The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Multicenter study of pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders.

BACKGROUND: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(-)M-PTLD] comprises approximately 10% of M-PTLD. No large multi-institutional pediatric-specific reports on treatment and outcome are available. METHODS: A multi-institutional retrospective review of solid organ recipients diagnosed with EBV(-)M-PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. RESULTS: Thirty-six patients were identified with EBV(-)M-PTLD. Twenty-three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(-)M-PTLD, and interval from transplant to PTLD were 2.2 years (0.1-17), 14 years (3.0-20), and 8.5 years (0.6-18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B-cell lymphoma (n = 31 [86.1%]) and B-non-Hodgkin lymphoma (B-NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B-NHL-specific regimen (n = 13 [36.1%]) and low-dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow-up from diagnosis was 3.0 years (0.3-11.0 years). Three-year event-free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. CONCLUSIONS: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B-NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi-institutional registry to design prospective studies. PLAIN LANGUAGE SUMMARY: Pediatric Epstein-Barr virus-negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(-)M-PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B-cell lymphoma in immunocompetent pediatric patients. The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes. The impact of treatment regimen on relapse risk could not be assessed because of small numbers. In the intensive pediatric B-non-Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years.

Burkitt lymphoma after solid-organ transplant: Treatment and outcomes in the paediatric PTLD collaborative.

Burkitt lymphoma arising in paediatric post-solid-organ transplantation-Burkitt lymphoma (PSOT-BL) is a clinically aggressive malignancy and a rare form of post-transplant lymphoproliferative disorder (PTLD). We evaluated 35 patients diagnosed with PSOT-BL at 14 paediatric medical centres in the United States. Median age at organ transplantation was 2.0 years (range: 0.1-14) and age at PSOT-BL diagnosis was 8.0 years (range: 1-17). All but one patient had late onset of PSOT-BL (≥2 years post-transplant), with a median interval from transplant to PSOT-BL diagnosis of 4.0 years (range: 0.4-12). Heart (n = 18 [51.4%]) and liver (n = 13 [37.1%]) were the most frequently transplanted organs. No patients had loss of graft or treatment-related mortality. A variety of treatment regimens were used, led by intensive Burkitt lymphoma-specific French-American-British/Lymphomes Malins B (FAB/LMB), n = 13 (37.1%), and a low-intensity regimen consisting of cyclophosphamide, prednisone and rituximab (CPR) n = 12 (34.3%). Median follow-up was 6.7 years (range: 0.5-17). Three-year event-free and overall survival were 66.2% and 88.0%, respectively. Outcomes of PSOT-BL patients receiving BL-specific intensive regimens are comparable to reported BL outcomes in immunocompetent children. Multi-institutional collaboration is feasible and provides the basis of prospective data collection to determine the optimal treatment regimen for PSOT-BL.

Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study.

Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.

Endogenous secretory receptor for advanced glycation end products and chronic kidney disease in the elderly population.

BACKGROUND/AIMS: The relationship of circulating endogenous secretory receptor for advanced glycation end products (esRAGE) and chronic kidney disease (CKD) has not been well characterized. The aim of the study was to determine whether plasma esRAGE is associated with CKD and is predictive of developing CKD in older adults. METHODS: The relationship between plasma esRAGE and CKD (more than stage 3 of the National Kidney Foundation classification; estimated glomerular filtration rate <60 ml/min/1.73 m(2)) and CKD over 6 years of follow-up was examined in a cross-sectional and prospective study design in 1,016 men and women, ≥65 years, in the InCHIANTI study, a population-based cohort study of aging in Tuscany, Italy. RESULTS: At enrollment, 158 (15.5%) had CKD. Mean (SD) plasma esRAGE was 0.45 (0.24) ng/ml. Plasma esRAGE (ng/ml) was associated with CKD (odds ratio per 1 SD = 1.30; 95% CI 1.1-1.6; p < 0.005) in a multivariable logistic regression model, adjusting for potential confounders. Plasma esRAGE was an independent predictor of incident CKD over 6 years of follow-up (hazard ratio per 1 SD = 1.37; 95% CI 1.1-1.7; p < 0.008) in a multivariable Cox proportional hazards model, adjusting for potential confounders. CONCLUSIONS: Elevated plasma esRAGE is independently associated with CKD and is an independent predictor of incident CKD in older community-dwelling adults.

Incidence and Risk Factors for 30-Day Readmission after Inpatient Chemotherapy among Acute Lymphoblastic Leukemia Patients.

Chemotherapy for acute lymphoblastic leukemia (ALL) patients is complex and intense, resulting in a high readmission rate. We aimed to identify the incidence, causes, and risk factors of readmission following inpatient chemotherapy among ALL patients, using 2016 National Readmission Database. We applied three different definitions of 30-day readmission: (1) nonelective readmission based on readmission type, (2) unplanned readmission defined by CMS, and (3) unintentional readmission, combining (1) and (2). We used unweighted multivariable Poisson regression with robust variance estimates for risk factors analysis, including patient-, hospital-, and admission-related characteristics. Percentage for nonelective, unplanned, and unintentional readmission were 33.3%, 22.4%, and 18.5%, respectively. The top three causes for unplanned readmissions were neutropenia/agranulocytosis (27.8%), septicemia (15.3%), and pancytopenia (11.5%). Risk ratios for unintentional readmission were 1.21 (1.08-1.36) for nonelective vs. elective admission, 1.19 (1.06-1.33) for public vs. private insurance enrollees, 0.96 (0.95-0.98) for each day of hospital stay, 0.77 (0.62-0.95) for large teaching and 0.87 (0.70-1.08) for small teaching vs. nonteaching hospitals. Possible strategies to reduce readmission among ALL patients could be shortening the gap in quality of care among teaching vs. non-teaching hospitals, understanding the difference between privately vs. publicly insured patients, and avoiding aggressive discharge after chemotherapy.

Life-Threatening Infectious Complications in Sickle Cell Disease: A Concise Narrative Review.

Sickle cell disease (SCD) results in chronic hemolytic anemia, recurrent vascular occlusion, insidious vital organ deterioration, early mortality, and diminished quality of life. Life-threatening acute physiologic crises may occur on a background of progressive diminishing vital organ function. Sickle hemoglobin polymerizes in the deoxygenated state, resulting in erythrocyte membrane deformation, vascular occlusion, and hemolysis. Vascular occlusion and increased blood viscosity results in functional asplenia and immune deficiency in early childhood, resulting in life-long increased susceptibility to serious bacterial infections. Infection remains a main cause of overall mortality in patients with SCD in low- and middle-income countries due to increased exposure to pathogens, increased co-morbidities such as malnutrition, lower vaccination rates, and diminished access to definitive care, including antibiotics and blood. Thus, the greatest gains in preventing infection-associated mortality can be achieved by addressing these factors for SCD patients in austere environments. In contrast, in high-income countries, perinatal diagnosis of SCD, antimicrobial prophylaxis, vaccination, aggressive use of antibiotics for febrile episodes, and the availability of contemporary critical care resources have resulted in a significant reduction in deaths from infection; however, chronic organ injury is problematic. All clinicians, regardless of their discipline, who assume the care of SCD patients must understand the importance of infectious disease as a contributor to death and disability. In this concise narrative review, we summarize the data that describes the importance of infectious diseases as a contributor to death and disability in SCD and discuss pathophysiology, prevalent organisms, prevention, management of acute episodes of critical illness, and ongoing care.

Advanced glycation end products and their circulating receptors and level of kidney function in older community-dwelling women.

BACKGROUND: Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the pathogenesis of kidney disease; however, their relation with level of kidney function has not been well characterized. STUDY DESIGN: Cross-sectional and prospective. SETTING & PARTICIPANTS: 548 moderately to severely disabled community-dwelling women in the Women's Health and Aging Study I in Baltimore, MD. PREDICTOR: Serum carboxymethyl-lysine (CML), a dominant AGE; total soluble RAGE (sRAGE); and endogenous secretory RAGE (esRAGE). OUTCOMES & MEASUREMENTS: Glomerular filtration rate (GFR), prevalent and incident decreased GFR (GFR < 60 mL/min/1.73 m(2)). Serum CML, sRAGE, and esRAGE. RESULTS: Of 548 women, 283 (51.6%) had decreased GFR at baseline. Serum CML level was associated with decreased GFR (OR [all expressed per 1 SD], 1.98; 95% CI, 1.41 to 2.76; P < 0.001) in a multivariate logistic regression model adjusting for age, race, hemoglobin A(1c) level, and chronic diseases. Serum sRAGE and esRAGE levels (both in nanograms per milliliter) were associated with decreased GFR (OR, 1.42; 95% CI, 1.12 to 1.79; P = 0.003; OR, 1.42; 95% CI, 1.14 to 1.77; P = 0.001, respectively) in separate multivariate logistic regression models adjusting for potential confounders. Of 230 women without decreased GFR at baseline, 32 (13.9%) developed decreased GFR by the follow-up visit 12 months later. Serum CML (in micrograms per milliliter), sRAGE, and esRAGE levels at baseline were associated with the prevalence of decreased GFR 12 months later (OR, 1.80; 95% CI, 1.19 to 2.71; P = 0.005; OR, 1.32; 95% CI, 1.01 to 1.74; P = 0.05; and OR, 1.33; 95% CI, 1.01 to 1.77; P = 0.05, respectively) in separate multivariate logistic regression models adjusting for potential confounders. LIMITATIONS: Small number of incident cases, limited follow-up, creatinine values not standardized. CONCLUSIONS: AGE and circulating RAGE levels are independently associated with decreased GFR and seem to predict decreased GFR. AGEs are amenable to interventions because serum AGE levels can be decreased by change in dietary pattern and pharmacological treatment.

Serum fibroblast growth factor-23 and risk of incident chronic kidney disease in older community-dwelling women.

BACKGROUND AND OBJECTIVES: Elevated circulating fibroblast growth factor 23 (FGF23) predicts progression of CKD, but it is unknown whether circulating FGF23 independently predicts incident CKD. This study aimed to determine whether circulating FGF23 predicts incident CKD in community-dwelling women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the relationship of intact serum FGF23, 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D), 25-hydroxyvitamin D (25[OH]D), parathyroid hormone, calcium, and phosphate with prevalent and incident CKD in 701 disabled women, ≥65 years of age, from the Women's Health and Aging Study I in Baltimore, Maryland, from 1993 to 1997. Incident CKD was defined as a low estimated GFR (eGFR) <60 ml/min per 1.73 m(2) only, low eGFR <60 ml/min per 1.73 m(2) and a ≥25% decline in eGFR from baseline, and an increase in serum creatinine (≥0.4 mg/dl) at follow-up. RESULTS: At baseline, 381 women (54.3%) had stage 3 CKD. Of 307 women without CKD at baseline, 63 (20.5%) developed stage 3 CKD over 24 months of follow-up. After excluding prevalent cases of CKD, FGF23 (per 1 SD increase) was associated with incident stage 3 CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.06, 2.16; P=0.02), low and declining eGFR (HR, 3.69; 95% CI, 1.68, 8.11; P=0.001), and increase in serum creatinine (HR, 5.35; 95% CI, 1.27, 22.54; P=0.02) in respective multivariable Cox proportional hazards models adjusting for baseline eGFR, age, race, phosphate, 1,25-dihydroxyvitamin D(3), parathyroid hormone, and other potential confounders. CONCLUSIONS: Elevated FGF23 is an independent risk factor for incident CKD in older, disabled, community-dwelling women.

Endogenous secretory receptor for advanced glycation end products is associated with low serum interleukin-1 receptor antagonist and elevated IL-6 in older community-dwelling adults.

BACKGROUND: Advanced glycation end products (AGEs) are thought to cause inflammation through interaction with the receptor for AGEs (RAGE), therefore contributing to adverse aging-related processes. The relationship between AGEs, RAGE, and inflammation has not been well characterized. METHODS: We examined the relationship of plasma endogenous secretory RAGE (esRAGE); carboxymethyl-lysine (CML), a circulating AGE; and inflammatory mediators in 1,298 adults, 20-97 years, who participated in the InCHIANTI study in Tuscany, Italy. Blood levels of esRAGE, CML, interleukin-1 receptor antagonist (IL-1RA), IL-1ß, tumor necrosis factor-α (TNF-α), IL-6, IL-6 receptor (IL-6R), IL-18, C-reactive protein (CRP), transforming growth factor-ß (TGF-ß), and fibrinogen were measured. RESULTS: Log plasma esRAGE was associated with log IL-1RA (ß = -0.069, SE = 0.036, p = .05) and log IL-6 (ß = 0.077, SE = 0.035, p = .03), respectively, in separate multivariable linear regression models, adjusting for potential confounders. Log plasma esRAGE was also negatively associated with log TGF-ß but did not reach statistical significance (ß = -0.091, SE = 0.053, p = .09). Log plasma esRAGE was not significantly associated with log IL-1ß, log TNF-α, IL-6R, log IL-18, or CRP. Log plasma CML was not associated with any of the inflammatory mediators except for IL-6R (ß = -14.10, SE = 5.94, p = .02) and fibrinogen (ß = 13.95, SE = 7.21, p = .05) in separate multivariable models, adjusting for potential confounders. CONCLUSIONS: Plasma esRAGE is correlated with higher IL-6 and lower IL-1RA. These findings suggest that plasma esRAGE plays a role in modulating inflammation, although the exact mechanisms remain to be elucidated.

Plasma klotho and cardiovascular disease in adults.

OBJECTIVES: To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease (CVD) in adults. DESIGN: Cross-sectional. SETTING: Population-based sample of adults residing in Tuscany, Italy. PARTICIPANTS: One thousand twenty-three men and women aged 24 to 102 participating in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS: Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, creatinine, C-reactive protein (CRP). Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent CVD. RESULTS: Of 1,023 participants, 259 (25.3%) had CVD. Median (25th, 75th percentile) plasma klotho concentrations were 676 pg/mL (530, 819 pg/mL). Plasma klotho was correlated with age (correlation coefficient (r) = -0.14, P < .001), HDL-C (r = 0.11, P<.001), and CRP (r = -0.10, P < .001) but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means were 626 pg/mL (95% confidence interval (CI) = 601-658 pg/mL) in participants with CVD and 671 pg/mL (95% CI = 652-692 pg/mL) in those without CVD (P = .001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL-C, systolic blood pressure, and diabetes mellitus), log plasma klotho was associated with prevalent CVD (odds ratio per 1 standard deviation increase = 0.85, 95% CI = 0.72-0.99). CONCLUSION: In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having CVD.

Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women.

OBJECTIVE: Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women. DESIGN AND METHODS: A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70-79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication. RESULTS: Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 s.d. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function. CONCLUSION: Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.

Plasma klotho and mortality risk in older community-dwelling adults.

BACKGROUND: The aging-suppressor gene klotho encodes a single-pass transmembrane protein that in mice is known to extend life span when overexpressed and resemble accelerated aging when expression is disrupted. It is not known whether there is a relationship between plasma levels of secreted klotho protein and longevity in humans. METHODS: We measured plasma klotho in 804 adults, greater than or equal to 65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. RESULTS: During 6 years of follow-up, 194 (24.1%) of the participants died. In a multivariate Cox proportional hazards model, adjusting for age, sex, education, body mass index, physical activity, total cholesterol, high-density lipoprotein cholesterol, cognition, 25-hydroxyvitamin D, parathyroid hormone, serum calcium, mean arterial pressure, and chronic diseases, participants in the lowest tertile of plasma klotho (<575 pg/mL) had an increased risk of death compared with participants in the highest tertile of plasma klotho (>763 pg/mL; hazards ratio 1.78, 95% confidence interval 1.20-2.63). CONCLUSIONS: In older community-dwelling adults, plasma klotho is an independent predictor of all-cause mortality. Further studies are needed to elucidate the potential biological mechanisms by which circulating klotho could affect longevity in humans.

Reduced retinal neovascularization, vascular permeability, and apoptosis in ischemic retinopathy in the absence of prolyl hydroxylase-1 due to the prevention of hyperoxia-induced vascular obliteration.

PURPOSE: Prolyl hydroxylases (PHDs) are oxygen sensors that stabilize hypoxia-inducible factors (HIFs) to induce proinflammatory, vasopermeability, and proapoptotic factors. These may be potential targets to reduce the complications of ischemic retinopathies. METHODS: Oxygen-induced ischemic retinopathy (OIR) was generated as a model for retinopathy of prematurity (ROP) by placing 7-day-old mice in 75% oxygen for 5 days and returning them to the relative hypoxia of room air for 5 days. Neovascularization (NV) and avascular areas were assessed on retinal flat-mounts by image analysis. Blood-retinal barrier breakdown was assessed using ³H-mannitol as a tracer. Apoptosis was detected with TUNEL staining. HIF-1α and VEGF were quantified using Western blot analysis and ELISA. RESULTS: PHD1-deficient mice demonstrated reduced hyperoxia-associated vascular obliteration during oxygen-induced ischemic retinopathy. This was associated with subsequent reduced avascularity, vascular leakage, and pathologic NV during the hypoxic phase, which could be accounted for by a reduced expression of HIF-1α and VEGF. Apoptosis in the retina was also reduced in PHD1-depleted mice after 2 days in hyperoxia. CONCLUSIONS: PHD1 deficiency is associated with a reduction of ischemia-induced retinal NV. The regulatory mechanism in this model appears to be: PHD1 depletion prevents HIF-1α degradation in hyperoxia, which induces VEGF, thus preventing hyperoxia-related vessel loss. Without a vessel deficiency, there would not be relative hypoxia when the mice are returned to room air and there would be no need to initiate angiogenesis signaling. Blocking PHD1 may be beneficial for ischemic retinopathies and inflammatory and neurodegenerative disorders.

Elevated serum advanced glycation end products and poor grip strength in older community-dwelling women.

BACKGROUND: Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetes, heart disease, and kidney failure and may potentially affect skeletal muscle. Whether AGEs are associated with poor muscle strength is unknown. METHODS: Serum carboxymethyl-lysine (CML), a dominant AGE, circulating soluble form of receptor for advanced glycation end products (sRAGE), and endogenous secretory receptor for advanced glycation end product (esRAGE) and grip strength were measured in 559 moderately to severely disabled women, age 65 and older, in the Women's Health and Aging Study I in Baltimore, Md. RESULTS: Mean (standard deviation) grip strength among women in the highest quartile of serum CML compared with women in the lower three quartiles was 18.6 and 20.0 kg, respectively (p = .002), adjusting for age, race, body mass index, cognitive dysfunction, depression, and diabetes. Serum sRAGE and esRAGE were not significantly associated with grip strength. CONCLUSIONS: Women with high serum AGEs have greater muscle weakness. Further studies are needed to determine whether AGEs, a potentially modifiable risk factor, are associated with physical performance and disability in older adults.

Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women.

AIMS: To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality. METHODS: The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, double dagger 65 years, in Baltimore, Maryland. RESULTS: During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [HR] for highest vs lower three quartiles, 1.94, 95% Confidence Interval [CI] 1.08-3.48, p=0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (HR per 1 Standard Deviation [SD] 1.27, 95% CI 0.98-1.65, p=0.07; HR 1.28, 95% CI 1.02-1.63, p=0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (HR for highest vs lower three quartiles, 2.29, 95% CI 1.21-4.34, p=0.01; HR per 1 SD, 1.24, 95% CI 0.92-1.65, p=0.16; HR per 1 SD 1.45, 95% CI 1.08-1.93, p=0.01), after adjusting for the same covariates. CONCLUSIONS: High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.