Lipid variability and risk of microvascular complications in Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: A post hoc analysis.

BACKGROUND: Greater lipid variability may cause adverse health events among diabetic patients. We aimed to examine the effect of lipid variability on the risk of diabetic microvascular outcomes among type 2 diabetes mellitus patients. METHODS: We assessed the association between visit-to-visit variability (measured by variability independent of mean) in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein-cholesterol (LDL), triglyceride, and remnant cholesterol (RC) measurements among participants involved in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the risk of incident microvascular outcomes, including nephropathy, neuropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: There were 2400, 2470, and 2468 cases of nephropathy, neuropathy, and retinopathy during a follow-up period of 22 600, 21 542, and 26 701 person-years, respectively. Higher levels of HDL, triglyceride, and RC variability were associated with an increased risk of incident nephropathy and neuropathy. Compared with the lowest quartile, the fully adjusted HRs (95% CI) for the highest quartile of HDL, triglyceride, and RC variability for nephropathy risk were 1.57 (1.22, 2.01), 1.50 (1.18, 1.92), and 1.40 (1.09, 1.80), respectively; and for neuropathy, the corresponding risks were 1.36 (1.05, 1.75), 1.47 (1.14, 1.91), and 1.35 (1.04, 1.74), respectively. Null association was observed between LDL variability and all microvascular complications. Additionally, all associations of variability in the other lipids with retinopathy risk were null. CONCLUSION: Among individuals with type 2 diabetes mellitus, HDL, triglyceride, and RC variability were associated with increased risks of nephropathy and neuropathy but not retinopathy. TRIAL REGISTRATION: ClinicalTrials.gov., no. NCT00000620.

Waist Circumference and Body Mass Index Variability and Incident Diabetic Microvascular Complications: A Post Hoc Analysis of ACCORD Trial.

BACKGROUND: Obesity is associated with adverse health events among diabetic patients, however, the relationship between obesity fluctuation and risk of microvascular complications among this specific population is unclear. We aimed to examine the effect of waist circumference (WC) and body mass index (BMI) variability on the risk of diabetic microvascular outcome. METHODS: Annually recorded anthropometric data in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used to examine the association of WC and BMI variability defined as variability independent of mean, with the risk of microvascular outcomes, including neuropathy, nephropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) (Trial registration: ClinicalTrials.gov., no. NCT00000620). RESULTS: There were 4,031, 5,369, and 2,601 cases of neuropathy, nephropathy, and retinopathy during a follow-up period of 22,524, 23,941, and 23,850 person-years, respectively. Higher levels of WC and BMI variability were associated with an increased risk of neuropathy. Compared with the lowest quartile, the fully-adjusted HR (95% CI) for the highest quartile of WC and BMI variability for neuropathy risk were 1.21 (1.05 to 1.40) and 1.16 (1.00 to 1.33), respectively. Also, higher quartiles of BMI variability but not WC variability were associated with increased risk of nephropathic events. The fully-adjusted HR (95% CI) for the highest quartile compared with the lowest quartile of BMI variability was 1.31 (1.18 to 1.46). However, the results for retinopathic events were all insignificant. CONCLUSION: Among participants with type 2 diabetes mellitus, WC and BMI variability were associated with a higher risk of neuropathic events, whereas BMI variability was associated with an increased risk of nephropathic events.

Association of Predicted Lean Body Mass and Fat Mass With Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus: A Post Hoc Analysis of ACCORD Trial.

Background: Lean body mass (LBM) and fat mass (FM) have been shown to have different associations with several chronic diseases but little is known about the sex-specific association of LBM and FM with diabetic nephropathy (DN) risk among participants with diabetes. Methods: Participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used in a post hoc analysis to examine the association of predicted LBM index (LBMI) and FM index (FMI) with incident DN risk (defined as a composite outcome of three types of predefined DN). Because of sex differences in body composition, analyses were conducted separately using sex-specific quartiles of predicted LBMI and FMI. Results: Of the 9,022 participants with type 2 diabetes (5,575 men and 3,447 women) included in this study, 5,374 individuals developed DN (3,396 in men and 1,978 in women). Higher quartiles of LBMI were associated with a reduced risk of DN while higher quartiles of FMI were associated with an increased higher risk of DN among men but not women. Compared with the lowest quartile, the fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)for the highest quartile of predicted LBMI and FMI were respectively 0.83 (95% CI 1.71 - 0.96) and 1.23 (95% CI 1.06-1.43) among men; and 0.92 (95% CI 0.63 - 1.33) and 1.14 (95% CI 0.79 - 1.63) among women. Conclusions: Among participants with diabetes, predicted LBMI was inversely associated with risk of DN while predicted FMI was positively associated with an increased risk of incident DN among men but not women. Trial registration: ClinicalTrials.gov., no. NCT00000620.

Anthropometric Measures and Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus.

Background: The prevalence of diabetes is on the rise globally coupled with its associated complications, such as diabetic nephropathy (DN). Obesity has been identified as a risk factor for the development of DN but it is still unclear which obesity index is the best predictor of incident DN. Methods: Data from the participants with type 2 diabetes mellitus (T2DM) in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study were used to examine the sex-specific association between waist circumference (WC), waist-to-height ratio (WHtR), and body mass index (BMI) with incident DN risk. Results: Among the 8,887 participants with T2DM (5,489 men and 3,398 women), 5,296 participants (3,345 men and 1,951 women) developed the DN composite outcome during a follow-up period of 24302 person-years. Among men, null associations were observed between all anthropometric measures with incident DN in the multivariate analysis although the 3rd quartile of WHtR showed marginally significant results (P = 0.052). However, among women, both central and general obesity measures were associated with increased risks of incident DN. Compared with participants in the WC <88 cm category, the fully adjusted HR and 95% CI for those in the ≥88 cm of WC was 1.35 (95% CI 1.15-1.57). Compared with the lowest quartile, the fully adjusted HRs and 95% CIs for the 2nd to the 4th quartile of WHtR were 1.09 (95% CI 0.96-1.25), 1.12 (95% CI 0.98-1.28), and 1.14 (95% CI 1.00-1.30) respectively; also, compared with the normal BMI category, the fully adjusted HRs and 95% CIs for class I - class III obese were 1.36 (95% CI 1.10 - 1.67), 1.43 (95% CI 1.16 - 1.78) and 1.32 (95% CI 1.05 - 1.66) respectively. Conclusions: Among participants with T2DM, higher levels of both central and general obesity indexes were associated with DN risk among women but not in men. Women with T2DM should maintain a healthy weight targeted at reducing both central and general obesity to enhance nephroprotection. Trial registration: ClinicalTrials.gov., no. NCT00000620.

Influence of Diabetes Duration and Glycemic Control on Dementia: A Cohort Study.

BACKGROUND: To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk of incident dementia. METHODS: The present study is a prospective study of 461 563 participants from the UK Biobank. The age at diabetes diagnosis was determined by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidential intervals (CIs). RESULTS: During a median follow-up of 8.1 years, 2 233 dementia cases were recorded. As compared with normoglycemic individuals, individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with participants with diabetes duration of <5 years, the multivariable-adjusted HRs (95% CIs) were 1.49 (1.12-1.97), 1.71 (1.21-2.41), and 2.15 (1.60-2.90) for those with diabetes durations ≥5 to < 10, ≥10 to <15, and ≥ 15 years, respectively (p for trend < .001). Among participants with diabetes, those with both longer diabetes duration (diabetes duration ≥ 10 years) and poor glycemic control (HbA1c ≥ 8%) had the highest risk of all-cause dementia (multivariable-adjusted HR = 2.07, 95% CI 1.45, 2.94), compared with patients with shorter duration of diabetes and better glycemic control (diabetes duration < 10 years and HbA1c < 8%). CONCLUSIONS: Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.

Depression as a Mediator of the Association Between Wealth Status and Risk of Cognitive Impairment and Dementia: A Longitudinal Population-Based Cohort Study.

BACKGROUND: Wealth and income are potential modifiable risk factors for dementia, but whether wealth status, which is composed of a combination of debt and poverty, and assessed by wealth and income, is associated with cognitive impairment among elderly adults remains unknown. OBJECTIVE: To examine the associations of different combinations of debt and poverty with the incidence of dementia and cognitive impairment without dementia (CIND) and to evaluate the mediating role of depression in these relationships. METHODS: We included 15,565 participants aged 51 years or older from the Health and Retirement Study (1992-2012) who were free of CIND and dementia at baseline. Dementia and CIND were assessed using either the modified Telephone Interview for Cognitive Status (mTICS) or a proxy assessment. Cox models with time-dependent covariates and mediation analysis were used. RESULTS: During a median of 14.4 years of follow-up, 4,484 participants experienced CIND and 1,774 were diagnosed with dementia. Both debt and poverty were independently associated with increased dementia and CIND risks, and the risks were augmented when both debt and poverty were present together (the hazard ratios [95% confidence intervals] were 1.35 [1.08-1.70] and 1.96 [1.48-2.60] for CIND and dementia, respectively). The associations between different wealth statuses and cognition were partially (mediation ratio range: 11.8-29.7%) mediated by depression. CONCLUSION: Debt and poverty were associated with an increased risk of dementia and CIND, and these associations were partially mediated by depression. Alleviating poverty and debt may be effective for improving mental health and therefore curbing the risk of cognitive impairment and dementia.

Diabetes duration and glycaemic control as predictors of cardiovascular disease and mortality.

AIMS: To assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin [HbA1c] level) with the risks of cardiovascular disease (CVD) and all-cause mortality and to determine whether the addition of either or both to the established CVD risk factors can improve predictions. MATERIALS AND METHODS: A total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C-index and net reclassification improvement (NRI). RESULTS: Compared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully-adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval [CI] 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P-trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol [8%]) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C-index (change in C-index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors. CONCLUSIONS: Both longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.

Isolated systolic and diastolic hypertension by the 2017 American College of Cardiology/American Heart Association guidelines and risk of cardiovascular disease: a large prospective cohort study.

OBJECTIVE: The 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines lowered the hypertension threshold from a SBP/DBP level of at least 140/90 mmHg to at least 130/80 mmHg. The cardiovascular impact of isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) under the new definition remains unclear. METHODS: We used data from the UK Biobank study, which is a prospective population-based cohort study. Participants were categorized into five groups: normal BP, normal high BP, ISH, IDH and systolic and diastolic hypertension. The primary endpoint for this study was the composite of nonfatal myocardial infarction (MI), nonfatal ischaemic stroke, nonfatal haemorrhagic stroke and cardiovascular disease (CVD) death. We also explored the results for the above-mentioned CVD outcomes separately. Baseline BP measurements were obtained twice after the participant had been at rest for at least 5 min in a seated position. RESULTS: We included 385 955 participants who were not taking antihypertensive medications, were free of CVD at baseline and had available data on BP measurements. During a median follow-up of 8.1 years, 8959 CVD events were recorded, including 4729 nonfatal MIs, 2287 nonfatal ischaemic strokes, 813 nonfatal haemorrhagic strokes, and 1826 CVD deaths. According to the hypertension threshold of at least 130/80 mmHg by the American College of Cardiology/American Heart Association guidelines, both ISH (hazard ratio 1.39; 95% confidence interval 1.27, 1.15) and IDH (hazard ratio 1.28; 95% confidence interval 1.15, 1.43) were significantly associated with a higher overall CVD risk than normal BP. ISH was associated with most CVD risk, except for ischaemic stroke, while the excess CVD risk associated with IDH appeared to be driven mainly by MI and CVD death. We found heterogeneity by sex and age regarding the effects of IDH on overall CVD risk, with significant associations in younger adults (age <60 years) and women and null associations in men and older adults (age ≥60 years). CONCLUSION: ISH was associated with the risk of most CVD events, while the association between IDH and CVD risk was mainly driven by MI incidence and CVD death. Further research is needed to identify participants with IDH who have a particular risk for developing CVD.

Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1), an important immunoregulatory enzyme ubiquitously expressed in various tissues and cells, plays a key role in tryptophan metabolism via the kynurenine pathway and has emerged as an attractive therapeutic target for the treatment of cancer and other diseases, such as Alzheimer's disease and arthritis. IDO1 has diverse biological roles in immune suppression and tumor progression by tryptophan catabolism. In addition, IDO1-mediated immune tolerance assists tumor cells in escaping the immune surveillance. Recently, extensive and enormous investigations have been made in the discovery of IDO1 inhibitors in both academia and pharmaceutical companies. In this review, IDO1 inhibitors are grouped as tryptophan derivatives, inhibitors with an imidazole, 1,2,3-triazole or tetrazole scaffold, inhibitors with quinone or iminoquinone, N-hydroxyamidines and other derivatives, and their enzymatic inhibitory activity, selectivity and other biological activities are also introduced and summarized.

Pharmacokinetic and Pharmacodynamics of Self-Assembled Cubic Liquid Crystalline Nanoparticle Gel After Transdermal Administration.

BACKGROUND The aim of this study was to assess the pharmacokinetics after transdermal administration by a novel skin microdialysis technology in rats. The guinea pig model was established by investigating the pharmacodynamics. MATERIAL AND METHODS Three different agents were given after hair removal, and the samples were extracted by microdialysis and detected by HPLC. Subcutaneous/plasma concentration-time curves of the 3 different agents were analyzed and the pharmacokinetic parameters were calculated. The SS-04B UV light therapy instrument was used in the modeling. Changes in melanin index and histopathology were observed with HE staining. RESULTS The increment and decrement results showed that the concentration had no significant effect on drug recovery both in vivo and in vitro. After the paeonol cubic liquid crystalline nanoparticles gel (PAE-LCNPs) was administered, the maximum peak time (tmax) of paeonol skin concentration appeared at 2.42±0.20 h, the maximum skin concentration Cmax was (926±105) ng/ml, and the area under the curve AUC0-8 was (8056±954) ng/h/ml. The tmax was shortened much more than in the other groups, and the performance of PAE-LCNPs targeting was good. Pharmacodynamic results showed that PAE-LCNPs can reduce melanocytes and reduce the melanin index, proving its utility in the treatment of melanin deposition. CONCLUSIONS The skin microdialysis study indicated PAE-LCNPs have good transdermal permeability and efficacy. Pharmacological experiments based on the study found that the topical pigmentation model of guinea pigs showed a better therapeutic effect.

[Gefitineb inhibits the growth and induces the apoptosis of mouse I-10 Leydig testicular cancer cells in vitro].

OBJECTIVE: To observe the inhibitory effect of gefitineb on the proliferation and its inducing effect on the apoptosis of mouse I-10 Leydig testicular cancer cells in vitro. METHODS: We treated I-10 Leydig testicular cancer cells of mice with gefitineb at 0, 1.25, 2.5, 5, 10, 20, and 40 µmol/L. Then we determined the inhibitory effect of gefitineb on the growth of the cells by MTT, detected their early and late apoptosis by Annexin V-FITC/propidium iodide double staining and Hoechst 33258 nuclear staining, respectively, and observed the expressions of apoptosis-related proteins Bcl-2, Bax and caspase 3/9 by Western blot. RESULTS: Compared with the blank control group, gefitineb significantly inhibited the proliferation of the I-10 cells at 10 and 20 µmol/L (P < 0.05). The survival rate of the cells was (32.4 ± 2.8)% (P < 0.01) and their early and late apoptosis rates were (26.7 ± 4.2)% and (59.33 ± 10.2)% in the 40 µmol/L group, significantly different from those in the control (P < 0.05 and P <0.01). In comparison with the blank control group, gefitineb at 10, 20, and 40 µmol/L increased the expression of pro-apoptotic protein Bax by (41.9 ± 7.1), (60.1 ± 9.8), and (69.0 ± 11.3)% (all P < 0.05), decreased that of apoptosis-inhibitory protein Bcl-2 by (50.3 ± 8.9), (63.9 ± 6.9), and (88.7 ± 13.9)% (all P < 0.05), and elevated that of the cleft proteins caspase-3 by (69.0 ± 6.9)% (P < 0.05), (71.5 ± 8.1)% (P < 0.05), and (110.9 ± 14.2)% (P < 0.01) and caspase-9 by (51.8 ± 4.9), (54.7 ± 6.7), and (43.8 ± 11.8)% (all P < 0.05). CONCLUSION: Gefitineb can increase the cytotoxicity of I-10 Leydig testicular cancer cells of mice and induce their apoptosis via the mitochondria-mediated apoptosis signaling pathway.

Self-Assembled Cubic Liquid Crystalline Nanoparticles for Transdermal Delivery of Paeonol.

BACKGROUND: The aim of this study was to optimize the preparation method for self-assembled glyceryl monoolein-based cubosomes containing paeonol and to characterize the properties of this transdermal delivery system to improve the drug penetration ability in the skin. MATERIAL AND METHODS: In this study, the cubic liquid crystalline nanoparticles loaded with paeonol were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel by high-pressure homogenization. We evaluated the Zeta potential of these promising skin-targeting drug-delivery systems using the Malvern Zeta sizer examination, and various microscopies and differential scanning calorimetry were also used for property investigation. Stimulating studies were evaluated based on the skin irritation reaction score standard and the skin stimulus intensity evaluation standard for paeonol cubosomes when compared with commercial paeonol ointment. In vitro tests were performed on excised rat skins in an improved Franz diffusion apparatus. The amount of paeonol over time in the in vitro penetration and retention experiments both was determined quantitatively by HPLC. RESULTS: Stimulating studies were compared with the commercial ointment which indicated that the paeonol cubic liquid crystalline nanoparticles could reduce the irritation in the skin stimulating test. Thus, based on the attractive characteristics of the cubic crystal system of paeonol, we will further exploit the cosmetic features in the future studies. CONCLUSIONS: The transdermal delivery system of paeonol with low-irritation based on the self-assembled cubic liquid crystalline nanoparticles prepared in this study might be a promising system of good tropical preparation for skin application.

Effects of age, breast density and volume on breast cancer diagnosis: a retrospective comparison of sensitivity of mammography and ultrasonography in China's rural areas.

PURPOSE: Mammography has been confirmed as the only effective mode to improve the prognosis of patients with breast cancer in Western developed countries, but might not be a good choice in other areas of the world. One of the major challenges in China is to determine an optimal imaging modality for breast cancer screening. This study was designed to clarify the sensitivity of ultrasonography compared with that of mammography in rural China. METHODS: We retrospectively studied the sensitivity of mammography and ultrasonography based on 306 breast cancer patients detected by the program of "screening for cervical cancer and breast cancer" performed in Chinese rural areas between January 2009 and December 2011, and analyzed the effects of age, breast density and volume on the sensitivity. RESULTS: Stratified analysis showed that the sensitivity of breast ultrasonography was significantly higher than that of mammography in premenopausal patients (81.4% vs. 61.1%, p=0.02), in women ≤ 55 years of age (82.2% vs. 63.4%, p<0.01), in the high breast density group (American College of Radiology [ACR] levels 3-4) (85.9% vs. 60.6%, p<0.01) and in the small breast volume group (≤ 400 ml) (87.1% vs. 66.7%, p<0.01). Age had a significant effect on sensitivity of mammography (breast density and volume-adjusted odds ratio, 6.39; 95% confidence interval, 2.8-14.4 in age group > 55 compared to age group ≤ 45), but not that of ultrasonography. Neither breast density nor volume had significant effect on sensitivity of mammography or ultrasonography. CONCLUSIONS: Ultrasonography is more sensitive than mammography in detecting breast cancer in women under 55 year-old Chinese, especially in those with high-density and relatively small breasts.

[Influences of Confucianism, Taoism and Buddhism on Chinese Medical Formulas in Jin-Tang Dynasties].

In the Jin-Tang Dynasties, when Confucianism, Taoism and Buddhism contended, conflicted and well blent, forming a state of mingled thoughts of the three sects. It exerted profound influences on Chinese Medical Formulas and promoted the academic fashion of compiling books about medical formulas characterized by collecting various formulas especially the simple and proved recipes. This plays a role in the formation of the formulas used in the Jin-Tang Dynasties, featuring simplicity, convenience, cheapness, and effectiveness, different from those of other periods.

Surgical treatment of thoracic esophageal carcinoma: report of 326 cases.

OBJECTIVE: To review our experience in surgical treatment of 326 cases of thoracic esophageal carcinoma. METHODS: The clinical data of 326 patients with thoracic esophageal carcinoma from January 1990 to January 2001 were analyzed retrospectively. Among the 326 patients, the lesions of 32 patients were identified in the upper thoracic segment of the esophagus, and were found in the middle segment in 213 cases with the left 81 cases having lesions in the lower segment. Left cervical esophagogastrostomy was performed through triple incision (left cervical, right thoracic and abdominal) in 79 cases. Esophagocolostomy through triple incision was performed in 5 cases. Another 156 patients received left cervical esophagogastrostomy through two incisions (left cervical and left thoracic). Supra-aorticarch esophagogastrostomy through left posterola- teral thoracotomy was performed in 53 cases, and sub-arch esophagogastrostomy through left posterolateral thoracotomy in 33 cases. RESULTS: The post-operative mortality was 1.23% (4/326), with a five-year survival rate of 35.3%. CONCLUSION: Subtotal esophagectomy combined with thorough lymph node dissection can be the first choice for thoracic esophageal carcinoma to improve the postoperative survival rate and the quality-of life-of the patients.