Osteoporosis and obesity are chronic disorders that are increasing in prevalence. The pathophysiology of these diseases is multifactorial and includes genetic, environmental and hormonal determinants. Long considered as distinct disorders that rarely are found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. Adiposity can influence bone remodeling through three possible mechanisms including secretion of cytokines that directly target bone, adipokines that influence the central nervous system thereby changing sympathetic impulses to bone, and paracrine influences on adjacent skeletal cells. This review will focus on our current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.
Genome-wide association studies have recently identified genetic polymorphisms associated with common, etiologically complex diseases, for which direct-to-consumer genetic testing with provision of absolute genetic risk estimates is marketed by commercial companies. Polymorphisms associated with atrial fibrillation (AF) have shown relatively large risk estimates but the robustness of such estimates across populations and study designs has not been studied.
A systematic literature review with meta-analysis and assessment of between-study heterogeneity was performed for single nucleotide polymorphisms (SNPs) in the six genetic regions associated with AF in genome-wide or candidate gene studies.
Data from 18 samples of European ancestry (n=12,100 cases; 115,702 controls) were identified for the SNP on chromosome 4q25 (rs220733), 16 samples (n=12,694 cases; 132,602 controls) for the SNP on 16q22 (rs2106261) and 4 samples (n=5,272 cases; 59,725 controls) for the SNP in KCNH2 (rs1805123). Only the discovery studies were identified for SNPs on 1q21 and in GJA5 and IL6R, why no meta-analyses were performed for those SNPs. In overall random-effects meta-analyses, association with AF was observed for both SNPs from genome-wide studies on 4q25 (OR 1.67, 95% CI=1.50–1.86, p=2×10−21) and 16q22 (OR 1.21, 95% CI=1.13–1.29, p=1×10−8), but not the SNP in KCNH2 from candidate gene studies (p=0.15). There was substantial effect heterogeneity across case-control and cross-sectional studies for both polymorphisms (I2=0.50–0.78, p<0.05), but not across prospective cohort studies (I2=0.39, p=0.15). Both polymorphisms were robustly associated with AF for each study design individually (p<0.05).
In meta-analyses including up to 150,000 individuals, polymorphisms in two genetic regions were robustly associated with AF across all study designs but with substantial context-dependency of risk estimates.
atrial fibrillation; genetics; genome-wide; prediction; SNP; meta-analysis
Beta cell regeneration represents a major goal of therapy for diabetes. Unraveling the origin of beta cells during pancreatic regeneration could help restore a functional beta cell mass in diabetes patients. This scientific question has represented a longstanding interest still intensively investigated today. This review focuses on pioneering observations and subsequent theories made hundred years ago and describes how technical innovation helped resolve some, but not all, of the controversies generated by these early investigators. At the end of the nineteenth century, complete pancreatectomy demonstrated the crucial physiological role of the pancreas and its link to diabetes. Pancreatic injury models, including pancreatectomy and ductal ligation, allowed investigators to describe islet function and to assess the regenerative capacity of the pancreas. Three main theories were proposed to explain the origins of newly formed islets: 1) transdifferentiation of acinar cells into islets, 2) islet neogenesis, a process reminiscent of islet formation during embryonic development, and 3) replication of preexisting islet cells. Despite considerable technical innovation in the last fifty years, the origin of new adult beta cells remains highly controversial and the same three theories are still debated today.
Regeneration; Diabetes; Islets; β-cells; Beta-cells; transdifferentiation; Neogenesis; Replication
To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease.
Cross-sectional analyses within the Secondary Manifestations of ARTerial disease (SMART) study, a single centre cohort study.
5,877 patients (mean age 57) with symptomatic and asymptomatic arterial disease who underwent a standardized vascular screening.
Main outcome measure
Self-rated physical and mental health assessed with the Short Form (SF)-36.
In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment was associated with poorer health status independent of important confounders including BP levels; adjusted mean differences (95%CI) in physical and mental health between 0 and ≥3 antihypertensives were -1.2 (-2.1, -0.3) and -3.5 (-4.4; -2.6). Furthermore, lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independently of antihypertensive treatment. Mean differences (95%CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03), and per SD decrease in diastolic BP -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20). The association between low BP and poor health status was particularly present in patients with coronary artery disease.
In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These results might indicate that there are different underlying mechanisms explaining these independent associations.
antihypertensive treatment; blood pressure; physical health; mental health; cardiovascular disease
Genomewide Association Studies (GWAS) have identified thousands of consistently replicated associations between genetic markers and complex disease risk, including cancers. Alone, these markers have limited utility in risk prediction; however, when several of these markers are used in combination, the predictive performance appears to be similar to currently many available clinical predictors. Despite this, there are divergent views regarding the clinical validity and utility of these genetic markers in risk prediction. There are valid concerns, thus providing a direction for new lines of research. Herein, we outline the debate, and use the example of prostate cancer to highlight emerging evidence from studies that aim to address potential concerns. We also describe a translational framework which could be used to guide the development of a new generation of comprehensive research studies aimed at capitalizing on these exciting new discoveries.
cancer; gene polymorphism; molecular medicine; risk factors
To what degree the associations between PCa risk and family history of prostate cancer (PCa) and/or breast cancer (BCa) are attributable to screening biases is unclear. We examined these questions within the REDUCE study, where biopsies were largely independent of prostate specific antigen (PSA) minimizing screening biases.
Data were from REDUCE, which tested dutasteride 0.5 mg daily for PCa risk reduction in men with PSA 2.5–10.0 ng mL−1 and a negative pre- study biopsy. Among men undergoing at least one on-study biopsy with complete data (n = 6415; 78.1%), the association between family history and PCa risk was tested using multivariate logistic regression adjusting for clinicodemographic characteristics.
A family history of PCa alone was associated with increased PCa diagnosis (OR: 1.47, 95%CI: 1.22–1.77). In North America, PCa family history was not related to PCa diagnosis (OR: 1.02, 95%CI: 0.731.44), whereas outside North America, PCa family history was significantly related to diagnosis (OR: 1.72, 95%CI: 1.38–2.15) (P-interaction = 0.01). A family history of both PCa and BCa (OR: 2.54, 95%CI: 1.72–3.75) but not BCa alone (OR: 1.04, 95%CI: 0.84–1.29) was associated with increased PCa risk versus no family history and irrespective of geographical region.
In REDUCE, PCa family history was significantly related to PCa diagnosis, although only for men outside North America. The presence of both PCa and BCa family history significantly increased risk versus PCa family history alone, irrespective of geographical region. Ultimately, our observations may support the need for changes in how we address family history in terms of both risk of PCa diagnosis and general risk stratification.
breast cancer; family history; prostate cancer; REDUCE
Peptide nanostructures containing bioactive signals offer exciting novel therapies of broad potential impact in regenerative medicine. These nanostructures can be designed through self-assembly strategies and supramolecular chemistry, and have the potential to combine bioactivity for multiple targets with biocompatibility. It is also possible to multiplex their functions by using them to deliver proteins, nucleic acids, drugs, and cells. In this review, we illustrate progress made in this new field by our group and others using peptide-based nanotechnology. Specifically, we highlight the use of self-assembling peptide amphiphiles towards applications in the regeneration of the central nervous system, vasculature and hard tissue along with the transplant of islets and the controlled release of nitric oxide to prevent neointimal hyperplasia. Also, we discuss other self-assembling oligopeptide technology and the progress made with these materials towards the development of potential therapies.
Understanding the mechanisms of human autoimmune rheumatic diseases presents a major challenge, due to marked complexity involving multiple domains, including genetics, environment and kinetics. In spite of this, the immune response in each of these diseases is largely specific, with distinct autoantibodies associated with different disease phenotypes. Defining the basis of such specificity will provide important insights into disease mechanism. Accumulating data suggest an interesting paradigm for antigen selection in autoimmunity, in which target tissue and immune effector pathways form a mutually reinforcing partnership. In this model, distinct autoantibody patterns in autoimmunity may be viewed as the integrated, amplified output of several interacting systems, including: (i) the specific target tissue, (ii) the immune effector pathways that modify antigen structure and cause tissue damage and dysfunction, and (iii) the homeostatic pathways activated in response to damage (e.g. regeneration/differentiation/cytokine effects). As unique antigen expression and structure may occur exclusively under these amplifying circumstances, it is useful to view the molecules targeted as ‘neo-antigens’, that is, antigens expressed under specific conditions, rather than ubiquitously. This model adds an important new dynamic element to selection of antigen targets in autoimmunity, and suggests that the amplifying loop will only be identified by studying the diseased target tissue in vivo.
autoantibody; autoantigen; cell death; repair
“The big C”, a common euphemism for cancer, has loomed large on the collective psyche of the mankind for centuries, not least because of the relative dearth of effective treatment against this disease but its ability to relentlessly evade them and come back to haunt us. However, the struggle against cancer took a decisive turn in 1971 when a relentless campaigning by health activists eventually led to signing of the National Cancer Act in the United States, an unprecedented event in the history of diseases. As we commemorate the 40th anniversary of the signing of that historic legislation, an assessment of the progress against cancer would naturally help us understand how we have fared so far in this struggle, and guide us in our efforts to re-strategize and re-deploy our limited resources to their best use against this immortal enemy.
Marjamaa A, Newton-Cheh C, Porthan K, Reunanen A, Lahermo P, Väänänen H, Jula A, Karanko H, Swan H, Toivonen L, Nieminen MS, Viitasalo M, Peltonen L, Oikarinen L, Palotie A, Kontula K, Salomaa V (Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Massachusetts General Hospital, Boston, MA, USA; University of Helsinki, Helsinki, Finland; National Public Health Institute, Helsinki, Finland; Finnish Genome Center, University of Helsinki, Helsinki, Finland; Laboratory of Biomedical Engineering, Helsinki University of Technology, Espoo, Finland; and University of Helsinki, Helsinki, Finland). Common candidate gene variants are associated with QT interval duration in the general population.
QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample.
We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population.
The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QTNc interval (P = 3.6 × 10−11) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QTNc interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P = 4.7 × 10−5], KCNH2 K897T [−2.6 ms (SE 0.5) or −0.14 SD, P = 2.1 × 10−7] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P = 3.2 × 10−24] under additive models.
We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.
epidemiology; genetics; KCNE1; long-QT syndrome; QT interval
Metabolism plays a key role in many major human diseases. Generation of high-throughput omics data has ushered in a new era of systems biology. Genome-scale metabolic network reconstructions provide a platform to interpret omics data in a biochemically meaningful manner. The release of the global human metabolic network, Recon 1, in 2007 has enabled new systems biology approaches to study human physiology, pathology, and pharmacology. There are currently over 20 publications that utilize Recon 1, including studies of cancer, diabetes, host-pathogen interactions, heritable metabolic disorders, and off-target drug binding effects. In this mini-review, we focus on the reconstruction of the global human metabolic network and four classes of its application. We show that computational simulations for numerous pathologies have yielded clinically relevant results, many corroborated by existing or newly generated experimental data.
human metabolism; systems biology; constraints-based modeling
Current vaccines primarily work by inducing protective antibodies. However, in many infections like HIV, malaria and tuberculosis as well as cancers there remains a need for durable and protective T-cell immunity. Here, we summarize our efforts to develop a safe T-cell based protein vaccine that exploits the pivotal role of dendritic cells (DC) in initiating adaptive immunity. Focusing on HIV, gag-p24 protein antigen is introduced into a monoclonal antibody (mAb) that efficiently and specifically targets the DEC-205 antigen uptake receptor on DC. When administered together with synthetic double stranded RNA, polyriboinosinic:polyribocytidylic acid (poly IC) or its analogue poly ICLC (poly IC stabilized with carboxymethylcellulose and poly-L-lysine), as adjuvant, HIV gag-p24 within anti-DEC-205 mAb is highly immunogenic in mice, rhesus macaques, and in ongoing research, healthy human volunteers. Human subjects form both T and B cell responses to DC-targeted protein. Thus, DC-targeted protein vaccines are a potential new vaccine platform, either alone or in combination with highly attenuated viral vectors, to induce integrated immune responses against microbial or cancer antigens, with improved ease of manufacturing and clinical use.
dendritic cells; protein vaccine; adjuvant; T cells; DEC-205; cross-presentation
One of the strongest associations with autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. This risk is 10-fold higher in women who have had a previously affected child with CHB. Anti-Ro/La antibodies are necessary but insufficient to cause disease. In vitro and in vivo experiments suggest that the pathogenesis involves exaggerated apoptosis, macrophage/myfibroblast crosstalk, TGFβ expression and extensive fibrosis in the conducting system and in some cases surrounding myocardium. A disturbing observation is the rapidity of disease progression, with advanced heart block and life-threatening cardiomyopathy observed <2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal has never been achieved, despite dexamethasone. Current strategies include the evaluation of an early echocardiographic marker of injury, such as a prolonged PR interval and the use of IVIG as a preventative measure for pregnancies of mothers with previously affected children.
anti-Ro/La antibodies; congenital heart block; PR interval
To determine mRNA expression differences in genes involved in signaling and modulating sensory fatigue, and muscle pain in patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia Syndrome (FM) at baseline, and following moderate exercise.
Forty eight Patients with CFS-only, or CFS with comorbid FM, 18 Patients with FM that did not meet criteria for CFS, and 49 healthy Controls underwent moderate exercise (25 minutes at 70% maximum age predicted heart-rate). Visual-analogue measures of fatigue and pain were taken before, during, and after exercise. Blood samples were taken before, and 0.5, 8, 24, and 48 hours after exercise. Leukocytes were immediately isolated from blood, number coded for blind processing and analyses, and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic, and immune functions was compared between groups at baseline, and following exercise. Changes in amounts of mRNA were correlated with behavioral measures, and functional clinical assessments.
No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor’s transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM only patients showed no post-exercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than Controls.
At least two subgroups of CFS patients can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the CFS patients with orthostatic intolerance, showed no post-exercise increases in any gene, and was defined by decreases in mRNA for α-2A. FM only patients can be identified by baseline increases in 3 genes. Post-exercise increases for 4 genes meet published criteria as an objective biomarker for CFS, and could be useful in guiding treatment selection for different subgroups.
chronic fatigue syndrome; fatigue; orthostatic symptoms; autonomic dysfunction; gene expression; fibromyalgia
Apolipoprotein A-V (apoAV) contributes to the regulation of triglyceride metabolism, which plays a role in the pathogenesis of atherosclerotic diseases. We therefore ascertained determinants of hepatic APOA5 transcript and apoAV plasma levels in humans.
We determined influences of anthropometric variables, biochemical factors related to lipid and glucose metabolism, hepatic mRNA levels transcribed from the APOA1/C3/A4/A5 cluster and transcription factor genes implicated in the regulation of APOA5 as well as common SNPs at the APOA5 locus on APOA5 expression in 89 obese patients and 22 non-obese controls.
Mean, age and sex adjusted, hepatic APOA5 mRNA or apoAV plasma levels did not differ by obesity status, HOMA-IR or inflammatory markers. In multivariate regression models, the c56C>G SNP, plasma apoCIII, plasma non-esterified fatty acids, hepatic APOA5 transcripts, sex and a weak association with obesity status explained 61% of the variance in apoAV plasma levels. Hepatic transcript levels of CPT1A1 and PPARA, plasma non-esterified fatty acids and the c56C>G SNP explained 48% of the variance in hepatic APOA5 transcript levels.
ApoAV plasma levels are independently associated with plasma free fatty acid and hepatic APOA5 mRNA levels. Associations of APOA5 transcripts with PPARA and CPT1A1 transcripts suggest that APOA5 expression is intimately linked to hepatic lipid metabolism.
Apolipoprotein A-V; APOA5; triglycerides; PPARA; CPT1A; SNP
Background and methods
Endogenous ouabain (EO) is markedly raised in patients with chronic renal failure. As high EO induces myocardial cell hypertrophy in vitro and it is associated with left ventricular hypertrophy (LVH) in essential hypertensives and in patients with heart failure we investigated the relationship between plasma EO and LV mass and geometry in 156 end-stage renal disease (ESRD) patients. EO was measured by a specific radioimmunoassay and by mass spectrometry.
On univariate analysis, plasma EO was directly related to LV mass (r = 0.26, P = 0.001) and LV end diastolic volume (r = 0.25, P = 0.002) and these relationships held true in multiple linear regression models including a series of potential confounders. Patients with eccentric LVH (n = 41, i.e. 26%) had the highest plasma levels of EO when compared to patients with other patterns of LV geometry (P = 0.001). Furthermore, plasma EO had diagnostic value for eccentric LVH because the area under the corresponding ROC curve (68%) was significantly greater (P = 0.002) than the threshold of diagnostic indifference. In this analysis, the sensitivity was 91% and the specificity was 36%. The positive predictive value was 33% but EO had a remarkably high negative predictive value (92%) for the exclusion of eccentric hypertrophy.
In ESRD patients, plasma EO is independently associated with LV mass, LV volume and eccentric LVH. The results of this study are compatible with the hypothesis that EO is involved in alterations of LV mass in ESRD.
dialysis; endogenous ouabain-like factor; left ventricular end diastolic volume; left ventricular hypertrophy
Concern has been recently raised about possible adverse cardio-metabolic effects of high selenium status, such as increased risks of diabetes and hyperlipidemia. However, most of the evidence comes from selenium-replete populations such as the US.
To examine cross-sectional and longitudinal associations of serum selenium with cardiovascular risk factors in Finland where selenium levels were among the lowest in the world until the early 1980s before the implementation of a nationwide selenium fertilization program.
Serum selenium was measured in 1,235 young Finns aged 3-18 years at baseline in 1980 (pre-fertilization), and in a subgroup (N=262) at the 6-year follow-up (1986, post-fertilization). During the 27-year follow-up, serum lipids, blood pressure, BMI, and smoking were assessed five times (1980, 1983, 1986, 2001, and 2007).
Mean (±SD) serum selenium concentrations were 74.3±14.0 ng/mL in 1980 and 106.6±12.5 ng/mL in 1986 (average increase 32.3 ng/mL; 95% CI: 30.3 to 34.3, p<0.0001). In univariate and multivariable cross-sectional models in 1980 and 1986, increased serum selenium levels were consistently associated with increased total, HDL- and LDL-cholesterol. However, the average longitudinal changes in lipids were −0.20 mmol/L (95% CI: −0.30 to −0.10, p<0.0001) for total cholesterol, 0.06 mmol/L (95% CI: 0.03 to 0.10, p<0.0001) for HDL-cholesterol, and −0.23 mmol/L (95% CI: −0.31 to −0.14, p<0.0001) for LDL-cholesterol. Selenium measured in 1986 was not associated with lipids assessed in 2001 and 2007.
Cross-sectional findings from the Young Finns study corroborate positive associations of selenium status with serum lipids. However, longitudinal evidence does not support the causality of this link.
cardiovascular; cross-sectional; follow-up; lipids; risk factors; selenium
Epidemiological evidence suggests that infections may contribute to atherogenesis. However, with the exception of Chlamydophila pneumoniae, cultivable bacteria have not been recovered from atherosclerotic lesions. Therefore, we aimed at developing an approach to recover uncultivable bacteria from atherectomy tissues.
We cultured homogenates from atherectomy specimens from seven non-septic patients undergoing surgery for arterial obstruction either alone or together with THP-1 monocyte-like cells. We performed 16S rDNA analysis, biochemical tests, random amplification of polymorphic DNA PCR analysis, quantitative polymerase chain reaction (qPCR) and immunohistofluorescence to identify the cultivated bacteria. Wilcoxon Signed-Rank Tests were used to determine whether THP-1 treatment yielded a higher number of isolates than did the untreated controls.
We recovered more bacteria from co-cultures of atherectomy specimens with THP-1 cells than atherectomy specimens cultured alone. On average, tissue homogenates incubated with THP-1 cells vs control yielded 124 vs 22 colony-forming units (CFUs), a median of 140 vs. 7, respectively (p = 0.02). We recovered 872 isolates of limited number of species, including Propionibacterium acnes, Staphylococcus epidermidis and Streptococcus infantis and the fastidious anaerobe Porphyromonas gingivalis, and confirmed its presence in tissue using double immunofluorescence imaging. qPCR demonstrated the presence of ≥3.5 × 103 P. gingivalis genomes/g of atheromatous tissue.
These results indicate that viable previously uncultivable bacterial species are present within atheromas. Our results suggest revisiting the hypothesis that infections may have a causative role in atherosclerotic inflammation and have implications for research regarding novel diagnostics and treatments for cardiovascular disease.
atherosclerosis; monocytes; Porphyromonas gingivalis; periodontal disease; bacterial infection
Long-chain omega-3 polyunsaturated fatty acids (LCω3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LCω3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated.
A cohort of 4,508 American adults aged 18–30, without hypertension at baseline in 1985, were enrolled. Six follow-ups were conducted at exams in 1987, 1990, 1992, 1995, 2000 and 2005. Diet was assessed by a validated interviewer-administered quantitative food frequency questionnaire at exams in 1985, 1992 and 2005. Incident hypertension was defined as first occurrence at any follow-up examination of systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or taking anti-hypertensive medication. Toenail clippings were collected in 1987, and Se and Hg levels were quantified by instrumental neutron-activation analysis.
Participants in the highest LCω3PUFAintake quartile had a significantly lower incidence of hypertension (Hazard Ratio: 0.65; 95% CI: 0.53–0.79; Ptrend<0.01) compared to those in the lowest quartile after adjustment for potential confounders. Docosahexaenoic acid showed a greater inverse association than eicosapentaenoic acid. The inverse association of LCω3PUFA intake with hypertension appeared more pronounced at higher Se and lower Hg levels, although interaction tests were statistically non-significant.
Out findings indicated that LCω3PUFA intake was inversely associated with incidence of hypertension. The prior hypothesis that the potential anti-hypertensive effect of LCω3PUFA intake varies depending on joint levels of Se and Hg received modest support, and cannot be ruled out.
omega-3 polyunsaturated fatty acids; selenium; mercury; hypertension; effect modification
Genescà M, McChesney MB, Miller CJ (Center for Comparative Medicine and California National Primate Research Center, University of California, Davis, CA, USA). Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6 (Review).
The recently failed clinical efficacy trial of an acquired immunodeficiency syndrome (AIDS) vaccine that elicits antiviral CD8+ T-cell responses has emphasized the challenge of producing an effective vaccine against human immunodeficiency virus (HIV). In the simian immunodeficiency virus (SIV)/rhesus monkey model of AIDS, live-attenuated lentivirus ‘vaccines’ provide the best protection from uncontrolled viral replication and clinical disease after pathogenic SIV challenge. This review summarizes a recent series of studies in which we show that after vaginal SIV challenge of rhesus macaques immunized with an attenuated lentivirus protection from uncontrolled viral replication is primarily mediated by CD8+ T cells in the vaginal mucosa. Immunization with a chimeric simian/human immunodeficiency virus (SHIV) results in a systemic infection that induces a moderate population of SIV-specific CD8+ and CD4+ T cells with cytolytic potential in the vaginal mucosa. Depletion of CD8+ T cells at the time of SIV challenge completely abrogates the protection mediated by prior infection with attenuated SHIV. Further after vaginal SIV challenge, the only significant expansion of SIV-specific T cells occurs in the vagina in these animals. No significant expansion of T-cell responses was observed in systemic lymphoid tissues. Thus, the presence of SIV-specific CD8+ T cells in the vagina on the day of vaginal SIV challenge and a modest expansion of local effector T cells is sufficient to stop uncontrolled SIV replication. It seems that T-cell based vaccine strategies that can elicit mucosal effector CD8+ T-cell populations and avoid inducing systemic T-cell proliferation upon exposure to HIV have the greatest potential for mimicking the success of live-attenuated lentiviral vaccines.
caspase-3; CD107; cytolytic T cells; Ki67; T-cell activation; vagina
The mechanisms responsible for heterosubtypic immunity to influenza virus are not well understood but might hold the key for new vaccine strategies capable of providing lasting protection against both seasonal and pandemic strains. Memory CD4 T cells are capable of providing substantial protection against influenza both through direct effector mechanisms as well as indirectly through regulatory and helper functions. Here, we discuss the broad impact of memory CD4 T cells on heterosubtypic immunity against influenza and the prospects of translating findings from animal models into improved human influenza vaccines.
influenza; CD4 T cell; immunological memory; vaccination
The clinical onset of type 1 diabetes or autoimmune diabetes occurs after a prodrome of islet autoimmunity. The warning signals for the ensuing loss of pancreatic islet beta cells are autoantibodies against insulin, GAD65, IA-2, and ZnT8, alone or in combinations. Autoantibodies against e.g. insulin alone have only a minor risk for type 1 diabetes. However, progression to clinical onset is increased by the induction of multiple islet autoantibodies. At the time of clinical onset, insulitis may be manifest, which seem to reduce the efficacy of immunosuppression. Autoantigen-specific immunotherapy with alum-formulated GAD65 (Diamyd®) show promise to reduce the loss of beta-cell function after the clinical onset of type 1 diabetes. The mechanisms are unclear but may involve the induction of T regulatory cells, which may suppress islet autoantigen reactivity. Past and on-going clinical trials have been safe. Future clinical trials, perhaps as combination autoantigen-specific immunotherapy may increase the efficacy to prevent the clinical onset in subjects with islet autoantibodies or preserve residual beta-cell function in newly diagnosed type 1 diabetes patients.
Coeliac disease is a widespread, lifelong disorder for which dietary control represents the only accepted form of therapy. There is an unmet need for non-dietary therapies to treat this condition. Most ongoing and emerging drug discovery programmes are based on the understanding that coeliac disease is caused by an inappropriate T-cell-mediated immune response to dietary gluten proteins. Recent genome-wide association studies lend further support to this pathogenic model. The central role of human leukocyte antigen genes has been validated, and a number of new risk loci have been identified, most of which are related to the biology of T cells and antigen-presenting cells. Here we review the status of potential non-dietary therapies under consideration for coeliac disease. We conclude that future development of novel therapies will be aided by the identification of new, preferably non-invasive, surrogate markers for coeliac disease activity.
Coeliac disease; gluten; T cell; HLA; transglutaminase; drug; therapy
Declining cell-mediated immunity to varicella zoster virus (VZV) in elderly individuals results in virus reactivation manifest by zoster (shingles) and postherpetic neuralgia (PHN). To prevent virus reactivation, a new VZV vaccine (Zostavax, Merck) that boosts cell-mediated immunity to VZV was developed. The 3-year Shingles Prevention Study showed that Zostavax significantly reduced burden of disease due to zoster and PHN. Despite its cost-effectiveness for adults ages 65 to 75 years, as determined in the US, Canada and UK, less than 2% of immunocompetent adults over age 60 years in the US were immunized in 2007. This was due to a combination of lack of patient awareness of the vaccine, physicians’ uncertainty about the duration of protection, and different cost-sharing plans for immunization. Nevertheless, zoster vaccine is safe, effective, and highly recommended for immunization of immunocompetent individuals over age 60 years with no history of recent zoster.
zoster; shingles; immunization; postherpetic neuralgia
Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.
autoantibodies; systemic lupus erythematosus; therapeutic strategy