Two-Year Responses of Renal Function to First Occupational Lead Exposure.

Introduction: Whether in advanced countries lead exposure still contributes to renal impairment is debated, because blood lead (BL) level is declining toward preindustrial levels and because longitudinal studies correlating renal function and BL changes over time are scarce. Methods: The Study for Promotion of Health in Recycling Lead (SPHERL) evaluated the 2-year renal function responses in 251 workers (mean age, 29.7 years) transiting from environmental to occupational exposure. Main study end point was the estimated glomerular filtration rate (eGFR) derived from serum creatinine (eGFRcrt), cystatin C (eGFRcys), or both (eGFRcc). BL level was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dl). Results: In the follow-up, mean baseline BL level of 4.13 µg/dl increased 3.30-fold. In fully adjusted mixed models, additionally accounting for the within-participant clustering of the 1- and 2-year follow-up data, a 3-fold BL level increment was not significantly correlated with changes in eGFR with estimates amounting to -0.86 (95% CI: -2.39 to 0.67), -1.58 (-3.34 to 0.18), and -1.32 (-2.66 to 0.03) ml/min per 1.73 m2 for eGFRcrt, eGFRcys, or eGFRcc, respectively. Baseline BL level and the cumulative lead burden did not materially modify these estimates, but baseline eGFR was a major determinant of eGFR changes showing regression to the mean during follow-up. Responses of serum osmolarity, urinary gravity, or the urinary albumin-to-creatinine ratio (ACR) were also unrelated to the BL level increment. The age-related decreases in eGFRcrt, eGFRcys, and eGFRcc were -1.41, -0.96, and -1.10 ml/min per 1.73 m2, respectively. Conclusion: In the current study, the 2-year changes in renal function were unrelated to the increase in BL level. However, given the CIs around the point estimates of the changes in eGFRcc and eGFRcys, a larger study with longer follow-up is being planned.

The Association Between Fecal Short-Chain Fatty Acids, Gut Microbiota, and Visceral Fat in Monozygotic Twin Pairs.

PURPOSE: To examine the association of short-chain fatty acids (SCFAs), gut microbiota and obesity in individual twins and to control for genetic and shared environmental effects by studying monozygotic intrapair differences. PATIENTS AND METHODS: The study recruited 20 pairs of monozygotic twins. Body composition measurements were performed by using the multi-frequency bioelectrical impedance technique. SCFAs were extracted from feces and quantified by gas chromatography-mass spectrometer. Gut microbiota was evaluated by 16S rRNA gene sequencing. RESULTS: Fecal SCFAs were negatively correlated with adiposity parameters including body mass index, visceral adipose tissue and waist circumference (all P < 0.05). Metastat analysis showed that the top 5 relatively abundant bacterial taxa of viscerally obese and non-obese groups were Bacteroides, Collinsella, Eubacterium rectale group, Lachnoclostridium, and Tyzzerella. Participants with visceral obesity had lower abundance of Bacteroides and Collinsella compared to non-obese patients (P < 0.05). Among them, the abundance of Collinsella was positively correlated with acetic acid concentrations (r = 0.63, P = 0.011). There were no significant intrapair differences in each SCFA concentrations between the twins in our study (P > 0.05). CONCLUSION: Low fecal concentrations of SCFAs were associated with visceral obesity, and the gut microbiota might be involved in the underlying mechanism.

Metabolites of gut microbiome are associated with glucose metabolism in non-diabetic obese adults: a Chinese monozygotic twin study.

BACKGROUND: Evidence suggests gut microbiome is associated with diabetes. However, it's unclear whether the association remains in non-diabetic participants. A Chinese monozygotic twin study, in which the participants are without diabetes, and are not taking any medications, was conducted to explore the potential association. METHODS: Nine pairs of adult monozygotic twins were enrolled and divided into two twin-pair groups (a and b). Clinical and laboratory measurements were conducted. Visceral adipose tissue (VAT) was assessed. Fecal samples were collected to analyze the microbiome composition by 16S rDNA gene amplicon sequencing. Liquid chromatography mass spectrometry was performed to detect the metabolites. RESULTS: The participants aged 53 years old averagely, with 8 (88.9%) pairs were women. All the participants were obese with VAT higher than 100 cm2 (152.2 ± 31.6). There was no significant difference of VAT between the twin groups (153.6 ± 30.4 cm2 vs. 150.8 ± 29.5 cm2, p = 0.54). Other clinical measurements, including BMI, lipid profiles, fasting insulin and blood glucose, were also not significantly different between groups (p ≥ 0.056), whereas HbA1c level of group a is significantly higher than group b (5.8 ± 0.3% vs. 5.6 ± 0.2%, p = 0.008). The number and richness of OTUs are relatively higher in group a, and 13 metabolites were significantly different between two groups. Furthermore, several of the 13 metabolites could be significantly linked to special taxons. The potential pathway involved drug metabolism-other enzymes, Tryptophan metabolism and Citrate cycle. CONCLUSIONS: Gut microbiome composition and their metabolites may modulate glucose metabolism in obese adults without diabetes, through Tryptophan metabolism, Citrate cycle and other pathways.

Two-Year Responses of Heart Rate and Heart Rate Variability to First Occupational Lead Exposure.

[Figure: see text].

Two-year neurocognitive responses to first occupational lead exposure.

Objectives Lead exposure causes neurocognitive dysfunction in children, but its association with neurocognition in adults at current occupational exposure levels is uncertain mainly due to the lack of longitudinal studies. In the Study for Promotion of Health in Recycling Lead (NCT02243904), we assessed the two-year responses of neurocognitive function among workers without previous known occupational exposure newly hired at lead recycling plants. Methods Workers completed the digit-symbol test (DST) and Stroop test (ST) at baseline and annual follow-up visits. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dL). Statistical methods included multivariable-adjusted mixed models with participants modelled as random effect. Results DST was administered to 260 participants (11.9% women; 46.9%/45.0% whites/Hispanics; mean age 29.4 years) and ST to 168 participants. Geometric means were 3.97 and 4.13 µg/dL for baseline BL, and 3.30 and 3.44 for the last-follow-up-to-baseline BL ratio in DST and ST cohorts, respectively. In partially adjusted models, a doubling of the BL ratio was associated with a 0.66% [95% confidence interval (CI) 0.03-1.30; P=0.040] increase in latency time (DST) and a 0.35% (95% CI ­1.63-1.63; P=0.59) decrease in the inference effect (ST). In fully adjusted models, none of the associations of the changes in the DST and ST test results with the blood lead changes reached statistical significance (P≥0.12). Conclusions An over 3-fold increase in blood lead over two years of occupational exposure was not associated with a relevant decline in cognitive performance.

Two-Year Responses of Office and Ambulatory Blood Pressure to First Occupational Lead Exposure.

Lead exposure causing hypertension is the mechanism commonly assumed to set off premature death and cardiovascular complications. However, at current exposure levels in the developed world, the link between hypertension and lead remains unproven. In the Study for Promotion of Health in Recycling Lead (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02243904), we recorded the 2-year responses of office blood pressure (average of 5 consecutive readings) and 24-hour ambulatory blood pressure to first occupational lead exposure in workers newly employed at lead recycling plants. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dL). Hypertension was defined according to the 2017 American College of Cardiology/American Heart Association guideline. Statistical methods included multivariable-adjusted mixed models with participants modeled as a random effect and interval-censored Cox regression. Office blood pressure was measured in 267 participants (11.6% women, mean age at enrollment, 28.6 years) and ambulatory blood pressure in 137 at 2 follow-up visits. Geometric means were 4.09 µg/dL for baseline BL and 3.30 for the last-follow-up-to-baseline BL ratio. Fully adjusted changes in systolic/diastolic blood pressure associated with a doubling of the BL ratio were 0.36/0.28 mm Hg (95% CI, -0.55 to 1.27/-0.48 to 1.04 mm Hg) for office blood pressure and -0.18/0.11 mm Hg (-2.09 to 1.74/-1.05 to 1.27 mm Hg) for 24-hour ambulatory blood pressure. The adjusted hazard ratios of moving up across hypertension categories for a doubling in BL were 1.13 (0.93-1.38) and 0.84 (0.57-1.22) for office blood pressure and ambulatory blood pressure, respectively. In conclusion, the 2-year blood pressure responses and incident hypertension were not associated with the BL increase on first occupational exposure.

Retinal and Renal Microvasculature in Relation to Central Hemodynamics in 11-Year-Old Children Born Preterm or At Term.

Background Prematurity disrupts the perinatal maturation of the microvasculature and macrovasculature and confers high risk of vascular dysfunction later in life. No previous studies have investigated the crosstalk between the microvasculature and macrovasculature in childhood. Methods and Results In a case-control study, we enrolled 55 children aged 11 years weighing <1000 g at birth and 71 matched controls (October 2014-November 2015). We derived central blood pressure (BP) wave by applanation tonometry and calculated the forward/backward pulse waves by an automated pressure-based wave separation algorithm. We measured the renal resistive index by pulsed wave Doppler and the central retinal arteriolar equivalent by computer-assisted program software. Compared with controls, patients had higher central systolic BP (101.5 versus 95.2 mm Hg, P<0.001) and backward wave amplitude (15.5 versus 14.2 mm Hg, P=0.029), and smaller central retinal arteriolar equivalent (163.2 versus 175.4 µm, P<0.001). In multivariable analyses, central retinal arteriolar equivalent was smaller with higher values (+1 SD) of central systolic BP (-2.94 µm; 95% CI, -5.18 to -0.70 µm [P=0.011]) and forward (-2.57 µm; CI, -4.81 to -0.32 µm [P=0.026]) and backward (-3.20 µm; CI, -5.47 to -0.94 µm [P=0.006]) wave amplitudes. Greater renal resistive index was associated with higher backward wave amplitude (0.92 mm Hg, P=0.036). Conclusions In childhood, prematurity compared with term birth is associated with higher central systolic BP and forward/backward wave amplitudes. Higher renal resistive index likely moves reflection points closer to the heart, thereby explaining the inverse association of central retinal arteriolar equivalent with central systolic BP and backward wave amplitude. These observations highlight the crosstalk between the microcirculation and macrocirculation in children. Registration URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02147457.

Interpretation of Population Health Metrics: Environmental Lead Exposure as Exemplary Case.

Our objective was to gain insight in the calculation and interpretation of population health metrics that inform disease prevention. Using as model environmental exposure to lead (ELE), a global pollutant, we assessed population health metrics derived from the Third National Health and Nutrition Examination Survey (1988 to 1994), the GBD (Global Burden of Disease Study 2010), and the Organization for Economic Co-operation and Development. In the National Health and Nutrition Examination Survey, the hazard ratio relating mortality over 19.3 years of follow-up to a blood lead increase at baseline from 1.0 to 6.7 µg/dL (10th-90th percentile interval) was 1.37 (95% CI, 1.17-1.60). The population-attributable fraction of blood lead was 18.0% (10.9%-26.1%). The number of preventable ELE-related deaths in the United States would be 412 000 per year (250 000-598 000). In GBD 2010, deaths and disability-adjusted life-years globally lost due to ELE were 0.67 million (0.58-0.78 million) and 0.56% (0.47%-0.66%), respectively. According to the 2017 Organization for Economic Co-operation and Development statistics, ELE-related welfare costs were $1 676 224 million worldwide. Extrapolations from the foregoing metrics assumed causality and reversibility of the association between mortality and blood lead, which at present-day ELE levels in developed nations is not established. Other issues limiting the interpretation of ELE-related population health metrics are the inflation of relative risk based on outdated blood lead levels, not differentiating relative from absolute risk, clustering of risk factors and exposures within individuals, residual confounding, and disregarding noncardiovascular disease and immigration in national ELE-associated welfare estimates. In conclusion, this review highlights the importance of critical thinking in translating population health metrics into cost-effective preventive strategies.

Central hemodynamics in relation to low-level environmental lead exposure.

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population.Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985-2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm.Results: BL averaged 2.93 µg/dL (interquartile range, 1.80-4.70) and UCd 4.79 µg (2.91-7.85). Mean values were 45.0 ± 15.2 mm Hg for cPP, 24.4 ± 12.4% for AI, 1.34 ± 0.21 for PA, 7.65 ± 1.74 m/s for aPWV, 32.7 ± 9.9 mm Hg for Pf, 21.8 ± 8.4 mm Hg for Pb, and 66.9 ± 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; -0.06 (-0.08, -0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI (p ≤ .045). In 206 participants never on antihypertensive drug treatment, association sizes were +2.59 mm Hg (0.39, 4.79) for cPP and +0.26 m/s (0.03, 0.50) for aPWV. Analyses adjusted for co-exposure to cadmium were consistent.Conclusion: In conclusion, low-level environmental lead exposure possibly contributes to arterial stiffening and wave reflection from peripheral sites.

Outcome-Driven Thresholds for Ambulatory Blood Pressure Based on the New American College of Cardiology/American Heart Association Classification of Hypertension.

The new American College of Cardiology/American Heart Association guideline reclassified office blood pressure and proposed thresholds for ambulatory blood pressure (ABP). We derived outcome-driven ABP thresholds corresponding with the new office blood pressure categories. We performed 24-hour ABP monitoring in 11 152 participants (48.9% women; mean age, 53.0 years) representative of 13 populations. We determined ABP thresholds resulting in multivariable-adjusted 10-year risks similar to those associated with elevated office blood pressure (120/80 mm Hg) and stages 1 and 2 of office hypertension (130/80 and 140/90 mm Hg). Over 13.9 years (median), 2728 (rate per 1000 person-years, 17.9) people died, 1033 (6.8) from cardiovascular disease; furthermore, 1988 (13.8), 893 (6.0), and 795 (5.4) cardiovascular and coronary events and strokes occurred. Using a composite cardiovascular end point, systolic/diastolic outcome-driven thresholds indicating elevated 24-hour, daytime, and nighttime ABP were 117.9/75.2, 121.4/79.6, and 105.3/66.2 mm Hg. For stages 1 and 2 ambulatory hypertension, thresholds were 123.3/75.2 and 128.7/80.7 mm Hg for 24-hour ABP, 128.5/79.6 and 135.6/87.1 mm Hg for daytime ABP, and 111.7/66.2 and 118.1/72.5 mm Hg for nighttime ABP. ABP thresholds derived from other end points were similar. After rounding, approximate thresholds for elevated 24-hour, daytime, and nighttime ABP were 120/75, 120/80, and 105/65 mm Hg, and for stages 1 and 2, ambulatory hypertension 125/75 and 130/80 mm Hg, 130/80 and 135/85 mm Hg, and 110/65 and 120/70 mm Hg. Outcome-driven ABP thresholds corresponding to elevated blood pressure and stages 1 and 2 of hypertension are similar to those proposed by the current American College of Cardiology/American Heart Association guideline.

Retinal Microvasculature in Relation to Central Hemodynamics in a Flemish Population.

Arterial stiffness and wave reflection predict cardiovascular mortality and morbidity and are associated with renal microvascular disease. We hypothesized that the retinal microvascular traits might be associated with central hemodynamic properties. In 735 randomly recruited Flemish (mean age, 50.3 years; 47.1% women), we derived central pulse pressure and carotid-femoral pulse wave velocity by applanation tonometry and calculated forward (Pf) and backward (Pb) pulse waves, using an automated pressure-based wave separation algorithm. We measured central retinal arteriolar (CRAE) and venular equivalent and their ratio, using IVAN software (Vasculomatic ala Nicola, version 1.1). Mean values for pulse wave velocity (n=554), Pf and Pb were 7.50 m/s, 32.0 mm Hg, and 21.5 mm Hg, respectively. In multivariable-adjusted analyses, CRAE was 4.62 µm and 1.26 µm smaller (P≤0.034) for a 1-SD increment in central mean arterial pressure (+11.3 mm Hg) and central pulse pressure (+15.2 mm Hg); a 1-SD increment in the augmentation ratio (+7.0%), aortic pulse wave velocity (+1.66 m/s), Pf (+10.0 mm Hg), and Pb (+8.5 mm Hg), was associated with smaller CRAE; the association sizes were -1.91 µm, -1.59 µm, -1.45 µm, and -2.38 µm (P≤0.014), respectively. Associations of arteriole-to-venule diameter ratio with the central hemodynamic traits mirrored those of CRAE. None of the multivariable-adjusted associations of central retinal venular diameter with the central hemodynamic traits reached significance with the exception of central diastolic blood pressure (-1.62 µm; P=0.030). In conclusion, in the general population, higher central pulse pressure, pulse wave velocity, Pf, and Pb were associated with smaller CRAE.

Central hemodynamics in relation to blood lead in young men prior to chronic occupational exposure.

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8-12 h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 µg/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for aPWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00-9.75) and 1.57 (CI, 0.20-2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60-6.88) and 3.37 mm Hg (CI, 0.22-6.53) smaller (p ≤ .036 for all). The other hemodynamic measurements were unrelated to BL. The reflected pulse peak time was inversely correlated with diastolic pressure (r = -0.20; p ≤ .017). Conclusion: At the exposure levels observed in our current study, aPWV, the gold standard to assess arterial stiffness, was not associated with BL. Increased peripheral arterial resistance, as reflected by higher diastolic pressure, might bring reflection points closer to the heart, thereby moving the backward wave into systole and increasing the augmentation ratio in relation to BL.

Heart rate variability and peripheral nerve conduction velocity in relation to blood lead in newly hired lead workers.

OBJECTIVES: Previous studies relating nervous activity to blood lead (BL) levels have limited relevance, because over time environmental and occupational exposure substantially dropped. We investigated the association of heart rate variability (HRV) and median nerve conduction velocity (NCV) with BL using the baseline measurements collected in the Study for Promotion of Health in Recycling Lead (NCT02243904). METHODS: In 328 newly hired men (mean age 28.3 years; participation rate 82.7%), we derived HRV measures (power expressed in normalised units (nu) in the high-frequency (HF) and low-frequency (LF) domains, and LF/HF) prior to long-term occupational lead exposure. Five-minute ECG recordings, obtained in the supine and standing positions, were analysed by Fourier transform or autoregressive modelling, using Cardiax software. Motor NCV was measured at the median nerve by a handheld device (Brevio Nerve Conduction Monitoring System, NeuMed, West Trenton, NJ, USA). BL was determined by inductively coupled plasma mass spectrometry. RESULTS: Mean BL was 4.54 µg/dL (IQR 2.60-8.90 µg/dL). Mean supine and standing values of LF, HF and LF/HF were 50.5 and 21.1 nu and 2.63, and 59.7 and 10.9 nu and 6.31, respectively. Orthostatic stress decreased HF and increased LF (p<0.001). NCV averaged 3.74 m/s. Analyses across thirds of the BL distribution and multivariable-adjusted regression analyses failed to demonstrate any association of HRV or NCV with BL. CONCLUSIONS: At the exposure levels observed in our study, autonomous nervous activity and NCV were not associated with BL. TRIAL REGISTRATION NUMBER: NCT02243904.

Central Hemodynamics in Relation to Circulating Desphospho-Uncarboxylated Matrix Gla Protein: A Population Study.

Background Stiffening and calcification of the large arteries are forerunners of cardiovascular complications. MGP (Matrix Gla protein), which requires vitamin K-dependent activation, is a potent locally acting inhibitor of arterial calcification. We hypothesized that the central hemodynamic properties might be associated with inactive desphospho-uncarboxylated MGP (dp-uc MGP ). Methods and Results In 835 randomly recruited Flemish individuals (mean age, 49.7 years; 45.6% women), we measured plasma dp-uc MGP , using an ELISA -based assay. We derived central pulse pressure and carotid-femoral pulse wave velocity (PWV) from applanation tonometry and calculated forward and backward pulse waves using an automated, pressure-based wave separation analysis algorithm. Aortic PWV (n=657), central pulse pressure, forward pulse wave, and backward pulse wave mean± SD values were 7.34±1.64 m/s, 45.2±15.3 mm Hg, 33.2±10.2 mm Hg, and 21.8±8.6 mm Hg, respectively. The geometric mean plasma concentration of dp-uc MGP was 4.09 µg/L. All hemodynamic indexes increased across tertiles of dp-uc MGP distribution. In multivariable-adjusted analyses, a doubling of dp-uc MGP was associated with higher PWV (0.15 m/s; 95% CI, 0.01-0.28 m/s), central pulse pressure (1.70 mm Hg; 95% CI, 0.49-2.91 mm Hg), forward pulse wave (0.93 mm Hg; 95% CI, 0.01-1.84 mm Hg), and backward pulse wave (0.71 mm Hg; 95% CI, 0.11-1.30 mm Hg). Categorization of aortic PWV by tertiles of its distribution highlighted a decreasing trend of PWV at low dp-uc MGP (<3.35 µg/L) and an increasing trend at high dp-uc MGP (≥5.31 µg/L). Conclusions In people representative for the general population, higher inactive dp-uc MGP was associated with greater PWV , central pulse pressure, forward pulse wave, and backward pulse wave. These observations highlight new avenues for preserving vascular integrity and preventing cardiovascular complications (eg, by improving a person's vitamin K status).

The association of calcium channel blockers with ß-cell function in type 2 diabetic patients: A cross-sectional study.

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with ß-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess ß-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-ß was computed by Homeostasis Model Assessment model to evaluate ß-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-ß. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with ß-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced ß-cell function.

Neurocognitive function in relation to blood lead among young men prior to chronic occupational exposure.

Objectives Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. Results Average values were 4.26 µg/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4‒11.5%; P=0.066) higher, whereas the error score was 42% (-10‒69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers <40, 35 and 30 years were confirmatory. Conclusions At the exposure levels in our current study, we failed to demonstrate a consistent inverse association of BL with neurocognitive performance in young American men.

Fighting Type-2 Diabetes: Present and Future Perspectives.

BACKGROUND: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic ß cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects. METHODS: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions. RESULTS: Glucagon-like peptide-1 receptor agonists stimulate ß cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve ß cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot. CONCLUSION: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.

Angiopoietin-like 3 Is a Potential Biomarker for Retinopathy in Type 2 Diabetic Patients.

PURPOSE: To investigate whether angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are differentially associated with the severity of retinopathy in patients with type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional study. METHODS: Serum levels of ANGPTL3, ANGPTL4, high-sensitivity C-reactive protein (CRP), vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF) were quantified by ELISA. Retinal images were recorded to assess the grade of diabetic retinopathy (DR). Multivariable-adjusted logistic analysis was performed to estimate the association of each biomarker and DR stage. RESULTS: Among 1192 T2DM patients, 426 (35.7%) had nonproliferative diabetic retinopathy (NPDR) and 56 (4.5%) had proliferative diabetic retinopathy (PDR). After adjusting for covariables, the odds ratios expressing the risk of having DR vs no DR (n = 710 vs 482) were 1.23 (95% confidence interval [CI], 1.08-1.40, P = .002) for ANGPTL3; 0.90 (95% CI, 0.79-1.02; P = .095) for ANGPTL4; and 1.14 (95% CI, 1.00-1.29; P = .044) for VEGF. The risk of having no DR vs NPDR (n = 710 vs 426) was 1.16 (95% CI, 1.01-1.32; P = .036) for ANGPTL3; 0.90 (95% CI, 0.79-1.04; P = .15) for ANGPTL4; and 1.14 (95% CI, 1.00-1.31; P = .045) for VEGF. The odds ratios of having NPDR vs PDR (n = 426 vs 56) was 1.47 (95% CI, 1.03-2.10; P = .035) for serum ANGPTL3; 0.96 (95% CI, 0.69-1.35; P = .83) for ANGPTL4; and 1.05 (95% CI, 0.77-1.45; P = .74) for VEGF. CONCLUSIONS: ANGPTL3 is independently and strongly associated with DR progression in all stages. Blockade of ANGPTL3 signal in retina might postpone the onset and development of DR in T2DM patients.

Reanalysis and External Validation of a Decision Tree Model for Detecting Unrecognized Diabetes in Rural Chinese Individuals.

We reanalyzed previous data to develop a more simplified decision tree model as a screening tool for unrecognized diabetes, using basic information in Beijing community health records. Then, the model was validated in another rural town. Only three non-laboratory-based risk factors (age, BMI, and presence of hypertension) with fewer branches were used in the new model. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC) for detecting diabetes were calculated. The AUC values in internal and external validation groups were 0.708 and 0.629, respectively. Subjects with high risk of diabetes had significantly higher HOMA-IR, but no significant difference in HOMA-B was observed. This simple tool will help general practitioners and residents assess the risk of diabetes quickly and easily. This study also validates the strong associations of insulin resistance and early stage of diabetes, suggesting that more attention should be paid to the current model in rural Chinese adult populations.

Angiopoietin-Like Protein 4 Is a High-Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type-2 Diabetic Patients.

BACKGROUND: ANGPTL4 (angiopoietin-like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high-density lipoprotein (HDL). However, it is not defined whether ANGPTL4 in HDLs could affect HDL metabolism and function in type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: ANGPTL4 levels in the circulation and HDLs were quantified in nondiabetic participants (n=201, 68.7% females) and T2DM patients (n=185, 66.5% females). HDLs were isolated from nondiabetic controls and T2DM patients to assess cholesterol efflux or subjected to endothelial lipase (EL)-overexpressed HEK293 cells for EL hydrolysis in vitro. The association between ANGPTL4 in HDLs and HDL components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or HDLs of ANGPTL4+/+ and ANGPTL4-/- mice was subjected for cholesterol efflux or EL hydrolysis, respectively. ANGPTL4 levels in the plasma and HDLs were 1.7- and 2.0-fold higher in T2DM patients than nondiabetic controls, respectively (P<0.0001). Multivariable analysis demonstrated that per 1 doubling increase of ANGPTL4 levels in HDLs, the changes amounted to +0.27% cholesterol efflux (P=0.03), +0.06 µg/mL apolipoprotein A-I (P=0.09) and -9.41 µg/L serum amyloid A (P=0.02) in nondiabetic controls. In T2DM patients, the corresponding estimates were -0.06% cholesterol efflux (P=0.10), -0.06 µg/mL apolipoprotein A-I (P=0.38), and +3.64 µg/L serum amyloid A (P=0.72). HDLs isolated from ANGPTL4-/- mice showed accelerated hydrolysis by EL and reduced cholesterol efflux compared with ANGPTL4+/+ littermates. CONCLUSIONS: Physically, ANGPTL4 in HDLs protected HDLs from hydrolysis. Resulting from increased circulating ANGPTL4 levels in T2DM, ANGPTL4 levels in HDLs were elevated but with compromised inhibitory effect on EL, leading to increased HDL hydrolysis and dysfunction.