The 24-month metabolic benefits of the healthy living partnerships to prevent diabetes: A community-based translational study.

AIMS: Large-scale clinical trials and translational studies have demonstrated that weight loss achieved through diet and physical activity reduced the development of diabetes in overweight individuals with prediabetes. These interventions also reduced the occurrence of metabolic syndrome and risk factors linked to other chronic conditions including obesity-driven cancers and cardiovascular disease. The Healthy Living Partnerships to Prevent Diabetes (HELP PD) was a clinical trial in which participants were randomized to receive a community-based lifestyle intervention translated from the Diabetes Prevention Program (DPP) or an enhanced usual care condition. The objective of this study is to compare the 12 and 24 month prevalence of metabolic syndrome in the two treatment arms of HELP PD. MATERIALS AND METHODS: The intervention involved a group-based, behavioral weight-loss program led by community health workers monitored by personnel from a local diabetes education program. The enhanced usual care condition included dietary counseling and written materials. RESULTS: HELP PD included 301 overweight or obese participants (BMI 25-39.9kg/m2) with elevated fasting glucose levels (95-125mg/dl). At 12 and 24 months of follow-up there were significant improvements in individual components of the metabolic syndrome: fasting blood glucose, waist circumference, HDL, triglycerides and blood pressure and the occurrence of the metabolic syndrome in the intervention group compared to the usual care group. CONCLUSIONS: This study demonstrates that a community diabetes prevention program in participants with prediabetes results in metabolic benefits and a reduction in the occurrence of the metabolic syndrome in the intervention group compared to the enhanced usual care group.

Genetic and Environmental Factors Affecting TNF-α Responses in Relation to Sudden Infant Death Syndrome.

Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide polymorphism (SNP) associated with high levels of tumor necrosis factor-α (TNF-α) responses, TNF G-308A, in sudden infant death syndrome (SIDS) infants, SIDS and control parents, and ethnic groups with different incidences of SIDS; (2) the effects of two risk factors for SIDS, cigarette smoke and virus infection, on TNF-α responses; and (3) to assess effects of genotype, cigarette smoke, and gender on TNF-α responses to bacterial toxins identified in SIDS infants. TNF G-308A genotypes were determined by real-time polymerase chain reaction for SIDS infants from Australia, Germany, and Hungary; parents of SIDS infants and their controls; and populations with high (Aboriginal Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. Leukocytes from Caucasian donors were stimulated in vitro with endotoxin or toxic shock syndrome toxin-1 (TSST-1). TNF-α responses were measured by L929 bioassay (IU/ml) and assessed in relation to genotype, smoking status, and gender. There was a significantly higher proportion of the minor allele AA genotype among Australian SIDS infants (6/24, 24%) compared to 3/62 (4.8%) controls (p = 0.03). There were no significant differences in TNF-α responses by TNF G-308A genotypes when assessed in relation to smoking status or gender. Given the rarity of the TNF G-308A A allele in Caucasian populations, the finding that 24% of the Australian SIDS infants tested had this genotype requires further investigation and cautious interpretation. Although non-smokers with the AA genotype had higher TNFα responses to both TSST-1 and endotoxin, there were too few subjects with this rare allele to obtain statistically valid results. No effects of genotype, smoking, or gender were observed for TNF-α responses to these toxins.

Cytokine Levels in Late Pregnancy: Are Female Infants Better Protected Against Inflammation?

Inflammatory responses have been implicated in several forms of infant deaths (sudden expected deaths and stillbirths) and the initiation of pre-term births. In this study, we examined matched samples of term maternal blood, cord blood, and amniotic fluid obtained from 24 elective cesarean deliveries for both pro- and anti-inflammatory cytokines thought to be important in maintaining a balanced response leading to successful pregnancy outcome. These included interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-10, and IL-1 receptor antagonist (IL-1ra). Amniotic fluid levels for each of the cytokines examined were significantly higher than those for cord blood or maternal plasma. While pro-inflammatory cytokines were higher in amniotic fluid associated with male fetuses compared with females, the major significant difference was higher levels of IL-1ra in amniotic fluid associated with female fetuses. Our study supports similar findings for cytokines during mid-trimester, which noted that amniotic fluid levels were higher than those in maternal blood. Our study suggests that maternal decidua secretes additional IL-ra in the presence of a female conceptus which improves the likelihood of a good outcome compared to pregnancies with male fetuses.

The Role of Infection and Inflammation in Stillbirths: Parallels with SIDS?

It has been suggested that stillbirths are part of the spectrum of infant deaths that includes sudden infant death syndrome (SIDS). This paper examines the hypothesis that risk factors associated with stillbirths might contribute to dysregulation of inflammatory responses to infections that could trigger the physiological responses leading to fetal loss. These include genetic factors (ethnic group, sex), environmental (infection, cigarette smoke, obesity), and developmental (testosterone levels) factors. Interactions between the genetic, environmental, and developmental risk factors are also considered, e.g., the excess of male stillborn infants in relation to the effects of testosterone levels during development on pro-inflammatory responses. In contrast to SIDS, inflammatory responses of both mother and fetus need to be considered. Approaches for examining the hypothesis are proposed.

Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ.

Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-γ (IFN-γ) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-γ on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-γ responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-γ on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-γ responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-γ. THP-1 cells showed a dose dependent effect of IFN-γ on cytokine responses to endotoxin. For PBMC, IFN-γ enhanced interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-γ. There was no effect of gender or genotype on IFN-γ responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.

Exploring the risk factors for sudden infant deaths and their role in inflammatory responses to infection.

The risk factors for sudden infant death syndrome (SIDS) parallel those associated with susceptibility to or severity of infectious diseases. There is no evidence that a single infectious agent is associated with SIDS; the common thread appears to be induction of inflammatory responses to infections. In this review, interactions between genetic and environmental risk factors for SIDS are assessed in relation to the hypothesis that many infant deaths result from dysregulation of inflammatory responses to "minor" infections. Risk factors are assessed in relation to three important stages of infection: (1) bacterial colonization (frequency or density); (2) induction of temperature-dependent toxins; (3) induction or control of inflammatory responses. In this article, we review the interactions among risk factors for SIDS for their effects on induction or control of inflammatory responses. The risk factors studied are genetic factors (sex, cytokine gene polymorphisms among ethnic groups at high or low risk of SIDS); developmental stage (changes in cortisol and testosterone levels associated with 2- to 4-month age range); environmental factors (virus infection, exposure to cigarette smoke). These interactions help to explain differences in the incidences of SIDS observed between ethnic groups prior to public health campaigns to reduce these infant deaths.

Effects of a community-based weight loss intervention on adipose tissue circulating factors.

AIMS: Obesity is associated with metabolic dysfunctions, which may be mediated by changes in adipose tissue signaling factors. These molecules are denoted as Adipose Tissue Generated Mediators of CardioVascular Risk (ATGMCVR) here, and include leptin, adiponectin, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and plasminogen activator inhibitor 1 (PAI-1). This study examined the effect of a weight loss program on ATGMCVR in obese adults with prediabetes. MATERIALS AND METHODS: Subjects were randomized to usual care (UC; n=15) or lifestyle weight loss groups (LWL; n=15). LWL was a community-based weight loss intervention to promote physical activity and healthy eating. ATGMCVR at 1-year were compared between groups by analysis of covariance; baseline value of the mediator was the covariate. Baseline means for ATGMCVR were compared between those with (n=21) and without (n=9) metabolic syndrome (MetS). RESULTS: At baseline, subjects were 58±9 (SD) years, 70% female, with a BMI of 34±4kg/m(2). One-year weight loss (%) was 7.8±6.0% for LWL and 1.7±4.5% for UC. Group differences at 1-year were noted (adjusted means [95%CI] for UC and LWL, respectively) for adiponectin (8526.3 [7397.7, 9827]; 10,870.9 [9432.0, 12,529.3]ng/ml; p=0.02), leptin (30.4 [26.1, 35.4]; 23.7 [20.3, 27.5]ng/ml; p=0.02), IL-6 (0.4 [0.3, 0.5]; 0.2 [0.1, 0.2] pg/ml; p=0.001), and PAI-1 (50 [42.7, 58.7]; 36.2 [30.8, 42.4]pg/ml; p=0.01). No differences in baseline ATGMCVR were seen between subjects with and without MetS. CONCLUSION: These findings suggest ATGMCVR can be improved with weight loss; larger studies are needed to determine if improvements in metabolic dysfunction are related to changes in ATGMCVR.

Development of an experimental model for assessing the effects of cigarette smoke and virus infections on inflammatory responses to bacterial antigens.

Interactions among major risk factors associated with bacterial infections were assessed in a model system using surrogates for virus infection; IFN-g, and exposure to cigarette smoke; cigarette smoke extract (CSE), nicotine and cotinine. Cytokine responses elicited by LPS from THP-1 cells in the presence of these components, or combinations of components, were assessed by multiplex bead assay, i.e. IL-1ß, IL-6, IL-8, IL-10, TNF-α and IFN-γ. IFN-γ-priming significantly increased pro-inflammatory cytokines induced by LPS. CSE suppressed production of pro-inflammatory cytokines IL-1ß, TNF-α and IFN-γ, but enhanced production of IL-8. Nicotine and cotinine suppressed all cytokine responses. In combination, IFN-γ masked the inhibitory effects of CSE. In relation to the objectives of the study, we concluded that (a) IFN-γ at biologically relevant concentrations significantly enhanced pro-inflammatory responses; (b) CSE, nicotine and cotinine dysregulated the inflammatory response and that the effects of CSE were different from those of the individual components, nicotine and cotinine; (c) when both IFN-γ and CSE were present, IFN-γ masked the effect of CSE. There is a need for clinical investigations on the increase in IL-8 responses in relation to exposure to cigarette smoke and increased pro-inflammatory responses in relation to recent viral infection.

Diabetes prevention, weight loss, and social support: program participants' perceived influence on the health behaviors of their social support system.

This study examined participants' perceptions of how their involvement in a well-established weight loss and diabetes prevention program influenced their social support persons (SSPs). Utilizing a mixed-methods approach, participants were surveyed to determine their perceived influence on SSPs. Compared to controls, intervention participants reported that SSPs' lifestyle changes were more positively influenced by their study participation, and their amount of weight loss was related to favorability of perceived changes in SSPs' eating habits. Themes of lifestyle changes, knowledge dissemination, and motivation emerged from responses. Future lifestyle change interventions could potentially capitalize on program participants' influence on their social support networks.

Healthy Living Partnerships to Prevent Diabetes (HELP PD): design and methods.

Although the Diabetes Prevention Program (DPP) developed a lifestyle weight loss intervention that has been demonstrated to prevent type 2 diabetes in high-risk individuals, it has yet to be widely adopted at the community level. The Healthy Living Partnership to Prevent Diabetes study (HELP PD) was designed to translate the DPP approach for use in community settings as a cost-effective intervention led by Community Health Workers (CHW's) and administered through a Diabetes Care Center (DCC). Approximately 300 overweight and obese (BMI 25-40 kg/m(2)) individuals with prediabetes (fasting blood glucose 95-124 mg/dl) were randomly assigned to either a lifestyle weight loss intervention (LW) or an enhanced usual care comparison condition (UC). The goal of LW is >or=7% weight loss achieved through increases in physical activity (180 min/wk) and decreases in caloric intake (approximately 1500 kcal/day). The intervention consists of CHW-led group-mediated cognitive behavioral meetings that occur weekly for 6 months and monthly thereafter for 18 months. UC consists of 2 individual meetings with a registered dietitian and a monthly newsletter. The primary outcome is change in fasting blood glucose. Secondary outcomes include cardiovascular risk factors, health-related quality of life, and social cognitive variables. Outcomes are masked and are collected every 6 months. The cost-effectiveness of the program will also be assessed. A community-based program that is administered through local DCC's and that harnesses the experience of community members (CHW's) may be a promising strategy for the widespread dissemination of interventions effective at preventing type 2 diabetes in high risk individuals.

Proinflammatory responses to lipo-oligosaccharide of Neisseria meningitidis immunotype strains in relation to virulence and disease.

Inflammatory responses to lipo-oligosaccharide (LOS) contribute to the severity of meningococcal disease. Strains that express the L(3,7,9) LOS immunotypes are isolated from the majority of patients, but other immunotypes are isolated predominantly from carriers. Inflammatory responses elicited from a human monocytic cell line (THP-1) that had been pretreated with vitamin D3 (VD3) were compared after stimulation with purified LOSs from standard immunotype strains. The neutralizing effects of normal human serum and serum from mice immunized with strain B:2a:P1.5,2:L3 were compared. LOSs of immunotypes L3, L7, L8, and L9 induced significantly higher levels of tumor necrosis factor-alpha and interleukin-6, compared with other immunotypes. Normal human serum neutralized the proinflammatory responses to LOSs of all immunotypes tested. Immune mouse serum neutralized inflammatory responses against LOSs from immunotypes with epitopes cross-reactive with L(3,7,9) moieties. Antibodies found in normal human serum and immune mouse serum to the oligosaccharide, core, and lipid A moieties of meningococcal endotoxin contribute to neutralizing activity.