Age at Adiposity Rebound Is Associated with Fat Mass in Young Adult Males—The GOOD Study

Objective

Age at adiposity rebound (AR) is associated with obesity and Type 2 Diabetes in adults. The aim of the present study was to investigate the role of age at AR in adult fat mass, fat distribution and pubertal timing for a Swedish cohort.

Patients and Methods

This is a retrospective cohort study. Detailed growth charts were retrieved for the men participating in the population-based GOOD (Gothenburg Osteoporosis and Obesity Determinants) study (n = 573). Body composition was analysed using dual X-ray absorptiometry and computed tomography at 18–20 years of age. Age and BMI at AR were calculated using pediatric growth charts and AR was defined as the lowest BMI between 3 and 9 years of age.

Results

Subjects were divided into early (age at AR below 5.4 years of age), middle (age at AR 5.4 to 6.8 years of age) and late (age at AR after 6.8 years of age) age at AR tertiles. Subjects in the early age at AR tertile had higher young adult BMI (+8%), whole body fat mass (+34%) and amount of subcutaneous adipose tissue (+61%) than the subjects in the middle and late tertiles (p<0.01). The early age at AR tertile had an increased risk of obesity (Odds Ratio 4.1 [95% CI 1.2–13.9]) compared with the middle and late tertiles. In addition, the early age at AR tertile had Peak Height Velocity (PHV) 7 months earlier than the late tertile.

Conclusions

Early age at AR was associated with young adult obesity as a consequence of a high amount of subcutaneous adipose tissue in men. In addition we made the novel observation that early age at AR was associated with an early puberty in men.     

Helicobacter pylori Infection Is Associated with Higher CD4 T Cell Counts and Lower HIV-1 Viral Loads in ART-Na?ve HIV-Positive Patients in Ghana

Background

Worldwide, there is a high co-endemicity of HIV and H. pylori infection and there is growing evidence that H. pylori co-infection is associated with parameters of HIV disease progression. The objective of this study was to investigate the prevalence of H. pylori infection, and the association with clinical, immunological and virological parameters in a large cohort of HIV-infected individuals and uninfected controls in a West African country.

Methods

HIV-patients (n = 1,095) and HIV-negative individuals (n = 107) were recruited at a university hospital in Ghana. H. pylori status was determined using stool antigen testing. HIV-related, clinical and socio-demographic parameters were recorded and analyzed according to H. pylori status.

Results

The prevalence of H. pylori infection was significantly lower in HIV-positive compared to HIV-negative individuals (51.5 vs. 88%, p<0.0001). In HIV patients, H. pylori prevalence decreased in parallel with CD4+ T cell counts. In ART-naïve HIV-infected individuals, but not in those taking ART, H. pylori infection was associated with higher CD4 cell counts (312 vs. 189 cells/μL, p<0.0001) and lower HIV-1 viral loads (4.92 vs. 5.21 log10 copies/mL, p = 0.006). The findings could not be explained by socio-demographic confounders or reported use of antibiotics. Having no access to tap water and higher CD4+ T cell counts were identified as risk factors for H. pylori infection.

Conclusions

H. pylori prevalence was inversely correlated with the degree of immunosuppression. In ART-naïve individuals, H. pylori infection is associated with favorable immunological and virological parameters. The underlying mechanisms for this association are unclear and warrant investigation.     

Clinical,Immunological and Treatment-Related Factors Associated with Normalised CD4+/CD8+ T-Cell Ratio: Effect of Na?ve and Memory T-Cell Subsets

Background

Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

Methods

A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

Results

We recruited 190 subjects, age 42(36–48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6–10.2) years. Nadir and current CD4+ counts were 200(112–309) and 465(335–607) cells/mm³ respectively. Median CD4+/CD8+ ratio was 0.6(0.4–1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0–38.3)% were naïve, 36.8(29.0–40.0)% central memory and 27.4(20.0–38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2–25.5)% were naïve, 19.9(12.7–26.6)% central memory and 41.0(31.8–52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0–36.0)% versus 14.4(9.4–21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5–567) versus 765(603–1084) cells/mm³, p<0.001.

Conclusions

Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.     

Hierarchy Low CD4+/CD8+ T-Cell Counts and IFN-γ Responses in HIV-1+ Individuals Correlate with Active TB and/or M.tb Co-Infection

Objective

Detailed studies of correlation between HIV-M.tb co-infection and hierarchy declines of CD8+/CD4+ T-cell counts and IFN-γ responses have not been done. We conducted case-control studies to address this issue.

Methods

164 HIV-1-infected individuals comprised of HIV-1⁺ATB, HIV-1⁺LTB and HIV-1⁺TB^- groups were evaluated. Immune phenotyping and complete blood count (CBC) were employed to measure CD4+ and CD8+ T-cell counts; T.SPOT.TB and intracellular cytokine staining (ICS) were utilized to detect ESAT6, CFP10 or PPD-specific IFN-γ responses.

Results

There were significant differences in median CD4+ T-cell counts between HIV-1⁺ATB (164/μL), HIV-1⁺LTB (447/μL) and HIV-1⁺TB^- (329/μL) groups. Hierarchy low CD4+ T-cell counts (<200/μL, 200-500/μL, >500/μL) were correlated significantly with active TB but not M.tb co-infection. Interestingly, hierarchy low CD8+ T-cell counts were not only associated significantly with active TB but also with M.tb co-infection (P<0.001). Immunologically, HIV-1⁺ATB group showed significantly lower numbers of ESAT-6-/CFP-10-specific IFN-γ+ T cells than HIV-1⁺LTB group. Consistently, PPD-specific IFN-γ+CD4+/CD8+ T effector cells in HIV-1⁺ATB group were significantly lower than those in HIV-1⁺LTB group (P<0.001).

Conclusions

Hierarchy low CD8+ T-cell counts and effector function in HIV-1-infected individuals are correlated with both M.tb co-infection and active TB. Hierarchy low CD4+ T-cell counts and Th1 effector function in HIV-1+ individuals are associated with increased frequencies of active TB, but not M.tb co-infection.     

The Gait Deviation Index Is Associated with Hip Muscle Strength and Patient-Reported Outcome in Patients with Severe Hip Osteoarthritis—A Cross-Sectional Study

BackgroundThe Gait Deviation Index summarizes overall gait ‘quality’, based on kinematic data from a 3-dimensional gait analysis. However, it is unknown which clinical outcomes may affect the Gait Deviation Index in patients with primary hip osteoarthritis. The aim of this study was to investigate associations between Gait Deviation Index as a measure of gait ‘quality’ and hip muscle strength and between Gait Deviation Index and patient-reported outcomes in patients with primary hip osteoarthritis.MethodForty-seven patients (34 males), aged 61.1 ± 6.7 years, with BMI 27.3 ± 3.4 (kg/m²) and with severe primary hip osteoarthritis underwent 3-dimensional gait analysis. Mean Gait Deviation Index, pain after walking and maximal isometric hip muscle strength (flexor, extensor, and abductor) were recorded. All patients completed the ‘Physical Function Short-form of the Hip disability and Osteoarthritis Outcome Score (HOOS-Physical Function) and the Hip disability and Osteoarthritis Outcome Score subscales for pain (HOOS-Pain) and quality-of-life (HOOS-QOL).ResultsMean Gait Deviation Index was positively associated with hip abduction strength (p<0.01, r = 0.40), hip flexion strength (p = 0.01, r = 0.37), HOOS-Physical Function (p<0.01, r = 0.41) HOOS-QOL (p<0.01, r = 0.41), and negatively associated with HOOS-Pain after walking (p<0.01, r = -0.45). Adjusting the analysis for walking speed did not affect the association.ConclusionPatients with the strongest hip abductor and hip flexor muscles had the best gait ‘quality’. Furthermore, patients with higher physical function, quality of life scores and lower pain levels demonstrated better gait ‘quality’. These findings indicate that interventions aimed at improving hip muscle strength and pain management may to a moderate degree improve the overall gait ‘quality’ in patients with primary hip OA.     

Apolipoprotein ε4 Is Associated with Lower Brain Volume in Cognitively Normal Chinese but Not White Older Adults

Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer’s disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (P_uncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (P_uncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (P_FWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.     

Is Clinical Practice Concordant with the Changes in Guidelines for Antiretroviral Therapy Initiation during Primary and Chronic HIV-1 Infection? The ANRS PRIMO and COPANA Cohorts

Objective

Guidelines for initiating HIV treatment are regularly revised. We explored how physicians in France have applied these evolving guidelines for ART initiation over the last decade in two different situations: chronic (CHI) and primary HIV-1 infection (PHI), since specific recommendations for PHI are also provided in France.

Methods

Data came from the ANRS PRIMO (1267 patients enrolled during PHI in 1996–2010) and COPANA (800 subjects enrolled at HIV diagnosis in 2004–2008) cohorts. We defined as guidelines-inconsistent during PHI and CHI, patients meeting criteria for ART initiation and not treated in the following month and during the next 6 months, respectively.

Results

ART initiation during PHI dramatically decreased from 91% of patients in 1996–99 to 22% in 2007 and increased to 60% in 2010, following changes in recommendations. In 2007, however, after the CD4 count threshold was raised to 350 cells/mm³ in 2006, only 55% of the patients with CD4≤350 were treated and 66% in 2008. During CHI, ART was more frequently initiated in patients who met the criteria at entry (96%) than during follow-up: 83% when recommendation to treat was 200 and 73% when it was 350 cells/mm³. Independent risk factors for not being treated during CHI despite meeting the criteria were lower viral load, lower educational level, and poorer living conditions.

Conclusion

HIV ART initiation guidelines are largely followed by practitioners in France. What can still be improved, however, is time to treat when CD4 cell counts reach the threshold to treat. Risk factors for lack of timely treatment highlight the need to understand better how patients’ living conditions and physicians’ perceptions influence the decision to initiate treatment.     

Clinical Prognostic Value of RNA Viral Load and CD4 Cell Counts during Untreated HIV-1 Infection—A Quantitative Review

Background

The prognostic value of CD4 counts and RNA viral load for identifying treatment need in HIV-infected individuals depends on (a) variation within and among individuals, and (b) relative risks of clinical progression per unit CD4 or RNA difference.

Methodology/Principal Findings

We reviewed these measurements across (a) 30 studies, and (b) 16 cohorts of untreated seropositive adults. Median within-population interquartile ranges were 74,000 copies/mL for RNA with no significant change during the course of infection; and 330 cells/µL for CD4, with a slight proportional increase over infection. Applying measurement and physiological fluctuations observed on chronically infected patients, we estimate that 45% of population-level variation in RNA, and 25% of variation in CD4, were due to within-patient fluctuations. Comparing a patient with RNA at upper 75^th centile with a patient at median RNA, 5-year relative risks were 1.4 (95% CI 1.2–1.7) for AIDS and 1.5 (1.3–1.9) for death, without change over the course of infection. In contrast, for a patient with CD4 count at the lower 75^th centile, relative risks increased from 1.0 at seroconversion to maxima of 6.3 (4.4–8.9) for AIDS and 5.5 (2.7–10.1) for death by year 6, when the population median had fallen to 300 cells/µL. Below 300 cells/µL, prognostic power did not increase, due to a narrower CD4 range.

Conclusions

Findings support the current WHO recommendation (used with clinical criteria) to start antiretroviral treatment in low-income settings at CD4 thresholds of 200–350 cells/µL, without pre-treatment RNA monitoring – while not precluding earlier treatment based on clinical, socio-demographic or public health criteria.     

The Use of Alendronate Is Associated with a Decreased Incidence of Type 2 Diabetes Mellitus—A Population-Based Cohort Study in Taiwan

Purpose

Bone remodeling has been linked to glucose metabolism in animal studies, but the results of human trials were inconclusive. Bisphosphonates may play a role in glucose metabolism through their impacts on bone remodeling enzymes. In this study, we aimed to examine the influence of alendronate usage on the incidence of type 2 diabetes mellitus (DM) among osteoporotic patients.

Methods

A retrospective cohort study was designed to include osteoporotic patients without DM from a population-based cohort containing 1,000,000 subjects. Patients treated with alendronate (exposed group, N=1,011) were compared with those who received no treatment (age and gender matched non-exposed group, N=3,033). Newly diagnosed DM was identified from medical records by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code. The incidence of DM in both groups was calculated for comparison.

Results

The non-exposed group had a significantly higher incidence of DM (Odds ratio 1.21, 95% confidence interval 1.03~1.41) when compared with the exposed group. In subgroup analysis, the DM risk reduction in exposed group was only significant among those younger than 65 years and those without hypertension or dyslipidemia. Patients who were prescribed alendronate more than or equal to 3 times had demonstrated a significant reduction in DM risk.

Conclusions

Our study showed alendronate might yield a protective effect for incident DM. This effect became insignificant in patients with older age, dyslipidemia or hypertension. The underlying mechanism needs further exploration with prospective data for confirmation of the observed findings.     

Selective support of a mouse thymus epithelial cell line （MTEC1） to the viability and proliferation of CD4＋CD8—,CD4^—CD8^—,and CD4^＋CD8^＋thymocytes in vitro

The MTEC1 cell line,established in our laboratory,is a normal epithelial cell line derived from thymus medulla of Balb/c mice and these cells constituteively produce multiple cytokines.The selection of thymic microenvironment on developing T cells was investigated in an in vitro system.Unseparated fresh thymocytes from Balb/c mice were cocultured with MTEC1 cells or/and MTEC1-SN,then,the viability,proliferation and phenotypes of cultured thymocytes were assessed.Without any exogenous stimulus,both MTEC1 cells and MTEC1-SN were able to maintain the viability of thymocytes,while only the MTEC1 cells,not the MTEC1-SN,could directly activate thymocytes to exhibit moderate proliferation,indicating that the proliferative signal is delivered through cell surface interatcions of MTEC1 cells and thymocytes.Phenotype analysis on FACS of viable thymocytes after coculture revealed that MTEC1 cells preferentially activate the subsets of CD4^ CD8^-,CD4^ CD^8 and CD^4- CD^8- thymocytes;whereas MTEC1-SN preferentially maintained the viability of CD4^ CD^8- and CD4^-CD8^ thymocyte subsets.For the Con A-activated thymocytes.both MTEC1 cells and MTEC1-SN provided accessory signal(s) to significantly increase the number of viable cells and to markedly enhance the proliferation of thymocytes with virtually equal potency,phenotyped as CD4^ CD8^-,CD4^-CD8^ ,and CD^4-CD8^-subests,In summary,MTEC1 cells displayed Selection of thymic epithelial cells on thymocyte subsets. selective support to the different thymocyte subsets,and the selectivity is dependent on the status of thymocytes.     

SDF1 Gene Variation Is Associated with Circulating SDF1α Level and Endothelial Progenitor Cell Number–The Bruneck Study

Background

Stromal cell-derived factor-1 (SDF1) and its receptor CXC chemokine receptor 4 (CXCR4) play a critical role in progenitor cell homing, mobilization and differentiation. It would be interesting to assess the predictive value of SDF-1alpha level for EPC number, and to ascertain whether there is a relationship between SDF1 gene variation, plasma SDF-1alpha level, and the number and function of circulating EPCs. We also tested whether EPC number and function was related to CXCR4 gene variation.

Methodology and Principal Findings

We genotyped a cohort of individuals who participated in the Bruneck Study for single nucleotide polymorphisms (SNPs) in the SDF1 and CXCR4 genes, and measured blood SDF1α level as well as EPC number and function. SDF1α levels were correlated with age, gender, alcohol consumption, circulating reticulocyte numbers, and concentrations of matrix metalloproteinase-9, C-reactive protein, cystatin C, fibrinogen and homocytein. In blood samples taken in 2005, EPC number was inversely associated with SDF1α level (p<0.001). EPC number in 2005 was also inversely associated with SDF1α level in 2000 (p = 0.009), suggesting a predictive value of plasma SDF1α level for EPC number. There was an association between the SDF1 gene rs2297630 SNP A/A genotype, increased SDF1α level (p = 0.002) and lower EPC number (p = 0.006).

Conclusions

Our data indicate that a SDF1 gene variation (rs2297630) has an influence on SDF1α level and circulating EPC number, and that plasma SDF1α level is a predictor of EPC number.     

Evidence for an Underlying CD4 Helper and CD8 T-Cell Defect in B-Cell-Deficient Mice: Failure To Clear Persistent Virus Infection after Adoptive Immunotherapy with Virus-Specific Memory Cells from μMT/μMT Mice

Adoptive transfer of virus-specific memory lymphocytes can be used to identify factors and mechanisms involved in the clearance of persistent virus infections. To analyze the role of B cells in clearing persistent infection with lymphocytic choriomeningitis virus (LCMV), we used B-cell-deficient μMT/μMT (B−/−) mice. B−/− mice controlled an acute LCMV infection with the same kinetics and efficiency as B-cell-competent (B+/+) mice via virus-specific, major histocompatibility complex (MHC) class I-restricted CD8⁺ cytotoxic T lymphocytes (CTL). CTL from B−/− and B+/+ mice were equivalent in affinity to known LCMV CTL epitopes and had similar CTL precursor frequencies (pCTL). Adoptive transfer of memory cells from B+/+ mice led to virus clearance from persistently infected B+/+ recipients even after in vitro depletion of B cells, indicating that B cells or immunoglobulins are not required in the transfer population. In contrast, transfer of memory splenocytes from B−/− mice failed to clear virus. Control of virus was restored neither by transferring higher numbers of pCTL nor by supplementing B−/− memory splenocytes with LCMV-immune B cells or immune sera. Instead, B−/− mice were found to have a profound CD4 helper defect. Furthermore, compared to cultured splenocytes from B+/+ mice, those from B−/− mice secreted less gamma interferon (IFN-γ) and interleukin 2, with differences most pronounced for CD8 T cells. While emphasizing the importance of CD4 T-cell help and IFN-γ in the control of persistent infections, the CD4 T-helper and CD8 T-cell defects in B−/− mice suggest that B cells contribute to the induction of competent T effector cells.Cytotoxic T lymphocytes (CTL) have in general been associated with the resolution of both acute and chronic viral infections. As first shown by studies of lymphocytic choriomeningitis virus (LCMV) in mice, its natural host, a critical component of immune responses to virus infection is the induction of virus-specific major histocompatibility complex (MHC) class I-restricted CTL (reviewed in reference 14). Evidence that these cells can curtail acute viral infections and clear virus and viral genetic material from sera, peripheral blood leukocytes, and infected tissues came from adoptive transfer of LCMV memory CTL into mice persistently infected with LCMV (1, 25, 33, 47, 53).Studies with humans have correlated the presence of CTL with the control of acute infection and clearance of virus and the absence of CTL activity with persistent viral infections. Hence, humans with genetic deficiencies in the humoral compartment of the immune system but with an intact T-cell compartment overcome most viral infections and display immunological memory when challenged or reinfected with the same virus. For example, agammaglobulinemic children recover from acute measles infection as well as do fully immunocompetent individuals and resist reinfection (23). In contrast, individuals with genetic or acquired defects in the T-cell compartment generally cannot control viral infections. Similarly, activity of CTL specific for hepatitis B virus (HBV) is associated with control of acute HBV infection; in the absence of CTL, HBV persists (39). Additionally, anti-HIV CTL dramatically decrease the load of human immunodeficiency virus (HIV) in infected patients, whereas loss of CTL function is accompanied by regress from a relatively healthy clinical stage to AIDS or rapid development of disease after HIV infection (9, 32). Finally, diminished or missing CTL responses to human cytomegalovirus (HCMV) facilitate HCMV disease in individuals undergoing bone marrow transplantation (40). Adoptive transfer of HCMV MHC-restricted CTL into such patients prevented CMV viremia or CMV disease (55). Thus, understanding the requirements for initiation and maintenance of CTL activity is essential.Earlier, we and others documented the requirement for CD4 T-cell help (5, 16, 29, 48) and gamma interferon (IFN-γ) (48) in maintaining sufficient CTL activity in vivo and resolution of a chronic LCMV infection. Here, we evaluate the role of B lymphocytes in this process. Under the appropriate signals, B lymphocytes can differentiate into plasma cells to function as antibody-secreting cells. Trapping of antibody-antigen complexes as well as processing of antigen and peptide presentation within the MHC complex allows B cells to also function as antigen-presenting cells (APC) to T cells (22). Furthermore, B cells release numerous growth factors and cytokines that regulate immune responses (44).To ascertain the role of B lymphocytes in the clearance of both acute and persistent LCMV infections, we used μMT/μMT B-cell-deficient (B−/−) mice which lack functional B cells and antibody. Earlier studies showed that CD8 T cells from these mice were capable of controlling an acute LCMV infection and that there was no defect in generating CTL precursors (3). Our results confirm and expand these findings. We demonstrate that while adoptive transfer of memory cells from B+/+ mice easily clears infectious virus and viral material in an MHC-matched persistently infected recipient, transfer of similar cells from B−/− mice does not. However, failure to terminate the persistent infection does not result from absence of B cells in the transfer population. Apparently, B−/− mice have a fundamental defect in CD4 helper function as well as a quantitative deficiency in IFN-γ and interleukin 2 (IL-2) preferentially produced by CD8 T cells after LCMV infection. These results emphasize the essential role for CD4 T-lymphocyte help and IFN-γ in achieving CTL activity necessary for clearing a persistent LCMV infection and point to an expanded role for B cells in the development and maintenance of CD4 and CD8 T-cell functions.     

Discordance in CD4+T-Cell Levels and Viral Loads with Co-Occurrence of Elevated Peripheral TNF-α and IL-4 in Newly Diagnosed HIV-TB Co-Infected Cases

Background

Cytokines are the hallmark of immune response to different pathogens and often dictate the disease outcome. HIV infection and tuberculosis (TB) are more destructive when confronted together than either alone. Clinical data related to the immune status of HIV-TB patients before the initiation of any drug therapy is not well documented. This study aimed to collect the baseline information pertaining to the immune status of HIV-TB co-infected patients and correlate the same with CD4+T cell levels and viral loads at the time of diagnosis prior to any drug therapy.

Methodology/Principal Findings

We analyzed the cytokines, CD4+T cell levels and viral loads to determine the immune environment in HIV-TB co-infection. The study involved four categories namely, Healthy controls (n = 57), TB infected (n = 57), HIV infected (n = 59) and HIV-TB co-infected (n = 57) patients. The multi-partite comparison and correlation between cytokines, CD4+T-cell levels and viral loads prior to drug therapy, showed an altered TH1 and TH2 response, as indicated by the cytokine profiles and skewed IFN-γ/IL-10 ratio. Inadequate CD4+T cell counts in HIV-TB patients did not correlate with high viral loads and vice-versa. When compared to HIV category, 34% of HIV-TB patients had concurrent high plasma levels of IL-4 and TNF-α at the time of diagnosis. TB relapse was observed in 5 of these HIV-TB co-infected patients who also displayed high IFN-γ/IL-10 ratio.

Conclusion/Significance

With these studies, we infer (i) CD4+T-cell levels as baseline criteria to report the disease progression in terms of viral load in HIV-TB co-infected patients can be misleading and (ii) co-occurrence of high TNF-α and IL-4 levels along with a high ratio of IFN-γ/IL-10, prior to drug therapy, may increase the susceptibility of HIV-TB co-infected patients to hyper-inflammation and TB relapse.     

Overweight and Class I Obesity Are Associated with Lower 10-Year Risk of Mortality in Brazilian Older Adults: The Bambuí Cohort Study of Ageing

Background

Prospective studies mostly with European and North-American populations have shown inconsistent results regarding the association of overweight/obesity and mortality in older adults. Our aim was to investigate the relationship between overweight/ obesity and mortality in an elderly Brazilian population.

Methods and Findings

Participants were 1,450 (90.2% from total) individuals aged 60 years and over from the community-based Bambuí (Brazil) Cohort Study of Ageing. From 1997 to 2007, 521 participants died and 89 were lost, leading to 12,905 person-years of observation. Body mass index (BMI) and waist circumference (WC) were assessed at baseline and at the 3rd and 5th years of follow-up. Multiple imputation was performed to deal with missing values. Hazard ratios (HR) of mortality for BMI or WC alone (continuous and categorical), and BMI and WC together (continuous) were estimated by extended Cox regression models, which were fitted for clinical, socioeconomic and behavioral confounders. Adjusted absolute rates of death at 10-year follow-up were estimated for the participants with complete data at baseline. Continuous BMI (HR 0.85; 95% CI 0.80–0.90) was inversely related to mortality, even after exclusion of smokers (HR 0.85; 0.80–0.90), and participants who had weight variation and died within the first 5 years of follow-up (HR 0.83; CI 95% 0.73–0.94). Overweight (BMI 25–30 kg/m²) was inversely (HR 0.76; 95%CI 0.61–0.93) and obesity (BMI ≥30 kg/m²; HR 0.85; 95% CI 0.64–1.14) not significantly associated with mortality. Subjects with BMI between 25–35 kg/m² (23.8–25.9%) had the lowest absolute rates of death at 10-years follow-up. The association between WC and death was not significant, except after adjusting WC for BMI levels, when the relationship turned into marginally positive (HR 1.01; CI 95% 1.00–1.02).

Conclusions

The usual BMI and WC cut-off points should not be used to guide public health and clinical weight control interventions in elderly in Brazil.     

The Overexpression of IQGAP1 and β-Catenin Is Associated with Tumor Progression in Hepatocellular Carcinoma In Vitro and In Vivo

The IQ-domain GTPase-activating protein 1 (IQGAP1) is a multifunctional scaffold protein, which interacts with diverse proteins to regulate cell adhesion and cell migration. The abnormal expression of IQGAP1 widely exists in many cancers, but biological roles of IQGAP1 cooperation with its interacting proteins to involve in tumorigenesis remain to clarify. In this study, we have found that IQGAP1 interacts with β-catenin and regulates β-catenin expression in hepatocellular carcinoma (HCC) cells. The expression levels of IQGAP1 and β-catenin and their associations have a positive correlation with cell metastasis ability in several HCC cell lines. The up-regulation of IQGAP1 and β-catenin improves cell proliferation and migration ability of HCC cells, whereas the knockdown of IQGAP1 by small interfering RNA can decrease β-catenin expression, which results in the reduction of cell proliferation and migration ability in vitro. In addition, a significantly higher expression of IQGAP1 and β-catenin also usually exists in human HCC tissues, especially their overexpression is clinicopathologically associated with tumor malignancy. Generally the overexpression and interactions of IQGAP1 and β-catenin contribute to HCC progression by promoting cell proliferation and migration.     

Expression of Cyclin D1 Is Associated with ��-Catenin Expression and Correlates with Good Prognosis in Colorectal Adenocarcinoma

Background

The aim of this study is to investigate the prevalence and prognostic impact of β-catenin and cyclin D1 expression in colorectal carcinoma (CRC) patients.

Method

We evaluated immunohistochemial expression of β-catenin and cyclin D1 using 2-mm cores from 220 CRC patients for tissue microarray, and its significance was statistically evaluated.

Result

Positive expression of β-catenin and cyclin D1 was found in 72.5% (158 of 218 cases) and 59.4% (129 of 217 cases) of CRC patients, respectively. Expression of β-catenin was significantly correlated with tumor location (P = .017), differentiation (P = .010), lymph node metastasis (P = .032), preoperative carcinoembryonic antigen level (P = .032), and cyclin D1 expression (P = .005). Expression of cyclin D1 was significantly correlated with recurrence and/or metastasis (P = .004). In univariate analysis, β-catenin expression predicted more favorable overall survival (P = .022) and cyclin D1 expression predicted both more favorable overall survival and relapse-free survival (P = .004 and P = .006, respectively). Multivariate analysis showed that tumor stage and expression of cyclin D1 were independent prognostic factors significantly associated with overall survival and relapse-free survival.

Conclusion

This study shows that expression of β-catenin and cyclin D1 is associated with favorable clinicopathologic variables and it is a clinically significant prognostic indicator for CRC patients.