Effects of Sacubitril/Valsartan Versus Telmisartan in Type 2 Diabetic or Pre-Diabetic Patients with Hypertension and Without Heart Failure: The Rationale and Design of A Randomized Clinical Trial.

BACKGROUND: Sacubitril/valsartan has revealed superior glycemic and blood pressure control compared with enalapril and irbesartan in patients with heart failure and type 2 diabetes and in individuals with chronic kidney disease. However, whether the effects of sacubitril/valsartan remain the same in those without heart failure is unknown. METHODS: A multicenter randomized double-blinded trial will be carried out in five military hospitals in Taiwan for a period of 1 year. Participants with prior cardiovascular diseases and heart failure will be excluded. The purpose of the study is to compare the effects of sacubitril/valsartan (97/103 mg once or twice daily) on the temporal changes in fasting blood glucose, HbA1c, insulin resistance and blood pressure levels with telmisartan (40 mg once or twice daily) in individuals with stage 1-3 hypertension and newly diagnosed type 2 diabetes or prediabetes who have an HbA1c ≥6.0% and a systolic blood pressure ≥130 mmHg or a diastolic blood pressure ≥85 mmHg. The inclusion criteria include the age of 35-70 years, women who are not pregnant, estimated glomerular filtration rate ≥45 ml/min per 1.73m2 and B-type natriuretic peptide levels <400 pg/ml. RESULTS: The sample size is estimated to be 502 participants for randomization according to an assumption of between-person standard deviation in systolic blood pressure of 15 mmHg or in HbA1c of 1.5%, which provides ≥80% power (at p =0.05) to detect a difference in systolic blood pressure of 4 mmHg or in HbA1c of 0.3% at the final follow-up. All participants will receive a comprehensive physical examination and tests for blood cell counts, blood biochemistry, urine analysis, 12-lead electrocardiography and an echocardiography every 3 months. CONCLUSION: All analyses will be performed based on the intention-to-treat principle among all randomized participants.

Cancer as an infectious disease: A different treatment alternative using a combination of tigecycline and pyrvinium pamoate - An example of breast cancer.

BACKGROUND: Tigecycline is an antibiotic that well tolerated for treating complicated infections. It has received attention as an anti-cancer agent and expected to solve two major obstacles, sides effects that accompany chemotherapy and drug resistance, in the breast cancer treatment. However, previous studies reported that the levels in the blood are typically low of tigecycline, so higher doses are needed to treat cancer, that may increase the risk of side effects. To achieve better anti-cancer effects for tigecycline, we need to find a novel adjunct agent. METHODS: In this study, we used different concentration of pyrvinium pamoate combined with tigecycline to treat cell. And assess the effect of two drugs in inhibit cell proliferation, induce cell autophagy, or increase cell apoptosis to evaluate the consequent of combined therapy. RESULTS: We observed that after the combined therapy, the cell cycle arrest at G1/s phase, the level of p21 increased, but decreased the levels of CDK2. Others, two drugs via different mechanisms to inhibit cancer cell proliferation and with selective cytotoxic to different cell lines. That could enhance the effect of breast cancer treatment. CONCLUSION: Combining low dose of tigecycline use with pyrvinium pamoate is a novel approach for breast cancer treatment. Appropriate combined therapy in breast cancer is recommended to improve outcomes. Other problems like drug resistance occur in patients or the microbes surrounding breast tissues would confer susceptibility to cancers then influence the effectiveness of treatment, which could be improved through combined therapy.

Pros and cons of continuous glucose monitoring in the intensive care unit.

Diabetes mellitus affects people worldwide, and management of its acute complications or treatment-related adverse events is particularly important in critically ill patients. Previous reports have confirmed that hyperglycemia can increase the risk of mortality in patients cared in the intensive care unit (ICU). In addition, severe and multiple hypoglycemia increases the risk of mortality when using insulin or intensive antidiabetic therapy. The innovation of continuous glucose monitoring (CGM) may help to alert medical caregivers with regard to the development of hyperglycemia and hypoglycemia, which may decrease the potential complications in patients in the ICU. The major limitation of CGM is the measurement of interstitial glucose levels rather than real-time blood glucose levels; thus, there will be a delay in the treatment of hyperglycemia and hypoglycemia in patients. Recently, the European Union approved a state-of-art artificial intelligence directed loop system coordinated by CGM and a continuous insulin pump for diabetes control, which may provide a practical way to prevent acute adverse glycemic events related to antidiabetic therapy in critically ill patients. In this mini-review paper, we describe the application of CGM to patients in the ICU and summarize the pros and cons of CGM.

Design optimisation and experimental evaluation of dorsal double plating fixation for distal radius fracture.

This study determines the relative effects of changes in osteoporosis condition, plate/screw design factors (plate angle/length/width/thickness and screw diameter) and fixation methods (screw number and screw length) on the biomechanical response of dorsal double plating (DDP) fixation at a distal radius fracture to determine the optimal design and evaluate its biomechanical strength using the dynamic fatigue test. Eighteen CAD and finite element (FE) models corresponding to a Taguchi L18 array were constructed to perform numerical simulations to simulate the mechanical responses of a DDP fixed in a simply distal radius fracture bone. The Taguchi method was employed to determine the significance of each design factor in controlling bone/plate/screw stress and distal fragment displacement under axial (100 N), bending (1 N m) and torsion (1 N m) loads. Simulation results indicated that the order rank to determine the mechanical response was the plate thickness, plate width, screw diameter, and number of screws. Dorsal intermediate (L) plate with 60 mm length, 1.8 mm thickness, 6.0 mm width and 2.8 mm diameter, 20 mm length dual-thread locking screw can be found for optimisation. The DDP, including an L plate with 0°, 30° and 60° angles and a straight I plate, were made with Ti6Al4V to fix onto the sawbones with three corresponding radius fractures to perform the dynamic testing. The specimens were oscillated with loads between 10 N and 150 N at 5 Hz for 20,000 cycles. The average stiffness in 20,000 test cycles was 425.7 N/mm, 461.1 N/mm and 532.1N/mm for the 0°, 30° and 60° constructs, respectively. No difference in stiffness was found in the same angled constructs throughout the 20,000 cycles of testing (p > 0.05). Lack of gross construct failures during cyclic testing and reasonable stiffness corroborated that our new constructs tested to date seem stable enough to support restricted post-operative loads.

Thyrotropin as an independent factor of renal function and chronic kidney disease in normoglycemic euthyroid adults.

OBJECTIVES: The relationship between thyroid status and renal function has been well characterized. However, renal function is affected by various factors, including sex and dysglycemia. Because these studies have yet to be undertaken in a normoglycemic population, this study sought to explore the association between thyroid and renal function in large population of normoglycemic euthyroid adults. DESIGN: Population-based cross-sectional survey. PATIENTS: A total of 8,418 normoglycemic euthyroid participants were recruited after excluding individuals with thyroid dysfunction (thyrotropin, TSH < 0.47 mU/L, TSH ≥ 5.0 mU/L) or dysglycemia (fasting glucose ≥100 mg/dL). MEASUREMENTS: Anthropometric measurements were collected, and creatinine, TSH, and fasting glucose levels were evaluated. Renal function was determined by the estimated glomerular filtration rate (e-GFR) calculated using the simplified Modification of Diet in Renal Disease formula. RESULTS: TSH levels were inversely correlated with e-GFR. After adjustment for confounding factors, multivariate analysis revealed that TSH remained an independent factor of e-GFR in both genders (beta = -1.512 in males and -1.685 in females), and TSH was an independent factor of chronic kidney disease (OR = 1.28, 95% CI = 1.021-1.604). CONCLUSIONS: TSH is an independent factor for determining renal function and chronic kidney disease in normoglycemic euthyroid adults.

Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men.

OBJECTIVES: We aimed to investigate levels of brain-derived neurotrophic factor (BDNF), adiponectin, and proinflammatory cytokines in various subtypes of depression in a cohort of young men. METHODS: Sixty-two men 18-30 years of age were recruited for the study. Forty-two were newly diagnosed with depression according to DSM-IV criteria and were divided into three subtypes: reactive depression (N = 13), major depression (N = 18), and bipolar depression (N = 10). Controls included 21 young men without significant clinical morbidity. Serum levels of BDNF, adiponectin, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured. RESULTS: Serum BDNF was significantly lower and TNF-alpha significantly higher than controls for all subtypes of depression. No statistically significant differences between subtypes were found for BDNF, adiponectin, hsCRP, TNF-alpha, or IL-6. Although established diagnosis of depression and level of TNF-alpha were found to independently affect BDNF level in depressed subjects, they executed inverse effects. No associations were found between BDNF and adiponectin, hsCRP, TNF-alpha, or IL-6 in any depressed subject, showing that decreased BDNF in depression is influenced by multiple factors and complex mechanisms, including environmental and genetic concerns. No influence of age on BDNF level was found in any depressive subtype. CONCLUSIONS: Our results lend support to the cytokine and neurotrophic hypotheses of depression by demonstrating significantly lower levels of BDNF in all subtypes of depression. The mechanism underlying this phenomenon is uncertain and assumed to be multifactorial. Development of novel antidepressant treatments will require a multidisciplinary approach.

3D micro-crack propagation simulation at enamel/adhesive interface using FE submodeling and element death techniques.

This study investigates micro-crack propagation at the enamel/adhesive interface using finite element (FE) submodeling and element death techniques. A three-dimensional (3D) FE macro-model of the enamel/adhesive/ceramic subjected to shear bond testing was generated and analyzed. A 3D micro-model with interfacial bonding structure was constructed at the upper enamel/adhesive interface where the stress concentration was found from the macro-model results. The morphology of this interfacial bonding structure (i.e., resin tag) was assigned based on resin tag geometry and enamel rod arrangement from a scanning electron microscopy micrograph. The boundary conditions for the micro-model were determined from the macro-model results. A custom iterative code combined with the element death technique was used to calculate the micro-crack propagation. Parallel experiments were performed to validate this FE simulation. The stress concentration within the adhesive occurred mainly at the upper corner near the enamel/adhesive interface and the resin tag base. A simulated fracture path was found at the resin tag base along the enamel/adhesive interface. A morphological observation of the fracture patterns obtained from in vitro testing corresponded with the simulation results. This study shows that the FE submodeling and element death techniques could be used to simulate the 3D micro-stress pattern and the crack propagation noted at the enamel/adhesive interface.

Baseline forced expiratory volume in the first second as an independent predictor of development of the metabolic syndrome.

A growing body of evidence strongly supports associations between reduced lung function and insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The present study was undertaken to explore the possibility that reduced lung function is an independent predictor of development of the metabolic syndrome (MetS) and to investigate potential links between reduced lung function and the MetS. A prospective cohort study of reduced lung function as a predictor of subsequent MetS was conducted using 2-year follow-up data for 450 middle-aged adults lacking the MetS at baseline. Data were obtained from the Taipei MJ Health Screening Centers in Taiwan. The MetS was defined according to the modified Adult Treatment Panel III criteria. Over 2 years of follow-up, 26 of the 450 subjects (5.78%) without the MetS at baseline subsequently developed the syndrome. In multiple logistic regression analysis with adjustments for age, sex, body mass index, cigarette smoking, alcohol consumption, and physical activities, reduced forced expiratory volume in the first second (FEV(1)) at baseline remained a predictor of subsequent MetS (relative risk of 4.644, P = .036 for the third [<2.31 L] vs first [>2.88 L] tertile). In Pearson and partial correlation analyses, white blood cell counts and C-reactive protein concentrations were both found to be significantly and negatively correlated with FEV(1). Lower FEV(1) is concluded to serve as an independent predictor of the MetS. Low-grade systemic inflammation is the possible link between reduced lung function and the MetS.

Antithyroid drug-induced agranulocytosis.

Antithyroid drugs are widely used to treat hyperthyroidism, especially Graves' disease, but they tend to cause agranulocytosis, which increases the mortality rate. Granulocyte colony-stimulating factor decreases the duration of recovery from agranulocytosis. We retrospectively studied cases of antithyroid drug-induced agranulocytosis over the past 10 years in a northern Taiwan medical center. A clinical evaluation was conducted, including a review of complete blood cell counts and differential counts. Four cases were included in this analysis. Agranulocytosis persisted in 2 cases despite a change in therapy from propylthiouracil to methimazole. Fever, sore throat, and diarrhea were common symptoms of agranulocytosis. Initial white blood cell counts ranged from 450 to 1,710/microL. Only 1 case had a positive result from a throat swab culture (Staphylococcus aureus). Three of 4 cases received granulocyte colony-stimulating factor therapy, and the recovery time ranged from 3 to 13 days. All of the patients recovered from agranulocytosis. We concluded that: (1) conducting a routine complete blood cell count is beneficial in alerting caregivers to the possibility of agranulocytosis; (2) educating patients about the common symptoms of agranulocytosis may contribute to an early diagnosis; (3) providing granulocyte colony-stimulating factor therapy to patients results in good prognosis; and (4) monitoring for cross-reactions between drugs should be performed to prevent further episodes of agranulocytosis.

Damage accumulation simulations in the adhesive of enamel/ceramic interface using the FE submodelling and the element deactivation approaches.

PURPOSE: To investigate the micromechanics and damage accumulation of the enamel/adhesive interface using sub-modelling and element deactivation methods. MATERIALS AND METHODS: A finite element (FE) macromodel of the enamel/adhesive/ceramic interface subjected to shear bond testing was generated for mechanical analysis. The FE micromodel was constructed at the upper enamel/adhesive interface where stress concentration was found. The morphology of the micromechanical interlockings at the bonded interface was assigned based on a scanning electron micrograph. Boundary conditions of the micromodel were determined from the macromodel's results. Furthermore, an iterative code with the element deactivation method was used to calculate the microdamage accumulation. Parallel experiments were performed to validate the simulation. RESULTS: The micromodel results demonstrated that stress concentration within the adhesive mainly occurred at the upper corner near the enamel/adhesive interface and the base of the resin tags. A simulated fracture path was found at the base of the resin tags along the enamel/adhesive interface. The morphological observation of fracture patterns obtained from in vitro testing corresponded with the simulation results. CONCLUSION: This study showed that the FE submodelling and the element deactivation approaches could better simulate the micromechanical responses and the microdamage accumulation noted at the enamel/adhesive interface.

Evaluation of differentially expressed genes by shear stress in human osteoarthritic chondrocytes in vitro.

BACKGROUND: The pathogenesis of osteoarthritis is related to abnormal mechanical stresses that alter cartilage metabolism and chondrocyte survival. Among the mechanical stresses, shear stress is held responsible for the development of arthritis. METHODS: Monolayer cultures of human osteoarthritic chondrocytes were subjected to fluid-induced shear stress in vitro. A cDNA microarray technology was used to screen the differentially regulated genes and quantitative real-time poly-merase chain reaction (Q-RT-PCR) was used to confirm the results. The significance of the expression ratio for each gene was determined on the lowest associated false discovery rate calculated from the changes of gene expression in relation to the standard deviation of repeated measurements for that gene. RESULTS: Exposure of human osteoarthritic chondrocytes to shear stress (0.82 Pa) for 2 hours differentially regulated 373 and 227 clones in two independent microarray analyses with at least a 1.7-fold change. By comparing the differentially regulated clones, 14 upregulated and 6 downregulated genes were identified. Many of the differentially expressed genes were related to cell proliferation/differentiation (TGF-beta, acidic FGF), cell survival/apoptosis (CYP1B1, BCL2L3, TNFRSF11B, chemokine ligands, ADM), and matrix homeostasis (DCN, SDC2, MGP, WISP2). CONCLUSION: The gene expression patterns following shear stress show a high similarity to the gene expression in the reparative process of osteoarthritis chondrocytes. Using microarray analysis, this study suggests a close interaction between shear stress and the pathogenesis of osteoarthritis.

Numerical investigation of macro- and micro-mechanics of a ceramic veneer bonded with various cement thicknesses using the typical and submodeling finite element approaches.

OBJECTIVES: This study investigates the influence of cement thickness on the macro- and micro-mechanical responses in a ceramic veneer adjacent to an incisal overlapped incisor. METHODS: Seven finite element (FE) ceramic veneer macro-models with different cement thicknesses (10-180mum) were generated. A 10N load was applied with an angulation of 60 degrees to the longitudinal tooth axis. Seven FE micro-models corresponding to the macro-models were constructed at an enamel-adhesive interface where the stress concentration was found. Based on an interfacial scanning electron microscope (SEM) micrograph, morphology of resin tags in the micro-models was generated. The micro-model boundary conditions were determined from the macro-model results. The principal stress on each node in the macro- and micro-models was calculated to investigate interfacial mechanics. A tensile test was performed to obtain an ultimate cement tensile strength to determine the material failure parameters. RESULTS: The highest stress concentration within the cement was found at the resin tag base of the enamel-adhesive interface in lingual side. Maximum stress values from 10.6 to 14.7MPa for the micro-models were higher (44-48%) than that from 7.2 to 10.0MPa for the macro-models when the cement layers increased. Based on the ultimate tensile strength (11.8MPa), bonding failure could found when the micro-models with the cement layers presented more than about 50mum. This seems to correspond with data from previous studies. CONCLUSIONS: Higher stresses develop in the adhesive as the cement thickness increases. Cement thicknesses less than 50mum might reduce the adhesive bonding failure.