|
Dewi FN, Wood CE, Lees CJ, Willson CJ, Register TC, Tooze JA, Franke AA, Cline JM.
Cancer Prev Res (Phila). 2013 Jun 14. [Epub ahead of print]
PMID: 23771522
While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for ~4.5 years: i) casein/lactalbumin (CL, n=12, as control) or ii) soy protein isolate with a human equivalent dose of 120 mg/day isoflavones (SOY, n=17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of 4 postmenarchal ultrasound measurements (P<0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P<0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P<0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood.
|
|
Houle TT, Turner DP, Penzien DB.
Headache. 2013 Jun 14. [Epub ahead of print]
PMID: 23773114
|
|
Gilliam LK, Pihoker C, Ellard S, Hattersley AT, Dabelea D, Davis C, Dolan LM, Greenbaum CJ, Imperatore G, Lawrence JM, Marcovina SM, Mayer-Davis E, Rodriguez BL, Steck AK, Williams DE, .
J Clin Endocrinol Metab. 2013 Jun 14. [Epub ahead of print]
PMID: 23771925
Aims:Our study aims were to determine the frequency of MODY mutations (HNF1A, HNF4A, Glucokinase) in a diverse population of youth with diabetes and to assess how well clinical features identify youth with MODY.Methods:The SEARCH for Diabetes in Youth study is a US multicenter, population-based study of youth with diabetes diagnosed at <20 years. We sequenced genomic DNA for mutations in the HNF1A, HNF4A, and glucokinase genes in 586 participants enrolled in SEARCH between 2001 and 2006. Selection criteria included diabetes autoantibody negativity and fasting C-peptide levels ≥0.8 ng/ml.Results:We identified a mutation in one of three MODY genes in 47 participants, or 8.0% of the tested sample, for a prevalence of at least 1.2% in the pediatric diabetes population. Of these, only three had a clinical diagnosis of MODY, and the majority was treated with insulin. Compared with the MODY-negative group, MODY-positive participants had lower FCP levels (2.2±1.4 ng/ml vs. 3.2±2.1 ng/ml, p<0.01) and fewer type 2 diabetes-like metabolic features. Parental history of diabetes did not significantly differ between the two groups.Conclusions/Interpretation:In this systematic study of MODY in a large pediatric US diabetes cohort, unselected by referral pattern or family history, MODY was usually misdiagnosed and incorrectly treated with insulin. While many type 2 diabetes-like metabolic features were less common in the mutation-positive group, no single characteristic identified all patients with mutations. Clinicians should be alert to the possibility of MODY diagnosis, particularly in antibody negative youth with diabetes.
|
|
Stem J, Christensen A, Davis D, Raffini L.
J Pediatr Hematol Oncol. 2013 Jun 14. [Epub ahead of print]
PMID: 23774158
The importance of preventing venous thromboembolism (VTE) in hospitalized adults is well recognized. We recently developed and published our institutional guidelines for the prevention of VTE in high-risk hospitalized patients in a pediatric hospital. The objective of this prospective observational study was to evaluate the safety of anticoagulation after these guidelines were instituted. The primary outcome was major bleeding and secondary outcomes included minor bleeding and VTE. Eighty-nine patients were enrolled, with a mean age of 16.6 years. The most common risk factors for VTE were impaired mobility, lower extremity orthopedic surgery, and obesity. The majority of patients (63%) had 3 or more risk factors. There were 2 major bleeding events, and minor bleeding occurred in 5 patients, all in patients who had undergone major orthopedic surgery. Therefore the risk of major bleeding in orthopedic surgery patients was 4% (2/51), and 0% (0/38) in the remaining patients. No patient developed a non-catheter-related VTE, which was the primary intent of our guidelines. Although there remains much work to be done to optimize VTE strategies in pediatric patients, this study provides information regarding the risks of VTE prophylaxis using a pragmatic approach in hospitalized patients with multiple risk factors for VTE. More studies are needed to better define the risk:benefit ratio in this population.
|
|
Loeser RF.
Osteoarthritis Cartilage. 2013 Jun 14. [Epub ahead of print]
PMID: 23774472
The purpose of this review was to present highlights from the published literature on the topic of the biology of osteoarthritis (OA). A PubMed search was conducted in order to locate original research manuscripts published since the last OARSI meeting in 2012. From review of the published literature, common themes emerged as active areas of research over the past year including studies in the areas of epigenetics, Wnt signaling, the role of inflammatory pathways in OA, lubricin, fibroblast growth factor signaling, and studies on OA biology in bone. Key findings in these areas were summarized and implications for future therapies were discussed.
|
|
Quandt SA, Wiggins Mts MF, Chen H, Bischoff WE, Arcury TA.
Am J Public Health. 2013 Jun 13. [Epub ahead of print]
PMID: 23763392
Although the health risk to farmworkers of working in hot conditions is recognized, potential for excessive heat exposure in housing affecting rest and recovery has been ignored. We assessed heat index in common and sleeping rooms in 170 North Carolina farmworker camps across a summer and examined associations with time of summer and air conditioning use. We recorded dangerous heat indexes in most rooms, regardless of time or air conditioning. Policies to reduce heat indexes in farmworker housing should be developed. (Am J Public Health. Published online ahead of print June 13, 2013: e1-e3. doi:10.2105/AJPH.2012.301135).
|
|
Vaughan L, Espeland MA, Snively B, Shumaker SA, Rapp SR, Shupe J, Robinson JG, Sarto GE, Resnick SM, .
Brain Res. 2013 Jun 13;1514():3-11.
PMID: 23578696
The Women's Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women's Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-55 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-55 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites. This article is part of a Special Issue entitled Hormone Therapy.
|
|
Ma X, Pearce JD, Wilson DB, English WP, Edwards MS, Geary RL.
J Vasc Surg. 2013 Jun 12. [Epub ahead of print]
PMID: 23768790
OBJECTIVE: Constrictive extracellular matrix (ECM) remodeling contributes significantly to restenosis after arterial reconstruction, but its molecular regulation is poorly defined. Hyaluronan (HA) accumulates within ECM at sites of injury where it is thought to facilitate smooth muscle cell (SMC) trafficking and collagen remodeling analogous to its role in cutaneous wound healing. SMC receptors for HA include receptor for hyaluronan-mediated motility (RHAMM), which mediates HA-induced migration. We hypothesized RHAMM would also mediate SMC-matrix interactions to alter the extent of constrictive remodeling. METHODS: We studied the role of RHAMM in SMC attachment to collagen, migration, and contraction of collagen gels using blocking antibodies and SMC from RHAMM -/- knockout mice. We then determined the role of RHAMM in constrictive artery wall remodeling by comparing changes in wall geometry in RHAMM -/- vs wild-type (WT) RHAMM +/+ controls 1 month after carotid ligation. RESULTS: HA increased SMC attachment to collagen-coated plates, but blocking RHAMM reduced adhesion (P = .025). RHAMM -/- SMC also demonstrated reduced adhesion (% adherent: 36.1 ± 2.2 vs 76.3 ± 1.9; P < .05). SMC contraction of collagen gels was enhanced by HA and further increased by RHAMM blockade (P < .01) or knockout (gel diameter, mm: RHAMM -/-, 6.7 ± 0.1 vs WT 9.8 ± 0.1; P < .01). RHAMM promoted constrictive remodeling in vivo as carotid artery size was significantly larger in knockout mice 1 month after ligation. Neointimal thickening, however, was not affected in RHAMM -/- (P = NS vs WT), but lumen size was significantly larger (lumen area, μm(2): 52.4 ± 1.4 × 10(3) vs 10.4 ± 1.8 × 10(3); P = .01) because artery size constricted less (external elastic lamina area, μm(2): RHAMM -/-, 92.4 ± 4.7 × 10(3) vs WT, 51.3 ± 5.9 × 10(3); P = .015). Adventitial thickening and collagen deposition were also more extensive in ligated RHAMM -/- carotids (adventitial thickness, μm: 218 ± 12.2 vs 109 ± 7.9; P = .01). CONCLUSIONS: HA activation of RHAMM significantly impacts SMC-ECM adhesive interactions and contributes to constrictive artery wall remodeling in mice. Strategies to block RHAMM at sites of vessel injury may prove useful in the prevention of clinical restenosis.
|
|
Abraham E.
Crit Care. 2013 Jun 11;17(3):152.[Epub ahead of print]
PMID: 23759070
Activation of nuclear factor kappa-B (NF-κB) results in its translocation from the cytoplasm to the nucleus and binding to the promoters of a large number of genes, including those encoding proinflammatory cytokines and other mediators that can contribute to organ system dysfunction in severe infection. While inhibition of NF-κB activation has been proposed as a therapeutic approach in critical illness, several studies have indicated that such an approach may have deleterious effects in persistent infectious states, such as pneumonia. A new report from Devaney and colleagues shows that while inhibition of NF-κB may be useful in severe pneumonia associated with rapid progression to mortality, it leads to worsened pulmonary injury with increased bacterial numbers in the lungs in a model of prolonged pneumonia. Such data raise concerns about therapeutic approaches targeting NF-κB in critically ill patients with persistent infection.
|
|
Koch SB, Cerci FB, Jorizzo JL, Krowchuk DP.
J Dermatolog Treat. 2013 Jun 11. [Epub ahead of print]
PMID: 23758214
Abstract Background: Linear morphea can lead to significant morbidity and functional disability in young patients. Methotrexate (MTX), with or without a short initiation with prednisone therapy, has been used and documented as a well-tolerated, effective treatment regimen. Purpose: To evaluate the long-term efficacy of MTX therapy in patients with linear morphea. Methods: A retrospective chart review was performed of pediatric and young adult patients with linear morphea evaluated in the Dermatology Clinic at Wake Forest University School of Medicine treated with MTX. Results: Seventeen patients met inclusion criteria and were followed for an average of 6.6 years. All patients improved with MTX therapy, with an average of 2.1 months to disease inactivity, and 19.6 months to discontinuation of MTX. Seven patients (41%) required a second course of MTX, following an average remission of 21 months. One patient (6%) required a third course, following 6.9 years of remission. Limitations: Retrospective chart review with a small patient sample size, and several patients were lost to follow-up. Conclusions: MTX is effective for achieving disease inactivity in pediatric and young adult patients with linear morphea. MTX is also effective in achieving disease remission off of therapy. However, many patients eventually required more than one course of MTX.
|
|
Eyster KM, Appt S, Chalpe A, Mark-Kappeler CJ, Register TC, Clarkson TB.
Menopause. 2013 Jun 10. [Epub ahead of print]
PMID: 23760433
OBJECTIVE: This study aimed to assess the in vivo effects of estradiol treatment on arterial gene expression in atherosclerotic postmenopausal female monkeys. METHODS: Eight ovariectomized cynomolgus monkeys were fed atherogenic diets for 6.5 years. The left iliac artery was biopsied before randomization to the estradiol group (human equivalent dose of 1 mg/d, n = 4) or the vehicle group (n = 4) for 8 months. The right iliac artery was obtained at necropsy. Transcriptional profiles in pretreatment versus posttreatment iliac arteries were compared to assess the responses of atherosclerotic arteries to estradiol. RESULTS: Iliac artery plaque size did not differ between the estradiol group and the placebo group at baseline or during the treatment period. Nevertheless, estradiol treatment was associated with increased expression of 106 genes and decreased expression of 26 genes in the iliac arteries. Estradiol treatment increased the expression of extracellular matrix genes, including the α1 chain of type I collagen, the α2 chain of type VI collagen, and fibulin 2, suggestive of an increase in the proportion or phenotype of smooth muscles or fibroblasts in lesions. Also increased were components of the insulin-like growth factor pathway (insulin-like growth factor 1, insulin-like growth factor binding protein 4, and insulin-like growth factor binding protein 5) and the Wnt signaling pathway (secreted frizzled-related protein 2, secreted frizzled-related protein 4, low-density lipoprotein receptor-related protein 6, and Wnt1-inducible signaling pathway protein 2). CONCLUSIONS: Estradiol treatment of monkeys with established atherosclerosis affected iliac artery gene expression, suggesting changes in the cellular composition of lesions. Moreover, it is probable that the presence of atherosclerotic plaque affected the gene expression responses of arteries to estrogen.
|
|
Laffer MS, Feldman SR.
Skin Res Technol. 2013 Jun 10. [Epub ahead of print]
PMID: 23750992
BACKGROUND: Poor adherence to medication is an enormous problem. While many measures to improve adherence have been proposed, patients may be a good source of novel approaches. The Managing Meds Video Challenge was designed, by the U.S. Department of Health and Human Services (HHS), in collaboration with the National Consumers League Script Your Future campaign, for patients to create short videos containing ideas on how to better take medications as directed. PURPOSE: Determine what forms of technology patients use to help adhere to their medication regimens. METHODS: The 17 available videos from the Managing Meds Video Challenge were analyzed to determine what forms of technology patients use to help adhere to their medication regimens. RESULTS: Approaches to improve adherence included calendar and reminder applications, and third-party applications such as MedCoach Medication Reminder, Walgreens Pharmacy, and CVS/Pharmacy. Patients also improved adherence by using the Internet to access websites such as www.rememberitnow.com to manage medications, access electronic health records, and to order medications from online pharmacies. LIMITATIONS: This study only analyzes the 17 available videos from the Managing Meds Video Challenge. CONCLUSIONS: Patients are using a variety of technology to manage their medications. They appear to rely primarily on reminder systems.
|
|
Palanisamy A, Reeves-Daniel AM, Freedman BI.
Pediatr Nephrol. 2013 Jun 9. [Epub ahead of print]
PMID: 23748364
Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long-term graft survival rates.
|
|
Ihemelandu CU, McQuellon R, Shen P, Stewart JH, Votanopoulos K, Levine EA.
Ann Surg Oncol. 2013 Jun 8. [Epub ahead of print]
PMID: 23748607
BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CS+HIPEC) is associated with significant perioperative morbidity. One goal of our ongoing patient-reported health-related quality of life (HRQoL) program is to describe the prognostic value of HRQoL measures for predicting postoperative morbidity and mortality following CS+HIPEC. METHODS: A retrospective analysis of a prospectively collected clinical database for all patients treated for peritoneal carcinomatosis and who participated in our patient-reported HRQoL program from 2001 to 2011 was done. Patients completed the Functional Assessment of Cancer Therapy questionnaire plus the colon symptom subscale, in addition to the Eastern Cooperative Oncology Group (ECOG) performance status rating prior to CS+HIPEC. The trial outcome index (TOI), a specific measure of function, symptoms, and physical well being of the patient, was analyzed. The TOI is a combination of the physical and functional well being subscales + the colon-specific subscale of the FACT-C. RESULTS: Of 855 patients, 387 (45.2 %) participated in the HRQoL trials. Mean age was 53.3 years, and 213 (55 %) were female versus 174 (45 %) males. There were 240 patients (62 %) who had a complication versus 147 (38 %) who had no complication. A 30-day mortality rate of 7.7 % (30) was documented. Patients who suffered a 30-day postoperative mortality demonstrated a lower mean preoperative score in the FACT-C TOI 52.7 versus 61.7; P < 0.001. Independent predictors of 30-day mortality on multivariate analysis included TOI (0.05), age (0.001), and smoking (0.001). Patients with a higher TOI score were less likely to suffer a mortality (95 % CI 0.9-1.0, P = 0.05). Patients with a higher emotional well being (EWB) score were less likely to suffer a complication 0.9 (95 % CI 0.87-1.0, P = 0.04). Other independent predictors of postoperative morbidity included diabetic status (P = 0.05), ECOG performance status (0.001), and gender (0.02). CONCLUSIONS: Preoperative HRQoL, as measured by FACT-C and ECOG performance status and added to traditional factors, helps predict postoperative morbidity and mortality following CS+HIPEC.
|
|
Stacey RB, Andersen MM, St Clair M, Hundley WG, Thohan V.
JACC Cardiovasc Imaging. 2013 Jun 8. [Epub ahead of print]
PMID: 23769489
OBJECTIVES: This study used cardiac magnetic resonance (CMR) to compare standard criteria for left ventricular noncompaction (LVNC). BACKGROUND: LVNC as a distinct cardiomyopathy is supported by a growing number of publications. Echocardiographic and CMR criteria have been established to diagnosis LVNC but have led to concerns of diagnostic accuracy. METHODS: Trabeculation/possible LVNC by CMR was retrospectively observed in 122 consecutive cases. We compared the standard end-systolic noncompacted-to-compacted ratio (ESNCCR), end-diastolic noncompacted:compacted ratio (EDNCCR), and trabecular mass-to-total mass ratio (TMTMR) along with deaths, embolic events, congestive heart failure (CHF) readmissions, ventricular arrhythmias, myocardial thickening (MT), left ventricular ejection fraction (LVEF), 3-dimensional sphericity index (3DSi), and left ventricular end-diastolic volume index. Adjusting for age, race, sex, body surface area, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, and CHF, logistic regression was used to compare combined events (death, CHF readmission, embolism, ventricular arrhythmia) between ESNCCR, EDNCCR, and TMTMR. Adjusting for same covariates except CHF, logistic regression was used to compare the odds of CHF for those who met criteria and those who did not. Using analysis of covariance, adjusted means for LVEF, MT, 3DSi, and left ventricular end-diastolic volume index were generated. RESULTS: ES criteria had a higher odds ratio (8.6; 95% confidence interval [CI]: 2.5 to 33) for combined events than ED criteria (1.8; 95% CI: 0.6 to 5.8) or TMTMR criteria (3.14; 95% CI: 1.09 to 10.2). The odds ratio of CHF for those who met ESNCCR criteria was 29.4 (95% CI: 6.6 to 125), but the odds ratio of CHF for those who met EDNCCR criteria was 3.3 (95% CI: 1.1 to 9.2). After adjustment, those who met criteria for noncompaction by ESNCCR had a lower LVEF and less MT than those who did not (p = 0.01 and p = 0.003, respectively), but there was no difference between those who met criteria for EDNCCR or the TMTMR criteria and those who did not. CONCLUSIONS: ES measures of LVNC have stronger associations with events, CHF, and systolic dysfunction than other measures.
|
|
Sutfin EL, McCoy TP, Morrell HE, Hoeppner BB, Wolfson M.
Drug Alcohol Depend. 2013 Jun 7. [Epub ahead of print]
PMID: 23746429
BACKGROUND: Electronic cigarettes, or e-cigarettes, are battery operated devices that deliver nicotine via inhaled vapor. There is considerable controversy about the disease risk and toxicity of e-cigarettes and empirical evidence on short- and long-term health effects is minimal. Limited data on e-cigarette use and correlates exist, and to our knowledge, no prevalence rates among U.S. college students have been reported. This study aimed to estimate the prevalence of e-cigarette use and identify correlates of use among a large, multi-institution, random sample of college students. METHODS: 4444 students from 8 colleges in North Carolina completed a Web-based survey in fall 2009. RESULTS: Ever use of e-cigarettes was reported by 4.9% of students, with 1.5% reporting past month use. Correlates of ever use included male gender, Hispanic or "Other race" (compared to non-Hispanic Whites), Greek affiliation, conventional cigarette smoking and e-cigarette harm perceptions. Although e-cigarette use was more common among conventional cigarette smokers, 12% of ever e-cigarette users had never smoked a conventional cigarette. Among current cigarette smokers, e-cigarette use was negatively associated with lack of knowledge about e-cigarette harm, but was not associated with intentions to quit. CONCLUSIONS: Although e-cigarette use was more common among conventional cigarette smokers, it was not exclusive to them. E-cigarette use was not associated with intentions to quit smoking among a sub-sample of conventional cigarette smokers. Unlike older, more established cigarette smokers, e-cigarette use by college students does not appear to be motivated by the desire to quit cigarette smoking.
|
|
Taheri A, Mansoori P, Al-Dabagh A, Feldman SR.
J Dermatolog Treat. 2013 Jun 7. [Epub ahead of print]
PMID: 23688200
Background: Superficial second-degree skin burns only need re-epithelialization to heal without a scar. After re-epithelialization, inflammation in the dermis contributes to changes in skin architecture and scarring. Suppression of inflammation and fibroblast activation immediately after re-epithelialization may prevent scar formation. Corticosteroids are the mainstay of treatment for keloids and hypertrophic scars. Objective: To assess the available data on use of corticosteroids for prevention of scars. Methods: A review of literature was performed seeking clinical trials using corticosteroids for prevention of scars. Results: Corticosteroids have been used to prevent recurrence after keloid or hypertrophic scar excision with variable success. We did not find any report involving the clinical use of corticosteroids for the prevention of scar formation in other settings, including after skin burns. Conclusion: Theoretically, topical corticosteroids can suppress inflammation and fibroblast activation after skin burn, decreasing the incidence of scar formation. However, there is no study evaluating this hypothesis.
|
|
Nader MA, Banks ML.
Neuropharmacology. 2013 Jun 7. [Epub ahead of print]
PMID: 23748095
The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
|
|
Mirmalek-Sani SH, Sullivan DC, Zimmerman C, Shupe TD, Petersen BE.
Am J Pathol. 2013 Jun 6. [Epub ahead of print]
PMID: 23747949
Liver disease affects millions of patients each year. The field of regenerative medicine promises alternative therapeutic approaches, including the potential to bioengineer replacement hepatic tissue. One approach combines cells with acellular scaffolds derived from animal tissue. The goal of this study was to scale up our rodent liver decellularization method to livers of a clinically relevant size. Porcine livers were cannulated via the hepatic artery, then perfused with PBS, followed by successive Triton X-100 and SDS solutions in saline buffer. After several days of rinsing, decellularized liver samples were histologically analyzed. In addition, biopsy specimens of decellularized scaffolds were seeded with hepatoblastoma cells for cytotoxicity testing or implanted s.c. into rodents to investigate scaffold immunogenicity. Histological staining confirmed cellular clearance from pig livers, with removal of nuclei and cytoskeletal components and widespread preservation of structural extracellular molecules. Scanning electron microscopy confirmed preservation of an intact liver capsule, a porous acellular lattice structure with intact vessels and striated basement membrane. Liver scaffolds supported cells over 21 days, and no increased immune response was seen with either allogeneic (rat-into-rat) or xenogeneic (pig-into-rat) transplants over 28 days, compared with sham-operated on controls. These studies demonstrate that successful decellularization of the porcine liver could be achieved with protocols developed for rat livers, yielding nonimmunogenic scaffolds for future hepatic bioengineering studies.
|
|
Raghavan S, Gilmont RR, Bitar KN.
Biomaterials. 2013 Jun 5. [Epub ahead of print]
PMID: 23746858
Enteric neuronal progenitor cells are neural crest-derived stem cells that can be isolated from fetal, post-natal and adult gut. Neural stem cell transplantation is an emerging therapeutic paradigm to replace dysfunctional or lost enteric neurons in several aganglionic disorders of the GI tract. The impetus to identify an appropriate microenvironment for enteric neuronal progenitor cells derives from the need to improve survival and phenotypic stability following implantation. Extracellular matrix composition can modulate stem cell fate and direct differentiation. Adult mammalian myenteric ganglia in vivo are surrounded by a matrix composed primarily of Collagen IV, Laminin and a Heparan sulfate proteoglycan. In these studies, adult mammalian enteric neuronal progenitor cells isolated from full thickness rabbit intestines were induced to differentiate when cultured on various combinations of neural ECM substrates. Neuronal and glial differentiation was studied as a function of ECM composition on coated glass coverslips. Poly-lysine coated coverslips (control) supported extensive glial differentiation but very minimal neuronal differentiation. Individual culture substrata (Laminin, Collagen I and Collagen IV) were conducive for both neuronal and glial differentiation. The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, significantly increased neurite lengths, branching and initiation of neuronal network formation. Glial differentiation was extensive on control poly lysine coated coverslips. Addition of laminin or heparan sulfate to composite collagen substrates significantly reduced glial immunofluorescence. Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neuronal progenitor cells. Our results indicate that specific ECM substrates that include type IV Collagen, laminin and heparan sulfate support and maintain neuronal and glial differentiation to different extents. Here, we identify a matrix composition optimized to tissue engineer transplantable innervated GI smooth muscle constructs to remedy aganglionic disorders.
|