Role of Peripheral Blood Mononuclear Cells in the Predisposition of Obese Individuals to Inflammation and Infection

ObjectiveTo compare the production of pro- and anti-inflammatory cytokines by peripheral blood mononuclear cells (PBMC) from obese but otherwise healthy individuals to that of normal-weight volunteers.Methods25 healthy normal-weight subjects and 41 obese individuals were enrolled. Weight and height were measured twice. PBMC were examined for their capacity to generate pro-inflammatory (TNF-α, IFN-γ, IL-1β, IL-6, IL-2) and anti-inflammatory IL-10 and IL-1ra) cytokines.ResultsPBMC from obese individuals, compared to those from subjects with normal weight showed an increased production of the pro-inflammatory cytokines IL-2 (6.7 ± 0.4. vs. 4.9 ± 0.3 ng/ml; p = 0.003), TNF-α (505 ± 45 vs. 277 ± 32 pg/ml; p = 0.001), and IFN-γ (93.8 ± 6.0 vs. 73.9 ± 2.7 ng/ml; p = 0.0016). However, PBMC from obese individuals produced a lower amount of the anti-inflammatory cytokine IL-10 (651 ±72 pg/ml) versus those from subjects with normal weight (951 ± 133 pg/ml; p = 0.039).ConclusionsThe findings imply that obese individuals are in a ‘low-grade inflammatory state’, presumed to be connected with metabolic and cardiovascular co morbidities. The surplus of pro-inflammatory cytokines produced by circulating mononuclear cells of obese individuals, together with those secreted by adipocytes and non-fat cells in the adipose tissue, may contribute to the predisposition of obese patients to inflammation and infections.Key Words: Obesity, Peripheral blood mononuclear cells, Cytokines, Inflammation, Infection     

Adipokine signatures of subcutaneous and visceral abdominal fat in normal-weight and obese women with different metabolic profiles

IntroductionMetabolic syndrome arises from abnormal adipose function accompanied by insulin resistance. As early factors reflecting/impacting lipid storage dysfunction of adipose tissues, we sought to determine adipokine levels in subcutaneous and visceral adipose tissues (SAT and VAT).Material and methodsGene and protein expression levels of leptin, adiponectin, and resistin were analysed in SAT and VAT of normal-weight and overweight/obese women, subclassified according to insulin resistance index, triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels into metabolically healthy and “at risk” groups.ResultsCompared with normal-weight women, obese women had higher serum leptin levels (p < 0.05), as well as increased leptin gene and protein expression in VAT. Conversely, expression levels of leptin were lower in SAT of obese women, and minor in the SAT of “at risk” groups of women, compared with weight-matched healthy groups. In addition, lower adiponectin levels were detected in SAT of metabolically healthy obese women (p < 0.01), and lower in SAT and VAT (p < 0.05) of “at risk” obese women compared to healthy, obese women. Significant differences in resistin levels were only observed in obese women; resistin gene expression was higher in VAT and SAT of obese, compared to normal-weight women. However, higher gene expression was not consistent with protein expression of resistin.ConclusionsLow adiponectin in both examined adipose tissues and inappropriate leptin expression levels in SAT appear to be important characteristics of obesity-related metabolic syndrome. Intriguingly, this adipokine dysregulation is primary seen in SAT, suggesting that endocrine dysfunction in this abdominal depot may be an early risk sign of metabolic syndrome.     

Neck fat and obstructive sleep apnea in obese adolescents

Study ObjectivesIncreased neck circumference, a surrogate for the neck fat that can narrow the upper airway in obese individuals, is a risk factor for obstructive sleep apnea syndrome (OSAS) in adults, but the association between neck fat and OSAS in adolescent males and females is unknown. We hypothesized that obese adolescents with OSAS have more neck fat than controls, females more neck fat than males, and that neck fat correlates with obesity and OSAS severity.MethodsObese adolescents with OSAS and obese and normal-weight controls underwent upper airway magnetic resonance imaging, polysomnography, and anthropometrics, including neck circumference measurement. Intra-neck and subcutaneous neck fat measurements were manually segmented and compared among the three groups using ANOVA and between males and females using t-tests. The relationship between polysomnographic parameters and neck fat measurements was assessed in adolescents with OSAS using Pearson correlations.ResultsOne-hundred nineteen adolescents (38 females) were studied: 39 obese with OSAS, 34 obese controls, and 46 normal-weight controls. Neck fat was not greater in adolescents with OSAS compared to obese controls (p=0.35), and neck fat volume was not related to OSAS severity (p = 0.36). However, obese adolescents had more neck fat than normal-weight controls (p < 0.001), and neck fat volume correlated with neck circumference (r = 0.53, p < 0.001). Females had significantly greater cross-sectional neck fat than males (p < 0.001).ConclusionsWhile neck fat is associated with obesity and neck circumference in adolescents and is greater in females versus males, it does not appear to correlate with presence and severity of OSAS.     

Anxiety and Depressed Mood in Obese Pregnant Women: A Prospective Controlled Cohort Study

BackgroundThe psychological health in obese women during pregnancy has been poorly studied.ObjectiveTo compare levels of anxiety and depressed mood during pregnancy in obese versus normal-weight women.Methods63 obese pregnant women and 156 normal-weight controls were included prospectively before 15 weeks of gestation. Levels of state and trait anxiety and depressed mood were measured during the first, second and third trimester of pregnancy. A linear mixed-effect model with repeated measures was used to evaluate group differences.ResultsThe levels of state anxiety significantly increased from trimester 1 to trimester 3 in obese pregnant women (beta = 3.70; p = 0.007), while this parameter remained constant throughout pregnancy in normal-weight women. Levels of trait anxiety and depressed mood significantly decreased from trimester 1 to trimester 2 in controls, but not in obese pregnant women. Variables such as maternal education, ethnicity, marital state, psychological history and miscarriages, parity and smoking behaviour had significant effects on anxiety and/or depressed moods during pregnancy. Obese pregnant women show higher levels of anxiety and depressive symptomatology compared to normal-weight pregnant women.ConclusionInterventional programmes aiming at preventing the deleterious influence of maternal obesity on perinatal outcomes should include a psycho-educational program specifically tailored to this high-risk group.Key Words: Obesity, Pregnancy, Body mass index, Anxiety, Depressed mood, Psychological aspects, Obesity management     

Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague

Currently, there is no FDA-approved vaccine against Yersinia pestis, the causative agent of bubonic and pneumonic plague. Since both humoral immunity and cell-mediated immunity are essential in providing the host with protection against plague, we developed a live-attenuated vaccine strain by deleting the Braun lipoprotein (lpp) and plasminogen-activating protease (pla) genes from Y. pestis CO92. The Δlpp Δpla double isogenic mutant was highly attenuated in evoking both bubonic and pneumonic plague in a mouse model. Further, animals immunized with the mutant by either the intranasal or the subcutaneous route were significantly protected from developing subsequent pneumonic plague. In mice, the mutant poorly disseminated to peripheral organs and the production of proinflammatory cytokines concurrently decreased. Histopathologically, reduced damage to the lungs and livers of mice infected with the Δlpp Δpla double mutant compared to the level of damage in wild-type (WT) CO92-challenged animals was observed. The Δlpp Δpla mutant-immunized mice elicited a humoral immune response to the WT bacterium, as well as to CO92-specific antigens. Moreover, T cells from mutant-immunized animals exhibited significantly higher proliferative responses, when stimulated ex vivo with heat-killed WT CO92 antigens, than mice immunized with the same sublethal dose of WT CO92. Likewise, T cells from the mutant-immunized mice produced more gamma interferon (IFN-γ) and interleukin-4. These animals had an increasing number of tumor necrosis factor alpha (TNF-α)-producing CD4⁺ and CD8⁺ T cells than WT CO92-infected mice. These data emphasize the role of TNF-α and IFN-γ in protecting mice against pneumonic plague. Overall, our studies provide evidence that deletion of the lpp and pla genes acts synergistically in protecting animals against pneumonic plague, and we have demonstrated an immunological basis for this protection.     

Correlation of Resistin with Inflammatory and Cardiometabolic Markers in Obese Adolescents with and without Metabolic Syndrome

ObjectiveThe link between plasma resistin and obesity-related cardiometabolic disorders in children remains debatable. This study assessed the relationships of plasma resistin with cardiovascular risk factors, pro-inflammatory markers and insulin resistance index (HOMA-IR) in obese (Ob) adolescents and obese adolescents with metabolic syndrome (Ob-MS) compared to healthy controls (CO).Methods114 obese adolescents (60 Ob, age 13.6 ± 0.9 years, BMI 28.0 ± 2.2 kg/m², and 54 Ob-MS, age 13.8 ± 1.0 years, BMI 32.5 ± 4.8 kg/m²) and 37 CO (age 13.7 ± 0.8 years, BMI 22.8 ± 0.8 kg/m²) were studied. Anthropometrics, cardiac variables as well as fasting plasma concentrations of lipids, glucose, insulin, and adipocytokines (resistin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP)) were measured. HOMA-IR was calculated, and the presence of MS was assessed.ResultsPlasma resistin was significantly higher in Ob-MS than in both Ob and CO and was correlated with anthropometric, cardiovascular, pro-inflammatory markers and several components of MS as was HOMA-IR in Ob and Ob-MS. With increasing the number of MS components, plasma resistin, pro-inflammatory markers, and HOMA-IR were also increased. Multiple regression models highlighted significant correlation between resistin and both HOMA-IR (r = 0.40, p < 0.05) and systolic blood pressure (r = 0.63, p < 0.01) in Ob-MS. Conclusion:These results support the hypothesis that there is an association between circulating resistin and childhood obesity-related inflammatory and cardiometabolic events.Key Words: Resistin, Metabolic syndrome, Insulin resistance, Childhood obesity, Inflammation     

Weight loss improves biomarkers endothelial function and systemic inflammation in obese postmenopausal Saudi women

BackgroundAlthough postmenopausal associated disorders are important public health problems worldwide, to date limited studies evaluated the endothelial function and systemic inflammation response to weight loss in obese postmenopausal women.ObjectiveThis study was done to evaluate the endothelial function and systemic inflammation response to weight loss in obese postmenopausal Saudi women.ResultsThe values of body mass index(BMI), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), inter-cellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1) and plasminogen activator inhibitor-1 activity (PAI-1:Ac) were significantly decreased in group (A), while changes were not significant in group (B). Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment.ConclusionWeight loss ameliorates inflammatory cytokines and markers of endothelial function in obese postmenopausal Saudi women.     

Left Ventricular Hypertrophy and Asymptomatic Cardiac Function Impairment in Chinese Patients with Simple Obesity using Echocardiography

BackgroundSimple obesity in China is rising rapidly and causing increasing concern. The objectives of our study are to investigate cardiac structure and function in individuals with simple obesity and to analyze the effect of BMI on left ventricular structure and function.MethodsBetween January 2012 and July 2014, echocardiography was performed in 361 consecutive patients visiting the outpatient echocardiography center for a health examination or cardiac evaluation before a weight loss operation in our hospital. Echocardiographic indices, waist-to-hip ratios, BMI, and metabolic markers were evaluated. We analyzed these data using Student''s t test (normally distributed) or a nonparametric test (not normally distributed) for continuous variables and chi-square test for categorical variables. Multivariate correlation and regression analysis were conducted for comparisons.ResultsThe study sample was divided into three groups: a normal/overweight group (BMI < 28.0 kg/m²), a mildly/moderately obese group (BMI 28-39.9 kg/m²), and a severely obese group (BMI ≥ 40 kg/m²). There were no significant differences in clinical and laboratory characteristics among the groups, except for BMI and waist-to-hip ratio. The severely obese group had a higher left ventricular end diastolic diameter (LVEDD; p < 0.01) and lower left ventricular ejection fraction (LVEF; p < 0.01) than the mildly/moderately obese group, which had a higher LVEDD and LV mass index (LVMI) than the normal/overweight group. BMI correlated well with LVEDD, left ventricular posterior wall thickness at end-diastole (LVPW), LV mass, LVMI, and E/e’. In addition, age was significantly associated with some echocardiographic parameters, including left atrial dimension (r = 0.366, p < 0.01), LVPW (r = 0.347, p < 0.01), interventricular septal thickness at end- diastole (r = 0.351, p< 0.01), and E/A (r = −0.47, p < 0.01).ConclusionsSimple obesity caused cardiac structural changes, including LV hypertrophy and LV enlargement, and severe obesity resulted in asymptomatic LV systolic and diastolic function impairment.Key Words: Obesity, Body mass index, Echocardiography, Tissue Doppler imaging, Left ventricular function     

Fibroblast growth factor 21 levels and liver inflammatory biomarkers in obese subjects after weight loss

IntroductionPrevious studies have hypothesized fibroblast growth factor 21 (FGF-21) as a potential biomarker of the inflammation associated with liver diseases, which is also receiving considerable attention for its potential application concerning the management of obesity and co-morbidities. This study aimed to analyze the response of FGF-21 after a weight loss intervention and the relationships with other putative inflammatory liver biomarkers.Material and methodsSixty-six obese participants from the RESMENA study were evaluated at baseline and following a 6-month energy restriction treatment. Anthropometric, body composition by DXA, routine laboratory measurements, which included transaminases and γ-glutamyl transferase (GGT) were analyzed by standardized methods. Moreover, FGF-21, M30 fragment (M30) and plasminogen activator inhibitor-1 (PAI-I) were analyzed as recognized liver inflammatory related biomarkers with specific ELISA kits.ResultsMost measurements related to hepatic damage, inflammation and adiposity status improved at the end of the 6-month nutritional intervention. In addition, ΔFGF-21 shifts showed statistical relationships with changes in ΔM30, ΔGGT and ΔPAI. The reduction of M30 showed significant associations with changes in transaminases. Furthermore, PAI-I changes were associated with ΔM30 and ΔGGT regardless of weight loss. A linear regression model was set up to assess the influence of ΔPAI-I and ΔM30 on the variability of ΔFGF-21 (23.8%) adjusted by weight loss.ConclusionsThese results demonstrated interactions of some liver inflammatory mediators, specifically M30 and PAI-I with FGF-21. Thus, more investigation about FGF-21 is required given that this protein could be a biomarker of the obesity-inflammation-liver process.     

Transmembrane Tumor Necrosis Factor Alpha Is Required for Enteropathy and Is Sufficient To Promote Parasite Expulsion in Gastrointestinal Helminth Infection

To study the specific role of transmembrane tumor necrosis factor (tmTNF) in protective and pathological responses against the gastrointestinal helminth Trichinella spiralis, we compared the immune responses of TNF-α/lymphotoxin alpha (LTα)^−/− mice expressing noncleavable transgenic tmTNF to those of TNF-α/LTα^−/− and wild-type mice. The susceptibility of TNF-α/LTα^−/− mice to T. spiralis infection was associated with impaired induction of a protective Th2 response and the lack of mucosal mastocytosis. Although tmTNF-expressing transgenic (tmTNF-tg) mice also had a reduced Th2 response, the mast cell response was greater than that observed in TNF-α/LTα^−/− mice and was sufficient to induce the expulsion of the parasite. T. spiralis infection of tmTNF-tg mice resulted in significant intestinal pathology characterized by villus atrophy and crypt hyperplasia comparable to that induced following the infection of wild-type mice, while pathology in TNF-α/LTα^−/− mice was significantly reduced. Our data thus indicate a role for tmTNF in host defense against gastrointestinal helminths and in the accompanying enteropathy. Furthermore, they also demonstrate that TNF-α is required for the induction of Th2 immune responses related to infection with gastrointestinal helminth parasites.Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine considered to play important roles in Th1-mediated protective immune responses. TNF-α is of particular importance in the control of intracellular pathogens such as Mycobacterium tuberculosis and Leishmania species (6). TNF-α is also implicated in a variety of immunopathological conditions; anti-TNF-α treatment inhibits collagen-induced arthritis in mice (46) and the development of intestinal and skin lesions in murine graft-versus-host disease (43). TNF-α also plays an important role in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn''s disease, with increased TNF-α secretion from mononuclear cells isolated from the lamina propriae of IBD patients (40). Furthermore, treatment of wild-type mice with exogenous TNF-α leads to rapid development of severe intestinal lesions characterized by villus atrophy, with apoptotic epithelial cells and edema (15, 20, 44).TNF-α is synthesized as a 26-kDa precursor, which may be proteolytically cleaved by the transmembrane matrix metalloprotease TNF-α-converting enzyme into a 17-kDa secreted monomer, while noncleaved TNF-α is present as a type II transmembrane protein, transmembrane TNF-α (tmTNF-α) (16, 36). Membrane-bound TNF has been shown to be the major activating ligand of the p75 TNF receptor (TNFR) and to suppress the proinflammatory activity of TNF-α signaling via the p55 TNFR (17, 42). Membrane-bound and soluble forms of TNF-α have been shown to exert different effects both in vitro and in vivo (37). The expression of tmTNF on CD4⁺ T cells provides a costimulatory signal to human B cells (5). Transgenic mice expressing a noncleavable mutant of tmTNF-α (tmTNF-tg mice) are resistant to Mycobacterium bovis bacillus Calmette-Guérin, while TNF-α/lymphotoxin alpha (LTα)^−/− mice succumb to infection (41). Mice overexpressing tmTNF are prone to developing arthritis (1), and mice expressing tmTNF but not soluble TNF-α are susceptible to concanavalin A-induced liver disease (30). Furthermore, tmTNF-tg mice treated with lipopolysaccharide and d-galactosamine have reduced mortality compared to wild-type mice.A number of studies also implicate TNF-α in Th2-mediated immune responses. TNF-α has been shown to be necessary for the development of allergic airway inflammation (38) and mast cell-mediated gastric allergic inflammation (14). The expulsion of gastrointestinal (GI) helminths has been shown to be dependent on Th2-mediated cytokine responses, and following the blockade of TNF-α in interleukin-4 (IL-4)^−/− mice, parasite expulsion is delayed, suggesting that TNF-α plays an important role in the IL-13-mediated expulsion of Trichuris muris (3).Results from previous studies using p55 TNFR^−/− mice suggest that TNF-α plays a role in the development of enteropathy but not in the expulsion of Trichinella spiralis from the small intestine (32) and that p75 TNFR^−/− mice develop increased pathology (C. E. Lawrence, unpublished data).The aim of this study was to evaluate the roles played by soluble TNF-α and tmTNF-α in the development of protective Th2 immune responses and pathological responses following T. spiralis infection of wild-type, TNF-α/LTα^−/−, and tmTNF-tg mice. Our results showed that soluble TNF-α but not tmTNF-α is required for the induction of protective Th2 responses and subsequent parasite loss and that tmTNF-α is required for the development of pathological responses.     

Intestinal Secretory Factor Released by Macrophages Stimulated with Clostridium difficile Toxin A: Role of Interleukin 1β

Clostridium difficile toxin A is associated with enterocolitis in animals and humans. However, the mechanisms of its secretory and damaging effects are not totally understood. In this work, we examined the intestinal secretion of electrolytes and water caused by supernatants from macrophages stimulated with toxin A in rabbit ileal mucosa mounted in Üssing chambers. We also investigated the mechanism by which the intestinal secretory factor (ISF) is released from stimulated macrophages. Supernatants from macrophages stimulated with toxin A caused potent intestinal secretion (change in short-circuit current [ΔIsc], 76 μA · cm⁻²; P < 0.01). The release of the ISF was pertussis toxin sensitive (reduction, 61%; P < 0.01) and was also reduced (P < 0.05) by a protein synthesis inhibitor (67%), protease inhibitors (57%), a phospholipase A₂ inhibitor (54%), a cyclo-oxygenase inhibitor (62%), a dual cyclo- and lipoxygenase inhibitor (48%), a platelet-activating factor (PAF) receptor antagonist (55%), and tumor necrosis factor alpha (TNF-α) synthesis inhibitors (48%). However, this release was not inhibited by a lipo-oxygenase inhibitor. Monoclonal anti-interleukin 1β (IL-1β) but not anti-IL-1α antibody blocked (72%; P < 0.01) the secretory action of the ISF, as did recombinant human IL-1 receptor antagonist (80%; P < 0.01). High levels of IL-1β (3,476 pg/ml) were detected by an enzyme-linked immunosorbent assay in the above supernatants. Furthermore, the addition of IL-1β to the serosal side caused a potent secretory effect (ΔIsc, 80 μA · cm⁻²; P < 0.01). These results show that macrophages stimulated with toxin A release an ISF capable of provoking intestinal secretion. The regulation of this factor is dependent upon the activation of the G protein. In addition, prostaglandins, PAF, and TNF-α are involved in the release of the ISF. We conclude that IL-1β is probably the ISF released by macrophages in response to toxin A.     

Depressed Type 1 Cytokine Synthesis by Superantigen-Activated CD4+ T Cells of Women with Human Papillomavirus-Related High-Grade Squamous Intraepithelial Lesions

Carcinoma of the cervix is causally related to infection with the human papillomavirus (HPV), and T cells play a pivotal role in the immune response of the host to rid itself of HPV infection. Therefore, we assessed the T-cell function of women with HPV-related cervical neoplasia against a superantigen, Staphylococcus enterotoxin B (SEB). Each woman provided a cervical brush specimen for HPV DNA testing and Papanicolaou (Pap) smears for the staging of cervical lesions. They also provided a blood specimen for determination of the ability of CD4⁺ T and CD8⁺ T cells to synthesize Th1 (interleukin-2 [IL-2], gamma interferon [IFN-γ], and tumor necrosis factor alpha [TNF-α]) and Th2 (IL-10) cytokines in response to activation with SEB. Compared with control subjects with self-attested negative Pap smears, women with high-grade squamous intraepithelial lesions (HSIL) had significantly lower percentages of activated CD4⁺ T cells that produced IL-2 (P = 0.045), IFN-γ (P = 0.040), and TNF-α (P = 0.015) and a significantly lower percentage of activated CD8⁺ T cells that produced IL-2 (P < 0.01). These data indicate that women with HPV-related cervical HSIL show a decrease in Th1 cytokine production by activated CD4⁺ T cells and suggested that compromised T-helper functions may negatively impact the function of cytotoxic CD8⁺ T cells.     

Reduced Frequency of a CD14+ CD16+ Monocyte Subset with High Toll-Like Receptor 4 Expression in Cord Blood Compared to Adult Blood Contributes to Lipopolysaccharide Hyporesponsiveness in Newborns

The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified by various responses to Toll-like receptor (TLR) agonists in newborns compared to adults. To better understand the mechanistic basis for this age-related difference in innate immunity, we compared tumor necrosis factor alpha (TNF-α) production by monocytes from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from Mycobacterium tuberculosis, a TLR2 ligand) and LPS (lipopolysaccharide from Escherichia coli, a TLR4 ligand). LPS or LAM-induced TNF-α production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1α (IL-1α) stimulated similar levels of TNF-α in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely to be due to differences in the MyD88-dependent signaling pathway. This impaired signaling was attributable, in part, to lower functional TLR4 expression, especially on CD14⁺ CD16⁺ monocytes, which are the primary cell subset for LPS-induced TNF-α production. Importantly, the frequency of CD14⁺ CD16⁺ monocytes in CB was 2.5-fold lower than in AB (P < 0.01). CB from Kenyan newborns sensitized to parasite antigens in utero had more CD14⁺ CD16⁺ monocytes (P = 0.02) and produced higher levels of TNF-α in response to LPS (P = 0.004) than CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14⁺ CD16⁺ activated/differentiated monocyte subset and a correspondingly lower level of functional TLR4 on monocytes contributes to the relatively low TNF-α response to LPS observed in immunologically naive newborns compared to the response in adults.     

Association Between Knee- and Hip-Extensor Strength and Running-Related Injury Biomechanics in Collegiate Distance Runners

ContextRunning-related injuries are common in distance runners. Strength training is used for performance enhancement and injury prevention. However, the association between maximal strength and distance-running biomechanics is unclear.ObjectiveTo determine the relationship between maximal knee- and hip-extensor strength and running biomechanics previously associated with injury risk.DesignCross-sectional study.SettingResearch laboratory.Patients or Other ParticipantsA total of 36 collegiate distance runners (26 men, 10 women; age = 20.0 ± 1.5 years, height = 1.74 ± 0.09 m, mass = 61.97 ± 8.26 kg).Main Outcome Measure(s)Strength was assessed using the 1-repetition maximum (1RM) back squat and maximal voluntary isometric contractions of the knee extensors and hip extensors. Three-dimensional running biomechanics were assessed overground at a self-selected speed. Running variables were the peak instantaneous vertical loading rate; peak forward trunk-lean angle; knee-flexion, internal-rotation, and -abduction angles and internal moments; and hip-extension, internal-rotation, and -adduction angles and internal moments. Separate stepwise linear regression models were used to examine the associations between strength and biomechanical outcomes (ΔR²) after accounting for sex, running speed, and foot-strike index.ResultsGreater 1RM back-squat strength was associated with a larger peak knee-flexion angle (ΔR² = 0.110, ΔP = .045) and smaller peak knee internal-rotation angle (ΔR² = 0.127, ΔP = .03) and internal-rotation moment (ΔR² = 0.129, ΔP = .03) after accounting for sex, speed, and foot-strike index. No associations were found between 1RM back-squat strength and vertical loading rate, trunk lean, or hip kinematics and kinetics. Hip- and knee-extensor maximal voluntary isometric contractions were also not associated with any biomechanical variables.ConclusionsGreater 1RM back-squat strength was weakly associated with a larger peak knee-flexion angle and smaller knee internal-rotation angle and moment in collegiate distance runners. Runners who are weaker in the back-squat exercise may exhibit running biomechanics associated with the development of knee-related injuries.     

Correlation between BOLD-MRI and HIF expression level in renal carcinoma

Occupying about 2%~3% of all malignant tumors, renal carcinoma is the most common primary cancer in kidney. The oxidative level of tumor cells is of vital role for optimizing treatment plan, evaluating efficacy and predicting prognosis. This study thus investigated the R2^* value in mouse renal carcinoma model and the correlation between tumor hypoxia and expression level of hypoxia inducible factor-1 (HIF-1). A total of 20 BALB/C nude mice (4~6 weeks old) were inoculated with human ACHN renal carcinoma cells to generate renal cancer model. After the tumor diameter reached 0.5 cm, all animals were examined by BOLD-MRI, both under normal inhalation (R2a^*) and carbogen treatment (R2b^*). The alternation of R2^* values (ΔR2^*=R2a^* - R2b^*) was calculated. Mice were then sacrificed for Immunohistochemical (IHC) staining targeting HIF-1α and HIF-2α. The positive score of HIF was then analyzed for its correlation with R2^* value. In 18 mice finished both experiments, Pearson correlation analysis revealed significant negative correlation between R2a^* and ΔR2^* (r=-0.48, P<0.05) and positive relationship between ΔR2^* and HIF-2α (r=0.38, P<0.05). HIF-1α level, however, did not correlated with tumor R^* values. The positive correlation between ΔR2^* and HIF-2α, but not HIF-1α, suggested potential role of combined BOLD-MRI technique and HIF-1α staining in clinical diagnosis of renal carcinoma. HIF-2α may work as biological marker for renal cancer.     

Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

The virulence of Candida albicans in a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase gene CHO1 (i.e., cho1Δ/Δ) eliminates PS and blocks the de novo pathway for PE biosynthesis. In addition, the cho1Δ/Δ mutant''s ability to cause invasive disease is severely compromised. The cho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-type C. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. The cho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS in C. albicans results in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.     

Tumor Necrosis Factor Alpha Enhances Antifungal Activities of Polymorphonuclear and Mononuclear Phagocytes against Aspergillus fumigatus

Invasive aspergillosis is a serious complication in immunocompromised patients. The effects of recombinant human tumor necrosis factor alpha (TNF-α) on antifungal activities of human neutrophils (polymorphonuclear leukocytes [PMNs]), human monocytes (MNCs), and rabbit pulmonary alveolar macrophages (PAMs) against Aspergillus fumigatus were studied. The percentage of PMN-induced hyphal damage was increased after 30 min of incubation of PMNs with 0.1 ng of TNF-α per ml at 37°C (P = 0.043). At 0.1 to 10 ng/ml, TNF-α also increased superoxide anion (O₂⁻) produced by PMNs in response to phorbol myristate acetate, N-formylmethionyl leucyl phenylalanine, and unopsonized hyphae (P < 0.01) but did not exert any effect on PMN phagocytosis of conidia in the presence of serum. By comparison, TNF-α induced only a slight increase in O₂⁻ production by MNCs in response to phorbol myristate acetate (P = 0.05) and no concomitant increase in the percentage of MNC-induced hyphal damage. Incubation of MNCs with TNF-α at 0.001 to 10 ng/ml for 2 days had no effect on phagocytosis or conidiocidal activity. By contrast, incubation of PAMs with TNF-α at 0.1 to 10 ng/ml for 2 days increased phagocytosis of conidia (P = 0.03). Thus, TNF-α augments the capacity of PMNs to damage Aspergillus hyphae, possibly through enhanced oxidative mechanisms, and increases PAM phagocytic activity against conidia. As such, TNF-α may have an important role in host defense against aspergillosis, and neutralization of its activity may be complicated by increased susceptibility to aspergillosis.     

Exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise are impaired in overweight/obese postmenopausal women

OBJECTIVE:

The purpose of this study was to compare the heart rate response to exercise and the exercise-induced improvements in muscle strength, cardiorespiratory fitness and heart rate response between normal-weight and overweight/obese postmenopausal women.

METHODS:

Sedentary women (n = 155) were divided into normal-weight (n = 79; BMI <25 kg/m²; 58.3±8.6 years) and overweight/obese (n = 76; BMI ≥25 kg/m²; 58.3±8.6 years) groups, and have their 1-repetition maximum strength (adjusted for body mass), cardiorespiratory fitness and heart rate response to a graded exercise test compared before and after 12 months of a three times-per-week exercise-training program.

RESULTS:

Overweight/obese women displayed decreased upper and lower extremity muscle strengths, decreased cardiorespiratory fitness, and lower peak and reserve heart rates compared to normal-weight women. After follow-up, both groups improved their upper (32.9% and 41.5% in normal-weight and overweight/obese women, respectively) and lower extremity(49.5% and 47.8% in normal-weight and overweight/obese women, respectively) muscle strength. However, only normal-weight women improved their cardiorespiratory fitness (6.6%) and recovery heart rate (5 bpm). Resting, reserve and peak heart rates did not change in either group.

CONCLUSIONS:

Overweight/obese women displayed impaired heart rate response to exercise. Both groups improved muscle strength, but only normal-weight women improved cardiorespiratory fitness and heart rate response to exercise. These results suggest that exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise may be impaired in overweight/obese postmenopausal women.     

The role of Ca2+/calmodulin-dependent protein kinase II and calcineurin in TNF-α-induced myocardial hypertrophy

We investigated whether Ca²⁺/calmodulin-dependent kinase II (CaMKII) and calcineurin (CaN) are involved in myocardial hypertrophy induced by tumor necrosis factor α (TNF-α). The cardiomyocytes of neonatal Wistar rats (1-2 days old) were cultured and stimulated by TNF-α (100 µg/L), and Ca²⁺ signal transduction was blocked by several antagonists, including BAPTA (4 µM), KN-93 (0.2 µM) and cyclosporin A (CsA, 0.2 µM). Protein content, protein synthesis, cardiomyocyte volumes, [Ca²⁺]_i transients, CaMKIIδ_B and CaN were evaluated by the Lowry method, [³H]-leucine incorporation, a computerized image analysis system, a Till imaging system, and Western blot analysis, respectively. TNF-α induced a significant increase in protein content in a dose-dependent manner from 10 µg/L (53.56 µg protein/well) to 100 µg/L (72.18 µg protein/well), and in a time-dependent manner from 12 h (37.42 µg protein/well) to 72 h (42.81 µg protein/well). TNF-α (100 µg/L) significantly increased the amplitude of spontaneous [Ca²⁺]_i transients, the total protein content, cell size, and [³H]-leucine incorporation in cultured cardiomyocytes, which was abolished by 4 µM BAPTA, an intracellular Ca²⁺ chelator. The increases in protein content, cell size and [³H]-leucine incorporation were abolished by 0.2 µM KN-93 or 0.2 µM CsA. TNF-α increased the expression of CaMKIIδ_B by 35.21% and that of CaN by 22.22% compared to control. These effects were abolished by 4 µM BAPTA, which itself had no effect. These results suggest that TNF-α induces increases in [Ca²⁺]_i, CaMKIIδ_B and CaN and promotes cardiac hypertrophy. Therefore, we hypothesize that the Ca²⁺/CaMKII- and CaN-dependent signaling pathways are involved in myocardial hypertrophy induced by TNF-α.