Publications by authors named "Robert M Cohen"

89 Publications

The Hygiene Hypothesis - Learning From but Not Living in the Past.

Front Immunol 2021 16;12:635935. Epub 2021 Mar 16.

German Center for Lung Research (DZL), Marburg, Germany.

Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.
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http://dx.doi.org/10.3389/fimmu.2021.635935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007786PMC
March 2021

Association of glycemia with insulin sensitivity and β-cell function in adults with early type 2 diabetes on metformin alone.

J Diabetes Complications 2021 May 17;35(5):107912. Epub 2021 Mar 17.

VA Puget Sound Health Care System and University of Washington, Seattle, WA, United States of America.

Aims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM).

Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes. A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-h oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-h glucose), measures of β-cell function and insulin sensitivity.

Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r - 0.22 to -0.35). Fasting and 2-h glucose were associated with early insulin and C-peptide responses (range: r - 0.37 to -0.40) as well as late insulin and total insulin and C-peptide responses (range: r - 0.50 to -0.60).

Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function. This Trial is registered in Clinicaltrials.gov as NCT01794143.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048071PMC
May 2021

Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort.

Diabetes Care 2021 02 17;44(2):340-349. Epub 2020 Dec 17.

Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and the University of Washington, Seattle, WA.

Objective: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA) and the associations with selected phenotypic characteristics.

Research Design And Methods: This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed <10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).

Results: The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m, HbA 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA, but Black/African Americans and Asians had lower HbA. However, when adjusted for glucose levels, Black/African Americans had higher HbA than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA, and TG/HDL-C.

Conclusions: In the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA. HbA also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity.
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http://dx.doi.org/10.2337/dc20-1787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818323PMC
February 2021

Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology.

Mech Ageing Dev 2020 10 8;191:111351. Epub 2020 Sep 8.

Dept. Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, United States; Brain Mapping Foundation, Society for Brain Mapping & Therapeutics, 860 Via De la Paz, Pacific Palisades, CA 90272, United States; T-Neuro Pharma, 1451 Innovation Parkway SE, Albuquerque, NM 87123, United States. Electronic address:

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.
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http://dx.doi.org/10.1016/j.mad.2020.111351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567339PMC
October 2020

Behavioral Phenotype in the TgF344-AD Rat Model of Alzheimer's Disease.

Front Neurosci 2020 16;14:601. Epub 2020 Jun 16.

Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States.

Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive decline. A unique rat model, TgF344-AD, recapitulates pathological hallmarks of AD. We used a longitudinal design to address the timing of expression of behavioral phenotypes in male and female TgF344-AD rats. In both sexes, we confirmed an age-dependent buildup of amyloid-β. In the open field, female, but not male, TgF344-AD rats were hypoactive at 6 and 12 months of age but at 18 months the two genotypes were similar in levels of activity response. Both male and female TgF344-AD rats had a deficit in performance on a learning and memory task. Male TgF344-AD, but not female, rats had evidence of hyposmia regardless of age. Rest-activity rhythms followed the typical active/inactive phase in all rats regardless of genotype or age. In males, home cage activity was similar across age and genotype; in females, regardless of genotype animals were less active as they aged. These changes highlight some behavioral markers of disease in the rat model. Early markers of disease may be important in early diagnosis and assessment of efficacy when treatment becomes available.
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http://dx.doi.org/10.3389/fnins.2020.00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308710PMC
June 2020

Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial.

Liver Transpl 2020 11 19;26(11):1430-1440. Epub 2020 Aug 19.

Divisions of, Division of, Digestive Diseases, University of Cincinnati, Cincinnati, OH.

Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.
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http://dx.doi.org/10.1002/lt.25837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606621PMC
November 2020

Prevalence of microvascular and macrovascular disease in the Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) Study cohort.

Diabetes Res Clin Pract 2020 Jul 23;165:108235. Epub 2020 May 23.

Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.

Aims: The Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) trial is a randomized clinical trial comparing glycemic effects of four diabetes medications added to metformin in type 2 diabetes (T2D). Microvascular and macrovascular diseases are secondary outcomes. We evaluated the prevalence and risk factor relationships for microvascular and macrovascular complications in the GRADE cohort at study entry.

Methods: Complication prevalence and risk factors were analyzed based on data from screening in all consenting participants meeting GRADE eligibility. Logistic regression and Z-statistics were used to assess risk factor relationships with complications.

Results: We enrolled 5047 T2D participants [mean age 57 years; 36% female; mean known T2D duration 4 years (all < 10 years); mean HbA1c 8.0% (∼64 mmol/mol) at screening]. Urinary albumin/creatinine ratio (ACR) ≥ 30 mg/gram was present in 15.9% participants; peripheral neuropathy (by Michigan Neuropathy Screening Instrument) in 21.5%; cardiovascular autonomic neuropathy by electrocardiography-derived indices in 9.7%; self-reported retinopathy in 1.0%. Myocardial infarction ascertained by self-report or electrocardiogram was present in 7.3%, and self-reported history of stroke in 2.0%.

Conclusions: In the GRADE cohort with < 10 years of T2D and a mean HbA1c of 8.0%, diabetes complications were present in a substantial fraction of participants, more so than might otherwise have been expected.
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http://dx.doi.org/10.1016/j.diabres.2020.108235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416515PMC
July 2020

Delayed Sleeve Gastrectomy Following Liver Transplantation: A 5-Year Experience.

Liver Transpl 2019 11 15;25(11):1673-1681. Epub 2019 Oct 15.

Department of Surgery, Section of Transplantation, University of Cincinnati School of Medicine, Cincinnati, OH.

Obesity has become an epidemic in the United States over the past decade, and recent studies have shown this trend in the liver transplantation (LT) population. These patients may be candidates for laparoscopic sleeve gastrectomy (LSG) to promote significant and sustained weight loss to prevent recurrence of nonalcoholic steatohepatitis. However, safety remains a concern, and efficacy in this setting is uncertain. A single-institution database from 2014 to 2018 was queried for patients undergoing LSG following LT. The selection criteria for surgery were consistent with National Institutes of Health guidelines, and patients were at least 6 months after LT. A total of 15 patients (median age, 59.0 years; Caucasian, 86.7%; and female, 60%) underwent LSG following LT. Median time from LT to LSG was 2.2 years with a median follow-up period of 2.6 years. The median hospital length of stay (LOS) was 2 days after LSG. Mortality and rate of liver allograft rejection was 0, and there was 1 postoperative complication (a surgical site infection). Following LSG, body mass index (BMI) decreased from 42.7 to 35.9 kg/m (P < 0.01), and in 12 patients with at least 1 year of follow-up, the total body weight loss was 20.6%. Following LSG in patients with diabetes, the median daily insulin requirements decreased from 98 (49-118) to 0 (0-29) units/day (P = 0.02), and 60% discontinued insulin. Post-LT patients had a similar decrease in BMI and reduction in comorbidities at 1 year compared with a matched non-LT patient cohort. In the largest patient series to date, we show that LSG following LT is safe, effective, and does not increase the incidence of liver allograft rejection. Larger longer-term studies are needed to confirm underlying metabolic changes following LSG.
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http://dx.doi.org/10.1002/lt.25637DOI Listing
November 2019

Rationale and Design for a GRADE Substudy of Continuous Glucose Monitoring.

Diabetes Technol Ther 2019 12 4;21(12):682-690. Epub 2019 Sep 4.

Advanced Research and Diagnostic Laboratory, University of Minnesota, Minneapolis, Minnesota.

The lycemia eduction pproaches in iabetes: A Comparative ffectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities.
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http://dx.doi.org/10.1089/dia.2019.0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207016PMC
December 2019

When HbA1c and Blood Glucose Do Not Match: How Much Is Determined by Race, by Genetics, by Differences in Mean Red Blood Cell Age?

J Clin Endocrinol Metab 2019 03;104(3):707-710

Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1210/jc.2018-02409DOI Listing
March 2019

Effect of vitamin D supplementation on cardiovascular risk in type 2 diabetes.

Clin Nutr 2019 10 9;38(5):2449-2453. Epub 2018 Oct 9.

Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, 800 Washington Street, #268, Boston, MA, 02111, USA. Electronic address:

Background & Aims: Whether vitamin D affects lipid profile and cardiovascular disease (CVD) risk is controversial. We evaluated the effect of oral daily vitamin D supplementation on lipid profile and CVD risk in patients with well-controlled type 2 diabetes.

Methods: Secondary analysis in the vitamin D for established type 2 diabetes (DDM2) study, a double-blind, randomized, placebo-controlled clinical trial. 127 patients (mean age 60 years) with stable (HbA1c ≤ 7.5%) diabetes managed with lifestyle only or lifestyle plus metformin were randomized to receive 4000 IU/day of vitamin D (n = 66) or placebo (n = 61) for 48 weeks. Changes in lipid profile (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides [TG] and TG/HDL ratio), C-reactive protein and CVD risk (calculated according the American College of Cardiology/American Heart Association [ACC/AHA] guidelines) were assessed at week 24 and 48.

Results: The mean [±SEM] plasma 25-hydroxyvitamin D [25(OH)D] level was higher in the vitamin D vs. the placebo group (20.5 ± 1.18 vs. -1.6 ± 1.2 ng/mL respectively; p < 0.001). There was no statistically significant change in lipid profile, C-reactive protein or CVD risk. Among patients who were not on cholesterol medication (n = 32), vitamin D supplementation reduced TG compared to placebo at week 48 (-18.74 ± 8.91 vs. 9.69 ± 8.60 mg/dL respectively; p = 0.032).

Conclusion: One year supplementation with vitamin D at 4000 IU/day did not affect lipid profile, C-reactive protein and CVD risk in patients with stable type 2 diabetes not selected for vitamin D deficiency, with the exception of improvement of TG among patients not on cholesterol medication.

Registration: ClinicalTrials.gov Identifier NCT01736865.
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http://dx.doi.org/10.1016/j.clnu.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456440PMC
October 2019

Hippocampal place cell dysfunction and the effects of muscarinic M receptor agonism in a rat model of Alzheimer's disease.

Hippocampus 2018 08 3;28(8):568-585. Epub 2018 Jul 3.

Department of Psychology, Emory University, Atlanta, Georgia.

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.
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http://dx.doi.org/10.1002/hipo.22961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133736PMC
August 2018

Vitamin D Supplementation in Patients With Type 2 Diabetes: The Vitamin D for Established Type 2 Diabetes (DDM2) Study.

J Endocr Soc 2018 Apr 26;2(4):310-321. Epub 2018 Feb 26.

Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts.

Context: Observational data support a role for vitamin D in type 2 diabetes, but evidence from trials is inconclusive.

Objective: To evaluate the effect of vitamin D supplementation on -cell function and hemoglobin A1c (HbA1c) in patients with well-controlled type 2 diabetes.

Design: Double-blind, randomized, placebo-controlled clinical trial.

Setting: Tufts Medical Center, Boston, MA; VA Medical Center, Cincinnati, OH.

Participants: A total of 127 patients (mean age, 60 years) with stable (HbA1c ≤7.5%) diabetes managed with lifestyle only or lifestyle plus metformin.

Intervention: Subjects were given 4000 units of vitamin D (cholecalciferol) daily or placebo for 48 weeks.

Main Outcome Measure: Insulin secretion rate (ISR) was estimated from peripheral plasma C-peptide levels after a 3-hour 75-g oral glucose tolerance test done at baseline and week 24. Changes in HbA1c were assessed at 16, 24, 36, and 48 weeks.

Results: Baseline mean plasma 25-hydroxyvitamin D [25(OH)D] concentration was 26.6 ng/mL, mean HbA1c was 6.6%, and 78% of patients were on metformin. At week 24, mean 25(OH)D changed by 20.5 and -1.6 ng/mL in the vitamin D and placebo groups, respectively ( < 0.001). The vitamin D and placebo groups did not differ in change in ISR or HbA1c. Among patients treated with lifestyle only (n = 28), vitamin D supplementation reduced HbA1c compared with placebo (-0.1% vs 0.3%, respectively; = 0.034) at week 24. This result was not observed at the other time points and could be due to chance.

Conclusion: Vitamin D at 4000 IU/d did not change ISR or HbA1c in patients with well-controlled type 2 diabetes on metformin not selected for vitamin D deficiency.
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http://dx.doi.org/10.1210/js.2018-00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848819PMC
April 2018

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

Brain 2017 11;140(11):3023-3038

Department of Human Genetics, Emory University School of Medicine, Atlanta GA 30322, USA.

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a suitable model of locus coeruleus pathology and dysfunction early in Alzheimer’s disease progression, and suggest that a substantial window of opportunity for locus coeruleus/ norepinephrine-based therapeutics exists.
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http://dx.doi.org/10.1093/brain/awx232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841201PMC
November 2017

Associations of Early Kidney Disease With Brain Magnetic Resonance Imaging and Cognitive Function in African Americans With Type 2 Diabetes Mellitus.

Am J Kidney Dis 2017 Nov 23;70(5):627-637. Epub 2017 Jun 23.

Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.

Background: Relationships between early kidney disease, neurocognitive function, and brain anatomy are poorly defined in African Americans with type 2 diabetes mellitus (T2DM).

Study Design: Cross-sectional associations were assessed between cerebral anatomy and cognitive performance with estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) in African Americans with T2DM.

Setting & Participants: African Americans with cognitive testing and cerebral magnetic resonance imaging (MRI) in the African American-Diabetes Heart Study Memory in Diabetes (AA-DHS MIND; n=512; 480 with MRI) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) MIND (n=484; 104 with MRI) studies.

Predictors: eGFR (CKD-EPI creatinine equation), spot UACR.

Measurements: MRI-based cerebral white matter volume (WMV), gray matter volume (GMV), and white matter lesion volume; cognitive performance (Mini-Mental State Examination, Digit Symbol Coding, Stroop Test, and Rey Auditory Verbal Learning Test). Multivariable models adjusted for age, sex, body mass index, scanner, intracranial volume, education, diabetes duration, hemoglobin A concentration, low-density lipoprotein cholesterol concentration, smoking, hypertension, and cardiovascular disease were used to test for associations between kidney phenotypes and the brain in each study; a meta-analysis was performed.

Results: Mean participant age was 60.1±7.9 (SD) years; diabetes duration, 12.1±7.7 years; hemoglobin A concentration, 8.3%±1.7%; eGFR, 88.7±21.6mL/min/1.73m; and UACR, 119.2±336.4mg/g. In the fully adjusted meta-analysis, higher GMV associated with lower UACR (P<0.05), with a trend toward association with higher eGFR. Higher white matter lesion volume was associated with higher UACR (P<0.05) and lower eGFR (P<0.001). WMV was not associated with either kidney parameter. Higher UACR was associated with lower Digit Symbol Coding performance (P<0.001) and a trend toward association with higher Stroop interference; eGFR was not associated with cognitive tests.

Limitations: Cross-sectional; single UACR measurement.

Conclusions: In African Americans with T2DM, mildly high UACR and mildly low eGFR were associated with smaller GMV and increased white matter lesion volume. UACR was associated with poorer processing speed and working memory.
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http://dx.doi.org/10.1053/j.ajkd.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651190PMC
November 2017

Antibodies to biotinylated red blood cells in adults and infants: improved detection, partial characterization, and dependence on red blood cell-biotin dose.

Transfusion 2017 06 5;57(6):1488-1496. Epub 2017 Mar 5.

Department of Pediatrics, Carver College of Medicine, Iowa City, Iowa.

Background: Biotin-labeled red blood cells (BioRBCs) are used for in vivo kinetic studies. Because BioRBC dosing occasionally induces antibodies, a sensitive and specific anti-BioRBC detection assay is needed.

Study Design And Methods: Aims were to 1) develop a gel card assay to evaluate existing, naturally occurring and BioRBC-induced plasma antibodies, 2) compare gel card and tube agglutination detection results, and 3) test for a relationship of antibody induction and BioRBC dose. Reagent BioRBCs were prepared using sulfo-NHS biotin ranging from densities 18 (BioRBC-18) to 1458 (BioRBC-1458) µg/mL RBCs.

Results: Among BioRBC-exposed subjects, gel card and tube agglutination results were concordant in 21 of 22 adults and all 19 infant plasma samples. Gel card antibody detection sensitivity was more than 10-fold greater than tube agglutination. Twelve to 16 weeks after BioRBC exposure, induced anti-antibodies were detected by gel card in three of 26 adults (12%) at reagent densities BioRBC-256 or less, but in none of 41 infants. Importantly, induced anti-BioRBC antibodies were associated with higher BioRBC dose (p = 0.008); no antibodies were detected in 18 subjects who received BioRBC doses less than or equal to BioRBC-18. For noninduced BioRBC antibodies, six of 1125 naïve adults (0.3%) and none of 46 naïve infants demonstrated existing anti-BioRBC antibodies using reagent BioRBC-140 or -162. Existing anti-BioRBCs were all neutralized by biotin compounds, while induced antibodies were not.

Conclusions: The gel card assay is more sensitive than the tube agglutination assay. We recommend reagent BioRBC-256 for identifying anti-BioRBCs. Use of a low total RBC biotin label dose (≤ BioRBC-18) may minimize antibody induction.
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http://dx.doi.org/10.1111/trf.14075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567754PMC
June 2017

Low-level laser therapy for beta amyloid toxicity in rat hippocampus.

Neurobiol Aging 2017 01 11;49:165-182. Epub 2016 Oct 11.

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. Electronic address:

Beta amyloid (Aβ) is well accepted to play a central role in the pathogenesis of Alzheimer's disease (AD). The present work evaluated the therapeutic effects of low-level laser irradiation (LLI) on Aβ-induced neurotoxicity in rat hippocampus. Aβ 1-42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and 2-minute daily LLI treatment was applied transcranially after Aβ injection for 5 consecutive days. LLI treatment suppressed Aβ-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: (1) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aβ-induced extensive fragmentation; (2) suppressed Aβ-induced collapse of mitochondrial membrane potential; (3) reduced oxidized mitochondrial DNA and excessive mitophagy; (4) facilitated mitochondrial homeostasis via modulation of the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and of mitochondrial antioxidant expression; (5) promoted cytochrome c oxidase activity and adenosine triphosphate synthesis; (6) suppressed Aβ-induced glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity; (7) enhanced the total antioxidant capacity of hippocampal CA1 neurons, whereas reduced the oxidative damage; and (8) suppressed Aβ-induced reactive gliosis, inflammation, and tau hyperphosphorylation. Although development of AD treatments has focused on reducing cerebral Aβ levels, by the time the clinical diagnosis of AD or mild cognitive impairment is made, the brain is likely to have already been exposed to years of elevated Aβ levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aβ-induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis, and tau pathology, LLI could represent a new promising therapeutic strategy for AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458630PMC
January 2017

The recovery index: A novel approach to measuring recovery and predicting remission in major depressive disorder.

J Affect Disord 2017 Jan 15;208:369-374. Epub 2016 Oct 15.

UCLA Graduate School of Education and Information Studies, United States.

Background: Clinicians view "recovery" as the reduction in severity of symptoms over time, whereas patients view it as the restoration of premorbid functioning level and quality of life (QOL). The main purpose of this study is to incorporate patient-reported measures of functioning and QOL into the assessment of patient outcomes in MDD and to use this data to define recovery.

Method: Using the STAR*D study of patients diagnosed with MDD, this present analysis grades patients' MDD severity, functioning level, and QOL at exit from each level of the study, as well as at follow-up. Using Item Response Theory, we combined patient data from functioning and QOL measures (WSAS, Q-LES-Q) in order to form a single latent dimension named the Recovery Index.

Results: Recovery Index - a latent measure assessing impact of illness on functioning and QOL - is able to predict remission of MDD in patients who participated in the STAR*D study.

Conclusions: By incorporating functioning and quality of life, the Recovery index creates a new dimension towards measuring restoration of health, in order to move beyond basic symptom measurement.
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http://dx.doi.org/10.1016/j.jad.2016.08.081DOI Listing
January 2017

Can Red Blood Cell Indices Act as Surrogate Markers for Discordance between Hemoglobin A1c and Fasting Blood Glucose?

Clin Chem 2016 12 30;62(12):1551-1553. Epub 2016 Sep 30.

Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

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http://dx.doi.org/10.1373/clinchem.2016.264705DOI Listing
December 2016

Biochemical surrogate markers of hemolysis do not correlate with directly measured erythrocyte survival in sickle cell anemia.

Am J Hematol 2016 12 8;91(12):1195-1201. Epub 2016 Nov 8.

Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Hemolysis is a key feature of sickle cell anemia (HbSS). Direct quantitation of hemolysis could be used as an objective outcome in clinical trials of new therapeutics for HbSS and would also enable better human studies of the pathogenesis of complications of HbSS that are ostensibly hemolysis-related, such as pulmonary hypertension. However, contemporary human studies in HbSS have used only surrogate markers of hemolysis rather than direct measurements of RBC survival. We directly quantified hemolysis in HbSS by measuring survival of an age cohort of RBCs labeled with a stable isotope, administered orally as N-glycine, a metabolic precursor of heme. The atomic excess of N in heme extracted from blood was monitored by mass spectrometry over time. We performed 13 labeling experiments in 11 individuals with HbSS. Mean RBC survival was 31.9 days (range 14.1-53.6). Both HbF level, a known determinant of hemolysis, and absolute reticulocyte count (ARC), an index of the marrow's response to hemolysis, correlated with directly measured RBC survival (r = 0.61, P < 0.002; r = -0.84, P < 0.001). However, commonly used biochemical surrogates of hemolysis (LDH, AST, bilirubin, and plasma free hemoglobin) did not correlate with directly measured RBC survival. These biochemical surrogates should be interpreted cautiously, at best, in clinical trials and human physiologic studies in HbSS. ARC was the best correlate of total hemolysis, but only 70% of the variation in RBC survival was reflected in this marker. If greater accuracy is required in human studies, N-glycine RBC labeling can directly and accurately quantify hemolysis. Am. J. Hematol. 91:1195-1201, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118160PMC
December 2016

Patient-reported functioning in major depressive disorder.

Ther Adv Chronic Dis 2016 May 31;7(3):160-9. Epub 2016 Mar 31.

Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA.

Objectives: Compared with the general population, patients with major depressive disorder (MDD) report substantial deficits in their functioning that often go beyond the clinical resolution of depressive symptoms. This study examines the impact of MDD and its treatment on functioning.

Methods: From the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, we analyzed complete data of 2280 adult outpatients with MDD at entry and exit points of each level of antidepressant treatment and again 12 months post treatment. Functioning was measured using the Work and Social Adjustment Scale (WSAS).

Results: The results show that only 7% of patients with MDD reported within-normal functioning before treatment. The proportion of patients achieving within-normal functioning (WSAS) scores significantly increased after treatment. However, the majority of patients (>60%) were still in the abnormal range on functioning at exit. Although remitted patients had greater improvements compared with nonremitters, a moderate proportion of remitted patients continued to experience ongoing deficits in functioning after treatment (20-40%). Follow-up data show that the proportions of patients experiencing normal scores for functioning after 12 months significantly decreased from the end of treatment to the follow-up phase, from 60.1% to 49% (p < 0.0001), a finding that was particularly significant in nonremitters. Limitations of this study include the reliance on self-report of functioning and the lack of information on patients who dropped out.

Conclusion: This study points to the importance of functional outcomes of MDD treatment as well as the need to develop personalized interventions to improve functioning in MDD.
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http://dx.doi.org/10.1177/2040622316639769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907070PMC
May 2016

Do Red Blood Cell Indices Explain Racial Differences in the Relationship between Hemoglobin A1c and Blood Glucose?

J Pediatr 2016 09 16;176:7-9. Epub 2016 Jun 16.

Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

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http://dx.doi.org/10.1016/j.jpeds.2016.05.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003710PMC
September 2016

Insulin Sensitivity and β-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.

J Pediatr 2015 Nov 9;167(5):1042-8.e1. Epub 2015 Sep 9.

Division of Endocrinology, Diabetes and Metabolism, Duke University Medical Center, Durham, NC; Durham Veteran's Affairs Medical Center, Durham, NC.

Objective: To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB).

Study Design: A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling.

Results: In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved β-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01).

Conclusions: RYGB reduced body mass index and improved both insulin sensitivity and β-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists.

Trial Registration: ClinicalTrials.gov: NCT00360373.
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http://dx.doi.org/10.1016/j.jpeds.2015.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843108PMC
November 2015

Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study.

J Clin Endocrinol Metab 2015 Nov 25;100(11):4059-66. Epub 2015 Aug 25.

University of California (A.V.S., E.V., D.C.B.), San Francisco, California 94143; Wake Forest School of Medicine (H.C., W.T.A., J.D.W.), Winston-Salem, North Carolina 27157; Louis Stokes VA Medical Center and Case Western Reserve University (A.S.), Cleveland, Ohio 44106; St. Michael's Hospital (R.G.J.), Toronto, ON M5B 1W8, Canada; National Heart Lung and Blood Institute (D.E.B.), National Institute of Health, Bethesda, Maryland 20892; Case Western Reserve University (A.M.S.), Cleveland, Ohio 44106; SUNY Downstate Medical Center and Kings County Hospital (M.A.B.), Brooklyn, New York 11203; University of Cincinnati College of Medicine (R.M.C.), Cincinnati, Ohio 45267; VA Medical Center and University of Maryland School of Medicine (B.P.H.), Baltimore, Maryland 21201; University of Miami (T.I.), Miami, Florida 33124; Division of Endocrinology (D.E.S.), Johns Hopkins School of Medicine, Baltimore, Maryland 21205; University of Utah and Salt Lake City Veterans Hospital (D.L.S.), Salt Lake City, Utah 84148; University of Iowa Carver College of Medicine (A.S.-R.), Iowa City, Iowa 52242; and Health Partners Institute for Education and Research (K.M.), Minneapolis, Minnesota 55425.

Context: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown.

Objective: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men.

Design: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2-4 months at clinic visits, were modeled as time-varying covariates in proportional hazards models for occurrence of first non-spine fracture.

Participants: We studied a total of 6865 participants in ACCORD BONE.

Main Outcome Measures: Main outcome measures were centrally adjudicated non-spine fracture.

Results: Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1-2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or >2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1-2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men.

Conclusions: TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated.
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http://dx.doi.org/10.1210/jc.2015-1215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702444PMC
November 2015

Physiologic Concepts That May Revise the Interpretation and Implications of HbA1C in Clinical Medicine: An American Perspective.

J Diabetes Sci Technol 2015 May 17;9(3):696-700. Epub 2015 Feb 17.

Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH, USA

HbA1c, a routinely used integrated measure of glycemic control, is traditionally thought to be equivalent to mean blood glucose in hematologically normal individuals. Therefore, particularly as the methodology of measuring HbA1c has been standardized, clinical decisions dependent on mean blood glucose are often predominantly decided based on the interpretation of measured HbA1c. In this commentary, however, now that a more routine method of measuring red cell life span has been developed, we present evidence that the relationship between HbA1c and mean blood glucose is influenced by variation in red blood cell survival even in the hematologically normal. This variation has consequences for the appropriate interpretation of HbA1c in diverse clinical conditions such as the diagnosis of diabetes and management of diabetes in chronic kidney disease.
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http://dx.doi.org/10.1177/1932296815572255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604523PMC
May 2015

Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation.

Am J Hematol 2015 Jan;90(1):50-55

Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

HbA1c is commonly used to monitor glycemic control. However, there is growing evidence that the relationship between HbA1c and mean blood glucose (MBG) is influenced by variation in red blood cell (RBC) lifespan in hematologically normal individuals. Correction of HbA1c for mean RBC age (MRBC ) requires a noninvasive, accurate, and affordable method to measure RBC survival. In this study, we evaluated whether a stable isotope approach would satisfy these requirements. RBC lifespan and MRBC were determined in a group of nine hematologically normal diabetic and nondiabetic subjects using oral (15) N-glycine to label heme in an age cohort of RBC. The MRBC was 58.7 ± 9.1 (2SD) days and RBC lifespan was 106 ± 21 (2SD) days. This degree of variation (±15-20%) is consistent with previous studies using other techniques. In a subset of seven subjects, MRBC determined with the biotin label technique were available from approximately five years prior, and strongly correlated with the stable isotope values (R(2) = 0.79). This study suggests that the MRBC is stable over time but varies substantially among individuals, and supports the importance of its variation in HbA1c interpretation. The characteristics of the stable isotope method support its suitability for studies to directly evaluate the impact of variation in MRBC on the interpretation of HbA1c.
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http://dx.doi.org/10.1002/ajh.23866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276493PMC
January 2015

Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes.

Kidney Int 2015 Mar 17;87(3):649-59. Epub 2014 Sep 17.

Veterans Affairs Medical Center, VA Clinical Center Network, Memphis, Tennessee, USA.

Results of the main Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicate that intensive glucose lowering increases cardiovascular and all-cause mortality. As the contribution of mild-to-moderate chronic kidney disease (CKD) to these risks is not known, we assessed the impact on cardiovascular outcomes in this population. Renal function data were available on 10,136 patients of the original ACCORD cohort. Of those, 6,506 were free of CKD at baseline and 3,636 met the criteria for CKD. Participants were randomly assigned to a treatment strategy of either intensive or standard glycemic goal. The primary outcome, all-cause and cardiovascular mortality, and prespecified secondary outcomes were evaluated. Risk for the primary outcome was 87% higher in patients with than in those without CKD (hazard ratio of 1.866; 95% CI: 1.651-2.110). All prespecified secondary outcomes were 1.5 to 3 times more frequent in patients with than in those without CKD. In patients with CKD, compared with standard therapy, intensive glucose lowering was significantly associated with both 31% higher all-cause mortality (1.306: 1.065-1.600) and 41% higher cardiovascular mortality (1.412: 1.052-1.892). No significant effects were found in patients without CKD. Thus, in high-risk patients with type II diabetes, mild and moderate CKD is associated with increased cardiovascular risk. Intensive glycemic control significantly increases the risk of cardiovascular and all-cause mortality in this population.
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http://dx.doi.org/10.1038/ki.2014.296DOI Listing
March 2015

Patient-reported outcomes before and after treatment of major depressive disorder.

Dialogues Clin Neurosci 2014 Jun;16(2):171-83

Department of Psychiatry, Emory University School of Medicine.

Patient reported outcomes (PROs) of quality of life (QoL), functioning, and depressive symptom severity are important in assessing the burden of illness of major depressive disorder (MDD) and to evaluate the impact of treatment. We sought to provide a detailed analysis of PROs before and after treatment of MDD from the large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. This analysis examines PROs before and after treatment in the second level of STAR*D. The complete data on QoL, functioning, and depressive symptom severity, were analyzed for each STAR*D level 2 treatment. PROs of QoL, functioning, and depressive symptom severity showed substantial impairments after failing a selective serotonin reuptake inhibitor trial using citalopram (level 1). The seven therapeutic options in level 2 had positive statistically (P values) and clinically (Cohen's standardized differences [Cohen's d]) significant impact on QoL, functioning, depressive symptom severity, and reduction in calculated burden of illness. There were no statistically significant differences between the interventions. However, a substantial proportion of patients still suffered from patient-reported QoL and functioning impairment after treatment, an effect that was more pronounced in nonremitters. PROs are crucial in understanding the impact of MDD and in examining the effects of treatment interventions, both in research and clinical settings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140511PMC
June 2014

Measurement of posttransfusion red cell survival with the biotin label.

Transfus Med Rev 2014 Jul 5;28(3):114-25. Epub 2014 Apr 5.

Department of Internal Medicine, The University of Cincinnati, Cincinnati, OH.

The goal of this review is to summarize and critically assess information concerning the biotin method to label red blood cells (RBC) for use in studies of RBC and transfusion biology-information that will prove useful to a broad audience of clinicians and scientists. A review of RBC biology, with emphasis on RBC senescence and in vivo survival, is included, followed by an analysis of the advantages and disadvantages of biotin-labeled RBC (BioRBC) for measuring circulating RBC volume, posttransfusion RBC recovery, RBC life span, and RBC age-dependent properties. The advantages of BioRBC over (51)Cr RBC labeling, the current reference method, are discussed. Because the biotin method is straightforward and robust, including the ability to follow the entire life spans of multiple RBC populations concurrently in the same subject, BioRBC offers distinct advantages for studying RBC biology and physiology, particularly RBC survival. The method for biotin labeling, validation of the method, and application of BioRBCs to studies of sickle cell disease, diabetes, and anemia of prematurity are reviewed. Studies documenting the safe use of BioRBC are reviewed; unanswered questions requiring future studies, remaining concerns, and regulatory barriers to broader application of BioRBC including adoption as a new reference method are also presented.
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http://dx.doi.org/10.1016/j.tmrv.2014.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122272PMC
July 2014