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Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Genes that are aberrantly expressed and/or mutated that lead to the dysplastic erythroid morphology seen in −7/del(7q) MDS have not been identified. In this study, we show that reduced expression of dedicator of cytokinesis 4 ( DOCK4 ) causes dysplasia by disrupting the actin cytoskeleton in developing red blood cells. In addition, our identification of the molecular pathway that leads to morphological defects in this type of MDS provides potential therapeutic targets downstream of DOCK4 that can be exploited to reverse the dysplasia in the erythroid lineage. Furthermore, we developed a novel single-cell multispectral flow cytometry assay for evaluation of disrupted F-actin filaments, which can be used for potential early detection of dysplastic cells in MDS. Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate thatDOCK4is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion ofDOCK4levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression ofDOCK4leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed thatDOCK4knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identifyDOCK4as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Aims/hypothesis This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in India. Methods A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose. Results Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status. Conclusions/interpretations We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.

For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic armamentarium. They have been used as monotherapy as well as combination therapy. Focus on newer drugs and concerns about the risk of severe hypoglycemia and weight gain with some SUs have led to discussion on their safety and utility. It has to be borne in mind that the adverse events associated with SUs should not be ascribed to the whole class, as many modern SUs, such as glimepiride and gliclazide modified release, are associated with better safety profiles. Furthermore, individualization of treatment, using SUs in combination with other drugs, backed with careful monitoring and patient education, ensures maximum benefits with minimal side effects. The current guidelines, developed by experts from Africa, Asia, and the Middle East, promote the safe and smart use of SUs in combination with other glucose-lowering drugs.

To study the pattern and prevalence of dyslipidemia in a large representative sample of four selected regions in India. Phase I of the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study was conducted in a representative population of three states of India [Tamil Nadu, Maharashtra and Jharkhand] and one Union Territory [Chandigarh], and covered a population of 213 million people using stratified multistage sampling design to recruit individuals ≥20 years of age. All the study subjects (n = 16,607) underwent anthropometric measurements and oral glucose tolerance tests were done using capillary blood (except in self-reported diabetes). In addition, in every 5th subject (n = 2042), a fasting venous sample was collected and assayed for lipids. Dyslipidemia was diagnosed using National Cholesterol Education Programme (NCEP) guidelines. Of the subjects studied, 13.9% had hypercholesterolemia, 29.5% had hypertriglyceridemia, 72.3% had low HDL-C, 11.8% had high LDL-C levels and 79% had abnormalities in one of the lipid parameters. Regional disparity exists with the highest rates of hypercholesterolemia observed in Tamilnadu (18.3%), highest rates of hypertriglyceridemia in Chandigarh (38.6%), highest rates of low HDL-C in Jharkhand (76.8%) and highest rates of high LDL-C in Tamilnadu (15.8%). Except for low HDL-C and in the state of Maharashtra, in all other states, urban residents had the highest prevalence of lipid abnormalities compared to rural residents. Low HDL-C was the most common lipid abnormality (72.3%) in all the four regions studied; in 44.9% of subjects, it was present as an isolated abnormality. Common significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia. The prevalence of dyslipidemia is very high in India, which calls for urgent lifestyle intervention strategies to prevent and manage this important cardiovascular risk factor.

Overweight and obesity are rapidly increasing in countries like India. This study was aimed at determining the prevalence of generalized, abdominal and combined obesity in urban and rural India. Phase I of the ICMR-INDIAB study was conducted in a representative population of three States [Tamil Nadu (TN), Maharashtra (MH) and Jharkhand (JH)] and one Union Territory (UT)[Chandigarh (CH)] of India. A stratified multi-stage sampling design was adopted and individuals ≥ 20 yr of age were included. WHO Asia Pacific guidelines were used to define overweight [body mass index (BMI) ≥ 23 kg/m [2] but < 25 kg/m [2]], generalized obesity (GO, BMI ≥ 25 kg/m [2], abdominal obesity (AO, waist circumference ≥ 90 cm for men and ≥ 80 cm for women) and combined obesity (CO, GO plus AO). Of the 14,277 participants, 13,800 subjects (response rate, 96.7%) were included for the analysis (urban: n = 4,063; rural: n = 9737). The prevalence of GO was 24.6, 16.6, 11.8 and 31.3 per cent among residents of TN, MH, JH and CH, while the prevalence of AO was 26.6, 18.7, 16.9 and 36.1 per cent, respectively. CO was present in 19.3, 13.0, 9.8 and 26.6 per cent of the TN, MH, JH and CH population. The prevalence of GO, AO and CO were significantly higher among urban residents compared to rural residents in all the four regions studied. The prevalence of overweight was 15.2, 11.3, 7.8 and 15.9 per cent among residents of TN, MH, JH and CH, respectively. Multiple logistic regression analysis showed that female gender, hypertension, diabetes, higher socio-economic status, physical inactivity and urban residence were significantly associated with GO, AO and CO in all the four regions studied. Age was significantly associated with AO and CO, but not with GO. Prevalence of AO as well as of GO were high in India. Extrapolated to the whole country, 135, 153 and 107 million individuals will have GO, AO and CO, respectively. However, these figures have been estimated from three States and one UT of India and the results may be viewed in this light.

As injectable therapies such as human insulin, insulin analogs, and glucagon-like peptide-1 receptor agonists are used to manage diabetes, correct injection technique is vital for the achievement of glycemic control. The forum for injection technique India acknowledged this need for the first time in India and worked to develop evidence-based recommendations on insulin injection technique, to assist healthcare practitioners in their clinical practice.

Representative data on knowledge and awareness about diabetes is scarce in India and is extremely important to plan public health policies aimed at preventing and controlling diabetes. The aim of the following study is to assess awareness and knowledge about diabetes in the general population, as well as in individuals with diabetes in four selected regions of India. The study subjects were drawn from a representative sample of four geographical regions of India, Chandigarh, Tamil Nadu, Jharkhand and Maharashtra representing North, South, East and West and covering a population of 213 million. A total of 16,607 individuals (5112 urban and 11,495 rural) aged ≥20 years were selected from 188 urban and 175 rural areas. Awareness of diabetes and knowledge of causative factors and complications of diabetes were assessed using an interviewer administered structured questionnaire in 14,274 individuals (response rate, 86.0%), which included 480 self-reported diabetic subjects. Only 43.2% (6160/14,274) of the overall study population had heard about a condition called diabetes. Overall urban residents had higher awareness rates (58.4%) compared to rural residents (36.8%) (P < 0.001). About 46.7% of males and 39.6% of females reported that they knew about a condition called diabetes (P < 0.001). Of the general population, 41.5% (5726/13,794) knew about a condition called diabetes. Among them, 80.7% (4620/5726) knew that the prevalence of diabetes was increasing, whereas among diabetic subjects, it was 93.0% (448/480). Among the general and diabetic population, 56.3% and 63.4% respectively, were aware that diabetes could be prevented. Regarding complications, 51.5% of the general population and 72.7% diabetic population knew that diabetes could affect other organs. Based on a composite knowledge score to assess knowledge among the general population, Tamil Nadu had the highest (31.7) and Jharkhand the lowest score (16.3). However among self-reported diabetic subjects, Maharashtra had the highest (70.1) and Tamil Nadu, the lowest score (56.5). Knowledge and awareness about diabetes in India, particularly in rural areas, is poor. This underscores the need for conducting large scale diabetes awareness and education programs.

Health-care professionals in India frequently manage injection or infusion therapies in persons with diabetes (PWD). Patients taking insulin should know the importance of proper needle size, correct injection process, complication avoidance, and all other aspects of injection technique from the first visit onward. To assist health-care practitioners in their clinical practice, Forum for Injection Technique and Therapy Expert Recommendations, India, has updated the practical advice and made it more comprehensive evidence-based best practice information. Adherence to these updated recommendations, learning, and translating them into clinical practice should lead to effective therapies, improved outcomes, and lower costs for PWD.