|
Rahmany MB, Hantgan RR, Van Dyke M.
Biomaterials. 2013 Mar ;34(10):2492-500.
PMID: 23332318
Uncontrolled bleeding continues to be one of the leading causes of death in individuals following traumatic injury. Prognosis is worsened with the onset of acute coagulopathy characterized by metabolic acidosis, hypothermia and hemodilution, which consequently perpetuates blood loss and increases mortality. While there are several limitations to biomaterials employed as hemostatic agents, keratin biomaterials have demonstrated efficacy in mitigating blood loss in an animal model of hemorrhage in prior studies. Here we investigate the hypothesis that keratins actively participate in coagulation and that a potential mechanism of action is independent of temperature and dilution of clotting factors. Data from this study show that keratins appear to contribute to hemostasis by significantly decreasing plasma clotting lag times and are able to maintain activity under simulated conditions of coagulopathy. Moreover, a system of isolated fibrin polymerization provided evidence of increased fibril lateral assembly in the presence of keratin. The data provided here provides a platform for further development of keratin biomaterials as hemostatic agents.
|
|
Sittadjody S, Saul JM, Joo S, Yoo JJ, Atala A, Opara EC.
Biomaterials. 2013 Mar ;34(10):2412-20.
PMID: 23274068
Although hormone replacement therapy is an option for the loss of ovarian function, hormone delivery through pharmacological means results in various clinical complications. The present study was designed to deliver sex steroids by a functional construct fabricated using encapsulation techniques. Theca and granulosa cells isolated from ovaries of 21-day old rats were encapsulated in multilayer alginate microcapsules to recapitulate the native follicular structure. Cells encapsulated in two other schemes were used as controls to assess the importance of the multilayer structure. The endocrine functions of the encapsulated cells were assessed in vitro for a period of 30 days. Encapsulated cells showed sustained viability during long-term in vitro culture with those encapsulated in multilayer capsules secreting significantly higher and sustained concentrations of 17 β-estradiol (E(2)) than the two other encapsulation schemes (p < 0.05, n = 6) in response to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In addition, cells in the multilayer microcapsules also secreted activin and inhibin in vitro. In contrast, when granulosa and theca cells were cultured in 2D culture, progesterone (P(4)) secretion increased while E(2) secretion decreased over a 30-day period. In summary, we have designed a multilayer engineered ovarian tissue that secretes sex steroids and peptide hormones and responds to gonadotropins, thus demonstrating the ability to recapitulate native ovarian structure ex vivo.
|
|
O'Shea TM, Shah B, Allred EN, Fichorova RN, Kuban KC, Dammann O, Leviton A, .
Brain Behav Immun. 2013 Mar ;29():104-12.
PMID: 23295265
Neonatal inflammation is associated with perinatal brain damage. We evaluated to what extent elevated blood levels of inflammation-related proteins supplement information about the risk of impaired early cognitive function provided by inflammation-related illnesses. From 800 infants born before the 28th week of gestation, we collected blood spots on days 1, 7 and 14, for analysis of 25 inflammation-related proteins, and data about culture-positive bacteremia, necrotizing enterocolitis (Bell stage IIIb), and isolated perforation of the intestine, during the first two weeks, and whether they were ventilated on postnatal day 14. We considered a protein to be persistently or recurrently elevated if its concentration was in the top quartile (for gestational age and day blood was collected) on two separate days one week apart. We assessed the children at 2 years of age with the Bayley Mental Development Index (MDI). The combinations of NEC and ventilation on day 14, and of bacteremia and ventilation on day 14 consistently provided information about elevated risk of MDI <55, regardless of whether or not a variable for an elevated protein concentration was included in the model. A variable for a persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1. We conclude that elevated blood concentrations of inflammation-related proteins provide information about the risk of impaired cognitive function at age 2 years that supplements information provided by inflammation-associated illnesses.
|
|
Gaines C, Poranki D, Du W, Clark RA, Van Dyke M.
Burns. 2013 Mar ;39(2):311-9.
PMID: 22981797
Swine are the preferred animal models to study the effects of burns on dermal wound healing. Various studies have been published in which little emphasis was placed on minimizing burn variability and inconsistency. We developed a novel method to create deep partial thickness burns that are highly consistent. A custom-made burn device was fabricated to control the pressure applied on the swine skin during burn creation. Cylindrical brass blocks, measuring 3 cm in diameter, are used to create the burns. A stainless steel post extends from the block for insertion into the device holder. In this study, burns were created in four female Yorkshire swine. Heating of the brass blocks was conducted using a boiling azeotropic solution of 80% polyethylene glycol (PEG) and 20% water and boiling water alone. Contact times ranging from 12 to 20 s were used. At 24 h and 7 d post-injury, two swine were euthanized and tissues collected for digital image evaluation and histological assessment using Gomori trichrome staining. Digital image analysis showed inconsistent healing in burns created using boiling water as compared to the boiling PEG:H(2)O solution. Additionally, histological analyses showed that burns created using boiling water were superficial and more variable compared to those created using the boiling PEG:H(2)O solution. With a burn contact time of 20 s, 48.5±5.7% tissue damage was demonstrated at 24 h when the PEG:H(2)O solution was used, whereas only 11.9±1.3% was observed with boiling water.
|
|
Weaver KE, Geiger AM, Lu L, Case LD.
Cancer. 2013 Mar 1;119(5):1050-7.
PMID: 23096263
Although rural residents are more likely to be diagnosed with more advanced cancers and to die of cancer, little is known about rural-urban disparities in self-reported health among survivors.
|
|
Swords DC, Al-Geizawi SM, Farney AC, Rogers J, Burkart JM, Assimos DG, Stratta RJ.
Clin Transplant. 2013 Mar-Apr;27(2):E199-205.
PMID: 23419131
Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive.
|
|
Shetty AK, Maldonado Y.
Curr HIV Res. 2013 Mar ;11(2):102-25.
PMID: 23432487
In low and middle-income countries (LMIC), transmission of HIV during breastfeeding represents a major public health challenge. Several viral, maternal clinical, immunological and genetic factors, as well as maternal-infant host factors and type of infant feeding may influence the risk of breastfeeding transmission of HIV. The mechanisms of breast milk HIV transmission are poorly understood. For mothers who are healthy and do not need combination antiretroviral therapy for their own health, randomized controlled trials have proven that administration of extended maternal triple-drug antiretroviral (ARV) prophylaxis or extended infant ARV prophylaxis can significantly reduce the risk of HIV transmission during breastfeeding. Based on this evidence, the World Health Organization (WHO) published new guidance in 2010 on the use of ARVs for treating pregnant women, and preventing mother-to-child HIV transmission (PMTCT). Although, remarkable advances have occurred in prevention of postnatal transmission during breastfeeding using antiretroviral strategies, a number of challenges remain. Future research must focus on field studies to evaluate programmatic implementation of new WHO PMTCT regimens, monitor long-term safety of ART exposure during pregnancy and lactation, and study emergence of ARV resistance (in mothers and infected infants despite prophylaxis).
|
|
Shetty AK.
Curr HIV Res. 2013 Mar ;11(2):81-92.
PMID: 23432485
The global epidemiology of HIV/AIDS is rapidly evolving in low and middle income countries. Women and adolescent females in Sub-Saharan Africa are at risk of HIV acquisition due to a myriad of complex biological, behavioral and structural factors. Primary HIV infection among women primarily drives the pediatric HIV epidemic. Postnatal transmission of HIV during breastfeeding is a major concern in LMIC, particularly in Sub-Saharan Africa where breastfeeding remains the only feasible, safe and culturally acceptable infant feeding choice. Given the remarkable discoveries in biomedical interventions to prevent sexual transmission of HIV and MTCT during breastfeeding, there is now a unique opportunity to rapidly implement combination HIV prevention packages, provide quality prevention of mother-to-child HIV transmission services, and improve maternal and infant survival. Although rapid scale-up of PMTCT interventions has occurred in Sub-Saharan Africa in the past five years, significant challenges remain towards reaching the ambitious goal of virtual elimination of new HIV infections among children on a global scale by 2015 and keeping their mothers alive. Rapid translation of scientific discoveries into policy and practice in conjunction with strong commitment from national leadership and global partners is crucial to end the pediatric AIDS and achieve a HIV-free generation.
|
|
Deford-Watts LM, Mintz A, Kridel SJ.
Curr Pharm Biotechnol. 2013 Mar 1;14(3):300-12.
PMID: 23597406
Positron emission tomography (PET) is a molecular imaging modality that provides the opportunity to rapidly and non-invasively visualize tumors derived from multiple organs. In order to do so, PET utilizes radiotracers, such as 18F-FDG and 11C-acetate, whose uptake coincides with altered metabolic pathways within tumors. Increased expression and activity of enzymes in the fatty acid synthesis pathway is a frequent hallmark of cancer cells. As a result, this pathway has become a prime target for therapeutic intervention. Although multiple drugs have been developed that both directly and indirectly interfere with fatty acid synthesis, an optimal means to assess their efficacy is lacking. Given that 11Cacetate is directly linked to the fatty acid synthesis pathway, this probe provides a unique opportunity to monitor lipogenic tumors by PET. Herein, we review the relevance of the fatty acid synthesis pathway in cancer. Furthermore, we address the potential utility of 11C-acetate PET in imaging tumors, especially those that are not FDG-avid. Last, we discuss several therapeutic interventions that could benefit from 11C-acetate PET to monitor therapeutic response in patients with certain types of cancers.
|
|
Zhang T, Birbrair A, Delbono O.
Cytoskeleton (Hoboken). 2013 Mar ;70(3):134-47.
PMID: 23378072
Troponin T (TnT) plays a major role in striated muscle contraction. We recently demonstrated that the fast skeletal muscle TnT3 isoform is localized in the muscle nucleus, and either its full-length or COOH-terminus leads to muscle cell apoptosis. Here, we further explored the mechanism by which it enters the nucleus and promotes cytotoxicity. Amino acid truncation and substitution showed that its COOH-terminus contains a dominant nuclear/nucleolar localization sequence (KLKRQK) and the basic lysine and arginine residues might play an important role in the nuclear retention and nucleolar enrichment of KLKRQK-DsRed fusion proteins. Deleting this domain or substituting lysine and arginine residues (KLAAQK) resulted in a dramatic loss of TnT3 nuclear and nucleolar localization. In contrast, the GATAKGKVGGRWK domain-DsRed construct localized exclusively in the cytoplasm, indicating that a nuclear exporting sequence is possibly localized in this region. Additionally, we identified a classical DNA-binding leucine zipper domain (LZD) which is conserved among TnT isoforms and species. Deletion of LZD or KLKRQK sequence significantly reduced cell apoptosis compared to full-length TnT3. We conclude that TnT3 contains both a nuclear localization signal and a DNA-binding domain, which may mediate nuclear/nucleolar signaling and muscle cell apoptosis.
|
|
Mudigonda T, Levender MM, O'Neill JL, West CE, Pearce DJ, Feldman SR.
Dermatol Surg. 2013 Mar ;39(3 Pt 1):345-64.
PMID: 23190408
Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs.
|
|
Yosipovitch G.
Dermatol Ther. 2013 Mar-Apr;26(2):83.
PMID: 23551364
|
|
Ng MC, Saxena R, Li J, Palmer ND, Dimitrov L, Xu J, Rasmussen-Torvik LJ, Zmuda JM, Siscovick DS, Patel SR, Crook ED, Sims M, Chen YD, Bertoni AG, Li M, Grant SF, Dupuis J, Meigs JB, Psaty BM, Pankow JS, Langefeld CD, Freedman BI, Rotter JI, Wilson JG, Bowden DW.
Diabetes. 2013 Mar ;62(3):965-76.
PMID: 23193183
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10⁻⁸). Locus-wide analysis demonstrated significant associations (P(emp) < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
|
|
Plonk DP, Browne JD.
Ear Nose Throat J. 2013 Mar ;92(3):E15-6.
PMID: 23532655
The potential for aberrant anatomy in the neck should be respected in order to avoid unexpected and potentially devastating injury during surgical and other procedures. Anatomic variations involving the internal carotid artery are believed to exist in as much as 6% of the population. We describe a case of a tortuous internal carotid artery that was found in zone IIb during a neck dissection in a 60-year-old man, and we discuss the implications of this anomaly.
|
|
Chen H, Quandt SA, Grzywacz JG, Arcury TA.
Environmetrics. 2013 Mar ;24(2):132-142.
PMID: 23504271
Environmental and biomedical research often produces data below the limit of detection (LOD), or left-censored data. Imputing explicit values for values < LOD in a multivariate setting, such as with longitudinal data, is difficult using a likelihood-based approach. A Bayesian multiple imputation (MI) method is introduced to handle left-censored multivariate data. A Gibbs sampler, which uses an iterative process, is employed to simulate the target multivariate distribution within a Bayesian framework. Following convergence, multiple plausible data sets are generated for analysis by standard statistical methods outside of a Bayesian framework. With explicit imputed values available variables can be analyzed as outcomes or predictors. We illustrate a practical application using longitudinal data from the Community Participatory Approach to Measuring Farmworker Pesticide Exposure (PACE3) study to evaluate the association between urinary acephate concentrations (indicating pesticide exposure) and self-reported potential pesticide poisoning symptoms. Additionally, a simulation study is used to evaluate the sampling property of the estimators for distributional parameters as well as regression coefficients estimated with the generalized estimating equation (GEE) approach. Results demonstrated that the Bayesian MI estimates performed well in most settings, and we recommend the use of this valid and feasible approach to analyze multivariate data with values < LOD.
|
|
Yorgason JT, España RA, Konstantopoulos JK, Weiner JL, Jones SR.
Eur J Neurosci. 2013 Mar ;37(6):1022-31.
PMID: 23294165
Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety-like behavior, impaired sensorimotor gating and increased self-administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2-type autoreceptor activity in the nucleus accumbens core. Long-Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28-77]. After this initial housing period, rats were assessed on the elevated plus-maze for an anxiety-like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety-like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety-like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH-reared rats that were isolated as adults did not develop the anxiety-like behavior or dopamine changes seen in SI-reared rats. Together, our data suggest that early life stress results in an anxiety-like phenotype, with lasting increases in dopamine terminal function.
|
|
Orabi H, AbouShwareb T, Zhang Y, Yoo JJ, Atala A.
Eur Urol. 2013 Mar ;63(3):531-8.
PMID: 22877501
The treatment options for patients requiring repair of a long segment of the urethra are limited by the availability of autologous tissues. We previously reported that acellular collagen-based tubularized constructs seeded with cells are able to repair small urethral defects in a rabbit model.
|
|
Able CM, Bright M, Frizzell B.
Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):828-33.
PMID: 22749631
Statistical process control (SPC) is a quality control method used to ensure that a process is well controlled and operates with little variation. This study determined whether SPC was a viable technique for evaluating the proper operation of a high-dose-rate (HDR) brachytherapy treatment delivery system.
|
|
Hall MA, McCue MJ.
Issue Brief (Commonw Fund). 2013 Mar ;14():1-9.
PMID: 23547337
The Affordable Care Act's medical loss ratio (MLR) regulation requires insurers to spend 80 percent or 85 percent of premiums on medical claims and quality improvements. In 2011, insurers falling below this minimum paid more than $1 billion in rebates. This brief examines how insurers spend their premium dollars--particularly their investment in quality improvement activities--focusing on differences among insurers based on corporate traits. In the aggregate, insurers paid less than 1 percent of premiums on either MLR rebates or quality improvement activities in 2011, with amounts varying by insurer type. Publicly traded insurers had significantly lower MLRs in each market segment (individual, small group, and large group), and were more likely to owe a rebate in most segments compared with non-publicly traded insurers. The median quality improvement expenditure per member among nonprofit and provider-sponsored insurers was more than the median among for-profit and non-provider-sponsored insurers.
|
|
Ahmad S, Wei CC, Tallaj J, Dell'Italia LJ, Moniwa N, Varagic J, Ferrario CM.
J Am Soc Hypertens. 2013 Mar-Apr;7(2):128-36.
PMID: 23312967
Identification of angiotensin-(1-12) [Ang-(1-12)] in forming angiotensin II (Ang II) by a non-renin dependent mechanism has increased knowledge on the paracrine/autocrine mechanisms regulating cardiac expression of Ang peptides. This study now describes in humans the identity of the enzyme accounting for Ang-(1-12) metabolism in the left ventricular (LV) tissue of normal subjects. Reverse phase HPLC characterized the products of (125)I-Ang-(1-12) metabolism in plasma membranes (PMs) from human LV in the absence and presence of inhibitors for chymase (chymostatin), angiotensin-converting enzyme (ACE) 1 (lisinopril) and 2 (MLN-4760), and neprilysin (SHC39370). In the presence of the inhibitor cocktail, ≥ 98% ± 2% of cardiac (125)I-Ang-(1-12) remained intact, whereas exclusion of chymostatin from the inhibitor cocktail led to significant conversion of Ang-(1-12) into Ang II. In addition, chymase-mediated hydrolysis of (125)I-Ang I was higher compared with Ang-(1-12). Negligible Ang-(1-12) hydrolysis occurred by ACE, ACE2, and neprilysin. A high chymase activity was detected for both (125)I-Ang-(1-12) and (125)I-Ang I substrates. Chymase accounts for the conversion of Ang-(1-12) and Ang I to Ang II in normal human LV. These novel findings expand knowledge of the alternate mechanism by which Ang-(1-12) contributes to the production of cardiac angiotensin peptides.
|