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1.  Effect of Age on Susceptibility to Salmonella typhimurium Infection in C57BL/6 Mice 
Journal of medical microbiology  2009;58(Pt 12):1559-1567.
Aging is associated with a decline in immune function, which predisposes the elderly to higher incidence of infections. Information on the mechanism of age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related difference. We employed the streptomycin (STREP)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related difference in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with 3×108 CFU or 1 ×106 CFU doses of S. Typhimurium had significantly greater S. Typhimurium colonization in ileum, colon, Peyer’s patches, spleen, and liver than those of young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 postinfection. In response to S. Typhimurium infection, the old mice failed to increase ex vivo production of IFN-γ and TNF-α in spleen and mesenteric lymph node cells to the same degree as those observed in the young mice, which was associated with their inability to maintain the presence of neutrophils and macrophages at a “youthful” level. These results indicate that STREP-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-γ and TNF-α production as well as the corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.
doi:10.1099/jmm.0.013250-0
PMCID: PMC2783761  PMID: 19729455
2.  Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice 
Journal of Medical Microbiology  2009;58(Pt 12):1559-1567.
Ageing is associated with a decline in immune function, which predisposes the elderly to a higher incidence of infections. Information on the mechanism of the age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related change. We employed streptomycin (Sm)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with doses of 3×108 or 1×106 c.f.u. S. Typhimurium had significantly greater S. Typhimurium colonization in the ileum, colon, Peyer's patches, spleen and liver than young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 post-infection. In response to S. Typhimurium infection, old mice failed to increase ex vivo production of IFN-γ and TNF-α in the spleen and mesenteric lymph node cells to the same degree as observed in young mice; this was associated with their inability to maintain the presence of neutrophils and macrophages at a ‘youthful’ level. These results indicate that Sm-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-γ and TNF-α production as well as a corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.
doi:10.1099/jmm.0.013250-0
PMCID: PMC2783761  PMID: 19729455
3.  Obesity during Pregnancy and Fetal Iron Status: is Hepcidin the link? 
Objective
To ascertain the effect of obesity-related inflammation on maternal and fetal iron status. We hypothesized that obese pregnant women would have increased inflammation, hepcidin levels, and that their infants would have impaired iron status compared to lean controls.
Study Design
Fifteen obese (Ob) and fifteen lean (Lc) women were recruited in their second trimester of pregnancy. Markers of iron status, inflammation and hepcidin were measured in maternal and cord blood. Student’s t test was used to compare obese and lean groups, and Pearson correlation coefficients were determined between maternal and cord blood values.
Results
Maternal C-reactive protein (CRP) (p<0.01) and hepcidin (p<0.01) were higher, and cord blood iron (p<0.01) was lower in the obese group. Maternal BMI (p<0.01) and hepcidin (p<0.05) were negatively correlated with cord blood iron status.
Conclusions
Maternal obesity is associated with impaired maternal-fetal iron transfer, potentially through hepcidin upregulation.
doi:10.1038/jp.2012.81
PMCID: PMC3718280  PMID: 22722675
Maternal obesity; iron deficiency; inflammation
5.  The Role of Nutrition in Enhancing Immunity in Aging 
Aging and Disease  2011;3(1):91-129.
Aging is associated with declined immune function, particularly T cell-mediated activity, which contributes to increased morbidity and mortality from infectious disease and cancer in the elderly. Studies have shown that nutritional intervention may be a promising approach to reversing impaired immune function and diminished resistance to infection with aging. However, controversy exists concerning every nutritional regimen tested to date. In this article, we will review the progress of research in this field with a focus on nutrition factor information that is relatively abundant in the literature. While vitamin E deficiency is rare, intake above recommended levels can enhance T cell function in aged animals and humans. This effect is believed to contribute toward increased resistance to influenza infection in animals and reduced incidence of upper respiratory infection in the elderly. Zinc deficiency, common in the elderly, is linked to impaired immune function and increased risk for acquiring infection, which can be rectified by zinc supplementation. However, higher than recommended upper limits of zinc may adversely affect immune function. Probiotics are increasingly being recognized as an effective, immune-modulating nutritional factor. However, to be effective, they require an adequate supplementation period; additionally, their effects are strain-specific and among certain strains, a synergistic effect is observed. Increased intake of fish or n-3 PUFA may be beneficial to inflammatory and autoimmune disorders as well as to several age-related diseases. Conversely, the immunosuppressive effect of fish oils on T cell-mediated function has raised concerns regarding their impact on resistance to infection. Caloric restriction (CR) is shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Timing for CR initiation may be important to determine whether CR is effective or even beneficial at all. Recent studies have suggested that CR, which is effective at improving the immune response of unchallenged animals, might compromise the host’s defense against pathogenic infection and result in higher morbidity and mortality. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, wholestic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases
PMCID: PMC3320807  PMID: 22500273
Aging; Immunity; Infection; Nutrition
6.  Calorie Restriction Enhances T-Cell–Mediated Immune Response in Adult Overweight Men and Women 
Calorie restriction (CR) enhances immune response and prolongs life span in animals. However, information on the applicability of these results to humans is limited. T-cell function declines with age. We examined effects of CR on T-cell function in humans. Forty-six overweight, nonobese participants aged 20–42 years were randomly assigned to 30% or 10% CR group for 6 months. Delayed-type hypersensitivity (DTH), T-cell proliferation (TP), and prostaglandin E2 (PGE2) productions were determined before and after CR. DTH and TP to T-cell mitogens were increased in both groups over baseline (p ≤ .019). However, number of positive responses to DTH antigens (p = .016) and TP to anti-CD3 reached statistical significance only after 30% CR (p = .001). Lipopolysaccharide-stimulated PGE2 was reduced in both groups but reached statistical significance after 30% CR (p ≤ .029). These results, for the first time, show that 6-month CR in humans improves T-cell function.
doi:10.1093/gerona/glp101
PMCID: PMC2759570  PMID: 19638417
Calorie restriction; T cell; Immune response; Aging; Obesity
7.  Long-Term Care Facilities: A Cornucopia of Viral Pathogens 
Objectives
To determine the frequency and types of respiratory viruses circulating in Boston long-term care facilities (LTCFs) during a 3-year period.
Design
Observational.
Setting
Thirty-three Boston-area LTCFs over a 3-year period.
Participants
Residents of long-term care who had previously participated in a trial of vitamin E supplementation and had paired serum samples available for viral analysis.
Measurements
Viral antibody titers to eight respiratory viruses (influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus serotype three (PIV-3), PIV-2, human metapneumovirus (hMPV), and coronaviruses 229E and OC43) were measured using enzyme immunoassay at baseline and 53 weeks. Infection was defined as a more than quadrupling of viral titers. Clinical data on respiratory illnesses were collected throughout the study period.
Results
A total of 617 persons were enrolled in the trial. Of these, 382 (62%) had sera available for viral analysis. A total of 204 viral infections were documented in 157 subjects. Serological responses to all eight viruses were documented, with hMPV (12.8%) and coronavirus 229E (10.5%) being the most common and PIV-2 (2.4%) the least common. The occurrence of bronchitis (P = .007), pneumonia (P = .02), and any lower respiratory tract infection (P = .002) was significantly associated with having a viral diagnosis.
Conclusion
A wide range of respiratory viruses cocirculates in LTCFs and contributes to respiratory illness morbidity in these populations.
doi:10.1111/j.1532-5415.2008.01775.x
PMCID: PMC2875942  PMID: 18557966
viral infections; long-term care; human metapneumovirus
8.  Cytokine response to vitamin E supplementation is dependent on pre-supplementation cytokine levels 
BioFactors (Oxford, England)  2008;33(3):191-200.
Vitamin E supplementation has been suggested to improve immune response in the aged in part by altering cytokine production. However, there is not a consensus regarding the effect of supplemental vitamin E on cytokine production in humans. There is evidence that baseline immune health can affect immune response to supplemental vitamin E in the elderly. Thus, the effect of vitamin E on cytokines may depend on their pre-supplementation cytokine response. Using data from a vitamin E intervention in elderly nursing home residents, we examined if the effect of vitamin E on ex vivo cytokine production of IL-1β, IL-6, TNF-α, and IFN-γ depended on baseline cytokine production. . We observed that the effect of vitamin E supplementation on cytokine production depended on pre-supplementation production of the respective cytokines. The interactions between vitamin E and baseline cytokine production were not explained covariates known to impact cytokine production. Our results offer evidence that baseline cytokine production should be considered in studies that examine the effect of supplemental vitamin E on immune and inflammatory responses. Our results could have implications in designing clinical trials to determine the impact of vitamin E on conditions in which cytokines are implicated such as infections and atherosclerotic disease.
PMCID: PMC2769508  PMID: 19478423
Vitamin E; elderly; cytokine production
9.  Fish oil supplementation inhibits NNK-induced lung carcinogenesis in the A/J mouse 
Nutrition and cancer  2009;61(5):663-669.
High intake of fish oil with a low omega-6 (n-6)/omega-3 (n-3) polyunsaturated fatty acid (PUFA) ratio has been suggested to protect against many chronic diseases. However, the effect of different ratios of dietary n-6 and n-3 PUFA on lung tumorigenesis has not been investigated. In this study, we examined the effect of a 4 month dietary supplementation with corn oil (with a high n-6/n-3 ratio) and fish oil (with a low n-6/n-3 ratio) as compared with soybean oil (isocaloric control with the same n-6/n-3 ratio as the base diet) on tumor incidence and tumor prevalence in the A/J mouse model of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis. We found that dietary supplementation had no effect on overall lung tumor incidence but fish oil supplementation was able to decrease lung tumor prevalence by 78% and 80%, compared to groups receiving soybean oil and corn oil supplementation, respectively. The inhibitory effect of fish oil on lung tumor prevalence was associated with increased expressions of cell cycle inhibitor p21Cip1 and lipoxygenase isoforms 15-LOX in the lungs. These data suggest that fish oil with a low ratio of n-6/n-3 PUFA could be beneficial in the prevention of lung carcinogenesis.
doi:10.1080/01635580902825589
PMCID: PMC2765662  PMID: 19838940
fish oil; omega-3 polyunsaturated fatty acids; lung cancer; lipoxygenase enzymes
10.  VITAMIN E AND RESPIRATORY INFECTIONS AMONG ELDERLY NURSING HOME RESIDENTS: A RANDOMIZED CONTROLLED TRIAL** 
Context
Respiratory infections are prevalent in the elderly, resulting in increased morbidity, mortality, and utilization of health care services. Vitamin E supplementation has been shown to improve immune response in the elderly. However, the clinical importance of these findings has not been determined.
Objective
To investigate the effect of 1-year vitamin E supplementation on respiratory infections in elderly nursing home residents
Design
A randomized, double-blind, placebo-controlled trial conducted from April 1998 to August 2001
Setting
33 long-term care facilities in the Boston, Massachusetts area
Participants
617 subjects ≥65 years old, who met the study’s eligibility criteria were enrolled, 73% of whom completed the study. The follow-up time (mean ± SD) was 317±104 and 321±97 days, E and placebo respectively, for all subjects enrolled in the study.
Intervention
A daily vitamin E (200 IU) or placebo capsule; all subjects received a capsule containing 1/2 the Recommended Daily Allowance of essential vitamins and minerals.
Main Outcome Measures
Incidence, number of subjects and number of days with respiratory infections (upper and lower), and number of new antibiotic prescriptions.
Results
There was no statistically significant effect of vitamin E on incidence or number of days with infection for all, upper, or lower respiratory infections. However, fewer vitamin E-supplemented subjects acquired one or more respiratory infections (65% vs 74%, risk ratio=0.88, 95% CI=0.75–0.99, p=0.036 for completed subjects; 60% vs 68%, risk ratio=0.88, 95% CI=0.76–1.00, p=0.048 for all subjects), or upper respiratory infections (50% vs 62%, risk ratio = 0.81, 95% CI=0.66–0.96, p=0.013 for completed subjects; 44% vs 52%, risk ratio=0.84, 95% CI=0.69–1.00, p=0.051 for all subjects). Post hoc sub-group analysis on common colds indicated that the vitamin E group had a lower incidence of common cold (0.66 vs 0.83 per subject-year, rate ratio=0.80, 95% CI=0.64–0.98, p=0.035 for completed subjects; 0.67 vs 0.81 per subject-year, rate ratio=0.83, 95% CI=0.68–1.01, p=0.057 for all subjects) and fewer subjects in the vitamin E group acquired one or more colds (46% vs 57%, risk ratio=0.80, 95% CI=0.64–0.96, p=0.016 for completed subjects; 40% vs 48%, risk ratio=0.83, 95% CI=0.67–1.00, p=0.052 for all subjects). There was no statistically significant vitamin E effect on antibiotic use.
Conclusions
Supplementation with 200 IU per day vitamin E did not have a statistically significant effect on lower respiratory infections in elderly nursing home residents. However, we observed a protective effect of vitamin E supplementation on upper respiratory infections, particularly the common cold, that merits further investigation.
doi:10.1001/jama.292.7.828
PMCID: PMC2377357  PMID: 15315997
Respiratory infections; Upper respiratory infections; Common cold; Vitamin E; Tocopherol; Elderly; Nursing home; Nutritional status
11.  Caloric restriction favorably impacts metabolic and immune/inflammatory profiles in obese mice but curcumin/piperine consumption adds no further benefit 
Background
Obesity is associated with low-grade inflammation and impaired immune response. Caloric restriction (CR) has been shown to inhibit inflammatory response and enhance cell-mediated immune function. Curcumin, the bioactive phenolic component of turmeric spice, is proposed to have anti-obesity and anti-inflammation properties while piperine, another bioactive phenolic compound present in pepper spice, can enhance the bioavailability and efficacy of curcumin. This study sought to determine if curcumin could potentiate CR’s beneficial effect on immune and inflammatory responses in obesity developed in mice by feeding high-fat diet (HFD).
Methods
Mice were fed a HFD for 22 wk and then randomized into 5 groups: one group remained on HFD ad libitum and the remaining 4 groups were fed a 10% CR (reduced intake of HFD by 10% but maintaining the same levels of micronutrients) in the presence or absence of curcumin and/or piperine for 5 wk, after which CR was increased to 20% for an additional 33 wk. At the end of the study, mice were sacrificed, and spleen cells were isolated. Cells were stimulated with T cell mitogens, anti-CD3/CD28 antibodies, or lipopolysaccharide to determine T cell proliferation, cytokine production, and CD4+ T cell subpopulations.
Results
Compared to HFD control group, all CR mice, regardless of the presence of curcumin and/or piperine, had lower body weight and fat mass, lower levels of blood glucose and insulin, and fewer total spleen cells but a higher percentage of CD4+ T cells. Additionally, they demonstrated lower production of pro-inflammatory cytokines IL-1β and TNF-α, a trend toward lower IL-6, and lower production of PGE2, a lipid molecule with pro-inflammatory and T cell-suppressive properties. Mice with CR alone had higher splenocyte proliferation and IL-2 production, but this effect of CR was diminished by spice supplementation. CR alone or in combination with spice supplementation had no effect on production of cytokines IL-4, IL-10, IFN-γ, and IL-17, or the proportion of different CD4+ T cell subsets.
Conclusion
CR on an HFD favorably impacts both metabolic and immune/inflammatory profiles; however, the presence of curcumin and/or piperine does not amplify CR’s beneficial effects.
doi:10.1186/1743-7075-10-29
PMCID: PMC3621165  PMID: 23531279
Obesity; Caloric restriction; Inflammation; T cells; Curcumin; Piperine
12.  Age-Dependent Changes in the Sphingolipid Composition of Mouse CD4+ T Cell Membranes and Immune Synapses Implicate Glucosylceramides in Age-Related T Cell Dysfunction 
PLoS ONE  2012;7(10):e47650.
To determine whether changes in sphingolipid composition are associated with age-related immune dysfunction, we analyzed the core sphingolipidome (i.e., all of the metabolites through the first headgroup additions) of young and aged CD4+ T cells. Since sphingolipids influence the biophysical properties of membranes, we evaluated the compositions of immune synapse (IS) and non-IS fractions prepared by magnetic immuno-isolation. Broadly, increased amounts of sphingomyelins, dihydrosphingomyelins and ceramides were found in aged CD4+ T cells. After normalizing for total sphingolipid content, a statistically significant decrease in the molar fraction of glucosylceramides was evident in both the non-IS and IS fractions of aged T cells. This change was balanced by less dramatic increases in the molar fractions of sphingomyelins and dihydrosphingomyelins in aged CD4+ T cells. In vitro, the direct or enzymatic enhancement of ceramide levels decreased CD4+ T cell proliferation without regard for the age of the responding T cells. In contrast, the in vitro inhibition of glucosylceramidase preferentially increased the proliferation of aged CD4+ T cells. These results suggest that reductions in glucosylceramide abundance contribute to age-related impairments in CD4+ T cell function.
doi:10.1371/journal.pone.0047650
PMCID: PMC3482221  PMID: 23110086

Results 1-12 (12)