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Steinman M.A.,University of California at San Francisco | Steinman M.A.,Health Services Research Enhancement Award Program | Lee S.J.,University of California at San Francisco | Lee S.J.,Health Services Research Enhancement Award Program | And 8 more authors.
Journal of the American Geriatrics Society | Year: 2012

Objectives To determine patterns of co-occurring diseases in older adults and the extent to which these patterns vary between the young-old and the old-old. Design Observational study. Setting Department of Veterans Affairs. Participants Veterans aged 65 years and older (1.9 million male, mean age 76 ± 7; 39,000 female, mean age 77 ± 8) with two or more visits to Department of Veterans Affairs (VA) or Medicare settings in 2007 and 2008. Measurements The presence of 23 common conditions was assessed using hospital discharge diagnoses and outpatient encounter diagnoses from the VA and Medicare. Results The mean number of chronic conditions (out of 23 possible) was 5.5 ± 2.6 for men and 5.1 ± 2.6 for women. The prevalence of most conditions increased with advancing age, although diabetes mellitus and hyperlipidemia were 11% to 13% less prevalent in men and women aged 85 and older than in those aged 65 to 74 (P <.001 for each). In men, the most common three-way combination of conditions was hypertension, hyperlipidemia, and coronary heart disease, which together were present in 37% of men. For women, the most common combination was hypertension, hyperlipidemia, and arthritis, which co-occurred in 25% of women. Reflecting their high population prevalence, hypertension and hyperlipidemia were both present in 9 of the 15 most common three-way disease combinations in men and in 11 of the 15 most common combinations in women. The prevalence of many disease combinations varied substantially between young-old and old-old adults. Conclusions Specific combinations of diseases are highly prevalent in older adults and inform the development of guidelines that account for the simultaneous presence of multiple chronic conditions. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.


Schwartz J.B.,University of California at San Francisco | Lai J.,University of California at San Francisco | Lizaola B.,University of California at San Francisco | Kane L.,Jewish Home of San Francisco | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Objective: Our goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions. Patients and Methods: Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitaminDbinding protein (DBP) (immunoassay), albumin,andiPTH (immunoassay) were measured. Results: Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P<.03), anddifferencesbetweenmeasuredand calculated free 25(OH)D were greatest in African Americans (P<.001). Measured free 25(OH)D was correlated with total 25(OH)D (P<.0001; r20.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not. Conclusions: Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed. © 2014 by the Endocrine Society.


Kane L.,Jewish Home of San Francisco | Moore K.,Jewish Home of San Francisco | Lutjohann D.,University of Bonn | Bikle D.,University of California at San Francisco | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Inverse associations between 25-OH vitamin D levels and cardiovascular morbidity and mortality have been reported. Objectives: Our goals were to 1) investigate effects of correcting inadequate D status on lipids, 2) determine whether free 25-OH D is better correlated with lipids than total 25-OH D. Design: A randomized, double-blind placebo-controlled trial was performed. Setting: Participants resided in the general community. Participants: Adults with inadequateDstatus were randomized to D3: 14 men, 12women,age 60± 8 years (mean ± SD) or placebo: 12 men, 11 women: 59 ±12 years. Intervention: Responses to 12-week oral vitamin D3 titrated (1000-3000 IU/d) to achieve 25-OH D levels ≥25 ng/mL were compared to placebo. Main Outcome Measures: Measurements were 25-OH D (tandem mass spectometry), free 25-OH D (direct immunoassay), lipids (directly measured triglyceride, cholesterol, and subfractions; plant sterols and cholesterol synthesis precursors), and safety labs before and after 6 and 12 weeks D3 or placebo. Data were analyzed by repeated measures ANOVA and linear regression. Results: Vitamin D3 was titrated to 1000 IU/d in 15/26 (58%), to 2000 IU/d in 10, and 3000 IU/d in one patient. D3 had no effect on cholesterol or cholesterol subfractions except for trends for decreases in atorvastatin-treated patients (cholesterol, P = .08; low-density lipoprotein [LDL] cholesterol, P = .05). Decreased campesterol concentrations (P = .05) were seen with D3 but not placebo in statin-treated patients. Relationships between total 25-OH D and lipids were not detected, but inverse linear relationships were detected between free 25-OH D and triglycerides (P= .03 for all participants [n = 49], P = .03 in all statin-treated [n = 19], and P = .0009 in atorvastatintreated [n = 11]), and between free 25-OH D and LDL cholesterol (P = .08 overall, P = .02 in all statin-treated, and P = .03 for atorvastatin-treated), and total cholesterol (P = .09 overall; P = .04 for all statin-treated, and P = .05 for atorvastatin-treated). Conclusions: Vitamin D lipid-lowering effects appear limited to statin-treated patients and are likely due to decreased cholesterol absorption. Relationships between lipids and D metabolites were only detected when free 25-OH D was measured, suggesting the superiority of determining free 25-OH D levels compared to total 25-OH vitamin D levels when analyzing biologic responses. Copyright © 2013 by The Endocrine Society.


Kamholz B.,Jewish Home of San Francisco | Blazer D.G.,Duke University
American Journal of Geriatric Psychiatry | Year: 2013

The articles in this issue provide several exciting points that can guide future research and practice. First, delirium science has advanced to the point that light has begun to penetrate the former "black box" of cause and effect relationships among diverse contributing factors to delirium, increasing the potential for translational studies. Second, there has been a significant increase in the number and sophistication of studies investigating the impact of pharmacologic strategies in delirium care (whether as disease-modifying or symptom-mitigating effects). Third, steady improvements in defining delirium's pathophysiologic mechanisms have significant potential to advance our knowledge of other syndromes involving cognitive loss, not the least of which is dementia. Finally, a plethora of new, tantalizing findings at the fringes of delirium investigation may now attract other scientists to join in the work. We are most appreciative of the opportunity to present this information to the readership of the American Journal of Geriatric Psychiatry. © 2013 American Association for Geriatric Psychiatry.


Schwartz J.B.,Jewish Home of San Francisco | Schwartz J.B.,University of California at San Francisco
Journal of the American Geriatrics Society | Year: 2016

Objectives: To determine the potential effect of substituting glomerular filtration rate (GFR) estimates for renal clearance estimated using the Cockcroft–Gault method (CrCL-CG) to calculate direct oral anticoagulant (DOAC) dosing. Design: Simulation and retrospective data analysis. Setting: Community, academic institution, nursing home. Participants: Noninstitutionalized individuals aged 19 to 80 from the National Health and Nutrition Examination Survey (NHANES) (2011/12) (n = 4,687) and medically stable research participants aged 25 to 105 (n = 208). Measurements: Age, height, weight, sex, race, serum creatinine, CrCL-CG, and GFR (according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations). Outcome measures were dosing errors if GFR were to be substituted for CrCL-CG. Results: Renal clearance estimates according to all methods were highly correlated (P <.001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P <.001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR esimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects. Conclusion: Substitution of GFR estimates for estimated CrCl can lead to failure to recognize indications for reducing DOAC dose and potentially higher bleeding rates than in randomized trials. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society


Schwartz J.B.,Jewish Home of San Francisco | Schwartz J.B.,University of California at San Francisco | Kane L.,Jewish Home of San Francisco | Bikle D.,University of California at San Francisco
Journal of the American Geriatrics Society | Year: 2016

Objectives To determine the dose-response relationship between 25-hydroxyVitamin D (25(OH)D) and supplemental Vitamin D3 in elderly nursing home residents. Design Randomized double-blind investigation. Setting Nursing home. Participants Of 81 women (n = 51) and men (n = 30) (mean age 87.4 ± 8) enrolled, 72 completed the study. Intervention Sixteen weeks of oral Vitamin D3 at 800, 2,000, or 4,000 IU/d or 50,000 IU/wk. Measurements The main outcome was 25(OH)D concentrations (tandem mass spectrometry) after 16 weeks. Free 25(OH)D and intact parathyroid hormone (iPTH) were also analyzed. Safety monitoring of calcium and estimated glomerular filtration rate was performed, and adherence and clinical status were measured. Results 25(OH)D concentrations increased with dose (P <.001) and were higher with 50,000 IU/wk (P <.001) than other doses and with 4,000 IU/d than 800 or 2,000 IU/d, but 800 IU and 2,000 IU/d did not differ. One subject receiving 800 IU/d had concentrations less than 20 ng/mL. All subjects receiving more than 2000 IU/d had concentrations of 20 ng/mL and greater. Free 25(OH)D concentrations rose with total 25(OH) Vitamin D. Total and free 25(OH)D were related to calcium concentrations; only free 25(OH)D was related to iPTH. Conclusion 25(OH)D increased linearly with 800 to 4,000 IU/d and 50,000 IU/wk of Vitamin D3, without a ceiling effect. Data suggest that some elderly adults will require more than 800 IU/d of Vitamin D3 to ensure adequate Vitamin D levels. Changes in 25(OH)D with Vitamin D3 were related to starting concentrations (greatest with the lowest concentrations and unchanged with 800 and 2,000 IU/d if 20-40 ng/mL). Relationships between serum calcium and iPTH and free 25(OH)D suggest the potential for free 25(OH)D in defining optimal 25(OH)D concentrations. © 2016, the Authors Journal compilation.


Kapogiannis D.,U.S. National Institute on Aging | Boxer A.,University of California at San Francisco | Schwartz J.B.,University of California at San Francisco | Abner E.L.,University of Kentucky | And 7 more authors.
FASEB Journal | Year: 2015

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pantyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset. © FASEB.


PubMed | University of California at San Francisco and Jewish Home of San Francisco
Type: Journal Article | Journal: Journal of the American Geriatrics Society | Year: 2016

To determine the dose-response relationship between 25-hydroxyvitamin D (25(OH)D) and supplemental vitamin D3 in elderly nursing home residents.Randomized double-blind investigation.Nursing home.Of 81 women (n=51) and men (n=30) (mean age 87.48) enrolled, 72 completed the study.Sixteen weeks of oral vitamin D3 at 800, 2,000, or 4,000 IU/d or 50,000 IU/wk.The main outcome was 25(OH)D concentrations (tandem mass spectrometry) after 16 weeks. Free 25(OH)D and intact parathyroid hormone (iPTH) were also analyzed. Safety monitoring of calcium and estimated glomerular filtration rate was performed, and adherence and clinical status were measured.25(OH)D concentrations increased with dose (P<.001) and were higher with 50,000 IU/wk (P<.001) than other doses and with 4,000 IU/d than 800 or 2,000 IU/d, but 800 IU and 2,000 IU/d did not differ. One subject receiving 800 IU/d had concentrations less than 20 ng/mL. All subjects receiving more than 2000 IU/d had concentrations of 20 ng/mL and greater. Free 25(OH)D concentrations rose with total 25(OH) vitamin D. Total and free 25(OH)D were related to calcium concentrations; only free 25(OH)D was related to iPTH.25(OH)D increased linearly with 800 to 4,000 IU/d and 50,000 IU/wk of vitamin D3, without a ceiling effect. Data suggest that some elderly adults will require more than 800 IU/d of vitamin D3 to ensure adequate vitamin D levels. Changes in 25(OH)D with vitamin D3 were related to starting concentrations (greatest with the lowest concentrations and unchanged with 800 and 2,000 IU/d if 20-40 ng/mL). Relationships between serum calcium and iPTH and free 25(OH)D suggest the potential for free 25(OH)D in defining optimal 25(OH)D concentrations.


Schwartz J.B.,University of California at San Francisco | Lai J.,University of California at San Francisco | Lizaola B.,University of California at San Francisco | Kane L.,Jewish Home of San Francisco | And 4 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

Our goal was to determine total and directly measured free 25-hydroxy vitamin D (25(OH)D) serum levels in humans with a range of 25(OH)D levels and clinical conditions associated with low and high vitamin D binding protein levels. Serum samples and clinical data were collected from 106 subjects: 62 without cirrhosis or pregnancy, 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women. Total 25(OH)D (LC/MS/MS) and "free" 25(OH)D (immunoassay) were measured. Total 25(OH)D was significantly lower in liver disease patients but free 25(OH)D concentrations were significantly higher in this group (p <.001). Neither total nor free 25(OH)D concentrations were significantly different in pregnant women vs. The comparator group. There were significant direct positive relationships between free 25(OH)D and total 25(OH)D concentrations for the entire dataset and for each group (p <.0001), however slopes of relationships differed in the cirrhotic group compared to pregnant women or the comparator group. In cirrhotics: y (free 25(OH)D) = 2.52 + 0.29 × X(total 25 (OH)D), r2 =.51, p <.001; y = 1.45 + 0.09 × X; r2 =.77, p <.0001 for pregnant women; and y = 1.11 + 0.12 × X; r2 =.72, p <.0001 for the comparator group). Conclusions: directly measured free 25(OH)D serum concentrations and relationships between total and free 25(OH)D vary with clinical conditions, and may differ from those predicted by indirect estimation methods. This article is part of a Special Issue entitled 'Vitamin D Workshop'. © 2013 Elsevier Ltd.


PubMed | U.S. National Institute on Aging, University of Kentucky, Memory and Aging Center, Mayo Medical School and 2 more.
Type: Journal Article | Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology | Year: 2015

Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimers disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.

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