroenterological diseases within the universal health insurance program among the population of local residents in Taiwan. METHODS: The data sources were the first 4 cohort datasets of 200,000 people from the National Health Insurance Research Database in Taipei. The ambulatory, inpatient and pharmacy claims of the cohort in 2001 were analyzed. Besides prevalence and medical costs of diseases, both amount and costs of utilization in procedures and drugs were calculated. RESULTS: Of the cohort with 183,976 eligible people, 44.2% had ever a gastroenterological diagnosis during the year. The age group 20-39 years had the lowest prevalence rate (39.2%) while the elderly had the highest (58.4%). The prevalence rate was higher in women than in men (48.5% vs. 40.0%). Totally, 30.4% of 14,888 inpatients had ever a gastroenterological diagnosis at discharge and 18.8% of 51,359 patients at clinics of traditional Chinese medicine had such a diagnosis there. If only the principal diagnosis on each claim was considered, 16.2% of admissions, 8.0% of outpatient visits, and 10.1% of the total medical costs (8,469,909 US dollars/83,830,239 US dollars) were attributed to gastroenterological diseases. On average, 46.0 US dollars per insured person in a year were spent in treating gastroenterological diseases. Diagnostic procedures related to gastroenterological diseases accounted for 24.2% of the costs for all diagnostic procedures and 2.3% of the total medical costs. Therapeutic procedures related to gastroenterological diseases accounted for 4.5% of the costs for all therapeutic procedures and 1.3% of the total medical costs. Drugs related to gastroenterological diseases accounted for 7.3% of the costs for all drugs and 1.9% of the total medical costs. CONCLUSION: Gastroenterological diseases are prevalent among the population of local residents in Taiwan, accounting for a tenth of the total medical costs. Further investigations are needed to differentiate costs in screening, ruling out, confirming, and treating.     

A Simple Risk Model to Predict Survival in Patients With Carcinoma of Unknown Primary Origin

Carcinoma of unknown primary origin (CUP) is characterized by diverse histological subtypes and clinical presentations, ranging from clinically indolent to frankly aggressive behaviors. This study aimed to identify prognostic factors of CUP and to develop a simple risk model to predict survival in a cohort of Asian patients.We retrospectively reviewed 190 patients diagnosed with CUP between 2007 and 2012 at a single medical center in Taiwan. The clinicopathological parameters and outcomes of our cohort were analyzed. A risk model was developed using multivariate logistic regression and a prognostic score was generated.The prognostic score was calculated based on 3 independent prognostic variables: the Eastern Cooperative Oncology Group (ECOG) scale (0 points if the score was 1, 2 points if it was 2–4), visceral organ involvement (0 points if no involvement, 1 point if involved), and the neutrophil-to-lymphocyte ratio (0 points if ≤3, 1 point if >3). Patients were stratified into good (score 0), intermediate (score 1–2), and poor (score 3–4) prognostic groups based on the risk model. The median survival (95% confidence interval) was 1086 days (500–1617, n = 42), 305 days (237–372, n = 75), and 64 days (44–84, n = 73) for the good, intermediate, and poor prognostic groups, respectively. The c-statistics using the risk model and ECOG scale for the outcome of 1-year mortality were 0.80 and 0.70 (P = 0.038), respectively.In this study, we developed a simple risk model that accurately predicted survival in patients with CUP. This scoring system may be used to help patients and clinicians determine appropriate treatments.     

Sitagliptin After Ischemic Stroke in Type 2 Diabetic Patients: A Nationwide Cohort Study

The cerebrovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) with ischemic stroke remains uncertain. The aim of this study was to assess the efficacy and safety of sitagliptin in patients with T2DM with recent ischemic stroke.We analyzed data from the Taiwan National Health Insurance Research Database between March 1, 2009, and December 31, 2011. Ischemic stroke patients were identified from individuals with T2DM. Patients who received sitagliptin were compared with those who did not to evaluate the cardiovascular safety and efficacy of sitagliptin. The primary outcome was a composite of ischemic stroke, myocardial infarction, or cardiovascular death.A total of 5145 type 2 diabetic patients with ischemic stroke met our inclusion criteria and were followed for up to 2.83 years (mean, 1.17 years). Overall, 1715 patients (33.3%) received sitagliptin and 3430 patients (66.7%) did not. The primary composite outcome occurred in 190 patients in the sitagliptin group (11.1%) and in 370 patients in the comparison group (10.8%) (hazard ratio [HR] = 1.02; 95% confidence interval [CI], 0.85–1.21). Patients treated with sitagliptin had a similar risk of ischemic stroke, hemorrhagic stroke, and all-cause mortality with an HR of 0.95 (95% CI, 0.78–1.16, P = 0.612), 1.07 (95% CI, 0.55–2.11, P = 0.834), and 1.00 (95% CI, 0.82–1.22, P = 0.989), respectively, compared with patients not treated with sitagliptin.Treatment with sitagliptin in type 2 diabetic patients with recent ischemic stroke was not associated with increased or decreased risks of adverse cerebrovascular outcomes.     

The potential impact of primary headache disorders on stroke risk

Background

Headache such as migraine is associated with stroke. Studies focused on primary headache disorders (PHDs) as a risk factor for stroke are limited. The purpose of this population-based cohort study was to explore whether patients with PHDs were at a high risk for developing stroke.

Methods

A total of 1346 patients with PHDs were enrolled and compared with 5384 age-, gender- and co-morbidity-matched control cohorts. International Classification of Diseases, Clinical Modification codes were administered for the definition of PHDs, stroke, and stroke risk factors. Cox proportional-hazards regressions were performed for investigating hazard ratios (HR).

Results

PHDs patients exhibited a 1.49 times (95% CI?:1.15–1.98, p < 0.01) higher risk for developing ischaemic stroke compared with that of control cohorts. Both migraine (HR = 1.22, 95% CI?:1.13–1.97, p < 0.05) and tension-type headache (HR = 2.29, 95% CI?:1.22–2.80, p < 0.01) were associated with an increased risk of ischemic stroke. Females with PHDs were at greater risk of developing ischaemic stroke (HR = 1.49, 95% CI?:1.13–1.90, p < 0.01) than those without PHDs. PHDs patient aged 45 to 64 years displayed significantly higher risk to develop ischaemic stroke (HR?=?1.50, 95% CI: 1.11–2.10, p < 0.05) than the matched controls. The impact of PHDs on ischaemic stroke risk became gradually apparent by different following time intervals beyond 2 years after first diagnosis.

Conclusion

PHDs is suggestive of an incremental risk for ischaemic stroke with gender-dependent, age-specific and time-dependent characteristics.

     

Electrocardiographic diagnosis of right ventricular infarction

The electrocardiographic findings in 11 cases of acute right ventricular infarction associated with acute left ventricular inferior wall myocardial infarction are described. The diagnosis of right ventricular infarction was proved by autopsy findings in five cases and supported by hemodynamic data in the other six. Ten of the 11 patients had typical electrocardiographic changes of acute inferior myocardial infarction and one had that of inferior wall injury. Transient S-T segment elevation was present in one (lead V₁) or more of the right precordial leads in eight cases. In the absence of other explanations for the S-T segment elevation, acute right ventricular infarction was most likely the cause. Therefore, when acute inferior myocardial infarction is accompanied by S-T segment elevation in the right precordial leads, the coexistence of right ventricular infarction should be suspected. The sensitivity and specificity of this electrocardiographic sign are yet to be determined.     

Recurrence Risk Factors Analysis for Stage I Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide. Even early-stage patients might encounter disease recurrence with relative high risk. Effective postoperative therapy is based on an accurate assessment of treatment failure after surgery. The aim of this study is to construct a disease-free survival (DFS) prediction model and stratify patients into different risk score groups.A total of 356 pathological stage I patients (7th American Joint Committee on Cancer) who underwent lung resection from January 2005 through June 2011 were retrospectively reviewed. Of these patients, 63 patients were eliminated for this study. A total of 293 p-stage I patients were included for further univariate and multivariate analysis. Clinical, surgical, and pathological factors associated with high risk of recurrence were analyzed, including age, gender, smoking status, additional primary malignancy (APM), operation method, histology, visceral pleural invasion, angiolymphatic invasion, tumor necrosis, and tumor size.Of the 293 p-stage I non-small cell lung cancer (NSCLC) patients examined, 143 were female and 150 were male, with a mean age of 62.8-years old (range: 25–83-years old). The 5-year DFS and overall survival rates after surgery were 58.9% and 75.3%, respectively. On multivariate analysis, current smoker (hazards ratio [HR]: 1.63), APM (HR: 1.86), tumor size (HR: 1.54, 2.03), nonanatomic resections (HR: 1.81), adenocarcinoma histology (HR: 2.07), visceral pleural invasion (HR: 1.54), and angiolymphatic invasion (HR: 1.53) were found to be associated with a higher risk of tumor recurrence. The final model showed a fair discrimination ability (C-statistic = 0.68). According to the difference risk group, we found patients with intermediate or higher risk group had a higher distal relapse tendency as compared with low risk group (P = 0.016, odds ratio: 3.31, 95% confidence interval: 1.21–9.03).Greater than 30% of disease recurrences occurred after surgery for stage I NSCLC patients. That is why we try to establish an effective DFS predicting model based on clinical, pathological, and surgical covariates. However, our initial results still need to be validated and refined into greater population for better application in clinical use.