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Mirmalek-Sani SH, Orlando G, McQuilling JP, Pareta R, Mack DL, Salvatori M, Farney AC, Stratta RJ, Atala A, Opara EC, Soker S.
Biomaterials. 2013 Jul ;34(22):5488-95.
PMID: 23583038
Emergent technologies of regenerative medicine have the potential to overcome the limitations of organ transplantation by supplying tissues and organs bioengineered in the laboratory. Pancreas bioengineering requires a scaffold that approximates the biochemical, spatial and vascular relationships of the native extracellular matrix (ECM). We describe the generation of a whole organ, three-dimensional pancreas scaffold using acellular porcine pancreas. Imaging studies confirm that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. The scaffold was seeded with human stem cells and porcine pancreatic islets, demonstrating that the decellularized pancreas can support cellular adhesion and maintenance of cell functions. These findings advance the field of regenerative medicine towards the development of a fully functional, bioengineered pancreas capable of establishing and sustaining euglycemia and may be used for transplantation to cure diabetes mellitus.
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Sun X, Kang Y, Bao J, Zhang Y, Yang Y, Zhou X.
Biomaterials. 2013 Jul ;34(21):4971-81.
PMID: 23566802
Osteogenetic microenvironment is a complex constitution in which extracellular matrix (ECM) molecules, stem cells and growth factors each interact to direct the coordinate regulation of bone tissue development. Importantly, angiogenesis improvement and revascularization are critical for osteogenesis during bone tissue regeneration processes. In this study, we developed a three-dimensional (3D) multi-scale system model to study cell response to growth factors released from a 3D biodegradable porous calcium phosphate (CaP) scaffold. Our model reconstructed the 3D bone regeneration system and examined the effects of pore size and porosity on bone formation and angiogenesis. The results suggested that scaffold porosity played a more dominant role in affecting bone formation and angiogenesis compared with pore size, while the pore size could be controlled to tailor the growth factor release rate and release fraction. Furthermore, a combination of gradient VEGF with BMP2 and Wnt released from the multi-layer scaffold promoted angiogenesis and bone formation more readily than single growth factors. These results demonstrated that the developed model can be potentially applied to predict vascularized bone regeneration with specific scaffold and growth factors.
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Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK, Shah R, Wilson MD, Dikkers A, Tietge UJ, Collet X, Rudel LL, Temel RE, Brown JM.
J Lipid Res. 2013 Jun ;54(6):1567-77.
PMID: 23564696
Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI in TICE has not been studied. To examine the role of intestinal SR-BI in TICE, sterol balance was measured in control mice and mice transgenically overexpressing SR-BI in the proximal small intestine (SR-BI(hApoCIII-ApoAIV-Tg)). SR-BI(hApoCIII-ApoAIV-Tg) mice had significantly lower plasma cholesterol levels compared with wild-type controls, yet SR-BI(hApoCIII-ApoAIV-Tg) mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. To specifically study effects of intestinal SR-BI on TICE we crossed SR-BI(hApoCIII-ApoAIV-Tg) mice into a mouse model that preferentially utilized the TICE pathway for RCT (Niemann-Pick C1-like 1 liver transgenic), and likewise found no alterations in cholesterol absorption or fecal sterol excretion. Finally, mice lacking SR-BI in all tissues also exhibited normal cholesterol absorption and fecal cholesterol disposal. Collectively, these results suggest that SR-BI is not rate limiting for intestinal cholesterol absorption or for fecal neutral sterol loss through the TICE pathway.
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Czoty PW, Martelle SE, Gould RW, Nader MA.
J Pharmacol Exp Ther. 2013 Jun ;345(3):374-82.
PMID: 23579044
It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressive-ratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hour, i.v.; or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine self-administration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence.
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Yamaleyeva LM, Neves LA, Coveleskie K, Diz DI, Gallagher PE, Brosnihan KB.
Placenta. 2013 Jun ;34(6):497-502.
PMID: 23602334
We investigated the expression of angiotensin receptors in early pregnancy and established whether normal pregnancy or preeclampsia alters the expression and distribution of the uteroplacental AT1R, AT2R and mas/AT1-7R at late gestation.
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Bellavia L, Dumond JF, Perlegas A, Bruce King S, Kim-Shapiro DB.
Nitric Oxide. 2013 May 31;31():38-47.
PMID: 23545404
Angeli's salt (Na2N2O3) decomposes into nitroxyl (HNO) and nitrite (NO2(-)), compounds of physiological and therapeutic interest for their impact on biological signaling both through nitric oxide and nitric oxide independent pathways. Both nitrite and HNO oxidize oxygenated hemoglobin to methemoglobin. Earlier work has shown that HNO catalyzes the reduction of nitrite by deoxygenated hemoglobin. In this work, we have shown that HNO accelerates the oxidation of oxygenated hemoglobin by NO2(-). We have demonstrated this HNO mediated acceleration of the nitrite/oxygenated hemoglobin reaction with oxygenated hemoglobin being in excess to HNO and nitrite (as would be found under physiological conditions) by monitoring the formation of methemoglobin in the presence of Angeli's salt with and without added NO2(-). In addition, this acceleration has been demonstrated using the HNO donor 4-nitrosotetrahydro-2H-pyran-4-yl pivalate, a water-soluble acyloxy nitroso compound that does not release NO2(-) but generates HNO in the presence of esterase. This HNO donor was used both with and without NO2(-) and acceleration of the NO2(-) induced formation of methemoglobin was observed. We found that the acceleration was not substantially affected by catalase, superoxide dismutase, c-PTIO, or IHP, suggesting that it is not due to formation of extramolecular peroxide, NO2 or H2O2, or to modulation of allosteric properties. In addition, we found that the acceleration is not likely to be related to HNO binding to free reduced hemoglobin, as we found HNO binding to reduced hemoglobin to be much weaker than has previously been proposed. We suggest that the mechanism of the acceleration involves local propagation of autocatalysis in the nitrite-oxygenated Hb reaction. This acceleration of the nitrite oxyhemoglobin reaction could affect studies aimed at understanding physiological roles of HNO and perhaps nitrite and use of these agents in therapeutics such as hemolytic anemias, heart failure, and ischemia reperfusion injury.
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Palmer NR, Geiger AM, Felder TM, Lu L, Case LD, Weaver KE.
Am J Public Health. 2013 May 16. [Epub ahead of print]
PMID: 23678936
Objectives. We examined racial/ethnic disparities in health care receipt among a nationally representative sample of male cancer survivors. Methods. We identified men aged 18 years and older from the 2006-2010 National Health Interview Survey who reported a history of cancer. We assessed health care receipt in 4 self-reported measures: primary care visit, specialist visit, flu vaccination, and pneumococcal vaccination. We used hierarchical logistic regression modeling, stratified by age (< 65 years vs ≥ 65 years). Results. In adjusted models, older African American and Hispanic survivors were approximately twice as likely as were non-Hispanic Whites to not see a specialist (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.19, 2.68 and OR = 2.09; 95% CI = 1.18, 3.70, respectively), not receive the flu vaccine (OR = 2.21; 95% CI = 1.45, 3.37 and OR = 2.20; 95% CI = 1.21, 4.01, respectively), and not receive the pneumococcal vaccine (OR = 2.24; 95% CI = 1.54, 3.24 and OR = 3.10; 95% CI = 1.75, 5.51, respectively). Conclusions. Racial/ethnic disparities in health care receipt are evident among older, but not younger, cancer survivors, despite access to Medicare. These survivors may be less likely to see specialists, including oncologists, and receive basic preventive care. (Am J Public Health. Published online ahead of print May 16, 2013: e1-e8. doi:10.2105/AJPH.2012.301096).
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Weaver KE, Palmer N, Lu L, Case LD, Geiger AM.
Cancer Causes Control. 2013 May 16. [Epub ahead of print]
PMID: 23677333
PURPOSE: Rural US adults have increased risk of poor outcomes after cancer, including increased cancer mortality. Rural-urban differences in health behaviors have been identified in the general population and may contribute to cancer health disparities, but have not yet been examined among US survivors. We examined rural-urban differences in health behaviors among cancer survivors and associations with self-reported health and health-related unemployment. METHODS: We identified rural (n = 1,642) and urban (n = 6,162) survivors from the cross-sectional National Health Interview Survey (2006-2010) and calculated the prevalence of smoking, physical activity, overweight/obesity, and alcohol consumption. Multivariable models were used to examine the associations of fair/poor health and health-related unemployment with health behaviors and rural-urban residence. RESULTS: The prevalence of fair/poor health (rural 36.7 %, urban 26.6 %), health-related unemployment (rural 18.5 %, urban 10.6 %), smoking (rural 25.3 %, urban 15.8 %), and physical inactivity (rural 50.7 %, urban 38.7 %) was significantly higher in rural survivors (all p < .05); alcohol consumption was lower (rural 46.3 %, urban 58.6 %), and there were no significant differences in overweight/obesity (rural 65.4 %, urban 62.6 %). All health behaviors were significantly associated with fair/poor health and health-related unemployment in both univariate and multivariable models. After adjustment for behaviors, rural survivors remained more likely than urban survivors to report fair/poor health (OR = 1.21, 95 % CI 1.03-1.43) and health-related unemployment (OR = 1.49, 95 % CI 1.18-1.88). CONCLUSIONS: Rural survivors may need tailored, accessible health promotion interventions to address health-compromising behaviors and improve outcomes after cancer.
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Andersson KE.
Curr Urol Rep. 2013 May 16. [Epub ahead of print]
PMID: 23677692
The new information generated over the last decade on the physiology/pharmacology of the normal bladder and on the pathophysiology of the overactive bladder has resulted in the introduction of a new therapeutic principle, β3-adrenoceptor (AR) agonism, and the approval of mirabegron, a selective agonist at β3-ARs. It may be asked in what respects the β3-AR agonists as a group, and mirabegron in particular, differ from the antimuscarinics, and what can clinically be gained by the β3-AR agonists. In this short review, the mechanisms of action, clinical efficacy, and adverse effect profiles of the two groups of drugs are compared and discussed.
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Cartwright MS, Walker FO.
Muscle Nerve. 2013 May 16. [Epub ahead of print]
PMID: 23681885
Neuromuscular ultrasound involves the use of high-resolution ultrasound to image the peripheral nervous system of patients with suspected neuromuscular diseases. It complements electrodiagnostic studies well by providing anatomic information regarding nerves, muscles, vessels, tendons, ligaments, bones, and other structures that cannot be obtained with nerve conduction studies and electromyography. Neuromuscular ultrasound has been studied closely over the past 10 years and has been used most often in the assessment of entrapment neuropathies. This review focuses on the use of neuromuscular ultrasound in 4 of the most common entrapment neuropathies: carpal tunnel syndrome, ulnar neuropathy at the elbow and wrist, and fibular neuropathy at the knee. © 2013 Wiley Periodicals, Inc.
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Gustafson CJ, Feldman SR, Quandt SA, Isom S, Chen H, Spears CR, Arcury TA.
Int J Dermatol. 2013 May 15. [Epub ahead of print]
PMID: 23675774
BACKGROUND: Skin conditions are common among Latino migrant farm workers. Although many skin conditions are related to occupational exposures, poor housing conditions may also contribute to skin ailments in migrant farm workers. OBJECTIVES: To evaluate the association between housing conditions and skin conditions among Latino migrant farm workers. MATERIALS AND METHODS: A cross-sectional study design using interview questionnaires, home inspections, and environmental sampling was implemented to document housing quality of farm worker camps/homes and the prevalence of self-reported skin conditions in Latino migrant farm workers. Interviews were completed with 371 farm workers residing in 186 of the 226 camps (camp response rate 82.3%). RESULTS: Self-reported pruritus (31%), rash (25%), scaling (12%), blisters (11%), and ingrown nails (10%) were common among the participants. Pruritus was more likely to be reported by farm workers living in dwellings without air-conditioning (P < 0.05). Rash was associated with dwellings reported to have a low humidity (P < 0.05). Scaling was more likely to be reported by farm workers living in dwellings with indoor temperatures in the thermal discomfort range (P < 0.05). No statistically significant associations were detected for indoor allergens and self-reported skin ailments among migrant farm workers. CONCLUSIONS: Skin conditions are common among migrant farm workers in North Carolina. The quality of housing conditions, particularly hot, dry indoor thermal environment, demonstrated significant associations with pruritus, rash, and scaling. The impact of housing characteristics on pruritus and blisters was greatest in new migrant farm workers. Further research is needed to delineate additional housing factors that could cause or exacerbate skin diseases in farm workers.
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Amoah S, Holbrook BC, Yammani RD, Alexander-Miller MA.
J Immunol. 2013 May 15;190(10):5020-9.
PMID: 23589620
Generating and maintaining a robust CD8(+) T cell response in the face of high viral burden is vital for host survival. Further, balancing the differentiation of effectors along the memory precursor effector cell pathway versus the short-lived effector cell (SLEC) pathway may be critical in controlling the outcome of virus infection with regard to clearance and establishing protection. Although recent studies have identified several factors that have the capacity to regulate effector CD8(+) T cell differentiation-for example, inflammatory cytokines-we are far from a complete understanding of how cells choose the memory precursor effector cell versus SLEC fate following infection. In this study, we have modulated the infectious dose of the poxvirus vaccinia virus as an approach to modulate the environment present during activation and expansion of virus-specific effector cells. Surprisingly, in the face of a high virus burden, the number of SLECs was decreased. This decrease was the result of increased natural regulatory T cells (Tregs) generated by high viral burden, as depletion of these cells restored SLECs. Our data suggest Treg modulation of differentiation occurs via competition for IL-2 during the late expansion period, as opposed to the time of T cell priming. These findings support a novel model wherein modulation of the Treg response as a result of high viral burden regulates late-stage SLEC number.
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Divers J, Núñez M, High KP, Murea M, Rocco MV, Ma L, Bowden DW, Hicks PJ, Spainhour M, Ornelles DA, Kleiboeker SB, Duncan K, Langefeld CD, Turner J, Freedman BI.
Kidney Int. 2013 May 15. [Epub ahead of print]
PMID: 23677244
Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.Kidney International advance online publication, 15 May 2013; doi:10.1038/ki.2013.173.
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Sukumar P, Maloney G, Muday GK.
Plant Physiol. 2013 May 15. [Epub ahead of print]
PMID: 23677937
Adventitious roots emerge from aerial plant tissues and the induction of these roots is essential for clonal propagation of agriculturally important plant species. This process has received extensive study in horticultural species, but much less focus in genetically tractable model species. We have explored the role of auxin transport in this process in Arabidopsis thaliana seedlings in which adventitious root initiation was induced by excising roots from low light grown hypocotyls. Inhibition of auxin transport from the shoot apex abolishes adventitious root formation under these conditions. Root excision was accompanied by a rapid increase in radioactive IAA transport and its accumulation in the hypocotyl above the point of excision where adventitious roots emerge. Local increases in auxin-responsive gene expression were also observed above the site of excision, using auxin responsive reporters, pIAA2:GUS, pGH3:GUS, and pDR5:GUS. These changes in auxin accumulation preceded cell division events, monitored by pCYCB1:GUS, and adventitious root initiation. We examined excision-induced adventitious root formation in auxin influx and efflux mutants, including aux1, pin1, pin2, pin3, and pin7, with the most profound reductions observed in abcb19. An ABCB19 overexpression line forms more adventitious roots than wild-type in intact seedlings. Examination of transcriptional and translational fusions between ABCB19 and GFP indicates that excision locally induced the accumulation of ABCB19 transcript and protein that is temporally and spatially linked to local IAA accumulation leading to adventitious root formation. These experiments are consistent with localized synthesis of ABCB19 protein leading to enhanced IAA transport and local IAA accumulation driving adventitious root formation.
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Mondal AK, Sharma NK, Elbein SC, Das SK.
Physiol Genomics. 2013 May 14. [Epub ahead of print]
PMID: 23673729
Type-2 diabetes (T2D)-associated SNPs are more likely to be eQTLs. The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (p<0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (≥10% mean AEI) on total gene expression further established the cis-eQTLs in THEM4 (rs13320, p=0.027), and IGSF8 (rs1131891, p=0.02). Examination of published genome-wide association data identified significant associations (p<0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI-SNPs, including rs13320 (p=1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (p=0.005) in those with TT/TC-genotype for rs13320. THEM4 expression in adipose was higher (p=0.005) in subjects carrying the T-allele; in vitro analysis with luciferase construct confirmed the higher expression of the T-allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding non-synonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis.
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Pace LA, Plate JF, Smith TL, Van Dyke ME.
Biomaterials. 2013 May 13. [Epub ahead of print]
PMID: 23680369
Peripheral nerve injuries requiring surgery can be repaired by autograft, the clinical "gold standard", allograft, or nerve conduits. Most published clinical studies show the effectiveness of nerve conduits in small size defects in sensory nerves. Many preclinical studies suggest that peripheral nerve regeneration through conduits can be enhanced and repair lengths increased with the use of a biomaterial filler in the conduit lumen. We have previously shown that a luminal hydrogel filler derived from human hair keratin (HHK) can improve electrophysiological and histological outcomes in mouse, rabbit, and non-human primate nerve injury models, but insight into potential mechanisms has been lacking. Based on the premise that a keratin biomaterial (KOS) hydrogel provides an instantaneous structural matrix within the lumen, the current study compares the cellular behavior elicited by KOS hydrogel to Matrigel (MAT) and saline (SAL) conduit fillers in a 1 cm rat sciatic nerve injury model at early stages of regeneration. While there was little difference in initial cellular influx, the KOS group showed earlier migration of dedifferentiated Schwann cells (SC) from the proximal nerve end compared to the other groups. The KOS group also showed faster SC dedifferentiation and myelin debris clearance, and decreased macrophage infiltration during Wallerian degeneration of the distal nerve tissue.
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Orlando G, Booth C, Wang Z, Totonelli G, Ross CL, Moran E, Salvatori M, Maghsoudlou P, Turmaine M, Delario G, Al-Shraideh Y, Farooq U, Farney AC, Rogers J, Iskandar SS, Burns A, Marini FC, De Coppi P, Stratta RJ, Soker S.
Biomaterials. 2013 May 13. [Epub ahead of print]
PMID: 23680364
In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals.
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Espeland MA, Rejeski WJ, West DS, Bray GA, Clark JM, Peters AL, Chen H, Johnson KC, Horton ES, Hazuda HP, .
J Am Geriatr Soc. 2013 May 13. [Epub ahead of print]
PMID: 23668423
OBJECTIVES: To compare the effects of 4 years of intensive lifestyle intervention on weight, fitness, and cardiovascular disease risk factors in older and younger individuals. DESIGN: Randomized controlled clinical trial. SETTING: Sixteen U.S. clinical sites. PARTICIPANTS: Individuals with type 2 diabetes mellitus: 1,053 aged 65 to 76 and 4,092 aged 45 to 64. INTERVENTIONS: An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity was compared with diabetes mellitus support and education. MEASUREMENTS: Standardized assessments of weight, fitness (based on graded exercise testing), and cardiovascular disease risk factors. RESULTS: Over 4 years, older individuals had greater intervention-related mean weight losses (6.2%) than younger participants (5.1%; interaction P = .006) and comparable relative mean increases in fitness (0.56 vs 0.53 metabolic equivalents; interaction P = .72). These benefits were seen consistently across subgroups of older adults formed according to many demographic and health factors. Of a panel of age-related health conditions, only self-reported worsening vision was associated with poorer intervention-related weight loss in older individuals. The intensive lifestyle intervention produced mean increases in high-density lipoprotein cholesterol (2.03 mg/dL; P < .001) and decreases in glycated hemoglobin (0.21%; P < .001) and waist circumference (3.52 cm; P < .001) over 4 years that were at least as large in older as in younger individuals. CONCLUSION: Intensive lifestyle intervention targeting weight loss and increased physical activity is effective in overweight and obese older individuals to produce sustained weight loss and improvements in fitness and cardiovascular risk factors.
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Clarkson TB, Ethun KF, Pajewski NM, Golden D, Floyd E, Appt SE.
Menopause. 2013 May 13. [Epub ahead of print]
PMID: 23676638
OBJECTIVE: This study aims to evaluate the effects of a new selective estrogen receptor modulator (bazedoxifene acetate [BZA]) and a tissue-specific estrogen complex (BZA combined with conjugated equine estrogens [CEE]) on the extent and severity of cerebral artery atherosclerosis. METHODS: Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and randomized to receive no treatment or women's equivalent doses of BZA (20 mg/d), CEE (0.45 mg/d), or BZA + CEE. After an experimental period of 20 months (approximately equivalent to 5 years of participant experience), the extent and severity of atherosclerosis in the common carotid artery, carotid bifurcation, internal carotid artery, and basilar artery were determined. Lesion severity was determined using the American Heart Association grading system (grades 0-V). RESULTS: BZA had no consistent adverse effects on the extent and severity of atherosclerosis in the cerebral arteries and did not attenuate the beneficial effects of CEE on the severity of common carotid artery atherosclerosis. Although CEE had only modest beneficial effects on the extent of carotid bifurcation atherosclerosis, the severity of lesions and the number of affected cases in the common carotid artery were reduced with CEE treatment. As reported previously, plasma lipid profiles did not differ among the treatment groups. CONCLUSIONS: In this long-term (equivalent to 5 human patient-years) nonhuman primate trial, BZA shows no consistent adverse effect on cerebral artery atherosclerosis and does not attenuate the modest beneficial effect of CEE on the common carotid artery. Furthermore, CEE inhibits the development of complicated plaques in the common carotid artery.
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Iwano H, Little WC.
J Cardiol. 2013 May 11. [Epub ahead of print]
PMID: 23672790
Heart failure (HF) occurs across the entire range of left ventricular (LV) ejection fractions (EF), not just reduced EF. Nearly half or more patients presenting with HF have a preserved EF>0.50 (HFpEF). Diastolic dysfunction is apparent in all patients with HF, regardless of EF. A preserved EF indicates that the end-diastolic volume is appropriate for the stroke volume, and a reduced EF indicates that the end-diastolic volume is enlarged relative to stroke volume (i.e. the LV is dilated). Most therapies proven to be effective in HF with a reduced EF (ACE-inhibitors, angiotensin receptor blockers, beta-blockers, and cardiac resynchronization) reverse LV dilation. These therapies have not been proven to be effective in HFpEF. Increasing c-GMP may be a treatment target in HFpEF, and potential ways of increasing c-GMP are being studied. Finally, comorbidities are important in HFpEF and are additional targets for therapy.
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