Association Between History of Severe Hypoglycemia and Risk of Falls in Younger and Older Patients With Diabetes

To compare the incidence and relative risk of falls between adults with and without diabetes, and to prospectively assess the role of history of severe hypoglycemia in the putative relationship between diabetes and falls in younger and older people, respectively.The National Health Insurance Research Database in Taiwan was used in this cohort study. Diabetic cases (with and without history of severe hypoglycemia) and nondiabetic people were followed from 2000 to 2009. There were 31,049 people enrolled in each of the 3 groups. Subdistribution hazard ratio (sHR) of falls was estimated with considering death as a competing risk by using Fine and Gray method. Demographic characteristics, diabetes-related complications, and comorbidities associated with falls were adjusted in multivariable Cox regression model.As compared to nondiabetic people, adjusted sHR was 1.13 for diabetes without history of severe hypoglycemia (DwoH) and 1.63 for diabetes with history of severe hypoglycemia (DwH), respectively. DwH group was associated with a higher risk than DwoH (adjusted sHR = 1.57). All of the excessive risks were more pronounced in people younger than 65 years old than in older people.Patients with diabetes had increased risk of falls. Severe hypoglycemia was further associated with a higher risk in diabetes, the increased hazards were particularly pronounced in people younger than 65 years old. Because falls in younger people may result in a greater economic and social loss, our study call for proper attentions to prevention of falls in younger patients (<65 years old) with diabetes.     

Increased Risks of Term Low-Birth-Weight Infants in a Petrochemical Industrial City with High Air Pollution Levels

This study investigated the influence of petrochemical air pollution on birth weight. Birth data on 92,288 singleton infants with gestational periods of 37–44 wk born in a petrochemical industrial city (Kaohsiung, n = 31,530) with severe pollution or a non-petrochemical industrial city (Taipei, n = 60,758) in Taiwan between 1995 and 1997 were included in this analysis. Air pollutant concentration derived from routinely monitored data showed significantly higher concentrations of SO₂, O₃, and PM₁₀ in Kaohsiung. Infants with low birth weight (LBW) were significantly more prevalent in Kaohsiung (2.4%) than in Taipei (2.1%). Multivariable logistic regression analysis with adjustment for gestation age, gender, birth order, season of birth, maternal age, and maternal education further suggested that LBW risk in Kaohsiung was 13% higher than that in Taipei (odds ratio [OR] = 1.13, 95%, confidence interval [Cl] = 1.03–1.24).     

Usefulness of live/real time three-dimensional transthoracic echocardiography in the identification of individual segment/scallop prolapse of the mitral valve

In this report, we present 34 patients in whom surgical intervention was undertaken for severe mitral insufficiency due to mitral valve prolapse (MVP). Location and severity of MVP and regurgitation were assessed preoperatively by live/real time three-dimensional transthoracic echocardiography and closely agreed with the surgical findings.     

Vaccination of monoglycosylated hemagglutinin induces cross-strain protection against influenza virus infections

The 2009 H1N1 pandemic and recent human cases of H5N1, H7N9, and H6N1 in Asia highlight the need for a universal influenza vaccine that can provide cross-strain or even cross-subtype protection. Here, we show that recombinant monoglycosylated hemagglutinin (HA_mg) with an intact protein structure from either seasonal or pandemic H1N1 can be used as a vaccine for cross-strain protection against various H1N1 viruses in circulation from 1933 to 2009 in mice and ferrets. In the HA_mg vaccine, highly conserved sequences that were originally covered by glycans in the fully glycosylated HA (HA_fg) are exposed and thus, are better engulfed by dendritic cells (DCs), stimulated better DC maturation, and induced more CD8+ memory T cells and IgG-secreting plasma cells. Single B-cell RT-PCR followed by sequence analysis revealed that the HA_mg vaccine activated more diverse B-cell repertoires than the HA_fg vaccine and produced antibodies with cross-strain binding ability. In summary, the HA_mg vaccine elicits cross-strain immune responses that may mitigate the current need for yearly reformulation of strain-specific inactivated vaccines. This strategy may also map a new direction for universal vaccine design.HA glycoprotein on the surface of influenza virus is a major target for infectivity-neutralizing antibodies. However, the antigenic drift and shift of this protein mean that influenza vaccines must be reformulated annually to include HA proteins of the viral strains predicted for the upcoming flu season (1). This time-consuming annual reconfiguration process has led to efforts to develop new strategies and identify conserved epitopes recognized by broadly neutralizing antibodies as the basis for designing universal vaccines to elicit antibodies with a broad protection against various strains of influenza infection (2–6). Previous studies have shown that the stem region of HA is more conserved and able to induce cross-reactive and broadly neutralizing antibodies (7–9) to prevent the critical fusion of viral and endosomal membranes in the influenza lifecycle (10–14). Other broadly neutralizing antibodies have been found to bind regions near the receptor binding site of the globular domain, although these antibodies are fewer in number (15, 16).Posttranslational glycosylation of HA plays an important role in the lifecycle of the influenza virus and also contributes to the structural integrity of HA and the poor immune response of the infected hosts. Previously, we trimmed down the size of glycans on avian influenza H5N1 HA with enzymes and showed that H5N1 HA with a single N-linked GlcNAc at each glycosylation site [monoglycosylated HA (HA_mg)] produces a superior vaccine with more enhanced antibody response and neutralization activity against the homologous influenza virus than the fully glycosylated HA (HA_fg) (17). Here, to test whether the removal of glycans from HA contributes to better immune responses and possibly protects against heterologous strains of influenza viruses, we compared and evaluated the efficacy of HA glycoproteins with various lengths of glycans as potential vaccine candidates.     

Separate and Joint Effects of Diabetes Mellitus and Chronic Kidney Disease on the Risk of Acute Coronary Syndrome: A Population-Based Cohort Study

Patient with diabetes (DM) and chronic kidney disease (CKD) are at a higher risk of developing acute coronary syndrome (ACS). However, only a few studies have investigated the separate and joint effects of DM and CKD on the risk of ACS, especially population-based studies under age-, sex- and various cardiovascular risk factor-stratifications. By using a national diabetes cohort derived from the Taiwan National Health Insurance Research Database, we identified a total of 416,143 DM and 541,724 non-DM patients, including 51,208 DM/CKD and 8,894 non-DM/CKD patients, in 2000 who did not have a history of ACS (ICD-9: 410.X, 413.9, 411.1) before 2000. We then prospectively investigated the incidence of ACS by linking to inpatient claims data from 2000 to 2007. A Cox proportional hazard model was used to estimate the relative risk of ACS in individuals with DM and/or CKD under various stratifications.Age- and sex-specific incidence rates were similar between the non-DM/CKD and DM/non-CKD groups, except for female patients under 45 years, in whom DM was associated with a higher risk of ACS than CKD (8.21 vs. 3.82 per 1000 person-years). In the group aged <45 years, the DM/non-CKD patients were associated with a higher relative hazard of ACS than those in the non-DM/CKD group when compared with the non-DM/non-CKD group (men: adjusted hazard ratios [AHR]:1.77; 95% confidence interval [CI]:1.61–1.93 vs. 1.42 [95% CI: 0.73–2.73]; women 1.97 [95% CI: 1.76–2.20] vs. 1.13 [95% CI: 0.36–3.52]). This discrepancy in AHR was reduced with increasing age. The co-existence of DM and CKD further enhanced the AHR in a multiplicative independent manner. A significant age-modification effect was noted in the DM individuals regardless of their CKD status, but not in the non-DM/CKD group. In stratification by various cardiovascular risk factors, diabetes had a higher risk of ACS than CKD in patients with ≤2 selected risk factors, with the exception of the hyperlipidemia and hypertension subgroup. When all three selected risk factors were included, CKD was associated with a higher risk of ACS than DM (AHR: 1.43 [1.27–1.60] vs. 1.25 [1.22–1.29]). In conclusion, DM and CKD were associated with different levels of risk for ACS according to age, sex and certain cardiovascular risk factors. Strategies aimed at preventing ACS should therefore be individualized according to the presence of DM, CKD and various cardiovascular risk factors.     

A Population-Based 16-Year Study on the Risk Factors of Surgical Site Infection in Patients after Bone Grafting: A Cross-Sectional Study in Taiwan

Bone grafting is a commonly used orthopedic surgical procedure that will provide bone formation in bone defects or regions of defective bone healing. A major complication following bone grafting is a postoperative recipient graft site infection that is associated with substantial mortality and increased use of medical resources. The purpose of the study was to identify the risk factors associated with infection after bone-grafting surgery.Data from 1,303,347 patients listed in the Taiwan National Health Insurance Research Database (NHIRD) and admitted to hospitals from 1997 through 2012 who underwent primary bone grafting (mean age: 46.57 years old; mean length of hospital stay: 8.04 days) were analyzed. The incidence of infection by age, hospital stay, gender, income, chronic disease (tuberculosis [TB]; diabetes mellitus [DM]; acquired immunodeficiency syndrome [AIDS]), fracture complications (nonunion; delayed union fracture), types of graft and hospital was evaluated.Three percent of the patients developed a postoperative recipient graft site infection. Multivariable analysis revealed that patients were more likely to develop a post bone-grafting surgery infection if they were older, had a longer hospital stay, were male, had a lower income, or had comorbid TB, DM, or AIDS. Patients were more likely to develop an infection if they had a nonunion, an alloplast graft, or treated in a local clinic.Our findings should provide a clinically relevant reference for surgeons who perform bone grafting. Patients should be informed of the potential risks.     

Risk of Malignant Neoplasms of Kidney and Bladder in a Cohort Study of the Diabetic Population in Taiwan With Age,Sex, and Geographic Area Stratifications

Diabetes has been reported to increase the risk of malignant neoplasms of kidney and bladder, but the studies’ results are still inconclusive. Age, sex, and geographical area-specific incidence and relative risks of above neoplasms are also scarce in the literature. We prospectively investigated the age, sex, geographical area-specific incidence and relative risks of kidney and bladder neoplasms in diabetic population of Taiwan.Diabetic patients (n = 615,532) and age- and sex-matched controls (n = 614,871) were linked to inpatient claims (2000–2008) to identify the admissions for malignant neoplasm of kidney (International Classification of Diagnosis, 9th version, Clinical Modification: 189) and bladder (International Classification of Diagnosis, 9th version, Clinical Modification: 188). The person-year approach with Poisson assumption was used to evaluate the incidence density. We also estimated the age, sex, and geographical area-specific relative risks of above malignancy in relation to diabetes with Cox proportional hazard regression model.The overall incidence density of malignant neoplasm of kidney for diabetic men and women were 3.87 and 4.28 per 10,000 patient-years, respectively; the corresponding figures for malignant neoplasm of bladder were 5.73 and 3.25 per 10,000 patient-years. Compared with the controls, diabetic men were at significantly increased hazards of kidney (covariate adjusted hazard ratio [aHR]: 1.31, 95% confidence interval [CI] 1.18–1.46) and bladder aHR: 1.13, 95% CI 1.04–1.23). Diabetic women, on the contrary, only experienced significantly elevated hazard of kidney neoplasm (aHR: 1.14, 95% CI 1.04–1.26). Diabetic men aged >65 years showed the most significantly increased hazard of developing neoplasm of kidney (aHR: 1.40) and bladder (aHR: 1.13). The most significantly increased hazard of kidney neoplasm was noted for women diabetic patients aged >65 years. There was also a significant interactive effect of geographic area with diabetes on the incidence of kidney and bladder neoplasms in both sexes.Diabetic men >45 years and diabetic women >65 years were found to have significantly increased hazard of malignant neoplasm of kidney, but only diabetic men >65 years were at significantly increased hazard of bladder neoplasm. The significant geographic variations in incidence and relative hazard of kidney and bladder neoplasms warrant further investigations of the underlying reasons.     

Small molecules targeting severe acute respiratory syndrome human coronavirus

Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).     

Successful intraoperative identification of an anomalous origin of the left coronary artery from the pulmonary artery using real time three-dimensional transesophageal echocardiography

Anomalous origin of the left coronary artery (LCA) from the pulmonary artery (ALCAPA) is a rare congenital defect that presents only infrequently in adults. An adult diagnosed with ALCAPA, heart failure, and mitral regurgitation underwent surgical ligation of the anomalous origin of the LCA from the pulmonary artery (PA) and coronary artery bypass grafting (CABG). The anomalous origin in the PA and proximal segment of the left anterior descending artery (LAD) was successfully delineated via real time, three-dimensional transesophageal echocardiography during surgery. This modality allows for fast assessment and novel views of complex cardiac abnormalities and can aid in perioperative monitoring.     

Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes

Carbohydrate-based vaccines have shown therapeutic efficacy for infectious disease and cancer. The mushroom Ganoderma lucidum (Reishi) containing complex polysaccharides has been used as antitumor supplement, but the mechanism of immune response has rarely been studied. Here, we show that the mice immunized with a l-fucose (Fuc)-enriched Reishi polysaccharide fraction (designated as FMS) induce antibodies against murine Lewis lung carcinoma cells, with increased antibody-mediated cytotoxicity and reduced production of tumor-associated inflammatory mediators (in particular, monocyte chemoattractant protein-1). The mice showed a significant increase in the peritoneal B1 B-cell population, suggesting FMS-mediated anti-glycan IgM production. Furthermore, the glycan microarray analysis of FMS-induced antisera displayed a high specificity toward tumor-associated glycans, with the antigenic structure located in the nonreducing termini (i.e., Fucα1-2Galβ1-3GalNAc-R, where Gal, GalNAc, and R represent, respectively, D-galactose, D-N-acetyl galactosamine, and reducing end), typically found in Globo H and related tumor antigens. The composition of FMS contains mainly the backbone of 1,4-mannan and 1,6-α-galactan and through the Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl, and Fucα1-2Fuc linkages (where Man and Xyl represent d-mannose and d-xylose, respectively), underlying the molecular basis of the FMS-induced IgM antibodies against tumor-specific glycans.