Lipid-Droplet Formation Drives Pathogenic Group 2 Innate Lymphoid Cells in Airway Inflammation.

Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated pathology. Here, we show that tissue-resident type 2 ILCs (ILC2s) display a distinct metabolic signature upon chronic activation. In the context of allergen-driven airway inflammation, ILC2s increase their uptake of both external lipids and glucose. Externally acquired fatty acids are transiently stored in lipid droplets and converted into phospholipids to promote the proliferation of ILC2s. This metabolic program is imprinted by interleukin-33 (IL-33) and regulated by the genes Pparg and Dgat1, which are both controlled by glucose availability and mTOR signaling. Restricting dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Together, these results reveal that pathogenic ILC2 responses require lipid metabolism and identify ketogenic diet as a potent intervention strategy to treat airway inflammation.

Enemy or ally? Fasting as an essential regulator of immune responses.

Nutrition is essential for supplying an organism with sufficient energy to maintain its bodily functions. Apart from serving as an energy supply, the immunomodulatory effects of diet are emerging as a central aspect of human health. The latest evidence suggests that dietary restriction may play an important regulatory role by influencing the activation and effector functions of immune cells. However, depending on the context, nutrient restriction may have both pathogenic and beneficial effects. Here, we discuss the diverse roles of fasting programs, including ketogenesis in infection and chronic inflammation, aiming to clarify their detrimental and/or beneficial effects. Understanding these differences may help identify conditions under which dietary interventions might serve as putative effective approaches to treat various diseases.

Prevalence of Metabolic Syndrome and its Association with Coronary Artery Disease Among an Urban Elderly South Indian Population (CURES- 145).

OBJECTIVE: The aim of this study was to assess the prevalence of metabolic syndrome (MS) and its association with coronary artery disease (CAD) among an elderly urban population in south India. METHODS: Individuals aged ≥60 years (n=222) were recruited from Phase 3 of the Chennai Urban Rural Epidemiology Study. Anthropometric and blood pressure measurements, oral glucose tolerance test, lipids and fasting insulin were carried out. Prevalence of MS was estimated using the World Health Organization (WHO), Modified National Cholesterol Education Program's Adult Treatment Panel III (ATP-III) and International Diabetes Federation (IDF) criteria. Diagnosis of CAD was made by resting 12 lead ECG and/or past history of documented myocardial infarction. RESULTS: MS was identified in 45.9% (n=102) by modified ATP-III, 37.4% (n=83) by IDF and 45.5% (n=101) by WHO criteria respectively. Only 61 subjects (27.5%) were identified by all the three criteria. Female subjects had a significantly higher prevalence of MS compared to their male counterparts (45.8 vs, 31.0%, p=0.023 respectively) according to IDF criteria. It was observed that 59.8%, 53% and 45.6% of the subjects had all five abnormalities according to modified ATP-III, IDF and WHO, respectively. Subjects with MS had significantly higher prevalence of CAD compared to those without MS using all the 3 criteria (modified ATP-III -20.6 vs.8.5%; IDF-20.5 vs.10.1%; WHO-19.8 vs.9.1% respectively). The odds ratio of developing CAD among MS subjects was 2.93, 2.39 and 2.48 compared to those without MS after adjusting for age, gender and family history of diabetes according to modified ATP-III, IDF and WHO, respectively. CONCLUSIONS: Nearly 40% of the elderly urban south Indians have MS and it is strongly associated with CAD.

Seroprevalence and Association of Toxoplasma gondii with Bone Health in a Cohort of Osteopenia and Osteoporosis Patients.

Considering the fact that Toxoplasma is a common parasite of humans and Toxoplasma bradyzoites can reside in skeletal muscle, T. gondii-mediated immune responses may modulate the progression and pathophysiology of another musculoskeletal disorder, osteoporosis. In the current study, we investigated the association of bone health and Toxoplasma gondii infection status. A total of 138 patients living in Germany with either osteopenia or osteoporosis were included in the study, and they were categorized into two groups, T. gondii uninfected (n = 74) and infected (n = 64), based on the presence of T. gondii-specific IgG antibodies. The demographic and clinical details of the study subjects were collected from the medical records. Logistic regression analysis was performed to delineate the association of bone health parameters with the infection status. The prevalence of toxoplasmosis was 46.4% in the study participants. The infected individuals with osteopenia and osteoporosis showed higher levels of mean spine and femoral T score, Z score, and bone mineral density (BMD), indicating improved bone health compared to the uninfected group. Logistic regression analysis showed that subjects with T. gondii infection displayed increased odds of having a higher mean femur T score, femur BMD, and femur Z score even after adjusting for age, creatinine, and urea levels. However, when the duration of drug intake for osteoporosis was taken into account, the association lost statistical significance. In summary, in this study, an improvement in osteopenia and osteoporosis was observed in Toxoplasma-infected patients, which may be partly due to the longer duration of drug intake for osteoporosis in the infected patient group.

Osteomyelitis is associated with increased anti-inflammatory response and immune exhaustion.

Introduction: Osteomyelitis (OMS) is a bone infection causing bone pain and severe complications. A balanced immune response is critical to eradicate infection without harming the host, yet pathogens manipulate immunity to establish a chronic infection. Understanding OMS-driven inflammation is essential for disease management, but comprehensive data on immune profiles and immune cell activation during OMS are lacking. Methods: Using high-dimensional flow cytometry, we investigated the detailed innate and adaptive systemic immune cell populations in OMS and age- and sex-matched controls. Results: Our study revealed that OMS is associated with increased levels of immune regulatory cells, namely T regulatory cells, B regulatory cells, and T follicular regulatory cells. In addition, the expression of immune activation markers HLA-DR and CD86 was decreased in OMS, while the expression of immune exhaustion markers TIM-3, PD-1, PD-L1, and VISTA was increased. Members of the T follicular helper (Tfh) cell family as well as classical and typical memory B cells were significantly increased in OMS individuals. We also found a strong correlation between memory B cells and Tfh cells. Discussion: We conclude that OMS skews the host immune system towards the immunomodulatory arm and that the Tfh memory B cell axis is evident in OMS. Therefore, immune-directed therapies may be a promising alternative for eradication and recurrence of infection in OMS, particularly in individuals and areas where antibiotic resistance is a major concern.

Value of Diagnostic Tools in the Diagnosis of Osteomyelitis: Pilot Study to Establish an Osteomyelitis Score.

Osteomyelitis (OM) remains one of the most feared complications in bone surgery and trauma. Its diagnosis remains a major challenge due to lack of guidelines. The aim of this study was to prospectively analyze the value of the most common and available diagnostic tools and to establish an OM score to derive treatment recommendations. All patients with suspected OM were included in a prospective pilot study. All patients underwent blood sampling for C-reactive protein and white blood cell count analysis. Magnetic resonance imaging (MRI), and microbiologic and histopathologic samples, were taken from representative sites of initial debridement. All patients were treated according to their OM test results and followed for at least one year. Subsequently, the value of individual or combined diagnostic tools was analyzed in patients with confirmed OM and in patients in whom OM was ruled out. Based on these findings, an OM score was developed that included MRI, microbiology, and histopathology. The score identified all control patients and all but one OM patient, resulting in a correct diagnosis of 93.3%, which was validated in a second independent larger cohort. This was the first study to analyze the value of the most commonly used tools to diagnose OM. The proposed OM score provides a simple scoring system to safely interpret test results with high accuracy.

The design and development of a study protocol to investigate Onchocerca volvulus, Loa loa and Mansonella perstans-mediated modulation of the metabolic and immunological profile in lean and obese individuals in Cameroon.

BACKGROUND: Life-style metabolic diseases are steadily rising, not only in developed countries, but also in low- and middle-income countries, presenting a global health problem. Metabolic disorders like type 2 diabetes and cardiovascular diseases are among the ten leading causes of death defined by the WHO in 2019. Results from animal and observational human studies suggest a connection between the decline in human helminth infections and rise of life-style-associated metabolic diseases in developing regions. This trial was designed to investigate filarial infections and their impact on metabolic diseases in Cameroon. We hypothesize that the induction of regulatory immune responses during filarial infection reduces obesity-induced low-grade inflammatory immune responses and thereby improves metabolic parameters, whereas anthelmintic treatment abolishes this protective effect. METHODS/DESIGN: Participants infected with Mansonella perstans, Onchocerca volvulus and/or Loa loa being lean (BMI <25), overweight (BMI >25 and <30) or clinically obese (BMI ≥30) from Littoral regions of Cameroon will be evaluated for their parasitological, immunological, metabolic and biochemical profile before and after treatment of their parasitic infections. Anthropomorphic measurements and a detailed questionnaire will complement our analysis. The investigation will assess blood immune cell populations, serum adipokines and cytokines that could be influenced by the parasite infection and/or metabolic diseases. Further, parameters like blood glucose, homeostatic model assessment of insulin resistance (HOMA-IR), circulating lipids and circulating makers of liver function will be monitored. Parameters will be assessed before treatment, 12 and 18 months after treatment. CONCLUSION: The focus of this study is to obtain a comprehensive metabolic profile of the participants in rural areas of Cameroon and to investigate the relationship between filarial immunomodulation and metabolic diseases. This study will elucidate the effect of anti-filarial treatment on the metabolic and immunological parameters that partake in the development of insulin resistance, narrowing in on a potential protective effect of filarial infections on metabolic diseases. TRIAL REGISTRATION: doi.org/10.1186/ISRCTN43845142, ISRCTN43845142 February 2020 Trial title Effects of filarial parasite infection on type 2 diabetes Issue date: 27.10.22, V.1.

Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

Even after successful weight reduction, obese adults tend to quickly regain the lost weight. This raises the question of whether weight loss improves the underlying chronic adipose tissue inflammation characteristic of obesity. In order to improve our understanding of the mechanisms that reshape metabolic organs during weight loss, we investigated the macrophage and T cell function of the liver and adipose tissue on reversing high fat diet (HFD) mice to normal control diet (NCD). Obese mice that were switched to NCD showed an improvement in their metabolic profile that included enhanced glucose and insulin tolerance, decreased cholesterol, triglyceride, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) levels that were comparable to NCD controls. However, despite weight loss, increased frequencies, but not total numbers, of IL-17+ and IL-22+ CD4+ T cells, IFN-γ+ and TNF+ CD8+ T cells and IL-17+ and IL-22+ CD8+ T cells were observed in the adipose tissue of mice switched from HFD to NCD compared to NCD and even HFD fed mice. Further, in the liver, IFN-γ+ and TNF+ CD8+ T cell, IL-17+ and IL-22+ CD8+ T cell, macrophage frequencies and their expression of antigen presenting molecules were increased. To determine if macrophages are the major determinants of the sustained inflammation observed during weight loss, we depleted macrophages, which significantly reduced IFN-γ+, TNF+, IL-17+, and IL-22+ CD8+ T cell frequencies in the liver and the adipose tissue. In conclusion, we show that although weight loss improves the metabolic profile, there is an active and ongoing CD8+ T cell inflammation in liver and adipose tissue mediated by macrophages.

S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis.

Neutrophils are essentially involved in protective immune responses against invading infective larvae of filarial nematodes. The present study investigated the impact of S100A8/S100A9 on protective immune responses against the rodent filarial nematode Litomosoides sigmodontis. S100A9 forms with S100A8 the heterodimer calprotectin, which is expressed by circulating neutrophils and monocytes and mitigates or amplifies tissue damage as well as inflammation depending on the immune environment. Mice deficient for S100A8/A9 had a significantly reduced worm burden in comparison to wildtype (WT) animals 12 days after infection (dpi) with infective L3 larvae, either by the vector or subcutaneous inoculation, the latter suggesting that circumventing natural immune responses within the epidermis and dermis do not alter the phenotype. Nevertheless, upon intradermal injection of L3 larvae, increased total numbers of neutrophils, eosinophils and macrophages were observed within the skin of S100A8/A9-/- mice. Furthermore, upon infection the bronchoalveolar and thoracic cavity lavage of S100A8/A9-/- mice showed increased concentrations of CXCL-1, CXCL-2, CXCL-5, as well as elastase in comparison to the WT controls. Neutrophils from S100A8/A9-/- mice exhibited an increased in vitro activation and reduced L3 larval motility more effectively in vitro compared to WT neutrophils. The depletion of neutrophils from S100A8/A9-/- mice prior to L. sigmodontis infection until 5dpi abrogated the protective effect and led to an increased worm burden, indicating that neutrophils mediate enhanced protective immune responses against invading L3 larvae in S100A8/A9-/- mice. Interestingly, complete circumvention of protective immune responses in the skin and the lymphatics by intravenous injection of L3 larvae reversed the phenotype and resulted in an increased worm burden in S100A8/A9-/- mice. In summary, our results reveal that lack of S100A8/S100A9 triggers L3-induced inflammatory responses, increasing chemokine levels, granulocyte recruitment as well as neutrophil activation and therefore impairs larval migration and susceptibility for filarial infection.

Susceptibility to L. sigmodontis infection is highest in animals lacking IL-4R/IL-5 compared to single knockouts of IL-4R, IL-5 or eosinophils.

BACKGROUND: Mice are susceptible to infections with the rodent filarial nematode Litomosoides sigmodontis and develop immune responses that resemble those of human filarial infections. Thus, the L. sigmodontis model is used to study filarial immunomodulation, protective immune responses against filariae and to screen drug candidates for human filarial diseases. While previous studies showed that type 2 immune responses are protective against L. sigmodontis, the present study directly compared the impact of eosinophils, IL-5, and the IL-4R on the outcome of L. sigmodontis infection. METHODS: Susceptible wildtype (WT) BALB/c mice, BALB/c mice lacking eosinophils (dblGATA mice), IL-5-/- mice, IL-4R-/- mice and IL-4R-/-/IL-5-/- mice were infected with L. sigmodontis. Analyses were performed during the peak of microfilaremia in WT animals (71 dpi) as well as after IL-4R-/-/IL-5-/- mice showed a decline in microfilaremia (119 dpi) and included adult worm counts, peripheral blood microfilariae levels, cytokine production from thoracic cavity lavage, the site of adult worm residence, and quantification of major immune cell types within the thoracic cavity and spleen. RESULTS: Our study reveals that thoracic cavity eosinophil numbers correlated negatively with the adult worm burden, whereas correlations of alternatively activated macrophage (AAM) numbers with the adult worm burden (positive correlation) were likely attributed to the accompanied changes in eosinophil numbers. IL-4R-/-/IL-5-/- mice exhibited an enhanced embryogenesis achieving the highest microfilaremia with all animals becoming microfilariae positive and had an increased adult worm burden combined with a prolonged adult worm survival. CONCLUSIONS: These data indicate that mice deficient for IL-4R-/-/IL-5-/- have the highest susceptibility for L. sigmodontis infection, which resulted in an earlier onset of microfilaremia, development of microfilaremia in all animals with highest microfilariae loads, and an extended adult worm survival.

Adiponectin Limits IFN-γ and IL-17 Producing CD4 T Cells in Obesity by Restraining Cell Intrinsic Glycolysis.

Compared to the innate immune system, the contribution of the adaptive immune response during obesity and insulin resistance is still not completely understood. Here we demonstrate that high fat diet (HFD) increases the frequencies of activated CD4+ and CD8+ T cells and frequencies of T cells positive for IFN-γ and IL-17 in the adipose tissue. The adipocyte-derived soluble factor adiponectin reduces IFN-γ and IL-17 positive CD4+ T cells from HFD mice and dampens the differentiation of naïve T cells into Th1 cells and Th17 cells. Adiponectin reduces Th17 cell differentiation and restrains glycolysis in an AMPK dependent fashion. Treatment with adult worm extracts of the rodent filarial nematode Litomosoides sigmodontis (LsAg) reduces adipose tissue Th1 and Th17 cell frequencies during HFD and increases adiponectin levels. Stimulation of T cells in the presence of adipocyte-conditioned media (ACM) from LsAg-treated mice reduces Th1 and Th17 frequencies and this effect was abolished when ACM was treated with an adiponectin neutralizing antibody. Collectively, these data reveal a novel role of adiponectin in controlling pro-inflammatory CD4+ T cells during obesity and suggest that the beneficial role of helminth infections and helminth-derived products on obesity and insulin resistance may be in part mediated by adiponectin.

Association of neutrophil-lymphocyte ratio with metabolic syndrome and its components in Asian Indians (CURES-143).

BACKGROUND: Metabolic syndrome (MS) is the state of chronic low grade inflammation. This study looks at the relationship of neutrophil-lymphocyte ratio (NLR) in subjects with and without MS in Asian Indians. METHODS: Study subjects (n=754) were recruited from the Chennai Urban Rural Epidemiology Study. MS was defined using the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III criteria modified for waist according to World Health Organization Asia Pacific guidelines. A complete hemogram was done in all subjects using a five-part hematology analyzer (model SF-3000; Sysmex, Kobe, Japan). The NLR was calculated as the ratio between counts for neutrophils and total lymphocytes in subjects with (n=422) and without (n332) MS and correlated with number of metabolic abnormalities in those with MS. RESULTS: Subjects with five metabolic abnormalities had the highest NLR, and with decreasing number of metabolic abnormalities, the NLR decreased linearly (p for trend <0.001). Logistic regression analysis revealed that even after adjusting for age, gender and body mass index, MS was strongly associated with NLR (p<0.001). CONCLUSION: Among Asian Indians, NLR is correlated with MS and also with the number of metabolic abnormalities.

Filarial Infection or Antigen Administration Improves Glucose Tolerance in Diet-Induced Obese Mice.

Helminths induce type 2 immune responses and establish an anti-inflammatory milieu in their hosts. This immunomodulation was previously shown to improve diet-induced insulin resistance which is linked to chronic inflammation. In the current study, we demonstrate that infection with the filarial nematode Litomosoides sigmodontis increased the eosinophil number and alternatively activated macrophage abundance within epididymal adipose tissue (EAT) and improved glucose tolerance in diet-induced obese mice in an eosinophil-dependent manner. L. sigmodontis antigen (LsAg) administration neither altered the body weight of animals nor adipose tissue mass or adipocyte size, but it triggered type 2 immune responses, eosinophils, alternatively activated macrophages, and type 2 innate lymphoid cells in EAT. Improvement in glucose tolerance by LsAg treatment remained even in the absence of Foxp3+ regulatory T cells. Furthermore, PCR array results revealed that LsAg treatment reduced inflammatory immune responses and increased the expression of genes related to insulin signaling (Glut4, Pde3b, Pik3r1, and Hk2) and fatty acid uptake (Fabp4 and Lpl). Our investigation demonstrates that L. sigmodontis infection and LsAg administration reduce diet-induced EAT inflammation and improve glucose tolerance. Helminth-derived products may, therefore, offer new options to improve insulin sensitivity, while loss of helminth infections in developing and developed countries may contribute to the recent increase in the prevalence of type 2 diabetes.

Association of depression with common carotid artery intima media thickness and augmentation index in a large Urban South Indian population- The Chennai Urban Rural Epidemiology Study (CURES - 138).

AIM: The aim of the study was to assess the relationship of depression with carotid intima media thickness and augmentation index in Asian Indians. RESEARCH DESIGN AND METHODS: For this study, 1505 subjects were randomly selected from a population based study conducted in Chennai, South India. Right common carotid artery intima medial thickness [IMT] was determined using high-resolution B-mode ultrasonography. Augmentation index [AI] was measured using the Sphygmocor apparatus. Depressive symptoms were assessed using a previously validated instrument, the Patient Health Questionnaire -12 (PHQ -12). RESULTS: Of the 1505 subjects included in this study, depressive symptoms were present in 16.6% (n = 250) of the subjects. The mean IMT and AI values among subjects with depression were significantly higher than those without depression [0.83 ± 0.43 mm vs 0.73 ± 0.12 mm, P < 0.001] and IMT was higher in females with depression while AI was higher in males with depression. However, both IMT and AI were higher among those with depression in both genders. In multiple logistic regression model, depressive symptoms were associated with IMT even after adjusting for age, gender, body mass index, fasting plasma glucose, serum cholesterol and hypertension (Odds ratio [OR] =2.17, 95% Confidence intervals [CI]:1.01- 4.63, P = 0.047) but in the case of AI, the significance was lost in the adjusted model (OR = 1.01, 95% CI: 0.991-1.02, P = 0.445). CONCLUSION: Among Asian Indians, presence of depressive symptoms was associated with carotid intima media thickness and Augmentation index, even after adjusting for potential confounders.

Metabolic obesity, adipocytokines, and inflammatory markers in Asian Indians--CURES-124.

AIM: This study looked at the association of adipokines, inflammatory and oxidative stress markers in subjects with the following phenotypes: metabolically healthy, nonobese (MHNO), metabolically healthy, obese (MHO), metabolically obese, nonobese (MONO), and metabolically obese, obese (MOO). MATERIALS AND METHODS: Subjects with MHNO (n=462), MHO (n=192), MONO (n=315), and MOO (n=335) were randomly selected from the Chennai Urban Rural Epidemiology Study. Adiponectin, visfatin, resistin, high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), oxidized low-density lipoprotein (LDL), and monocyte chemoattractant protein-1 (MCP-1) were measured by enzyme-linked immunosorbent assay. RESULTS: Levels of adiponectin were lowest in the MOO group, followed by the MONO, MHO, and the MHNO groups (P=0.042), whereas the levels of visfatin (P=0.042) and resistin (P=0.043) were highest in the MOO group, followed by the MONO, MHO, and the MHNO groups. Levels of hs-CRP (P=0.029), TNF-α (P=0.036), IL-6 (P=0.042), oxidized LDL (P=0.036), and MCP-1 (P=0.039) increased from the MHNO to MHO to MONO to MOO phenotypes. Linear regression analysis of the parameters with body mass index (BMI) and metabolic syndrome components showed that adiponectin is negatively associated with abdominal obesity (ß=-0.060; P=0.039) and BMI (ß=-0.076; P=0.009) and that TNF-α is negatively associated with high-density lipoprotein levels (ß=0.114, P=0.049) even after adjusting for age and gender. hs-CRP (ß=0.112, P=0.020) and oxidized LDL (ß=0.114, P=0.050) showed a positive association with systolic blood pressure even after adjusting for age and gender. CONCLUSIONS: The metabolically obese phenotype is characterized by altered adipokine and inflammatory profiles, which could make this phenotype at high risk for type 2 diabetes mellitus and cardiovascular diseases.

Relationship of diabetic retinopathy with coronary artery disease in Asian Indians with type 2 diabetes: the Chennai Urban Rural Epidemiology Study (CURES) Eye Study--3.

OBJECTIVES: This study assessed the relationship between diabetic retinopathy (DR) and coronary artery diseases (CAD) in Asian Indians, who are known to be at high risk of CAD and diabetes but have lower prevalence of DR. SUBJECTS AND METHODS: Type 2 diabetes subjects (n=1,736) were selected from the urban component of the population-based Chennai Urban Rural Epidemiology Study Eye Study. Four-field stereo retinal color photography was done, and DR when present was classified according to the Early Treatment Diabetic Retinopathy Study grading system. Among the 1,723 subjects with gradable fundus photographs, 12-lead electrocardiogram (ECG) was performed in 1,602 individuals, and analysis was restricted to this group. CAD was diagnosed based on documented medical history of CAD or Minnesota coding of ECGs. RESULTS: The prevalence of CAD was significantly higher among subjects with DR compared with those without (11.3% vs. 6.7%; P=0.007). A significant association was observed between DR and CAD in subjects with glycated hemoglobin (HbA1c) levels >7% (P=0.002). After controlling for age and gender, only hard exudates were associated with CAD (P=0.032). Logistic regression analysis revealed that even after adjusting for age, gender, HbA1c, mean arterial blood pressure, smoking, serum cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, DR was significantly associated with CAD among the study subjects (odds ratio [OR]=1.58; 95% confidence interval [CI], 1.00-2.49; P=0.049) and those subjects with duration of diabetes >10 years (OR=4.06; 95% CI, 1.55-10.60; P=0.004). CONCLUSIONS: This cross-sectional study shows a significant association between DR and CAD in South Indian subjects with type 2 diabetes.

Prevalence of peripheral vascular disease and its association with carotid intima-media thickness and arterial stiffness in type 2 diabetes: the Chennai urban rural epidemiology study (CURES 111).

We investigated the prevalence of peripheral vascular disease (PVD) and its association with preclinical atherosclerotic markers [intima-media thickness (IMT)] and arterial stiffness among 1755 urban south Indian type 2 diabetic subjects recruited from the Chennai Urban Rural Epidemiology Study (CURES). Doppler studies were performed, and PVD was defined as ankle-brachial index (ABI) of ≤0.9. IMT of the common carotid artery was determined using high-resolution B-mode ultrasonography, and augmentation index (AGI) was measured using the Sphygmocor apparatus. The overall prevalence of PVD was 8.3% (age-standardized 6.5%). The prevalence of PVD was higher among known diabetic subjects (n = 1401) compared to newly detected diabetic subjects (n = 354) (8.6% vs 6.8%, p = 0.250). The mean IMT and AGI in subjects with PVD were significantly higher compared to subjects without PVD (IMT: 0.99 ± 0.26 mm vs 0.83 ± 0.19 mm; AGI: 28.1 ± 9.6% vs 25.7 ± 9.8%, respectively). IMT was independently associated with PVD even after adjusting for age [odds ratio (OR) = 2.9 (1.2-6.7), p = 0.016 for second tertile and OR = 3.9 (1.7-9.3), p = 0.002 for third tertile compared to first tertile]. AGI was also associated with PVD in the unadjusted model [OR = 1.8 (1.1-3.1), p = 0.027 for second tertile compared to first tertile]. However, when adjusted for age, the significance was lost. In conclusion, among urban south Indian type 2 diabetic subjects, the prevalence of PVD is 8.3% and IMT is more strongly associated with PVD than AGI.

Increased levels of serum granulocyte-macrophage colony-stimulating factor is associated with activated peripheral dendritic cells in type 2 diabetes subjects (CURES-99).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine with growth factor-like properties for monocytes and dendritic cells (DCs). In the present study, serum GM-CSF levels and the activation status of DCs were studied in type 2 diabetes mellitus (T2DM) subjects. METHODS: Study subjects were recruited from the Chennai Urban Rural Epidemiology Study. Healthy controls (n=45) and T2DM patients (n=45) were included in the study. Serum levels of GM-CSF, interleukin-1ß, interleukin-6, and tumor necrosis factor-α were measured. Enumeration of circulating DCs (myeloid [m] and plasmocytoid [p]) and its surface antigen expression were quantified by flow cytometry. RESULTS: The serum GM-CSF levels were significantly higher among diabetes subjects compared with subjects without diabetes and showed a positive correlation with glycated hemoglobin (r=0.208, P=0.018). The serum GM-CSF levels were lower in subjects on combined insulin and oral hypoglycemic agents (OHA) treatment (1.09 pg/mL) compared with those taking OHA alone (1.9 pg/mL). The increased GM-CSF levels were associated with the activated phenotype of mDCs and pDCs, as determined by up-regulation of the lineage markers. CONCLUSION: The activated state of mDCs and pDCs seen among diabetes subjects might be due to the increased levels of GM-CSF and other pro-inflammatory cytokines.

Effect of filarial infection on serum inflammatory and atherogenic biomarkers in coronary artery disease (CURES-121).

Helminth infections can potentially confer protection against metabolic disorders, possibly through immunomodulation. In this study, the baseline prevalence of lymphatic filariasis (LF) among subjects without (N = 236) and with (N = 217) coronary artery disease (CAD) was examined as part of the Chennai Urban Rural Epidemiological Study (CURES). The prevalence of LF was not significantly different between CAD(-) and CAD(+) subjects. The LF antigen load and antibody levels indicated comparable levels of infection and exposure between the groups. Within the CAD group, LF(+) and LF(-) subjects had no significant difference in the intimal medial thickness and high-sensitivity C-reactive protein values. However, LF infection was associated with augmented levels of tumor necrosis factor-α and interleukin-6 among CAD(+) subjects. The LF infection had no effect on serum adipocytokine profile. In conclusion, unlike type-2 diabetes, there is no association between the prevalence of LF and CAD and also no evidence of protective immunomodulation of LF infection on CAD in the Asian Indian population.