Prevalence and associated factors of dysglycemia among patients with chronic obstructive pulmonary disease.

OBJECTIVES: Dysglycemia is known to be a common comorbidity of chronic obstructive pulmonary disease (COPD). However, undiagnosed dysglycemia and the associated factors remain under-reported. This study aimed to determine the prevalence and the associated factors of dysglycemia among COPD patients. METHODS: This was a cross-sectional, single-center study involving adults with established COPD (n = 186) divided into those with or without hospital admissions for acute exacerbation. Oral glucose tolerance test (OGTT) was performed in patients with no known history of dysglycemia. RESULTS: There were 16 patients who had overt diabetes, and 32 had prediabetes following the OGTT. Forty percent had histories of hospital admissions for COPD exacerbations. Both groups demonstrated similar 2-h post prandial glucose, glycated hemoglobin (HbA1c) and fasting blood glucose. The incidences of newly diagnosed dysglycemia were higher in both groups (40.8% vs 34.6%, p = 0.57). Cumulative days of admission (≥6 days/year) and weight (≥65 kg) were identified as predictors for dysglycemia within the study population. DISCUSSION: This study demonstrated a high number of overt and newly diagnosed dysglycemia among COPD patients who had no previous history of abnormal glucose. Recent acute exacerbations of COPD could have a negative impact on glycemia, although the results did not attain statistical significance. However, there is a need for adequate screening for dysglycemia, particularly among those with frequent acute exacerbations of their condition.

Natural selection and local adaptation of blood pressure regulation and their perspectives on precision medicine in hypertension.

Prevalence of hypertension (HTN) varies substantially across different populations. HTN is not only common - affecting at least one third of the world's adult population - but is also the most important driver for cardiovascular diseases. Yet up to a third of hypertensive patients are resistant to therapy, contributed by secondary hypertension but more commonly the hitherto inability to precisely predict response to specific antihypertensive agents. Population and individual genomics information could be useful in guiding the selection and predicting the response to treatment - an approach known as precision medicine. However this cannot be achieved without the knowledge of genetic variations that influence blood pressure (BP). A number of evolutionary factors including population demographics and forces of natural selection may be involved. This article explores some ideas on how natural selection influences BP regulation in ethnically and geographically diverse populations that could lead to them being susceptible to HTN. We explore how such evolutionary factors could impact the implementation of precision medicine in HTN. Finally, in order to ensure the success of precision medicine in HTN, we call for more initiatives to understand the genetic architecture within and between diverse populations with ancestry from different parts of the world, and to precisely classify the intermediate phenotypes of HTN.

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using a next generation sequencing platform.

BACKGROUND: CYP3A5 is the predominant sub-family of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of inter-individual and inter-ethnic differences in CYP3A-mediated drug disposition and response. AIM: This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using a next generation sequencing platform. METHODS: Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed. RESULTS: A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524, which is in the 3'UTR, and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3). CONCLUSIONS: The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unravelled and the findings in this study may serve as a guide for the optimisation of pharmacotherapy for the Orang Asli community.

Study protocol of EMPOWER participatory action research (EMPOWER-PAR): a pragmatic cluster randomised controlled trial of multifaceted chronic disease management strategies to improve diabetes and hypertension outcomes in primary care.

BACKGROUND: Chronic disease management presents enormous challenges to the primary care workforce because of the rising epidemic of cardiovascular risk factors. The chronic care model was proven effective in improving chronic disease outcomes in developed countries, but there is little evidence of its effectiveness in developing countries. The aim of this study was to evaluate the effectiveness of the EMPOWER-PAR intervention (multifaceted chronic disease management strategies based on the chronic care model) in improving outcomes for type 2 diabetes mellitus and hypertension using readily available resources in the Malaysian public primary care setting. This paper presents the study protocol. METHODS/DESIGN: A pragmatic cluster randomised controlled trial using participatory action research is underway in 10 public primary care clinics in Selangor and Kuala Lumpur, Malaysia. Five clinics were randomly selected to provide the EMPOWER-PAR intervention for 1 year and another five clinics continued with usual care. Each clinic consecutively recruits type 2 diabetes mellitus and hypertension patients fulfilling the inclusion and exclusion criteria over a 2-week period. The EMPOWER-PAR intervention consists of creating/strengthening a multidisciplinary chronic disease management team, training the team to use the Global Cardiovascular Risks Self-Management Booklet to support patient care and reinforcing the use of relevant clinical practice guidelines for management and prescribing. For type 2 diabetes mellitus, the primary outcome is the change in the proportion of patients achieving HbA1c < 6.5%. For hypertension without type 2 diabetes mellitus, the primary outcome is the change in the proportion of patients achieving blood pressure < 140/90 mmHg. Secondary outcomes include the proportion of patients achieving targets for serum lipid profile, body mass index and waist circumference. Other outcome measures include medication adherence levels, process of care and prescribing patterns. Patients' assessment of their chronic disease care and providers' perceptions, attitudes and perceived barriers in care delivery and cost-effectiveness of the intervention are also evaluated. DISCUSSION: Results from this study will provide objective evidence of the effectiveness and cost-effectiveness of a multifaceted intervention based on the chronic care model in resource-constrained public primary care settings. The evidence should instigate crucial primary care system change in Malaysia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01545401.

Effects of magnesium taurate on the onset and progression of galactose-induced experimental cataract: in vivo and in vitro evaluation.

Cataract, a leading cause of blindness, is characterized by lenticular opacities resulting from denaturation of lens proteins due to activation of calcium-dependent enzyme, calpain. Magnesium (Mg(2+)) plays an important role not only in maintaining a low lenticular calcium (Ca(2+)) and sodium concentration but also in preserving the lens redox status. Taurine has also been shown to reduce lenticular oxidative stress. Present study evaluated the anticataract effects of magnesium taurate in vivo and in vitro. Among the five groups of 9 Sprague Dawley rats each, two groups received 30% galactose diet with topical (GDMT) or oral treatment (GDMO) with magnesium taurate. Two groups received 30% galactose diet with topical (GDT) or oral vehicle (GDO). Remaining 1 group received normal diet (ND). Weekly slit lamp examination was done during 21 days experimental period and then all rats were sacrificed; Ca/Mg ratio and antioxidant parameters including reduced glutathione (GSH), catalase and superoxide dismutase (SOD) activities were measured in the isolated lenses using ELISA. In the in vitro study, 2 groups of 10 normal rat lenses were incubated in Dulbecco's Modified Eagle's Medium (DMEM) with galactose while 1 similar group was incubated in DMEM without galactose. In one of the groups, galactose containing medium was supplemented with magnesium taurate. After 48 h of incubation, lenses were photographed and Ca(2+)/Mg(2+) ratio and antioxidant parameters were measured as for in vivo study. The in vivo study, at the end of experimental period, demonstrated delay in the development of cataract with a mean opacity index of 0.53 ± 0.04 and 0.51 ± 0.03 in GDMO (p < 0.05 versus GDO) and GDMT (p < 0.01 versus GDT) respectively. Histopathological grading showed a lower mean value in treated groups, however, the differences from corresponding controls were not significant. Lenticular Ca(2+)/Mg(2+) ratio with a mean value of 1.20 ± 0.26 and 1.05 ± 0.26 in GDMO and GDMT was significantly lower than corresponding controls (p < 0.05) and in GDMT no significant difference was observed from ND. Lenticular GSH and catalase activities were significantly lower and SOD activity was significantly higher in all galactose fed groups. However, in GDMT, GSH and catalase were significantly higher than corresponding control with mean values of 0.96 ± 0.30 µmol/gm lens weight and 56.98 ± 9.86 µmol/g lens protein respectively (p < 0.05 for GSH and p < 0.01 for catalase). SOD activity with mean values of 13.05 ± 6.35 and 13.27 ± 7.61 units/mg lens protein in GDMO and GDMT respectively was significantly lower compared to corresponding controls (p < 0.05) signifying lesser upregulation of SOD due to lesser oxidative stress in treated groups. In the in vitro study, lenses incubated in magnesium taurate containing medium showed less opacity and a lower mean Ca(2+)/Mg(2+) ratio of 1.64 ± 0.03, which was not significantly different from lenses incubated in DMEM without galactose. Lens GSH and catalase activities were restored to normal in lenses incubated in magnesium taurate containing medium. Both in vivo and in vitro studies demonstrated that treatment with magnesium taurate delays the onset and progression of cataract in galactose fed rats by restoring the lens Ca(2+)/Mg(2+) ratio and lens redox status.

High prevalence of undiagnosed impaired glucose tolerance in patients with rheumatoid arthritis.

Objectives: Although the risk of diabetes mellitus has been recognised in rheumatoid arthritis, undiagnosed dysglycaemia remained under-reported. The study aimed to determine the prevalence and associated factors of dysglycaemia among patients with rheumatoid arthritis, utilising the oral glucose tolerance test. Methods: This cross-sectional study involved patients with rheumatoid arthritis, aged ⩾30 years. Following an oral glucose tolerance test, they were divided into two: dysglycaemia and normoglycaemia. Demographic and laboratory parameters were compared using logistic regression analyses. Results: There were 35.5% (55/155) patients with dysglycaemia (including 25.8% impaired glucose tolerance, 7.1% diabetes mellitus and 1.9% with both impaired fasting glucose and impaired glucose tolerance). Patients with dysglycaemia were heavier (65.5 ± 12.3 versus 60.7 ± 10.6 kg, p = 0.01), had wider waist (89.0 ± 12.5 versus 83.1 ± 9.6 cm, p < 0.01), lower high-density lipoprotein cholesterol (1.4 ± 0.3 versus 1.5 ± 0.4 mmol/L, p = 0.02), higher triglyceride (1.3 (0.9-1.8) versus 0.9 (0.8-1.2) mmol/L, p < 0.01) and intercellular adhesion molecule-1 (361.79 (290.38-481.84) versus 315.92 (251.45-407.93) ng/mL, p = 0.01). History of smoking (odds ratio: 5.70, confidence interval: 1.27-25.7), elevated triglyceride (odds ratio: 2.87, confidence interval: 1.33-6.22) and intercellular adhesion molecule-1 (odds ratio: 1.003, confidence interval: 1.001-1.006) were significantly associated with dysglycaemia. Conclusions: Prevalence of undiagnosed dysglycaemia, particularly impaired glucose tolerance, was high in these patients with rheumatoid arthritis, using a 75-g oral glucose tolerance test, which was not associated with disease activity or corticosteroid use. Those with high triglyceride, history of smoking and elevated intercellular adhesion molecule-1 were the two significant predictors for dysglycaemia in our patients with rheumatoid arthritis. Oral glucose tolerance test could be an important laboratory investigation for dysglycaemia in these high-risk patients.

Significantly higher atherosclerosis risks in patients with obstructive sleep apnea and non-alcoholic fatty liver disease.

INTRODUCTION: There is limited data on the relationship between Obstructive Sleep Apnea (OSA) and Non-Alcoholic Fatty Liver Disease (NAFLD), each associated with increased cardiovascular risk. This study aimed to determine the relationships between severity of OSA, degree of steatosis in NAFLD and cardiovascular risk via CIMT and atherosclerosis markers ie intracellular adhesion molecule-1 (ICAM-1) an Lipoprotein-a (Lp(a)) in a group of patients with OSA. MATERIALS AND METHODS: This was a cross-sectional, single center study. A total of 110 subjects between 18 to 65 years of age and diagnosed with OSA following sleep study examinations were recruited. Exclusion criteria included seropositive Hepatitis B or Hepatitis C, and significant alcohol intake. RESULT: The prevalence of NAFLD was 81.8%. The mean CIMT (0.08±0.03 vs 0.06±0.01 cm, p = 0.001), ICAM-1 (334.53±72.86 vs 265.46±102.92 ng/mL, p = 0.001) and Lp(a) (85.41±52.56 vs 23.55±23.66 nmol/L, p<0.001) were significantly higher in the NAFLD group compared to the non-NAFLD group. Comparisons between the different groups showed significantly increasing levels of CIMT, ICAM-1 and Lp(a), lowest within the non-NAFLD, followed by the NAFLD 1 and NAFLD 2+3 groups. There was a significant positive correlation between degree of steatosis and the severity of OSA (r = 0.453, p<0.001). Logistic regression analysis revealed that patients with apnea/hypopnea index (AHI) of >30 were 52.77 (CI 6.34, 439.14) times more likely to have NAFLD compared to those with mild AHI (p<0.001). CONCLUSION: The prevalence of NAFLD is alarmingly high in this group of OSA patients. The degree of steatosis in patients with NAFLD was significantly correlated with severity of OSA, CIMT measurements, ICAM-1 and Lp(a). Our findings underscore screening for NAFLD in patients with OSA to ensure prompt risk stratification and management.

Safety and efficacy of very low carbohydrate diet in patients with diabetic kidney disease-A randomized controlled trial.

INTRODUCTION: There is limited data on the effects of low carbohydrate diets on renal outcomes particularly in patients with underlying diabetic kidney disease. Therefore, this study determined the safety and effects of very low carbohydrate (VLCBD) in addition to low protein diet (LPD) on renal outcomes, anthropometric, metabolic and inflammatory parameters in patients with T2DM and underlying mild to moderate kidney disease (DKD). MATERIALS AND METHODS: This was an investigator-initiated, single-center, randomized, controlled, clinical trial in patients with T2DM and DKD, comparing 12-weeks of low carbohydrate diet (<20g daily intake) versus standard low protein (0.8g/kg/day) and low salt diet. Patients in the VLCBD group underwent 2-weekly monitoring including their 3-day food diaries. In addition, Dual-energy x-ray absorptiometry (DEXA) was performed to estimate body fat percentages. RESULTS: The study population (n = 30) had a median age of 57 years old and a BMI of 30.68kg/m2. Both groups showed similar total calorie intake, i.e. 739.33 (IQR288.48) vs 789.92 (IQR522.4) kcal, by the end of the study. The VLCBD group showed significantly lower daily carbohydrate intake 27 (IQR25) g vs 89.33 (IQR77.4) g, p<0.001, significantly higher protein intake per day 44.08 (IQR21.98) g vs 29.63 (IQR16.35) g, p<0.05 and no difference in in daily fat intake. Both groups showed no worsening of serum creatinine at study end, with consistent declines in HbA1c (1.3(1.1) vs 0.7(1.25) %) and fasting blood glucose (1.5(3.37) vs 1.3(5.7) mmol/L). The VLCBD group showed significant reductions in total daily insulin dose (39(22) vs 0 IU, p<0.001), increased LDL-C and HDL-C, decline in IL-6 levels; with contrasting results in the control group. This was associated with significant weight reduction (-4.0(3.9) vs 0.2(4.2) kg, p = <0.001) and improvements in body fat percentages. WC was significantly reduced in the VLCBD group, even after adjustments to age, HbA1c, weight and creatinine changes. Both dietary interventions were well received with no reported adverse events. CONCLUSION: This study demonstrated that dietary intervention of very low carbohydrate diet in patients with underlying diabetic kidney disease was safe and associated with significant improvements in glycemic control, anthropometric measurements including weight, abdominal adiposity and IL-6. Renal outcomes remained unchanged. These findings would strengthen the importance of this dietary intervention as part of the management of patients with diabetic kidney disease.

Observational study of the status of coronary risk biomarkers among Negritos with metabolic syndrome in the east coast of Malaysia.

OBJECTIVES: To determine the prevalence of metabolic syndrome (MS), ascertain the status of coronary risk biomarkers and establish the independent predictors of these biomarkers among the Negritos. SETTINGS: Health screening programme conducted in three inland settlements in the east coast of Malaysia and Peninsular Malaysia. SUBJECTS: 150 Negritos who were still living in three inland settlements in the east coast of Malaysia and 1227 Malays in Peninsular Malaysia. These subjects were then categorised into MS and non-MS groups based on the International Diabetes Federation (IDF) consensus worldwide definition of MS and were recruited between 2010 and 2015. The subjects were randomly selected and on a voluntary basis. PRIMARY AND SECONDARY OUTCOME MEASURES: This study was a cross-sectional study. Serum samples were collected for analysis of inflammatory (hsCRP), endothelial activation (sICAM-1) and prothrombogenesis [lp(a)] biomarkers. RESULTS: MS was significantly higher among the Malays compared with Negritos (27.7%vs12.0%). Among the Malays, MS subjects had higher hsCRP (p=0.01) and sICAM-1 (p<0.05) than their non-MS counterpart. There were no significant differences in all the biomarkers between MS and the non-MS Negritos. However, when compared between ethnicity, all biomarkers were higher in Negritos compared with Malays (p<0.001). Binary logistic regression analysis affirmed that Negritos were an independent predictor for Lp(a) concentration (p<0.001). CONCLUSIONS: This study suggests that there may possibly be a genetic influence other than lifestyle, which could explain the lack of difference in biomarkers concentration between MS and non-MS Negritos and for Negritos predicting Lp(a).

Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data.

AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of a CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study was designed to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli. METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods. RESULTS: A total of 72 single nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population. CONCLUSION: The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in the Orang Asli of Peninsular Malaysia.

Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data.

The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme's activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.