Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

Age-specific differences in the association between prediabetes and cardiovascular diseases in China: A national cross-sectional study.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, the global burden of which is rising. It is still unclear the extent to which prediabetes contributes to the risk of CVD in various age brackets among adults. To develop a focused screening plan and treatment for Chinese adults with prediabetes, it is crucial to identify variations in the connection between prediabetes and the risk of CVD based on age. AIM: To examine the clinical features of prediabetes and identify risk factors for CVD in different age groups in China. METHODS: The cross-sectional study involved a total of 46239 participants from June 2007 through May 2008. A thorough evaluation was conducted. Individuals with prediabetes were categorized into two groups based on age. Chinese atherosclerotic CVD risk prediction model was employed to evaluate the risk of developing CVD over 10 years. Random forest was established in both age groups. SHapley Additive exPlanation method prioritized the importance of features from the perspective of assessment contribution. RESULTS: In total, 6948 people were diagnosed with prediabetes in this study. In pre-diabetes, prevalences of CVD were 5 (0.29%) in the younger group and 148 (2.85%) in the older group. Overall, 11.11% of the younger group and 29.59% of the older group were intermediate/high-risk of CVD for prediabetes without CVD based on the Prediction for ASCVD Risk in China equation in ten years. In the younger age group, the 10-year risk of CVD was found to be more closely linked to family history of CVD rather than lifestyle, whereas in the older age group, resident status was more closely linked. CONCLUSION: The susceptibility to CVD is age-specific in newly diagnosed prediabetes. It is necessary to develop targeted approaches for the prevention and management of CVD in adults across various age brackets.

Epidemiology and genotypic diversity of canine circovirus identified in pet dogs in Harbin, China.

Canine circovirus (CanineCV) is a single-stranded DNA virus that circulates in dogs and wild carnivores around the world. It has been suggested to be associated with diseases of respiratory and gastrointestinal systems, though its pathogenic potential remains unclear. Currently, CanineCV is divided into six genotypes (genotype 1-6), and genotypes 2, 3, and 4 have been described in China. In this study, 359 blood samples from pet dogs with or without clinical signs were collected in Harbin city. After PCR screening, a total of 34 samples were tested positive for CanineCV, and nine full-length genome sequences were recovered from positive samples. Pairwise sequence comparison showed that they shared 82.4-99.3% genome-wide identity with other CanineCVs available in GenBank. Additionally, recombination events were detected, all of which were determined to be associated with sequences obtained in China. The reconstructed phylogenetic tree based on the recombination-free complete genome sequences revealed that the complete genome sequences generated herein were clustered into genotypes 1 and 3. Furthermore, purifying selection was the dominant evolutionary pressure acting on the genomes of CanineCV. These results expand the knowledge about the genetic diversity of CanineCV circulating in China, and also promote us to better understand the evolution of CanineCV.

Molecular detection and genetic characterization of bovine hepacivirus identified in ticks collected from cattle in Harbin, northeastern China.

Bovine hepacivirus (BovHepV) is a member of the genus Hepacivirus of the family Flaviviridae, which can cause acute or persistent infections in cattle. Currently, BovHepV strains identified in cattle populations worldwide can be classified into two genotypes with eight subtypes in genotype 1. BovHepV has been identified in a wide geographic area in China. Interestingly, the viral RNA of BovHepV has also been detected in ticks in Guangdong province, China. In this study, Rhipicephalus microplus tick samples were collected in Heilongjiang province, northeastern China, and BovHepV was screened with an overall positive rate of 10.9%. Sequence comparison and phylogenetic analysis showed that the BovHepV strains detected in this study belong to the subtype G. This is the first report about the detection of BovHepV in ticks in Heilongjiang province, China, which expands our knowledge that ticks may be a transmission vector of BovHepV.

Research note: genetic diversity of duck circoviruses circulating in partial areas of Guangdong province, southern China.

Duck circovirus (DuCV) is the smallest known virus in waterfowl that infects both domestic and wild duck. Infected ducks often show stunted growth and immunosuppression, which increases the rate of secondary infection with other pathogens. In this study, 270 liver tissue samples were collected to screen the presence of DuCV in Guangdong province, China, and the complete genome sequences were recovered and systematically analyzed. Genetic analyses revealed that sequences determined in this study shared 81.6% to 100.0% genome-wide pairwise identity with previously identified DuCV genomes. Phylogenetic analyses showed that 2 DuCV genotypes with a high infection rate were co-circulating in duck population in Guangdong province, and extensive recombination events have occurred during the evolution of DuCV. Our results expand upon the knowledge regarding the genetic diversity and evolution of DuCV, and also indicate that extensive genetically divergent DuCV are co-circulating in the duck populations in Guangdong, southern China.

Epidemiology and Genetic Diversity of Bartonella in Rodents in Urban Areas of Guangzhou, Southern China.

Bartonella spp. are gram-negative bacteria that can infect a wide spectrum of mammals. Rodents are considered to be the natural reservoir of many Bartonella species that are transmitted by various blood-sucking arthropods. The close contact between rodents and humans in urban areas increased the chance of transmitting rodent-borne Bartonella to humans. Investigation of the epidemiological characteristics of Bartonella infection in rodents is of great significance for the prevention and control of human Bartonellosis. In this study, rodents were captured to monitor the prevalence of Bartonella in urban areas of Guangzhou city. Six official or candidate species of Bartonella, including two confirmed zoonotic species, were detected with an overall prevalence of 6.4% in rodents captured herein. In addition, Rattus norvegicus was the predominant host species for Bartonella infection, and B. queenslandensis was the dominant species circulating in rodents in these areas. These results provide insights into the prevalence and genetic diversity of Bartonella species circulating in rodents in the urban areas of Guangzhou, and also urged the surveillance of rodent-associated Bartonella species in these areas.

Extensive genetic diversity and recombination events identified in goose circoviruses circulating in partial areas of Guangdong province, Southern China.

Circoviruses represent a group of small viruses with circular single-strand DNA genome that infect a wide range of both domesticated and wild animals. Domesticated geese infected with circovirus have been confirmed in many parts of the world, and is considered to cause immunosuppression and facilitate the secondary infections caused by other pathogens. In the present study, extensive genetically diversified goose circoviruses (GoCVs) were identified in the liver samples of domesticated geese from Guangdong province, southern China. Genetic analysis revealed that the sequences generated in this study shared 81.5 to 99.7% genome-wide pairwise identity with previously identified GoCV genomes. More importantly, nine recombination events were identified among all known complete genomome sequences of GoCV including those obtained herein, and the majority was determined associate with the sequences identified from Guangdong province, suggesting that recombination is the primary driver for the diversification of GoCVs. Additionally, purifying selection was the dominant evolutionary pressure acting on the genomes of GoCVs, and the ORF C1 gene of GoCV showed a higher genetic variation than ORF V1 gene. These results expand the knowledge about the genetic diversity and evolution of GoCV, and also indicate extensive genetically divergent GoCV strains were co-circulating in goose population in partial areas of Guangdong province, southern China.

A Highly Divergent Hepacivirus Identified in Domestic Ducks Further Reveals the Genetic Diversity of Hepaciviruses.

Hepaciviruses represent a group of viruses that pose a significant threat to the health of humans and animals. During the last decade, new members of the genus Hepacivirus have been identified in various host species worldwide, indicating the widespread distribution of genetically diversified hepaciviruses among animals. By applying unbiased high-throughput sequencing, a novel hepacivirus, provisionally designated Hepacivirus Q, was discovered in duck liver samples collected in Guangdong province of China. Genetic analysis revealed that the complete polyprotein of Hepacivirus Q shares 23.9-46.6% amino acid identity with other representatives of the genus Hepacivirus. Considering the species demarcation criteria for hepaciviruses, Hepacivirus Q should be regarded as a novel hepacivirus species of the genus Hepacivirus within the family Flaviviridae. Phylogenetic analyses also indicate the large genetic distance between Hepacivirus Q and other known hepaciviruses. Molecular detection of this novel hepacivirus showed an overall prevalence of 15.9% in duck populations in partial areas of Guangdong province. These results expand knowledge about the genetic diversity and evolution of hepaciviruses and indicate that genetically divergent hepaciviruses are circulating in duck populations in China.

Angiotensin(1-7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic ß-cells: the association with type 2 diabetes.

Objective: The beneficial effect of angiotensin(1-7) (Ang(1-7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1-7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1-7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1-7)'s effect on insulin secretion and measured the level of Ang(1-7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Ang(1-7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic ß-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1-7), MAS-1 and CFTR levels in the human blood were determined by ELISA. Results: In RINm5F cells, Ang(1-7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1-7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects. Conclusion: These results suggested that MAS-1 and CFTR as key players in mediating Ang(1-7)-promoted insulin secretion in pancreatic ß-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

Neck circumference and waist circumference associated with cardiovascular events in type 2 diabetes (Beijing Community Diabetes Study 23).

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

Guan Xin Dan Shen formulation protects db/db mice against diabetic cardiomyopathy via activation of Nrf2 signaling.

Guan Xin Dan Shen formulation (GXDSF) is a widely used treatment for the management of coronary heart disease in China and is composed of three primary components: Dalbergiae odoriferae Lignum, Salviae miltiorrhizae Radix et Rhizoma and Panax notoginseng Radix et Rhizoma. However, the potential use of GXDSF for the management of diabetic cardiomyopathy (DCM) has not been previously assessed. The present study aimed to assess the effects of GXDSF on DCM, as well as the underlying mechanism. In the present study, db/db mice were used. Following treatment with GXDSF for 10 weeks, fasting blood glucose, insulin sensitivity, serum lipid levels and cardiac enzyme levels were detected. Cardiac pathological alterations and cardiac function were assessed by performing hematoxylin and eosin staining and echocardiograms, respectively. TUNEL assays were conducted to assess cardiomyocyte apoptosis. Additionally, reverse transcription­quantitative PCR and western blotting were performed to evaluate the expression of apoptosis­associated genes and proteins, respectively. In the model group, the db/db mice displayed obesity, hyperlipidemia and hyperglycemia, accompanied by noticeable myocardial hypertrophy and diastolic dysfunction. Following treatment with GXDSF for 10 weeks, serum triglyceride levels were lower and insulin sensitivity was enhanced in db/db mice compared with the model group, which indicated improvement in condition. Cardiac hypertrophy and dysfunction were also improved in db/db mice following treatment with GXDSF, resulting in significantly increased left ventricular ejection fraction and fractional shortening compared with the model group. Following treatment with metformin or GXDSF, model­induced increases in levels of myocardial enzymes were decreased in the moderate and high dose groups. Moreover, the results indicated that, compared with the model group, GXDSF significantly inhibited cardiomyocyte apoptosis in diabetic heart tissues by increasing Bcl­2 expression and decreasing the expression levels of Bax, cleaved caspase­3 and cleaved caspase­9. Mechanistically, GXDSF enhanced Akt phosphorylation, which upregulated antioxidant enzymes mediated by nuclear factor erythroid 2­related factor 2 (Nrf2) signaling. Collectively, the results of the present study indicated that GXDSF attenuated cardiac dysfunction and inhibited cardiomyocyte apoptosis in diabetic mice via activation of Akt/Nrf2 signaling. Therefore, GXDSF may serve as a potential therapeutic agent for the management of DCM.

Molecular detection and genetic diversity of Rickettsia spp. in pet dogs and their infesting ticks in Harbin, northeastern China.

BACKGROUND: Pet dogs are important companion animals that share the environment within households, and play an important role in local community life. In addition, pet dogs also are reservoirs of zoonotic agents, including Rickettsia spp., thus increasing the risk of rickettsial infections in humans. It's meaningful to investigate the epidemiology of rickettsial agents in pet dogs, and make contribute to the surveillance of rickettsioses in human in China. RESULTS: In this study, a total of 496 pet dogs' blood samples and 343 ticks infested in pet dogs were collected, and the presence and prevalence of Rickettsia were determined by amplifying the partial gltA and 17-kDa genes, with an overall positive rate of 8.1 % in blood samples and 14.0 % in tick samples. In addition, the rrs, gltA, groEL, and ompA genes of rickettsial were also recovered to determine the species of Rickettsia detected furtherly. Sequencing blast and phylogenetic analyses revealed the presence of three human pathogenic Rickettsia species (Rickettsia raoultii, Candidatus Rickettsia tarasevichiae and Rickettsia felis) in samples associated with pet dogs. Moreover, all the sequences of Rickettsia that we obtained presented close relationship with others available in GenBank, and Rickettsia raoultii was the most predominant Rickettsia species infected in pet dogs' blood samples or in tick samples. CONCLUSIONS: This study provides the molecular epidemiology data about the Rickettsia spp. infection associated with pet dogs in urban areas of Harbin city. Three rickettisae species pathogenic to humans were identified from pet dogs' blood and the infested ticks in urban areas of Harbin city. Considering the intimate relationship between human and pets, these results indicate the potential transmission risk of human rickettisal infections from pet dogs through ectoparasites, and also highlighting that more attention should be paid to rickettsial infection in pet dogs and the infested ticks from the "One health" perspective.

The effects of acarbose therapy on reductions of myocardial infarction and all-cause death in T2DM during 10-year multifactorial interventions (The Beijing Community Diabetes Study 24).

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

Potential of RASSF1A promoter methylation as a biomarker for colorectal cancer: Meta-analysis and TCGA analysis.

The RAS association domain family protein 1A (RASSF1A) is a tumor suppressor in colorectal cancer (CRC), and is often inactived by hypermethylation. Therefore, we evaluated the association between RASSF1A hypermethylation and the risk and prognosis in CRC. We identified literature through searching PubMed and China National Knowledge Infrastructure databases, and then validated and supplemented the meta-analysis with TCGA analysis. Twenty-three studies involving 2886 subjects of CRC were examined. The meta-analysis showed that RASSF1A promoter methylation inferred high CRC risk (odds ratio, 6.53, 95% confidence interval 3.88-11.01, P < .001) and poor overall survival (hazard ratio 2.85, 95% CI 1.88-4.31, P < .001). The TCGA analysis suggested that effect of RASSF1A promotor methylation was affected by tumor localization (colon vs. rectum). RASSF1A promoter methylation was a predictor of high risk (OR 2.38, 95%CI 1.02-5.6, P = .046) and poor disease free survival(HR 2.25, 95%CI 1.27-3.99, P = .006)in colon adenocarcinoma, but the association was statistically insignificant in rectum adenocarcinoma(HR 1.58, 95% CI 0.69-3.59, P = .28). These results suggested RASSF1A hypermethylation is a risk and a potential prognostic biomarker in CRC.

[Effect of Guanxin Danshen Formulation on diabetic kidney disease in db/db mice through regulation of Nrf2 pathway].

Diabetic kidney disease(DKD) has become a primary cause of end-stage kidney disease, without any effective treatment available. In this study, we assessed the protective effect of Guanxin Danshen Formulation(GXDSF) on diabetic nephropathy in db/db mice. The db/m and db/db mice were randomly divided into 4 groups: control group, model group, metformin group, and GXDSF group. After 8 weeks' treatment with GXDSF, metformin or normal saline, the mice were sacrificed, and the blood and kidney tissues were collected for the further analysis. Compared with the model group, TG, TCH and LDL levels significantly decreased in the GXDSF group. The results from HE and PAS staining showed that db/db mice exhibited abnormal kidney tissues with increased glomerular volume, basement-membrane thickening and mesangial cell proliferation, which could be significantly alleviated by GXDSF treatment. GXDSF treatment also reduced serum creatinine and BUN. Meanwhile, GXDSF treatment markedly elevated GSH-PX levels, while reduced LDH and MDA levels in the kidney tissues. Western blot assay showed that GXDSF evidently up-regulated protein levels of ERα and p-Akt, and subsequently promoted HO-1 expression mediated by Nrf2. These data collectively indicated that GXDSF protects db/db mice against DN by regulating ERα and Nrf2-mediated HO-1 expression.

Distribution and molecular characterization of rickettsiae in ticks in Harbin area of Northeastern China.

Tick-borne rickettsioses are world-spreading infectious zoonoses. Ticks serve as reservoirs and vectors for Rickettsia and play a key role in transmission of rickettsioses. Most of the Chinese rickettsiosis patients are reported from Northeastern China but the distribution of tick and tick-borne Rickettsia species in Northeastern China remain poorly studied. In this study, a total of 1,286 ticks were captured from the seven counties of Harbin, an area in Northeastern China, and the tick-borne Rickettsia species were identified by PCR and sequencing of rrs, gltA, groEL, ompA and 17-kDa antigen-encoding genes. Of the 5 identified tick species, Haemaphysalis longicornis and Ixodes persulcatus were the predominant tick species in the livestock and vegetation, respectively. Rickettsia raoultii and "Candidatus Rickettsia tarasevichiae" were the two detectable Rickettsia species in the ticks with a 28.8% positive rate but no rickettsiae were found in ticks of Haemaphysalis concinna. R. raoultii detected in 37.6% of the Dermacentor nuttalli, Dermacentor silvarum and H. longicornis ticks while "Ca. R. tarasevichiae" was only present in 22.8% of the I. persulcatus ticks. In particular, the positive rate of both R. raoultii and "Ca. R. tarasevichiae" in ticks from the livestock (40.7%) was significantly higher than that from the vegetation (19.5%). The results indicate that the tick and tick-borne Rickettsia species are diverse in different regions of Harbin due to geographic difference and the ticks from livestock may play a more important role in transmission of rickettsioses to human.

Prevalence and molecular characterization of Babesia in pet dogs in Shenzhen, China.

Canine babesiosis is an important global tick-borne infectious disease of domestic dogs and wild canids. B. gibsoni and B. vogeli are the most widespread species mainly endemic in dog population in southern and eastern regions of China. In this study, 272 blood samples were collected from pet dogs in five districts of Shenzhen, China. Babesia DNA was detected in 30 samples with an overall prevalence of 11.0 % in pet dogs in Shenzhen. The difference in the positive rate between female and male pet dogs, among different breed, and among the five sampling sites was not significant, while the age and health status of pet dogs significantly influence the positive rate of Babesia spp. infection. Sequencing results showed the presence of only B. vogeli in all of the samples tested. Sequence comparison and phylogenetic analysis revealed that all 30 strains of Babesia identified in this study shared the highest identity with B. vogeli. In sum, all results of this study showed a considerable high infection rate of Babesia spp. in pet dogs, and B. vogeli was the only Babesia species infecting pet dogs in Shenzhen city. Such information is necessary to help to elucidate the epidemiology of canine babesiosis in Shenzhen, and it is necessary to actively monitor this disease in pet dogs.