Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

Neuronal activities in the rostral ventromedial medulla associated with experimental occlusal interference-induced orofacial hyperalgesia.

The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds (HWTs), orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the kappa-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia which could however be reversed by intra-RVM microinjection of the NK-1 receptor antagonist L-733060. The activity of ON-cells and OFF-cells did not change during both the initial 3 and 6 days of EOI. When EOI was removed on postoperative day 3, OFF-cell responses decreased, contributing to the reversal of hyperalgesia. When EOI lasted for 8 days or was removed on postoperative day 8, spontaneous activity and stimulus-evoked responses of ON-cell increased, contributing to the maintained hyperalgesia. In contrast, when the EOI lasted for 14 days, OFF-cell responses decreased, possibly participating in the maintenance of hyperalgesia with persistent EOI. Our results reveal that adaptive changes in the RVM were associated with orofacial pain following EOI placement and removal.SIGNIFICANCE STATEMENTA considerable proportion of patients suffered from chronic orofacial pain throughout life despite the therapies given or removal of potential etiological factors. However, current therapies lack effectiveness due to limited knowledge of the chronicity mechanisms. Using electrophysiological recording, combined with a behavioral test, we found that the prevailing descending facilitation in the rostral ventromedial medulla (RVM) participates in the maintenance of orofacial hyperalgesia following late removal of nociceptive stimuli, while the prevailing descending inhibition from the RVM may contribute to the reversal of orofacial hyperalgesia following early removal of nociceptive stimuli. Thus, variable clinical outcomes of orofacial pain may be associated with descending modulation and an optimal window of time may exist in the management of chronic orofacial pain.

[Effects of intermittent hypoxia intestinal bacterial translocation on mesenteric lymph node injury].

Objective: To observe the effect of intermittent hypoxia on intestinal bacterial translocation and mesenteric lymph node (MLN) structure and explore its mechanism. Methods: Twenty-four adult male Wistar rats were randomly divided into an experimental group (HI group) and a control group (UC group), with 12 rats in each. During the experiment, both groups were fed under the same conditions, but the HI group received simulated sleep apnea with hypoxic treatment. On the last day of the 2nd and 4th week of the experiment, 20% urethane(0.7 ml/100g) was used for anesthesia, and MLNs and corresponding small intestinal tissues were aseptically collected.HE staining was used to observe the microscopic changes of the tissues. The lymph node tissue was sent for pathogenic culture. The levels of oxide dismutase (SOD), lipid peroxide (MDA) and reactive oxygen species (ROS) were measured for the extent of oxidative stress. Serum diamine oxidase (DAO) was measured to assess the extent of intestinal mucosal damage. Result: MLNs and their corresponding small intestines were damaged in the HI group as compared to the UC group. With the prolongation of intermittent hypoxic time, the number of germinal centers in MLNs was significantly reduced, with the volume reduced, cortical medullary fusion aggravated, and the area ratio increased. The intestinal tissue showed severe damage to the intestinal epithelium, increased permeability, mucosal edema, and changes of the crypts. At the 4th week, MLNs in the HI group grew Clostridium perfringens under anaerobic conditions, confirming intestinal bacterial translocation. The contents of ROS, SOD and MDA in MLNs of the HI group were significantly higher than those in the UC group (P<0.05). At the 2nd week and the 4th week, the contents of ROS, SOD and MDA were not significantly changed in the UC group(P>0.05). While the content of ROS and MDA in MLNs of the HI group at 4th week was significantly higher than that in the second week (P<0.05), but no change of SOD was observed (P>0.05). Serum DAO levels in the HI group were higher than those in the UC group at week 2 and week 4 (P<0.05), suggesting that the degree of intestinal mucosal injury in the HI group was more serious than that in the UC group. Conclusion: Hypoxic exposure aggravated the degree of oxidative stress in rats. With the prolongation of intermittent hypoxia, the intestinal mucosa of rats was seriously damaged. The intestinal flora shifted to damage the structure of mesenteric lymph nodes, and oxidative stress was further aggravated, which in turn affected the integrity of the intestinal autoimmune function.

Spatiotemporally Skewed Activation of Programmed Cell Death Receptor 1-Positive T Cells after Epstein-Barr Virus Infection and Tumor Development in Long-Term Fully Humanized Mice.

Humanized mice developing functional human T cells endogenously and capable of recognizing cognate human leukocyte antigen-matched tumors are emerging as relevant models for studying human immuno-oncology in vivo. Herein, mice transplanted with human CD34+ stem cells and bearing endogenously developed human T cells for >15 weeks were infected with an oncogenic recombinant Epstein-Barr virus (EBV), encoding enhanced firefly luciferase and green fluorescent protein. EBV-firefly luciferase was detectable 1 week after infection by noninvasive optical imaging in the spleen, from where it spread rapidly and systemically. EBV infection resulted into a pronounced immunologic skewing regarding the expansion of CD8+ T cells in the blood outnumbering the CD4+ T and CD19+ B cells. Furthermore, within 10 weeks of infections, mice developing EBV-induced tumors had significantly higher absolute numbers of CD8+ T cells in lymphatic tissues than mice controlling tumor development. Tumor outgrowth was paralleled by an up-regulation of the programmed cell death receptor 1 on CD8+ and CD4+ T cells, indicative for T-cell dysfunction. Histopathological examinations and in situ hybridizations for EBV in tumors, spleen, liver, and kidney revealed foci of EBV-infected cells in perivascular regions in close association with programmed cell death receptor 1-positive infiltrating lymphocytes. The strong spatiotemporal correlation between tumor development and the T-cell dysfunctional status seen in this viral oncogenesis humanized model replicates observations obtained in the clinical setting.

Effects of AIF-1 inflammatory factors on the regulation of proliferation of breast cancer cells.

The purpose of this study was to explore the effect of Allograft Inflammatory Factor 1 (AIF-1) on the regulation of proliferation of breast cancer cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), cell culture and counting, and mass spectrometry were performed. The biologically active high-purity recombinant protein rhAIF-1 was obtained by optimizing the rhAIF-1 protein purification system, and MDA-MB-231 and MDA-MB-361 breast cancer cell lines were used. After adding to the culture medium, rhAIF-1 was found to promote cell proliferation in dose-dependent and time-dependent manners. The purified protein rhAIF-1 was marked with rhodamine and incubated with the cells. Confocal imaging analysis revealed that the foreign protein was localized in the cytoplasm, and rhAIF-1 was unevenly distributed in the cytoplasm. Although AIF-1 accumulates around the nucleus, it can not enter the nucleus, suggesting that other factors might be involved in the regulation of cell proliferation. In order to find the possible interacting protein of rhAIF-1, protein immunoprecipitation technique and mass spectrometry were employed, and it was indicated that ADAM28m was the possible interacting protein of rhAIF-1. The interaction between rhAIF-1 and ADAM28m was validated by immunoprecipitation along with Western blotting. It was found that rhAIF-1 could precipitate ADAM28m protein by immunoprecipitation. The results indicated that IF-1 participates in the development of breast cancer by interacting with ADAM28m and activating downstream signaling pathways. It was concluded that AIF-1 provides a new idea for the molecular mechanism of breast cancer cell proliferation and acts as a new target for the prevention and treatment of breast cancer in the future.

Association between anemia and cognitive decline among Chinese middle-aged and elderly: evidence from the China health and retirement longitudinal study.

BACKGROUND: Our objective was to characterize the relationship of anemia and hemoglobin concentrations with cross-sectional cognitive functions and changes in cognitive functions over 2 years in a large sample of Chinese middle aged and elderly. METHODS: Ten thousand nine hundred eighteen adults aged 45 years or older participating in the China Health and Retirement Longitudinal Study (CHARLS) were used for cross-sectional analyses and 9324 were used for longitudinal analysis. Cognitive functions were assessed by memory recall (episodic memory), mental status (TICS), and global cognitive function at baseline survey (Visit 1) and first follow-up survey (Visit 2). The lower the cognitive test score, the worse the cognitive function. Anemia was defined as hemoglobin concentrations lower than 13 g/dl for men and lower than 12 g/dl for women. Adjusted multivariate regression analyses were used to explore the relationships of different cognitive domains with anemia and hemoglobin concentration. RESULTS: Overall, the prevalence of anemia was 12.86% and the mean hemoglobin concentration was 14.37 ± 2.20 g/dl. After adjusting for socio-demographic and health-related covariates, the cross-sectional association between anemia and global cognitive function [ß (95%CI) = - 0.49(- 0.69~ - 0.29)], episodic memory [ß (95%CI) = - 0.14(- 0.23~ - 0.05)], and TICS [ß (95%CI) = - 0.23(- 0.38~ - 0.08)] were significant and did not differ by gender. The hemoglobin concentration was also associated with global cognitive function among the whole sample (P < 0.05 for all). The longitudinal analyses showed global cognitive function and episodic memory were associated with anemia independent of covariates (P < 0.05 for all). Sensitivity analyses further provided significant results showing the association between anemia and cognition decline (P < 0.05). CONCLUSION: There was a cross-sectional and longitudinal association between anemia and accelerated decline in cognitive functions in Chinese middle-aged and elderly. This suggests that anemia and low hemoglobin concentrations are independent risk factors of cognitive decline.

Expression and purification of antimicrobial peptide AP2 using SUMO fusion partner technology in Escherichia coli.

Apidaecins (APs) are proline-rich antimicrobial peptides that were isolated from Apismelifera. APs possess broad-spectrum activities against Gram-negative bacteria and exhibit immune-modulatory functions. AP2, an artificial mutant AP peptide with improved activities, was expressed in Escherichia coli expression system using small ubiquitin-related modifier (SUMO) fusion technology and ZYM-5052 auto-induction medium. Approximately 23 mg of recombinant fusion protein smt3AP2 was purified per litre cultivated medium. After SUMO protease (Ulp) cleavage of smt3AP2, recombinant AP2 was further purified by affinity and cation exchange chromatography. The pure recombinant AP2 with calculated value of 2·23 kDa reached a yield of 2·7 mg l-1 and exhibited powerful antibacterial activity towards E. coli K88 with minimum inhibitory concentration at 5 µg ml-1 . The recombinant fusion strategy presented in this study allows convenient high yield and easy purification of recombinant AP2. SIGNIFICANCE AND IMPACT OF THE STUDY: AP2, an artificial mutant apidaecin (AP) peptide based on APs, has improved activities and may be regarded as a promising antibiotic alternatives. The secreted expression of antimicrobial peptide is of the greatest challenges because the antibacterial activity is not beneficial to the host. Our data suggest that the recombinant fusion strategy allows convenient high yield and easy purification of recombinant AP2.

Treatment intensification for patients with type 2 diabetes and poor glycaemic control.

AIMS: To identify the time to and patient characteristics associated with treatment intensification in patients with type 2 diabetes (T2D) and poor glycaemic control. METHODS: Using a large US insurance claims database, we conducted a retrospective cohort study among adult patients with T2D and glycated haemoglobin (HbA1c) ≥8% (index date) after ≥3 months of therapy including metformin. Patients were required to have continuous enrolment for at least 12 months before (baseline) and after index date, and no injectable antidiabetes medications. We defined treatment intensification as prescription fill for injectable or additional oral antidiabetic drugs (OADs). Cox modelling was performed to identify factors associated with time to treatment intensification. RESULTS: For the 11 525 patients meeting the inclusion criteria, the mean age at index date was 57 years, 40% were female and the mean index HbA1c was 9.1%. Overall, 37% of patients had their treatment intensified <6 months after, 11% had their treatment intensified 6-12 months after, and 52% did not have their treatment intensified <12 months after the index date. A higher index HbA1c was associated with early intensification [hazard ratio (HR) 1.18 for HbA1c ≥9 to <10% and HR 1.41 for HbA1c ≥10% compared with HbA1c ≥8 to <9%; p < 0.0001), and later line of therapy was associated with late intensification (HR 0.78 for metformin with one OAD and HR 0.68 for metformin with ≥2 OADs compared with metformin monotherapy; p < 0.0001). CONCLUSIONS: Fewer than half of patients with T2D and treatment failure received intensification within 12 months in a real-world US population. Factors associated with treatment inertia can be used to target clinical care for these patients.

Association between age at first sexual intercourse and knowledge, attitudes and practices regarding reproductive health and unplanned pregnancy: a cross-sectional study.

BACKGROUND: Age at first sexual intercourse (AFSI) is decreasing among adolescents in developed nations. An early sexual debut has been associated, to some extent, with multiple sexual partners, infrequent use of condoms, unplanned pregnancy, unsafe abortion, and sexually transmitted disease and human immunodeficiency virus infection. Unplanned pregnancy among adolescents has both physical and social adverse effects. METHODS: In total, 78,400 self-administered anonymous questionnaires were distributed to college students in seven cities in China to determine the age at which Chinese college students first engage in sexual activity, and the association between AFSI and knowledge, attitudes and practices (KAP) regarding reproductive health and unplanned pregnancy. RESULTS: Approximately 10,164 students reported that they were sexually active, and most reported that they had engaged in sexual intercourse for the first time during college. The average AFSI was 20.14 [standard deviation (SD) 2.98] years, and the average AFSI by gender was 19.97 (SD 2.97) years for males and 20.41 (SD 2.97) years for females. The unplanned pregnancy rate among the participants was 34.03%. Participants lacked knowledge about contraception and reproductive health, although most believed that it is necessary to have this knowledge. Participants' attitudes towards premarital sex were varied. Factors that were found to be associated with unplanned pregnancy were AFSI, contraceptive methods used for first sexual act, and whether contraceptive methods were used for every sexual act. CONCLUSIONS: The college period is a key time for Chinese students in terms of becoming sexually active. As such, comprehensive and informative reproductive health education should be provided before and during the college period. Furthermore, reproductive health education should include appropriate sexual morality education and comprehensive sex education. Gender traits and needs should be considered in sex education.

Cloning, Prokaryotic Expression and Purification of CpfS1 Gene from Arabidopsis Thaliana.

CpfS1 Gene cloned from arabidopsis thaliana was expressed in Escherichia coli DH5α. A cDNA fragment about 320 bp was amplified from the total RNA of arabidopsis thaliana seeds by reverse transcription PCR (RT-PCR) with a pair of specific primers based on the sequences of the AtCpfS1 gene. The recombinant prokaryotic expression vector pET30a-AtCpfS1 was constructed by inserting the cDNA fragment encoding the mature peptide into the prokaryotic expression vector pET30a, and then transformed into E. coli DH5α. Sequence analysis showed that the fragment length was 346 bp containing a full coding region of 332 bp encoding 76 amino acid residues with a molecular mass of 21.5 kD. The SDS-PAGE electrophoresis analysis showed that the best expression was induced by 21oC and 3.6×10-3 mol/L IPTG, under which a relative molecular weight of 82.5 kD recombinant protein was produced. The nickel chelating resin was used to purify the protein in size exclusion chromatography (SEC) and the results indicated that AtCpfS1 protein was present in the form of tetramer.

Arabidopsis thaliana SEPALLATA3 protein prokaryotic expression and purification.

SEPALLATA3 (SEP3) can be attributed to E class gene of the ABCE model of floral organ development. In order to reveal how SEP3 proteins form polymers, and the relationship between the polymers and their biological functions, the experiments of Arabidopsis thaliana AtSEP3 protein soluble expression in vitro were performed to construct a vector of prokaryotic expression, and investigate induced expression of recombinant proteins in Escherichia coli cells. The protein soluble expression was analyzed through the aspects of different protein domains, induction time, induction temperature, etc. Different structural domains and expression conditions were screened, and 0.1% IPTG inducing at 22 oC for 15 h was estimated as an optimal expression strategy. The nickel chelating resin was used to purify the protein in size exclusion chromatography (SEC) and the results indicated that AtSEP3 protein was present in the form of tetramer.

Risk of cardiovascular adverse events from trastuzumab (Herceptin(®)) in elderly persons with breast cancer: a population-based study.

Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin (®) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox-proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab-associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66-75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab.

"Primer shot" fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer.

PURPOSE: Radiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC). METHODS: Previously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP). RESULTS: Optimal schedules consistently favored a "primer shot" fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3). CONCLUSION: A validated simulation model clearly supports non-standard "primer shot" fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study.

BACKGROUND: Cardiovascular risk attributable to bevacizumab (Avastin(®), BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged ≥ 65. PATIENTS AND METHODS: We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events. RESULTS: We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20-2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF. CONCLUSIONS: In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.

Basiliximab with delayed introduction of calcineurin inhibitors as a renal-sparing protocol following liver transplantation in children with renal impairment.

Renal impairment is frequently compromised in patients with end-stage liver disease and is associated with increased long-term mortality post-LT. In contrast to CNI, basiliximab is an immunosuppressive agent with minimal nephrotoxic potential. This study reviews the experience of a single pediatric liver transplant center's renal-sparing approach with the use of basiliximab and MMF to compensate for delayed entry of CNI in children with renal impairment at the time of organ availability. There were no differences in renal function between pediatric patients with and without pre-LT renal impairment within the first year (cGFR: 135 mL/min/1.73 m2 vs. 144 mL/min/1.73 m2 ; p = 0.56) or at 5-8 yr following LT, (129 mL/min/1.73 m2 vs. 130 mL/min/1.73 m2 ; p = 0.97). In addition, there was no difference in ACR rates (50% vs. 43%, p = 0.62) between patients in the basiliximab group and those patients receiving standard CNI and steroid strategies. The utilization of a renal-sparing approach with basiliximab alongside delayed entry and lower early target trough levels of CNI in children with renal impairment at the time of LT is safe and maintains excellent long-term kidney function.

Predicting preference-based SF-6D index scores from the SF-8 health survey.

PURPOSE: To develop and test functions for predicting the preference-based SF-6D index scores from the SF-8 health survey. METHODS: This study was a secondary analysis of data collected in a population health survey in which respondents (n = 7,529) completed both the SF-36 and the SF-8 questionnaires. We examined seven ordinary least-square estimators for their performance in predicting SF-6D scores from the SF-8 at both the individual and the group levels. RESULTS: In general, all functions performed similarly well in predicting SF-6D scores, and the predictions at the group level were better than predictions at the individual level. At the individual level, 42.5-51.5% of prediction errors were smaller than the minimally important difference (MID) of the SF-6D scores, depending on the function specifications, while almost all prediction errors of the tested functions were smaller than the MID of SF-6D at the group level. At both individual and group levels, the tested functions predicted lower than actual scores at the higher end of the SF-6D scale. CONCLUSIONS: Our study developed functions to generate preference-based SF-6D index scores from the SF-8 health survey, the first of its kind. Further research is needed to evaluate the performance and validity of the prediction functions.

Itaconic acid and dimethyl itaconate exert antibacterial activity in carbon-enriched environments through the TCA cycle.

Itaconic acid (IA), a metabolite generated by the tricarboxylic acid (TCA) cycle in eukaryotic immune cells, and its derivative dimethyl itaconate (DI) exert antibacterial functions in intracellular environments. Previous studies suggested that IA and DI only inhibit bacterial growth in carbon-limited environments; however, whether IA and DI maintain antibacterial activity in carbon-enriched environments remains unknown. Here, IA and DI inhibited the bacteria with minimum inhibitory concentrations of 24.02 mM and 39.52 mM, respectively, in a carbon-enriched environment. The reduced bacterial pathogenicity was reflected in cell membrane integrity, motility, biofilm formation, AI-2/luxS, and virulence. Mechanistically, succinate dehydrogenase (SDH) activity and fumaric acid levels decreased in the IA and DI treatments, while isocitrate lyase (ICL) activity was upregulated. Inhibited TCA circulation was also observed through untargeted metabolomics. In addition, energy-related aspartate metabolism and lysine degradation were suppressed. In summary, these results indicated that IA and DI reduced bacterial pathogenicity while exerting antibacterial functions by inhibiting TCA circulation. This study enriches knowledge on the inhibition of bacteria by IA and DI in a carbon-mixed environment, suggesting an alternative method for treating bacterial infections by immune metabolites.

Probiotic characterization and comparison of broiler-derived lactobacillus strains based on technique for order preference by similarity to ideal solution analysis.

A total of 10 lactobacillus strains were isolated from broiler chickens and their probiotic properties including tolerance to gastrointestinal fluids and heat treatment, antimicrobial activity, adhesion capacity to intestinal cells, surface hydrophobicity, autoaggregation, antioxidative activity, and immunomodulatory effects on chicken macrophages were evaluated. The Limosilactobacillus reuteri (LR) was the most frequently isolated species, followed by Lactobacillus johnsonii (LJ) and Ligilactobacillus salivarius (LS). All isolates showed good resistance to simulated gastrointestinal conditions and antimicrobial activity against 4 indicator strains including Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, and Proteus mirabilis LR 21 exhibited excellent performances on autoaggregation, hydrophobicity and adhesion capacity to Caco-2 intestinal cells. In the meantime, this strain also possessed considerable tolerance to heat treatment, which indicated great potential to be used in the feed industry. However, LJ 20 strain had the highest free radical scavenging activity compared with the other strains. Furthermore, qRT-PCR results revealed that all isolated strains significantly increased the transcriptional levels of proinflammatory genes and tended to induce the M1-type polarization on HD11 macrophages. Particularly, the technique for order preference by similarity to ideal solution (TOPSIS) was adopted in our study to compare and select the most promising probiotic candidate based on in vitro evaluation tests.

An environmental epigenetic study of ADRB2 5'-UTR methylation and childhood asthma severity.

BACKGROUND: Beta-2 adrenergic receptor (ADRB2) is the primary target of both short- and long-acting beta-agonist asthma medications. ADRB2 5'-UTR methylation changes in blood have the potential to act as a surrogate biomarker of responsiveness to beta-agonist treatment and childhood asthma severity. OBJECTIVE: To study the association between ADRB2 5'-UTR methylation, NO (2) exposure and childhood asthma severity. METHODS: We compared ADRB2 5'-UTR methylation levels in blood between 60 children with mild asthma and 122 children with severe asthma using methylation-specific PCR. We also investigated potential joint effects between NO (2) exposure and ADRB2 5'-UTR methylation. RESULTS: We found a significant association between intermediate (OR: 4.11, 95% CI: 1.58-10.73) and high levels (OR: 7.63, 95% CI: 3.02-19.26) of ADRB2 methylation and severe childhood asthma. In addition, we found a significant association between indoor exposure to NO (2) , an air pollutant and known asthmogen, and severe asthma among children exhibiting high ADRB2 methylation (OR: 4.59, 95% CI: 1.03-20.55) but no association among children exhibiting low levels of ADRB2 methylation (OR: 0.35, 95% CI: 0.01-14.13). CONCLUSIONS AND CLINICAL RELEVANCE: These findings support the potential use of ADRB2 5'-UTR methylation as a biomarker of both asthma severity and risk for NO (2) -associated asthma exacerbations in children, and present the first evidence of an epigenetic link between an important environmental exposure and childhood asthma severity.

Treatment intensification in patients with type 2 diabetes who failed metformin monotherapy.

AIM: To evaluate the time to and factors associated with treatment intensification in patients with type 2 diabetes who failed metformin monotherapy. METHODS: In a retrospective analysis using a large US electronic medical record database, eligible patients included those with type 2 diabetes and an HbA(1c) of ≥7.0% or at least two fasting blood glucose levels of ≥126 mg/dl while on metformin monotherapy for at least 6 months within the period of 1 January 1997 to 31 December 2008. Time to treatment intensification was calculated as the time between index date (date on which HbA(1c) ≥ 7% after metformin monotherapy for at least 6 months) and first prescription for additional antihyperglycaemic agent during follow-up period. All patients were required to have data for at least 12 months prior to and following the index date. A Cox proportional hazards model was employed to determine patient baseline characteristics associated with time to treatment intensification. RESULTS: Of the 12 566 patients identified, mean age at index date was 63 years and 51% were female. Mean index HbA(1c) was 8.0% overall, with 66, 19 and 15% of patients having an index HbA(1c) of 7 to <8%, 8 to <9% and ≥9%, respectively. Median time to treatment intensification was 14.0 months overall and 19.0, 8.7 and 4.5 months for patients with index HbA(1c) of 7 to <8%, 8 to <9% and ≥9%, respectively. Factors associated with treatment intensification included higher index HbA(1c) , younger age, higher Charlson co-morbidity index, metformin daily dose ≥ 1500 mg and later index date (all p < 0.05). CONCLUSIONS: In US clinical practice, median time to receive additional antihyperglycaemic medication is more than 1 year for patients with type 2 diabetes who failed metformin monotherapy.