As an obligatory pathogen, influenza virus co-opts host cell machinery to harbor infection and to produce progeny viruses. In order to characterize the virus-host cell interactions, several genome-wide siRNA screens and proteomic analyses have been performed recently to identify host factors involved in influenza virus infection. CD81 has emerged as one of the top candidates in two siRNA screens and one proteomic study. The exact role played by CD81 in influenza infection, however, has not been elucidated thus far. In this work, we examined the effect of CD81 depletion on the major steps of the influenza infection. We found that CD81 primarily affected virus infection at two stages: viral uncoating during entry and virus budding. CD81 marked a specific endosomal population and about half of the fused influenza virus particles underwent fusion within the CD81-positive endosomes. Depletion of CD81 resulted in a substantial defect in viral fusion and infection. During virus assembly, CD81 was recruited to virus budding site on the plasma membrane, and in particular, to specific sub-viral locations. For spherical and slightly elongated influenza virus, CD81 was localized at both the growing tip and the budding neck of the progeny viruses. CD81 knockdown led to a budding defect and resulted in elongated budding virions with a higher propensity to remain attached to the plasma membrane. Progeny virus production was markedly reduced in CD81-knockdown cells even when the uncoating defect was compensated. In filamentous virus, CD81 was distributed at multiple sites along the viral filament. Taken together, these results demonstrate important roles of CD81 in both entry and budding stages of the influenza infection cycle.
As a “Trojan Horse” that only encodes 13 viral proteins, influenza hijacks host cell machinery for productive infection. In this work, we studied the role of the host protein CD81 in influenza infection. We found that CD81 was important for influenza infection at two distinct stages: virus uncoating and virus budding. Specifically, during virus entry, more than half of internalized virus particles were trafficked into a specific CD81-positive endosomal population for virus uncoating. Depleting CD81 led to a significant defect in viral uncoating and infection. During virus egress, CD81 was recruited to virus assembly site, and incorporated into individual virions at specific sub-viral locations. CD81 depletion resulted in virions that failed to detach from the plasma membrane and a marked decrease in progeny virus production.
Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well characterized.
We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors.
Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels.
These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.
The Coronary Heart Disease (CHD) Policy Model-China, a national scale cardiovascular disease computer simulation model, was used to project future impact of urbanization.
Populations and cardiovascular disease incidence rates were stratified into four submodels: North-Urban, South-Urban, North-Rural, and South-Rural. 2010 was the base year, and high and low urbanization rate scenarios were used to project 2030 populations.
Rural-to-urban migration, population growth, and aging were projected to more than double cardiovascular disease events in urban areas and increase by 27.0–45.6% in rural areas. Urbanization is estimated to raise age-standardized coronary heart disease incidence by 73–81 per 100,000 and stroke incidence only slightly.
Rural-to-urban migration will likely be a major demographic driver of the cardiovascular disease epidemic in China.
urbanization; migration; cardiovascular disease; China
The relation between parental history of hypertension and blood pressure response to potassium intake is unknown. A 7-day high-sodium followed by a 7-day high-sodium plus potassium dietary-feeding study was conducted from 2003 to 2005 among 1,871 Chinese participants. Those with a maternal history of hypertension had larger systolic blood pressure responses to potassium compared with those without: −4.31 (95% confidence interval (CI): −4.99, −3.62) mm Hg versus −3.35 (95% CI: −4.00, −2.70) mm Hg, respectively (Pdifference = 0.002). A consistent trend was observed for diastolic blood pressure responses: −1.80 (95% CI: −2.41, −1.20) mm Hg versus −1.35 (95% CI: −1.95, −0.74) mm Hg, respectively (P = 0.07). Stronger associations between early onset maternal hypertension and blood pressure responses were noted, with systolic blood pressure decreases of −4.80 (95% CI: −5.65, −3.95) mm Hg versus −3.55 (95% CI: −4.17, −2.93) mm Hg and diastolic blood pressure decreases of −2.25 (95% CI: −3.01, −1.50) mm Hg versus −1.42 (95% CI: −1.99, −0.85) mm Hg among those with early onset maternal hypertension versus those without, respectively (P = 0.001 and 0.009, respectively). Odds ratios for high potassium sensitivity were 1.36 (95% CI: 0.96, 1.92) and 1.60 (95% CI: 1.08, 2.36) for those with maternal hypertension and early onset maternal hypertension, respectively (P = 0.08 and 0.02, respectively). Potassium supplementation could help to reduce blood pressure among those with a maternal history of hypertension.
blood pressure; dietary potassium; family history; hypertension
The current study comprehensively examined the association between common genetic variants of the kallikrein-kinin system (KKS) and blood pressure salt sensitivity. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1,906 Han Chinese participants recruited from 2003 to 2005. Blood pressure was measured by using a random-zero sphygmomanometer through the study. A total of 205 single nucleotide polymorphisms (SNPs) covering 11 genes of the KKS were selected for the analyses. Genetic variants of the bradykinin receptor B2 gene (BDKRB2) and the endothelin converting enzyme 1 gene (ECE1) showed significant associations with the salt-sensitivity phenotypes even after adjustment for multiple testing. Compared with the major G allele, the BDKRB2 rs11847625 minor C allele was significantly associated with increased systolic blood pressure responses to low-sodium intervention (P = 0.0001). Furthermore, a haplotype containing allele C was associated with an increased systolic blood pressure response to high-sodium intervention (P = 0.0009). Seven highly correlated ECE1 SNPs were shown to increase the diastolic blood pressure response to low-sodium intervention (P values ranged from 0.0003 to 0.002), with 2 haplotypes containing these 7 SNPs also associated with this same phenotype (P values ranged from 0.0004 to 0.002). In summary, genetic variants of the genes involved in the regulation of KKS may contribute to the salt sensitivity of blood pressure.
blood pressure; genetics; kallikreins; kinins; polymorphism; sodium, dietary
The effects of low-carbohydrate diets (≤45% of energy from carbohydrates) versus low-fat diets (≤30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (−14.0 mg/dL; 95% confidence interval: −19.4, −8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low-carbohydrate diets on cardiovascular events were warranted.
carbohydrate-restricted diet; fat-restricted diet; meta-analysis; metabolic syndrome; obesity
The authors conducted a genome-wide linkage scan and positional association analysis to identify the genetic determinants of salt sensitivity of blood pressure (BP) in a large family-based, dietary-feeding study. The dietary intervention was conducted among 1,906 participants in rural China (2003–2005). A 7-day low-sodium intervention was followed by a 7-day high-sodium intervention. Salt sensitivity was defined as BP responses to low- and high-sodium interventions. Signals of the logarithm of the odds to the base 10 (LOD ≥ 3) were detected at 33–42 centimorgans of chromosome 2 (2p24.3-2p24.1), with a maximum LOD score of 3.33 for diastolic blood pressure responses to high-sodium intervention. LOD scores were 2.35–2.91 for mean arterial pressure (MAP) and 0.80–1.49 for systolic blood pressure responses in this region, respectively. Correcting for multiple tests, single nucleotide polymorphism (SNP) rs11674786 (2.7 kilobases upstream of the family with sequence similarity 84, member A, gene (FAM84A)) in the linkage region was significantly associated with diastolic blood pressure (P = 0.0007) and MAP responses (P = 0.0007), and SNP rs16983422 (2.8 kilobases upstream of the visinin-like 1 gene (VSNL1)) was marginally associated with diastolic blood pressure (P = 0.005) and MAP responses (P = 0.005). An additive interaction between SNPs rs11674786 and rs16983422 was observed, with P = 7.00 × 10−5 and P = 7.23 × 10−5 for diastolic blood pressure and MAP responses, respectively. The authors concluded that genetic region 2p24.3-2p24.1 might harbor functional variants for the salt sensitivity of BP.
allelic association; blood pressure; genetic linkage; salt sensitivity
Salt sensitivity of blood pressure (BP) is influenced by genetic and environmental factors. A dietary feeding study was conducted from October 2003 to July 2005 that included a 7-day low-sodium intervention (51.3 mmol sodium/day) followed by a 7-day high-sodium intervention (307.8 mmol sodium/day) among 1,906 individuals who were 16 years of age or older and living in rural northern China. Salt sensitivity of BP was defined as mean BP change from the low-sodium intervention to the high-sodium intervention. Usual physical activity during the past 12 months was assessed at baseline using a standard questionnaire. The multivariable-adjusted means of systolic BP responses to high-sodium intervention were 5.21 mm Hg (95% confidence interval (CI): 4.55, 5.88), 4.97 mm Hg (95% CI: 4.35, 5.59), 5.02 mm Hg (95% CI: 4.38, 5.67), and 3.96 mm Hg (95% CI: 3.29, 4.63) among participants from the lowest to the highest quartiles of physical activity, respectively (P = 0.003 for linear trend). The multivariable-adjusted odds ratio of high salt sensitivity of systolic BP was 0.66 (95% CI: 0.49, 0.88) for persons in the highest quartile of physical activity compared with those in the lowest quartile. Physical activity is significantly, independently, and inversely related to salt sensitivity of BP and may be particularly effective in lowering BP among salt-sensitive individuals.
blood pressure; dietary sodium; physical activity; salt sensitivity
An elevated blood pressure (BP) response to the cold pressor test (CPT) is associated with increased risk of hypertension and cardiovascular disease. However, it is still unclear whether BP response to the CPT is a stable and reproducible trait over time. Using the same study protocol, the authors repeated the CPT 4.5 years after initial administration among 568 Han Chinese in rural northern China (2003–2005 and 2008–2009). BP was measured using a standard mercury sphygmomanometer prior to and 0, 1, 2, and 4 minutes after the participants immersed their hand in ice water (3°C–5°C) for 1 minute. Absolute BP levels and BP responses during the CPT in the initial and repeated administrations were highly correlated. For example, the correlation coefficients were 0.67, 0.73, 0.71, and 0.72 for absolute systolic BP levels at 0, 1, 2, and 4 minutes after ice-water immersion (all P 's < 0.0001). The correlation coefficients for systolic BP response were 0.41 at 0 minutes, 0.37 at 1 minute, 0.42 for maximum response, and 0.39 for the area under the curve during CPT (all P 's < 0.0001). These data indicate that BP response to the CPT is a long-term reproducible and stable characteristic in the general population.
blood pressure; cardiovascular diseases; hypertension; reproducibility of results; stress, physiological
As an obligate pathogen, influenza virus requires host cell factors and compartments to mediate productive infection and to produce infectious progeny virus. Recently, several small interfering RNA (siRNA) knockdown screens revealed influenza virus host dependency proteins, all of which identified at least two subunits of the coat protein I (COPI) complex. COPI proteins oligomerize to form coated vesicles that transport contents between the Golgi apparatus and the endoplasmic reticulum, and they have also been reported to mediate endosomal trafficking. However, it remains unclear which steps in the influenza virus infection cycle rely on the COPI complex. Upon systematic dissection of the influenza virus infection cycle, from entry to progeny virion production, we found that prolonged exposure to COPI complex disruption through siRNA depletion resulted in significant defects in virus internalization and trafficking to late endosomes. Acute inhibition of COPI complex recruitment to the Golgi apparatus with pharmacological compounds failed to recapitulate the same entry defects as observed with the COPI-depleted cells but did result in specific decreases in viral membrane protein expression and assembly, leading to defects in progeny virion production. Taken together, our findings suggest that COPI complexes likely function indirectly in influenza virus entry but play direct roles in viral membrane protein expression and assembly.
DNAzymes are synthetic, single-stranded, catalytic nucleic acids that bind and cleave target mRNA in a sequence-specific manner, and have been explored for genotherapeutics. One bottleneck restricting their application is the lack of an efficient delivery system. As an inorganic nanomaterial with potentially wide application, nano-hydroxyapatite particles (nHAP) have attracted increasing attention as new candidates for nonviral vectors. In this study, we developed an nHAP-based delivery system and explored its cellular uptake mechanisms, intracellular localization, and biological effects. Absorption of arginine-modified nanohydroxyapatite particles (Arg-nHAP) and DZ1 (latent membrane protein 1 [LMP1]-targeted) reached nearly 100% efficiency under in vitro conditions. Using specific inhibitors, cellular uptake of the Arg-nHAP/DZ1 complex was shown to be mediated by the energy-dependent endocytosis pathway. Further, effective intracellular delivery and nuclear localization of the complex was confirmed by confocal microscopy. Biologically, the complex successfully downregulated the expression of LMP1 in nasopharyngeal carcinoma cells. In a mouse tumor xenograft model, the complex was shown to be delivered efficiently to tumor tissue, downregulating expression of LMP1 and suppressing tumor growth. These results suggest that Arg-nHAP may be an efficient vector for nucleic acid-based drugs with potential clinical application.
hydroxyapatite nanoparticles; DNAzymes; latent membrane protein 1; transfection efficiency; cellular uptake
Surface sediment and water samples were collected from Daihai Lake to study the biogeochemical characteristics of nitrogen and phosphorus, to estimate the loads of these nutrients, and to assess their effects on water quality. The contents and spatial distributions of total phosphorus (TP), total nitrogen (TN), and different nitrogen forms in sediments were analyzed. The results showed that concentrations of TN and TP in surface sediments ranged from 0.27 to 1.78 g/kg and from 558.31 to 891.29 mg/kg, respectively. Ratios of C : N ranged between 8.2 and 12.1, which indicated that nitrogen accumulated came mainly from terrestrial source. Ratios of N : P in all sampling sites were below 10, which indicated that N was the limiting nutrient for algal growth in this lake. Effects of environment factors on the release of nitrogen and phosphorus in lake sediments were also determined; high pH values could encourage the release of nitrogen and phosphorus. Modified Carlson's trophic state index (TSIM) and comprehensive trophic state index (TSIC) were applied to ascertain the trophic classification of the studied lake, and the values of TSIM and TSIC ranged from 53.72 to 70.61 and from 47.73 to 53.67, respectively, which indicated that the Daihai Lake was in the stage of hypereutropher.
Is urinary angiotensinogen ready for prime time as a biomarker of CKD?… Mills et al represent a leap forward in this exciting field and holds considerable promise to one day positively impact the care of patients with CKD…
The effect of intrarenal renin–angiotensin system (RAS) activity on risk of chronic kidney disease (CKD) has not been well studied in human subjects.
We investigated the association between urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, and risk of CKD in 201 patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or presence of albuminuria ( ≥ 30 mg/24 h).
Compared to controls, median urinary angiotensinogen excretion (45.4 versus 7.4 μg/24 h, P < 0.0001) and angiotensinogen-to-creatinine ratio (26.3 versus 4.4 μg/g, P < 0.0001) were significantly higher in patients with CKD. Log-transformed urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were inversely correlated with eGFR (r = −0.59 and −0.57, both P < 0.0001) and positively correlated with log-transformed urinary albumin excretion (r = 0.89 and 0.87, both P < 0.0001). After adjusting for multiple covariables, including the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diuretics and statins, the odds ratios (95% confidence interval) for CKD comparing the highest tertile to the lowest two tertiles of urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were 6.70 (3.43, 13.1; P < 0.0001) and 6.45 (3.34, 12.4; P < 0.0001), respectively.
These data indicate the intrarenal RAS may play an important role in the etiology of CKD, and urinary angiotensinogen may be a useful clinical biomarker for the identification of patients at a high risk for CKD.
albuminuria; angiotensinogen; chronic kidney disease; estimated glomerular filtration rate; renin–angiotensin system
Patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). We examined the cross-sectional association between novel risk factors and prevalent PAD among patients with CKD. A total of 3,758 patients with an estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 who participated in the chronic renal insufficiency cohort (CRIC) study were included in the current analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, sex, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, eGFR, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios (95% confidence intervals) for a one standard deviation higher level of risk factors were 1.18 (1.08–1.29) for log-transformed high sensitivity-C reactive protein, 1.18 (1.08–1.29) for white blood cell count, 1.15 (1.05–1.25) for fibrinogen, 1.13 (1.03–1.24) for uric acid, 1.14 (1.02–1.26) for hemoglobin A1c, 1.11 (1.00–1.23) for log-transformed homeostasis model assessment-insulin resistance, and 1.35 (1.18–1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in CKD patients.
peripheral arterial disease; novel risk factors; chronic kidney disease
Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD).
We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or presence of albuminuria (≥30 mg/24 h).
After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = −0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of −26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001).
These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.
Albuminuria; Antiangiogenic factor; Chronic kidney disease; Endostatin; Estimated glomerular filtration rate
To evaluate the feasibility of a reporter gene/probe system, namely the human estrogen receptor ligand binding domain (hERL)/16α-[18F] fluoro-17β-estradiol (18F-FES), for monitoring gene and cell therapy.
The recombinant adenovirus vector Ad5-hERL-IRES-VEGF (Ad-EIV), carrying a reporter gene (hERL) and a therapeutic gene (vascular endothelial growth factor, VEGF165) through an internal ribosome entry site (IRES), was constructed. After transfection of Ad-EIV into bone marrow mesenchymal stem cells (Ad-EIV-MSCs), hERL and VEGF165 mRNA and protein expressions were identified using Real-Time qRT-PCR and immunofluorescence. The uptake of 18F-FES was measured in both Ad-EIV-MSCs and nontransfected MSCs after different incubation time. Micro-PET/CT images were obtained at 1 day after injection of Ad-EIV-MSCs into the left foreleg of the rat. The right foreleg was injected with nontransfected MSCs, which served as self-control.
After transfection with Ad-EIV, the mRNA and protein expression of hERL and VEGF165 were successfully detected in MSCs, and correlated well with each other (R2 = 0.9840, P<0.05). This indicated the reporter gene could reflect the therapeutic gene indirectly. Ad-EIV-MSCs uptake of 18F-FES increased with incubation time with a peak value of 9.13%±0.33% at 150 min, which was significantly higher than that of the control group. A far higher level of radioactivity could be seen in the left foreleg on the micro-PET/CT image than in the opposite foreleg.
These preliminary in vitro and in vivo studies confirmed that hERL/18F-FES might be used as a novel reporter gene/probe system for monitoring gene and cell therapy. This imaging platform may have broad applications for basic research and clinical studies.
The metabolism of potato (Solanum tuberosum) roots constitutively over- and underexpressing hexokinase (HK, EC 220.127.116.11) was examined. An 11-fold variation in HK activity resulted in altered root growth, with antisense roots growing better than sense roots. Quantification of sugars, organic acids and amino acids in transgenic roots demonstrated that the manipulation of HK activity had very little effect on the intracellular pools of these metabolites. However, adenylate and free Pi levels were negatively affected by an increase in HK activity. The flux control coefficient of HK over the phosphorylation of glucose was measured for the first time in plants. Its value varied with HK level. It reached 1.71 at or below normal HK activity value and was much lower (0.32) at very high HK levels. Measurements of glycolytic flux and O2 uptake rates demonstrated that the differences in glucose phosphorylation did not affect significantly glycolytic and respiratory metabolism. We hypothesized that these results could be explained by the existence of a futile cycle between the pools of hexose-Ps and carbohydrates. This view is supported by several lines of evidence. Firstly, activities of enzymes capable of catalyzing these reactions were detected in roots, including a hexose-P phosphatase. Secondly, metabolic tracer experiments using 14C-glucose as precursor showed the formation of 14C-fructose and 14C-sucrose. We conclude that futile cycling of hexose-P could be partially responsible for the differences in energetic status in roots with high and low HK activity and possibly cause the observed alterations in growth in transgenic roots. The involvement of HK and futile cycles in the control of glucose-6P metabolism is discussed.
Gender divergence on the impact of multiple cardiovascular (CV) risk factors on the femoral artery intima-media thickness (IMT) has not studied in a biracial (black-white) community based asymptomatic young adults.
Femoral IMT was measured by B-mode ultrasonography in 1080 individuals (aged 24- 43 years; 71%white, 43% male) enrolled in the Bogalusa Heart Study.
Femoral IMT showed a gender difference (males > females, p= 0.001), but no racial difference. In a multivariate model, age, cigarette smoking, systolic blood pressure and total to HDL cholesterol ratio related independently, in that order, to IMT in females; age and LDL cholesterol in males. In females, mean IMT increased with increasing number of risk factors defined as values above the age- race- and gender- specific 75th percentile of systolic blood pressure, waist circumference, total to HDL cholesterol ratio and insulin along with positive smoking status (p for trend = 0.001), with respective mean IMT (mm) values of 0.61, 0.65, 0.72, and 0.77, for 0, 1-2, 3 and 4-5 risk factors. There was no such significant trend in males.
Although males vs females had thicker IMT, the observed increasing trend of femoral IMT with increasing number of risk factors in asymptomatic young females suggests that females may be relatively more susceptible to the burden of multiple risk factors.
Femoral artery; intima-media thickness; risk factors; gender difference; ultrasonography
Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We conducted a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 East Asians, followed by in silico and de novo replication in 37,691 and 17,642 additional East Asians, respectively. We identified ten BMI-associated loci at the genome-wide significance level (P<5.0×10−8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR/QPCTL, ADCY3/RBJ, BDNF, and MAP2K5) and three novel loci in or near the CDKAL1,PCSK1, and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a new locus near PAX6, which all had P<5.0×10−7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.
Observational studies have reported an inverse association between dietary protein intake and blood pressure (BP). We compared the effect of soy protein, milk protein, and carbohydrate supplementation on BP among healthy adults.
Methods and Results
We conducted a randomized double-blind crossover trial with 3-intervention phases among 352 adults with prehypertension or stage-1 hypertension in New Orleans, Louisiana and Jackson, Mississippi from September 2003 to April 2008. The trial participants were assigned to take 40 grams/day of soy protein, milk protein, or carbohydrate supplementation each for 8 weeks in a random order. A 3-week washout period was implemented between the interventions. Three BPs were measured at 2 baseline and 2 termination visits during each of 3 intervention phases using a random-zero sphygmomanometer. Compared to carbohydrate controls, soy protein and milk protein supplementations were significantly associated with −2.0 mmHg (95% confidence interval −3.2 to −0.7, p=0.002) and −2.3 mmHg (−3.7 to −1.0, p=0.0007) net change in systolic BP, respectively. Diastolic BP was also reduced but this change did not reach statistical significance. There was no significant difference in the BP reductions achieved between soy or milk protein supplementation.
The results from this randomized controlled trial indicate that both soy and milk protein intake reduce systolic BP compared to a high glycemic index refined carbohydrate among patients with prehypertension and stage-1 hypertension. Furthermore, these findings suggest that partially replacing carbohydrate with soy or milk protein might be an important component of nutrition intervention strategies for the prevention and treatment of hypertension.
blood pressure; diet; clinical trials; nutrition; proteins
Oligonucleotides radiolabeled with isotopes emitting γ-rays (for SPECT imaging) or positrons (for PET imaging) can be useful for targeting messenger RNA (mRNA) thereby serving as non-invasive imaging tools for detection of gene expression in vivo (antisense imaging). Radiolabeled oligonucleotides may also be used for monitoring their in vivo fate, thereby helping us better understand the barriers to its delivery for antisense targeting. These developments have led to a new area of molecular imaging and targeting, utilizing radiolabeled antisense oligonucleotides. However, the success of antisense imaging relies heavily on overcoming the barriers for its targeted delivery in vivo. Furthermore, the low ability of the radiolabeled antisense oligonucleotide to subsequently internalize into the cell and hybridize with its target mRNA poses additional challenges in realizing its potentials. This review covers the advances in the antisense imaging probe development for PET and SPECT, with an emphasis on radiolabeling strategies, stability, delivery and in vivo targeting.
antisense imaging; antisense therapy; molecular imaging; mRNA; SPECT; PET; radiopharmaceuticals
Rare mutations of the epithelial sodium channel (ENaC) lead to Mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt-sensitivity of blood pressure (BP).
Methods and Results
A total of 1,906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/day) followed by a 7-day high-sodium intake (307.8 mmol sodium/day). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single nucleotide polymorphisms (SNPs), both tagging and functional, from the three ENaC subunits, α, β, and γ (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common SNPs in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, p=1.7×10-5; rs4073291, p=1.1×10-5; rs7404408, p=1.9×10-5; rs5735, p=3.0×10-4; rs4299163, p=0.004; and rs4499238, p=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mmHg lower systolic BP (SBP) reduction during low-sodium intervention.
This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt-sensitivity.
blood pressure; epithelial sodium channel; genetic variant; salt-sensitivity
Few data are available evaluating the associations of formal public health education with long-term career choice and professional outcomes among medical school graduates. The objective of this study was to determine if formal public health education via completion of a masters of public health (MPH) degree among US medical school graduates was associated with early and long-term career choice, professional satisfaction, or research productivity.
We conducted a retrospective cohort study in 1108 physicians (17.1% completed a MPH degree) who had 10–20 years of follow-up post medical school graduation. Multivariable logistic regression analyses were conducted.
Compared to their counterparts with no MPH, medical school graduates with a MPH were more likely to have completed a generalist primary care residency only [relative risk (RR) 1.79, 95% confidence interval (CI) 1.35–2.29], obtain employment in an academic institution (RR 1.81; 95% CI 1.33–2.37) or government agency (RR 3.26; 95% CI 1.89–5.38), and practice public health (RR 39.84; 95% CI 12.13–107.38) or primary care (RR 1.59; 95% CI 1.18–2.05). Furthermore, medical school graduates with a MPH were more likely to conduct public health research (RR 8.79; 95% CI: 5.20–13.82), receive NIH or other federal funding (RR 3.11, 95% CI 1.74–5.33), have four or more peer-reviewed publications (RR 2.07; 95% CI 1.56–2.60), and have five or more scientific presentations (RR 2.31, 95% CI 1.70–2.98).
Formal public health education via a MPH was associated with career choice and professional outcomes among physicians.
Impact of multiple cardiovascular (CV) risk factors on the intima-media thickness (IMT) of femoral and carotid artery segments measured simultaneously has not been studied in asymptomatic adults. This study examined the impact of multiple CV risk factors on the IMT in asymptomatic adults.
Femoral and carotid IMT were measured by B-mode ultrasonography in 1080 asymptomatic subjects (aged 24–43 years) of the Bogalusa Heart Study.
In multivariate analyses, systolic blood pressure, age, male, total cholesterol/HDL cholesterol ratio and smoking were common independent predictor variables for the femoral and carotid IMT. Systolic blood pressure followed by age were the major determinant risk factors for the IMT of all arterial segments except carotid bulb for which age was the major predictor. The independent variables listed explained 11% of the variability in femoral IMT, 28% in common carotid, 18% in carotid bulb, 10% in internal carotid and 27% in composite carotid segments. Mean IMT increased with increasing number of risk factors in all arterial segments; p for trend = 0.003 for femoral and 0.001 for all carotid segments.
The observed deleterious trend of increasing IMT of the femoral and different segments of the carotid artery with increasing number of CV risk factors provide evidence of silent systemic atherosclerosis in asymptomatic young adults. These findings underscore the importance of multiple for risk factors profiling in early life. Studies of the femoral and carotid IMT may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.
femoral and carotid artery; intima-media thickness; risk factors; ultrasonography; arterial disease
Immunoliposomes (ILs) anchored with internalizing human antibodies capable of targeting all subtypes of mesothelioma can be useful for targeted imaging and therapy of this malignant disease. The objectives of this study were to evaluate both the in vitro and in vivo tumor targeted internalization of novel internalizing human single chain antibody (scFv) anchored ILs on both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of human mesothelioma. ILs were prepared by post-insertion of mesothelioma-targeting human scFv (M1) onto preformed liposomes and radiolabeled with 111In (111In-IL-M1), along with control non-targeted liposomes (111In-CL). Incubation of 111In-IL-M1 with M28, VAMT-1, and a control non-tumorigenic cell-line (BPH-1) at 37°C for 24 h revealed efficient binding and rapid internalization of ILs into both subtypes of tumor cells but not into the BPH-1 cells; internalization accounted for approximately 81-94% of total cell accumulation in mesothelioma cells compared to 37-55% in control cells. In tumor bearing mice intravenous (i.v.) injection of 111In-IL-M1 led to remarkable tumor accumulation: 4 % and 4.7% injected dose per gram (% ID/g) for M28 and VAMT-1 tumors, respectively, 48 h after injection. Furthermore, tumor uptake of 111In-IL-M1 in live xenograft animal models was verified by single photon emission computed tomography (SPECT/CT). In contrast, i.v. injection of 111In-CL in tumor-bearing mice revealed very low uptake in both subtypes of mesothelioma, 48 h after injection. In conclusion, M1 scFv-anchored ILs showed selective tumor targeting and rapid internalization into both epithelioid and sarcomatoid subtypes of human mesothelioma, demonstrating its potential as a promising vector for enhanced tumor drug targeting.
Immunoliposomes; scFv antibody; mesothelioma; SPECT/CT imaging; tumor targeting