Effect of high dose vitamin D supplementation on subsequent immune responses to administration of the live herpes zoster vaccine to long-term care residents.

Thirty-three long-term care residents (mean age 76.5 years), who were participating in a study in which they were randomized to receive either oral daily standard dose (400-1000 IU/day) 25-hydroxy vitamin D (vitamin D3) (SD) or high dose (3000-4000 IU/day) (HD) vitamin D3, were vaccinated with the live, attenuated herpes zoster vaccine. Blood was drawn at vaccination and three weeks later to determine varicella-zoster virus (VZV) antibody and T-cell mediated immune responses. ELISA and neutralizing antibodies increased significantly, but to the same extent, in both groups. The antibody avidity significantly increased from pre- to post-vaccination only in the HD group. VZV-CMI, as measured by FLUOROSPOT significantly increased post-vaccination in both groups, but the difference in interferon-γ spot-forming cells (SFC) and interleukin-2 SFC was lower in the HD than SD group. The increase in VZV-CMI correlated inversely with circulating regulatory T cells in the HD group. We conclude that pre-treatment with HD vitamin D3 does not appreciably enhance the antibody response to a live vaccine and that VZV-CMI responses were diminished in HD vitamin D3 recipients.

High-Dose Monthly Vitamin D for Prevention of Acute Respiratory Infection in Older Long-Term Care Residents: A Randomized Clinical Trial.

OBJECTIVES: To determine the efficacy and safety of high-dose vitamin D supplementation for prevention of acute respiratory infection (ARI) in older long-term care residents. DESIGN: Randomized controlled trial investigating high-dose vs standard-dose vitamin D from 2010 to 2014. SETTING: Colorado long-term care facilities. PARTICIPANTS: Long-term care residents aged 60 and older (n = 107). INTERVENTION: The high-dose group received monthly supplement of vitamin D3 100,000 IU, the standard-dose group received a monthly placebo (for participants taking 400-1,000 IU/d as part of usual care) or a monthly supplement of 12,000 IU of vitamin D3 (for participants taking <400 IU/d as part of usual care). MEASUREMENTS: The primary outcome was incidence of ARI during the 12-month intervention. Secondary outcomes were falls and fractures, 25-hydroxyvitamin D levels, hypercalcemia, and kidney stones. RESULTS: Participants (55 high dose, 52 standard dose) were randomized and included in the final analysis. The high-dose group had 0.67 ARIs per person-year and the standard-dose group had 1.11 (incidence rate ratio (IRR) = 0.60, 95% confidence interval (CI) = 0.38-0.94, P = .02). Falls were more common in the high-dose group (1.47 per person-year vs 0.63 in standard-dose group; IRR = 2.33, 95% CI = 1.49-3.63, P < .001). Fractures were uncommon and similar in both groups (high dose 0.10 vs standard dose 0.19 per person-year; P = .31). Mean trough 25-hydroxyvitamin D levels during the trial were 32. ng/mL in the high-dose group and 25.1 ng/mL in the standard-dose group. There was no hypercalcemia or kidney stones in either group. CONCLUSION: Monthly high-dose vitamin D3 supplementation reduced the incidence of ARI in older long-term care residents but was associated with a higher rate of falls without an increase in fractures.

Relationship between intensity of quadriceps muscle neuromuscular electrical stimulation and strength recovery after total knee arthroplasty.

BACKGROUND: Neuromuscular electrical stimulation (NMES) can facilitate the recovery of quadriceps muscle strength after total knee arthroplasty (TKA), yet the optimal intensity (dosage) of NMES and its effect on strength after TKA have yet to be determined. OBJECTIVE: The primary objective of this study was to determine whether the intensity of NMES application was related to the recovery of quadriceps muscle strength early after TKA. A secondary objective was to quantify quadriceps muscle fatigue and activation immediately after NMES to guide decisions about the timing of NMES during rehabilitation sessions. DESIGN: This study was an observational experimental investigation. METHODS: Data were collected from 30 people who were 50 to 85 years of age and who received NMES after TKA. These people participated in a randomized controlled trial in which they received either standard rehabilitation or standard rehabilitation plus NMES to the quadriceps muscle to mitigate strength loss. For the NMES intervention group, NMES was applied 2 times per day at the maximal tolerable intensity for 15 contractions beginning 48 hours after surgery over the first 6 weeks after TKA. Neuromuscular electrical stimulation training intensity and quadriceps muscle strength and activation were assessed before surgery and 3.5 and 6.5 weeks after TKA. RESULTS: At 3.5 weeks, there was a significant association between NMES training intensity and a change in quadriceps muscle strength (R(2)=.68) and activation (R(2)=.22). At 6.5 weeks, NMES training intensity was related to a change in strength (R(2)=.25) but not to a change in activation (R(2)=.00). Furthermore, quadriceps muscle fatigue occurred during NMES sessions at 3.5 and 6.5 weeks, whereas quadriceps muscle activation did not change. LIMITATIONS: Some participants reached the maximal stimulator output during at least 1 treatment session and might have tolerated more stimulation. CONCLUSIONS: Higher NMES training intensities were associated with greater quadriceps muscle strength and activation after TKA.

Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults.

OBJECTIVES: To evaluate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and mortality in a representative U.S. sample of older adults. DESIGN: Prospective cohort from the Third National Health and Nutrition Examination Survey (NHANES III) and linked mortality files. SETTING: Noninstitutionalized U.S. civilian population. PARTICIPANTS: Three thousand four hundred eight NHANES III participants aged 65 and older enrolled from 1988 to 1994 and followed for mortality through 2000. MEASUREMENTS: Primary exposure was serum 25(OH)D level at enrollment. Primary and secondary outcomes were all-cause and cardiovascular disease (CVD) mortality, respectively. RESULTS: During the median 7.3 years of follow-up, there were 1,493 (44%) deaths, including 767 CVD-related deaths. Median 25(OH)D level was 66 nmol/L. Adjusting for demographics, season, and cardiovascular risk factors, baseline 25(OH)D levels were inversely associated with all-cause mortality risk (adjusted hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.92-0.98, per 10 nmol/L 25[OH]D). Compared with subjects with 25(OH)D levels of 100 nmol/L or higher, the adjusted HR for subjects with levels less than 25.0 nmol/L was 1.83 (95% CI=1.14-2.94) and for levels of 25.0 to 49.9 nmol/L was 1.47 (95% CI=1.09-1.97). The association appeared stronger for CVD mortality (adjusted HR=2.36, 95% CI=1.17-4.75, for subjects with 25[OH]D levels<25.0 nmol/L vs those > or =100.0 nmol/L) than for non-CVD mortality (adjusted HR=1.42, 95% CI=0.73-2.79, for subjects with 25[OH]D levels<25.0 nmol/L vs those > or =100.0 nmol/L). CONCLUSION: In noninstitutionalized older adults, a group at high risk for all-cause mortality, serum 25(OH)D levels had an independent, inverse association with CVD and all-cause mortality. Randomized controlled trials of vitamin D supplementation in older adults are warranted to determine whether this association is causal and reversible.

Drug-eluting stents in preclinical studies: updated consensus recommendations for preclinical evaluation.

Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time.

Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy.

Pregnancy-associated plasma protein-A (PAPP-A) was associated with atherosclerotic plaque vulnerability, whereas statin therapy was associated with increased plaque stability. Eighty-six patients presenting with clinical indications (non-ST-elevation myocardial infarction, unstable angina, and stable angina) for invasive coronary angiography and subsequent verified coronary artery disease (CAD) were randomly assigned in a double-blind manner to atorvastatin 10 or 80 mg/day. PAPP-A, high-sensitivity C-reactive protein (hs-CRP), and lipids were measured at baseline (before statin therapy) and at 1 and 6 months. PAPP-A was significantly increased in 35 patients with acute coronary syndrome (ACS) compared with 51 patients with stable CAD (p <0.001). Patients randomly assigned to atorvastatin 10 mg did not show a significant decrease in PAPP-A from baseline at 1 or 6 months. Patients treated with atorvastatin 80 mg showed a significant decrease at 1 month compared with baseline, but not at 6 months. hs-CRP was not significantly different between the ACS and stable CAD groups. Patients receiving atorvastatin 10 mg showed no hs-CRP decrease at 1 or 6 months, whereas it significantly decreased in the 80-mg group at 6 months, but not at 1 month. In conclusion, PAPP-A significantly increased in patients with ACS compared with those with stable coronary disease. High-dose atorvastatin significantly decreased PAPP-A at 1 month and hs-CRP at 6 months in patients with verified CAD. Low-dose atorvastatin did not produce this effect.

Preclinical restenosis models: challenges and successes.

Coronary artery disease remains a major problem for Western societies. The advent of percutaneous interventions, including stents has brought clinical care to a new level of efficacy, yet problems remain. Restenosis following stenting in human coronary arteries appears at last to be yielding to therapeutic strategies, especially drug eluting stents. Because therapeutic percutaneous coronary intervention is widely dominated by the intracoronary stent, restenosis therapies must include the stented coronary artery. Animal models and in particular the porcine coronary model seem to represent the human coronary artery reaction to stenting. It mimics several clinical conditions including thrombosis and neointimal formation. A key question in the era of intravascular technologies is how well this and other models can predict clinical events. This paper discusses the models and their application.

Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature.

OBJECTIVE: Hypercholesterolemia (HC) and hypertension (HT) are both major risk factors for the development and progression of atherosclerotic heart disease, and their co-existence has been associated with an increased incidence of cardiac events in clinical studies. HC and HT are individually associated with abnormal myocardial vascular function, but whether HT exacerbates the HC-induced myocardial vascular dysfunction remains unclear. METHODS: We studied in pigs the effect of renovascular HT superimposed on diet-induced HC (HC+HT) on myocardial perfusion and microvascular permeability in vivo (using electron-beam computed tomography) in response to cardiac challenge (i.v. adenosine and dobutamine). The involvement of systemic and myocardial tissue oxidative stress in vitro was assessed by oxidizability of LDL, levels of endogenous antioxidants, and tissue activities of radical-scavenger systems. RESULTS: While in normal animals myocardial perfusion increased in response to i.v. adenosine (+36+/-13%, P<0.05), in HC and HT alone the increase was blunted. In HC+HT myocardial perfusion response was further attenuated and significantly lower than normal, and myocardial vascular resistance failed to decrease (+7.6+/-8.8 vs. -21.0+/-5.8%, P=0.02 versus normal). HC+HT also showed blunted response to dobutamine, and augmented increases in microvascular permeability in vivo. These functional abnormalities were associated with increased systemic and myocardial tissue oxidative stress compared to HC or HT alone, and a synergistic decrease in endogenous antioxidant defenses in myocardial tissue. Furthermore, chronic antioxidant vitamin supplementation in combined HC and HT improved myocardial vascular responses. CONCLUSION: HT amplifies the HC-induced myocardial microvascular dysfunction in vivo and increased oxidative stress in vitro. These alterations may potentially play a role in the increased incidence of cardiac events observed when HC and HT co-exist.