Chronic kidney disease-related osteoporosis is associated with incident frailty among patients with diabetic kidney disease: a propensity score-matched cohort study.

Chronic kidney disease (CKD)-related osteoporosis is a major complication in patients with CKD, conferring a higher risk of adverse outcomes. We found that among those with diabetic kidney disease, this complication increased the risk of incident frailty, an important mediator of adverse outcomes. INTRODUCTION: Renal osteodystrophy and chronic kidney disease (CKD)-related osteoporosis increases complications for patients with diabetic kidney disease (DKD). Since musculoskeletal degeneration is central to frailty development, we investigated the relationship between baseline osteoporosis and the subsequent frailty risk in patients with DKD. METHODS: From the Longitudinal Cohort of Diabetes Patients in Taiwan (n = 840,000), we identified 12,027 patients having DKD with osteoporosis and 24,054 propensity score-matched controls having DKD but without osteoporosis. The primary endpoint was incident frailty on the basis of a modified FRAIL scale. Patients were prospectively followed-up until the development of endpoints or the end of this study. The Kaplan-Meier technique and Cox proportional hazard regression were used to analyze the association between osteoporosis at baseline and incident frailty in these patients. RESULTS: The mean age of the DKD patients was 67.2 years, with 55.4% female and a 12.6% prevalence of osteoporosis at baseline. After 3.5 ± 2.2 years of follow up, the incidence rate of frailty in patients having DKD with osteoporosis was higher than that in DKD patients without (6.6 vs. 5.7 per 1000 patient-year, p = 0.04). A Cox proportional hazard regression showed that after accounting for age, gender, obesity, comorbidities, and medications, patients having DKD with osteoporosis had a significantly higher risk of developing frailty (hazard ratio, 1.19; 95% confidence interval, 1.02-1.38) than those without osteoporosis. CONCLUSIONS: CKD-related osteoporosis is associated with a higher risk of incident frailty in patients with DKD.

Superselective endovascular tissue access using trans-vessel wall technique: feasibility study for treatment applications in heart, pancreas and kidney in swine.

OBJECTIVES: With the emergence of targeted cell transplantation and gene therapy, there is a need for minimally invasive tissue access to facilitate delivery of therapeutic substrate. The objective of this study was to demonstrate the suitability of an endovascular device which is able to directly access tissue and deliver therapeutic agent to the heart, kidney and pancreas without need to seal the penetration site. METHODS: In vivo experiments were performed in 30 swine, including subgroups with follow-up to evaluate complications. The previously described trans-vessel wall (VW) device was modified to be sharper and not require tip detachment to seal the VW. Injections into targets in the heart (n = 13, 24-h follow-up n = 5, 72-h follow-up n = 3), kidney (n = 8, 14-day follow-up n = 3) and pancreas (n = 5) were performed. Some animals were used for multiple organ injections. Follow-up consisted of clinical monitoring, angiography and necropsy. Transvenous (in heart) and transarterial approaches (in heart, kidney and pancreas) were used. Injections were targeted towards the subepicardium, endomyocardium, pancreas head and tail, and kidney subcapsular space and cortex. RESULTS: Injections were successful in target organs, visualized by intraparenchymal contrast on fluoroscopy and by necropsy. No serious complications (defined as heart failure or persistent arrhythmia, haemorrhage requiring treatment or acute kidney injury) were encountered over a total of 157 injections. CONCLUSIONS: The trans-VW device can achieve superselective injections to the heart, pancreas and kidney for delivery of therapeutic substances without tip detachment. All parts of these organs including the subepicardium, pancreas tail and renal subcapsular space can be efficiently reached.

Sports interest mediating exercise and compulsive internet use among undergraduates.

With the massive growth in Internet technologies, people have become wary of excessive Internet usage, known as compulsive Internet usage or Internet addiction. This study looks into how exercise is related to compulsive Internet usage. Previous research showed varying results regarding the relationship between sports habit and Internet usage; this project clarifies the relationship by investigating mediating variables in terms of interest in different aspects of sports, such as physical education, mastering sport skills, sports participation, and watching sports. Two survey studies were conducted. The participants were 232 male and 107 female Taiwanese undergraduate students in the first survey, totaling 339 students. The second survey had 233 males, 98 female students, and 2 who did not disclose their gender, with a final total of 333. The results reveal that interest in physical education (IPE) mediates sports habit and compulsive Internet usage. As long as the student had a habit of doing sports that increased IPE, this would in turn decrease compulsive Internet use. The importance of igniting students' IPE is discussed.

Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study.

BACKGROUND: Randomized controlled trials on the post-admission use of statins in sepsis patients have not shown a survival benefit. Whether preadmission use of statins would confer any beneficial effects in sepsis patients has not been well studied. METHODS: We conducted a population-based cohort study on a national health insurance claims database between 1999 and 2011. Sepsis patients were identified by ICD-9 codes compatible with the third International consensus definitions for sepsis. Use of statin was defined as the cumulative use of any statin for more than 30 days before the indexed sepsis admission. We determined the association between statin use and sepsis outcome by multivariate-adjusted Cox proportional hazard models and propensity score matched analysis. To minimize baseline imbalance between statin users and non-statin users, we matched/adjusted for social economic status, comorbidities, proxies for healthy lifestyle, health care facility utilization, and use of medications. RESULTS: We identified 52 737 sepsis patients, of which 3599 received statin treatment. Statins use was associated with a reduced 30-day mortality after multivariable adjustment (HR 0.86, 95% CI, 0.78-0.94) and propensity score matching (HR, 0.88; 95% CI, 0.78-0.99). On subgroup analysis, the beneficial effects of statins were not significant in patients receiving ventilator support or requiring ICU admission. CONCLUSIONS: In this national cohort study, preadmission statin therapy before sepsis development was associated with a 12% reduction in mortality when compared with patients who never received a statin. There were no consistent beneficial effects of statins in all patient subgroups.

Fentanyl-induced cough is a risk factor for postoperative nausea and vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) and fentanyl-induced cough (FIC) are two common anaesthesia-related events, which seem to have common risk factors. In this prospective cohort study, we investigate whether patients who have FIC during induction of anaesthesia have an increased incidence of PONV. METHODS: We studied adult non-smoking gynaecological surgical patients enrolled between July 1, 2011 and July 30, 2012. The presence of FIC during induction and the occurrence of PONV were recorded. Fentanyl-induced cough and other perioperative variables were subjected to multivariate analysis to determine the association between FIC and PONV. RESULTS: All 502 patients enrolled in this study had at least two risk factors for PONV, and 154 (31%) developed FIC. The incidence of PONV in the FIC group was higher than in the non-FIC group (56.5 vs 38.2%; P<0.0001). Multivariate logistic regression analysis found FIC to be a predictive risk factor for the development of PONV (adjusted odds ratio 2.08, 95% confidence interval 1.41-3.07). CONCLUSIONS: Non-smoking women undergoing gynaecological surgery who develop FIC during induction of anaesthesia have a higher incidence of PONV.

Effect of Liquid Feed-Stock Composition on the Morphology of Titanium Dioxide Films Deposited by Thermal Plasma Spray.

Titanium dioxide coatings were deposited on the surface of titanium foils by Thermal Plasma Spray (TPS) process. Three different TiO2 coatings were prepared using the commercial TiO2-P25 nanopowder and titanium isopropoxide precursor solution as feed-stocks. Structure and morphology of the TiO2-P25 powder and the plasma sprayed coatings were analyzed by X-ray diffraction (XRD), Raman spectroscopy, N2 adsorption-desorption isotherms, UV-visible spectroscopy and Scanning Electron Microscopy (SEM). XRD and Raman results indicate that the TiO2 coatings were composed of an anatase/rutile mixture that is conditioned by the suspension composition used to be sprayed. Coatings prepared from TiO2-P25 nanoparticles in water suspension (NW-P25) and titanium isopropoxide solution suspension (NSP-P25) are incorporated into the coatings without phase transformation and their anatase/rutile ratio percentage remains very similar to the starting TiO2-P25 powder. On the contrary, when titanium isopropoxide solution is used for spraying (SP), the amount of rutile increases in the final TiO2 coating. SEM analysis also reveals different microstructure morphology, coating thickness, density and porosity of the three TiO2 films that depend significantly on the type of feed-stock employed. Interestingly, we have observed the role of titanium isopropoxide in the formation of more porous and cohesive layers of TiO2. The NSP-P25 coating, prepared with a mix of titanium isopropoxide solution based on TiO2 nanoparticles, presents higher deposition efficiencies and higher coating thickness than the film prepared with nanoparticles suspended in water (NW-P25) or with titanium isopropoxide solutions (SP). This is due to the precursor solution is acting as the cement between TiO2 nanoparticles, improving the cohesive strength of the coating. In sum, NSP-P25 and NW-P25 coatings display a good photocatalytic potential, based on their light absorption properties and mechanical stability. Band gap of the nanoparticulated coatings displays a light absorption at wavelengths below 379 and 399 nm for NW-P25 and NSP-P25 respectively. On the contrary, the SP coating, despite to present lower band-gap value, has bad cohesive properties with surface crackings that makes it mechanically unstable. Therefore, mixtures of P25 nanoparticles with titanium isopropoxide as feed-stock materials can produce promising photocatalytic coatings.

Anaphylactic responses to histamine in mice utilize both histamine receptors 1 and 2.

BACKGROUND: Anaphylaxis is a severe, potentially life-threatening reaction that can occur in response to common triggers, including food allergens (e.g., peanut), insect stings, and several medications. Activation of mast cells and basophils to release preformed mediators, such as histamine, is thought to be an important process that underlies reactions. Histamine can exert effects through four different receptors, termed H1R-H4R. Despite clinical use of both H1R and H2R blockers in the therapy for acute allergic reactions, there is little mechanistic evidence to support the necessity for blocking H2R, a receptor best characterized for its role in stomach acid production. METHODS: Here, we sought to define the necessity for histamine receptors in the pathology of anaphylaxis using H1R and H2R knockout (KO) mice, as well as a H1R/H2R double KO strain. RESULTS: In response to IgE-mediated systemic anaphylaxis, the symptoms and decreases in core body temperature observed in wild-type mice were reduced but not ablated in either H1R or H2R KO. In contrast, H1R/H2R KO were significantly protected and were indistinguishable from histamine-deficient mice. Intravenous injection of histamine was sufficient to elicit these responses, and similar to IgE-mediated anaphylaxis, loss of both H1R and H2R was necessary for complete protection. CONCLUSION: Our data demonstrate definitively that both H1R and H2R participate in the immediate systemic responses during histamine-associated pathophysiology and mechanistically support the utility of H2R-blocking therapeutics in alleviating symptoms of anaphylaxis.

Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis.

AIM: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis. RESULTS: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon-like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, α-glucosidase inhibitors and DPP-4 inhibitors [-0.20% (95% CI -0.34 to -0.04%), -0.31% (95% CI -0.61 to -0.02%), -0.20% (95% CI -0.38 to -0.00), -0.36% (95% CI -0.64 to -0.07%), -0.32% (95% CI -0.47 to -0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [-0.12% (-0.23 to -0.03%)], and for biphasic insulin compared with glinides (-0.36%; 95% CI -0.82 to -0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with α-glucosidase inhibitors and GLP-1 analogues. CONCLUSIONS: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain.

Relationship of initial glucose level and all-cause death in patients with ischaemic stroke: the roles of diabetes mellitus and glycated hemoglobin level.

BACKGROUND AND PURPOSE: Previous studies demonstrated that post-stroke hyperglycemia was associated with poor outcome in non-diabetic patients. However, evidence was inconclusive amongst patients with diabetes. The aim of this study was to evaluate the relationship between initial glucose levels and mortality amongst patients with acute ischaemic stroke, and further, to assess whether the association varied by diabetes mellitus and glycated hemoglobin (HbA(1c) ) levels. METHODS: Data were collected from the medical records of 1277 first-ever stroke patients admitted to the emergency room between January 1, 2008 and June 30, 2009. Cox regression analysis was performed to assess the relationship between initial glucose level and mortality. RESULTS: Compared with the lowest quartile of initial glucose level, a significant association with all-cause death [hazard ratio (HR), 2.18; 95% CI, 1.36-3.48] and cardiovascular death (HR, 1.91; 95% CI, 1.01-3.61) was seen in the highest quartile. In non-diabetic subgroup, those patients within the highest quartile of initial glucose level had a 3.29-fold relative risks (RR) [95% confidence interval (CI), 1.62-6.68] for all-cause and a 2.54-fold RR (95% CI, 1.43-8.77) for cardiovascular death compared with those within the lowest quartile. However, the association between initial glucose levels and the risk of death was not significant amongst those with diabetes (P for interaction = 0.01). In addition, the risk amongst patients with diabetes varied by the HbA(1c) levels. CONCLUSIONS: A significant association was confirmed between initial glucose level and mortality in non-diabetic ischaemic stroke patients. The possible relationship between initial glucose level, HbA(1c) level, and mortality amongst ischaemic stroke patients with diabetes warrants further research.

Surface CD3-negative monomorphic epitheliotropic intestinal T-cell lymphoma.

Intestinal T/NK-cell lymphomas include enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), indolent T-cell lymphoproliferative disorders of the GI tract (ITCLPD), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and intestinal T-cell lymphoma NOS (ITCL-NOS). Here we describe a case of surface CD3-negative MEITL. A 63-year-old Japanese female had a tumor located in the conglomerated ileum, which formed multiple mass lesions. The resected tissue showed a diffuse infiltration of monomorphic medium-sized lymphocytes with epitheliotropism. Flowcytometry using a fresh specimen of the tumor revealed positivity for CD7, CD8, CD38, and CD56, but not surface CD3. On immunohistochemistry, the tumor showed positivity for cytoplasmic CD3, CD8, CD56, TIA-1, Granzyme B, and perforin. EBER with in situ hybridization was negative. Moreover, H3K36me3, which is negative in MEITL with SETD2-mutation, was positive. This is an important case of MEITL due to its oncogenesis.

Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes.

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.

Adult mice deficient in actinin-associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy.

Although cytoskeletal mutations are known causes of genetically based forms of dilated cardiomyopathy, the pathways that link these defects with cardiomyopathy are unclear. Here we report that the alpha-actinin-associated LIM protein (ALP; Alp in mice) has an essential role in the embryonic development of the right ventricular (RV) chamber during its exposure to high biomechanical workloads in utero. Disruption of the gene encoding Alp (Alp) is associated with RV chamber dilation and dysfunction, directly implicating alpha-actinin-associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of alpha-actinin to cross-link actin filaments, indicating that the loss of Alp function contributes to destabilization of actin anchorage sites in cardiac muscle. Alp also colocalizes at the intercalated disc with alpha-actinin and gamma-catenin, the latter being a known disease gene for human RV dysplasia. Taken together, these studies point to a novel developmental pathway for RV dilated cardiomyopathy via instability of alpha-actinin complexes.

Relationship of adiposity and body composition to the status of metabolic syndrome among ethnic Chinese Taiwanese.

BACKGROUND AND AIMS: The predictive power of adiposity and body compositions measured from bioelectrical impedance analysis (BIA) for identifying the risk of metabolic syndrome is unknown among ethnic Chinese. METHODS AND RESULTS: We designed a nested case-control study by recruiting 1000 cases of metabolic syndrome and 986 matched controls from a health checkup center. For identifying the metabolic syndrome status, the highest areas under receiver operating characteristic curve (AUCs) were waist-height ratio (WHtR) (0.967, 95% confidence interval [CI], 0.960-0.976). The body fat mass vs. lean body mass and body mass index (BMI) had a similar AUC (0.896 for fat mass vs. lean body mass, 0886 for BMI, P=0.07). WHtR and waist circumference had the highest correctly classified proportions (0.89-0.90) and the highest Youden's index (0.77-0.81). The optimal cut point for WHtR was 52.5, with a sensitivity of 0.92 and specificity of 0.89 for discriminating metabolic syndrome risk. The incremental values of AUC, net reclassification improvement and integrated discrimination improvement values were still highest among WHtR, waist circumference and the percent body fat in the multivariate logistic model. CONCLUSION: Waist circumference and BIA-derived body component measures are suitable for clinical application in identifying the metabolic syndrome status among ethnic Chinese in Taiwan.

Effects of Exercise Alone or in Combination with High-Protein Diet on Muscle Function, Aerobic Capacity, and Physical Function in Middle-Aged Obese Adults: A Randomized Controlled Trial.

BACKGROUND: Obesity accelerates and exacerbates the age-related changes on muscle function and exercise capacity. In addition, the middle-aged population is often overlooked when talking about the prevention of sarcopenia. This study investigated the effects of exercise alone or in combination with a high-protein diet on muscle function and physical fitness in middle-aged obese adults. MATERIALS AND METHODS: Sixty-nine middle-aged (50-64 years old) obese adults were randomly assigned to one of the following groups: control group (C; n=23), exercise group (E; n=23) or exercise plus high-protein group (EP; n=23). Individuals within the E and EP groups received 12 weeks of exercise training; whereas, the individuals in the EP group also received a high-protein diet intervention (1.6g/kg/day). Individuals within the C group were asked to maintain their lifestyle for 12 weeks. Participants were evaluated before and after the intervention. Outcome measures included maximal exercise capacity, muscle function and functional physical performance. Analysis of covariance was used to determine the effects of the intervention. RESULTS: After the intervention, the E and EP groups had greater maximal work rate, peak oxygen consumption, and muscle power during muscle contractions at 180°/sec than that in the C group (P<0.05). The EP group, but not the E group, showed significant improvement in the sit-to-stand test and climbing stairs test than the C group after the intervention (P<0.05). Within group comparisons showed that the anaerobic threshold only increased in the EP group (+12% from pre-test). CONCLUSIONS: For middle-aged obese adults, exercise with a high-protein diet not only improved muscle power and exercise capacity but also enhanced their functional physical performance.

Human opioid µ-receptor A118G polymorphism may protect against central pruritus by epidural morphine for post-cesarean analgesia.

BACKGROUND: Intrathecal or epidural morphine used for post-operative analgesia frequently induces central type pruritus. The purpose of this study was to investigate the association between the severity of central type pruritus induced by epidural morphine for post-cesarean analgesia and the A118G polymorphism of the human µ-opioid receptor gene (OPRM1). METHODS: Pregnant women (212) received pure epidural morphine (2 mg) twice per day for post-cesarean analgesia. Blood samples were collected and sequenced with high-resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG and GG). We interviewed all candidates 24 h post-operatively to record the clinical phenotype with subjective complaints and objective observations. RESULTS: The genotyping revealed that 99 women (46.7%) were AA, 88 (41.5%) were AG and 25 (11.8%) were GG. Sixty-two of 212 women suffered from significant pruritus (29.2%), and 150 of 212 women had non-significant pruritus (70.8%). In genotype AA, 33 patients (53.2%) experienced significant pruritus, 26 (41.9%) in genotype AG and 3 (4.8%) in genotype GG. The G allele was a statistically independent protective factor for individuals developing pruritus, and the multivariate-adjusted odds ratio was 0.27. There was a trend for progressively decreasing severity scores among the three groups, with the lowest severity score (0.72) for pruritus in the GG group. CONCLUSIONS: The incidence of significant pruritus in the recessive type (GG) was significantly lower compared with the dominant types (AA+AG). The recessive G allele in the A118G polymorphism may have protective effects against significant pruritus after epidural morphine for post-cesarean analgesia.

A prediction model for type 2 diabetes risk among Chinese people.

AIMS/HYPOTHESIS: A range of prediction rules for the onset of type 2 diabetes have been proposed. However, most studies have been conducted in white groups and it is not clear whether these models apply to Asian populations. The purpose of this study was to construct a simple points model for predicting incident diabetes among Chinese people. METHODS: We estimated the 10 year risk of diabetes in a cohort study of middle-aged and elderly participants who were free from diabetes at baseline. Cox regression coefficients were used to construct the simple points model and the discriminatory ability of the resulting prediction rule was determined using AUC and net reclassification improvement and integrated discrimination improvement statistics. Fivefold random splitting was used to test the internal validity and obtain bootstrap estimates of the AUC. RESULTS: Of the 2,960 participants without diabetes at the baseline examination, 548 developed type 2 diabetes during a median 10 year follow-up period. Age (four points), elevated fasting glucose (11 points), body mass index (eight points), triacylglycerol (five points), white blood cell count (four points) and a higher HDL-cholesterol (negative four points) were found to strongly predict diabetes incidence in a multivariate model. The estimated AUC for the model was 0.702 (95% CI 0.676-0.727). This model performed better than existing prediction models developed in other populations, including the Prospective Cardiovascular Münster, Cambridge, San Antonia and Framingham models for diabetes risk. CONCLUSIONS/INTERPRETATION: We have constructed a model for predicting the 10 year incidence of diabetes in Chinese people that could be useful for identifying individuals at high risk of diabetes in the Chinese population.

Point mutations in human beta cardiac myosin heavy chain have differential effects on sarcomeric structure and assembly: an ATP binding site change disrupts both thick and thin filaments, whereas hypertrophic cardiomyopathy mutations display normal assembly.

Hypertrophic cardiomyopathy is a human heart disease characterized by increased ventricular mass, focal areas of fibrosis, myocyte, and myofibrillar disorganization. This genetically dominant disease can be caused by mutations in any one of several contractile proteins, including beta cardiac myosin heavy chain (beta MHC). To determine whether point mutations in human beta MHC have direct effects on interfering with filament assembly and sarcomeric structure, full-length wild-type and mutant human beta MHC cDNAs were cloned and expressed in primary cultures of neonatal rat ventricular cardiomyocytes (NRC) under conditions that promote myofibrillogenesis. A lysine to arginine change at amino acid 184 in the consensus ATP binding sequence of human beta MHC resulted in abnormal subcellular localization and disrupted both thick and thin filament structure in transfected NRC. Diffuse beta MHC K184R protein appeared to colocalize with actin throughout the myocyte, suggesting a tight interaction of these two proteins. Human beta MHC with S472V mutation assembled normally into thick filaments and did not affect sarcomeric structure. Two mutant myosins previously described as causing human hypertrophic cardiomyopathy, R249Q and R403Q, were competent to assemble into thick filaments producing myofibrils with well defined I bands, A bands, and H zones. Coexpression and detection of wild-type beta MHC and either R249Q or R403Q proteins in the same myocyte showed these proteins are equally able to assemble into the sarcomere and provided no discernible differences in subcellular localization. Thus, human beta MHC R249Q and R403Q mutant proteins were readily incorporated into NRC sarcomeres and did not disrupt myofilament formation. This study indicates that the phenotype of myofibrillar disarray seen in HCM patients which harbor either of these two mutations may not be directly due to the failure of the mutant myosin heavy chain protein to assemble and form normal sarcomeres, but may rather be a secondary effect possibly resulting from the chronic stress of decreased beta MHC function.

Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.

Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol. These results illustrate a useful approach for studying the effect of gene expression on cardiac contractility. Because chronic heart failure in humans is accompanied by a reduction in the number of myocardial beta-adrenergic receptors and in inotropic responsiveness, these results suggest a potential gene therapy approach to this disease state.

Legionella prevalence in wastewater treatment plants of Taiwan.

Legionella is a bacterium that is ubiquitous in natural and artificial aquatic environments. Some species of Legionella are recognized as opportunistic potential human pathogens. We investigated the distribution of Legionella at seventeen WWTPs throughout Taiwan. Legionella were detected in 10 of the 17 WWTPs (58.8%) and 25 of 41 samples (61.0%). In the integrated, hospital, industrial and domestic wastewater systems were 13/18 (72.2%), 7/12 (58.3%), 2/7 (28.6%) and 3/4 (75.0%) of the samples were positive for Legionella, respectively. The most frequently encountered species were L. donaldsonii and uncultured L. spp., which were both found in 10 samples (24.4% of all samples), then followed by L. lytica (4.9%) and L. pneumophila (4.9%). L. anisa was detected in one sample (2.4%). The results of this survey confirm that Legionella are ubiquitous in WWTPs in Taiwan. Therefore, long-term investigations should be conducted to evaluate the overall occurrence of Legionella in WWTPs in Taiwan.

Risk of Myocardial Infarction and Ischemic Stroke after Dental Treatments.

The association between invasive dental treatments (IDTs) and a short-term risk of myocardial infarction (MI) and ischemic stroke (IS) remains controversial. Bacterial dissemination from the oral cavity and systemic inflammation linked to IDT can induce a state of acute vascular dysfunction. The aim of study is to investigate the relation of IDTs to MI and IS by using case-only study designs to analyze data from a large Taiwanese cohort. A nationwide population-based study was undertaken by using the case-crossover and self-controlled case series design to analyze the Taiwanese National Health Care Claim database. Conditional logistic regression model and conditional Poisson regression model were used to estimate the risks of MI/IS. In addition, we used burn patients as negative controls to explore the potential effect of residual confounding. In total, 123,819 MI patients and 327,179 IS patients in the case-crossover design and 117,655 MI patients and 298,757 IS patients were included in the self-controlled case series design. Results from both study designs showed that the risk of MI within the first 24 wk after IDT was not significantly different from or close to unity except for a modest risk during the first week for patients without other comorbidities (odds ratios [95% confidence intervals] of 1.31 [1.08-1.58] and 1.15 [1.01-1.31] for 3 d and 7 d, respectively). We also observed no association between IDTs and IS, or the risk ratio was close to unity. IDTs did not appear to be associated with a transient risk of MI and IS in the Taiwanese population, with consistent findings from both case-only study designs. However, we cannot exclude that dental infections and diseases may yield a long-term risk of MI and IS.