Recent Research Articles from UNTHSC

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Smad3 is necessary for transforming growth factor-beta2 induced ocular hypertension in mice.

Thu, 02/13/2014 - 5:42am
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Smad3 is necessary for transforming growth factor-beta2 induced ocular hypertension in mice.

Exp Eye Res. 2013 Nov;116:419-23

Authors: McDowell CM, Tebow HE, Wordinger RJ, Clark AF

Abstract
TGFβ2 induces extracellular matrix (ECM) remodeling and alters the cytoskeleton by both the canonical Smad and non-canonical signaling pathways. TGFβ2 regulates the expression of ECM proteins in trabecular meshwork (TM) cells, increases intraocular pressure (IOP) in an ex vivo perfusion organ culture model, and induces ocular hypertension in rodent eyes. A necessary step in the canonical Smad signaling pathway is phosphorylation of receptor protein Smad3 by the TGF-β receptor complex. The purpose of this study was to determine whether TGFβ2 signals in vivo through the canonical Smad signaling pathway in the TM using Smad3 knockout (KO) mice. Ad5.hTGFβ2(226/228) (2.5 × 10(7) pfu) was injected intravitreally into one eye of homozygous (WT), heterozygous (HET), and homozygous (KO) 129-Smad3(tm1Par)/J mice (n = 9-10 mice/group), with the uninjected contralateral eye serving as the control. IOP measurements were taken using a rebound tonometer. To test the effect of TGFβ2 signaling on the ECM, fibronectin expression was determined by immunohistochemistry and qPCR analysis. Transduction of the TM with viral vector Ad5.hTGFβ2(226/228) caused a statistically significant difference in IOP exposure between Smad3 genotypes: WT, 187.7 ± 23.9 mmHg*day (n = 9); HET, 95.6 ± 24.5 mmHg*day (n = 9); KO, 52.8 ± 25.2 mmHg*day (n = 10); (p < 0.05 WT versus HET, p < 0.01 WT versus KO). Immunohistochemistry and qPCR analysis showed that Ad5.hTGFβ2(226/228) increased fibronectin expression in the TM of WT mice (2.23 ± 0.24 fold) compared to Smad3 KO mice (0.99 ± 0.19 fold), p < 0.05. These results demonstrate Smad3 is a necessary signaling protein for TGFβ2-induced ocular hypertension and fibronectin deposition in the TM.

PMID: 24184030 [PubMed - indexed for MEDLINE]

Role of the Alternatively Spliced Glucocorticoid Receptor Isoform GRβ in Steroid Responsiveness and Glaucoma.

Wed, 02/12/2014 - 5:07am

Role of the Alternatively Spliced Glucocorticoid Receptor Isoform GRβ in Steroid Responsiveness and Glaucoma.

J Ocul Pharmacol Ther. 2014 Feb 7;

Authors: Jain A, Wordinger RJ, Yorio T, Clark AF

Abstract
Abstract Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side effect of GC therapy in susceptible individuals. This OHT is due to increased aqueous humor (AH) outflow resistance in the trabecular meshwork (TM) caused by GC-mediated changes in TM structure and function. GCs may also play a role in the development of primary open-angle glaucoma (POAG). Elevated cortisol levels in the AH or enhanced GC sensitivity may be one of the reasons for elevated intraocular pressure in POAG patients. The GC OHT responder population is at greater risk of developing POAG compared with non-responders. We recently have gained insight into the molecular mechanisms responsible for this differential GC responsiveness, which is attributed to differences in GC receptor isoform expression in the TM. This article summarizes current knowledge on alternative GC receptor splicing to generate GC receptor alpha (GRα) and GRβ and their roles in the regulation of GC responsiveness in normal and glaucoma TM.

PMID: 24506296 [PubMed - as supplied by publisher]

Lineage(-)CD34(+)CD31(+) Cells That Appear in Association with Severe Burn Injury Are Inhibitory on the Production of Antimicrobial Peptides by Epidermal Keratinocytes.

Tue, 02/11/2014 - 4:24am

Lineage(-)CD34(+)CD31(+) Cells That Appear in Association with Severe Burn Injury Are Inhibitory on the Production of Antimicrobial Peptides by Epidermal Keratinocytes.

PLoS One. 2014;9(2):e82926

Authors: Yoshida S, Lee JO, Nakamura K, Suzuki S, Hendon DN, Kobayashi M, Suzuki F

Abstract
Antimicrobial peptides are major host defense effectors against Pseudomonas aeruginosa skin infections. Due to the lack of such peptide production, severely burned hosts are greatly susceptible to P. aeruginosa burn wound infection. β-Defensin (HBD) production by normal human epidermal keratinocytes (NHEK) was inhibited by lineage(-)CD34(+) cells isolated from peripheral blood of severely burned patients. Lineage(-)CD34(+) cells obtained from severely burned patients were characterized as CD31(+), while healthy donor lineage(-)CD34(+) cells were shown to be CD31(-) cells. Lineage(-)CD34(+)CD31(-) cells did not show any inhibitory activities on HBD-1 production by NHEK. CCL2 and IL-10 released from lineage(-)CD34(+)CD31(+) cells were shown to be inhibitory on the peptide production by NHEK, while these soluble factors were not produced by lineage(-)CD34(+)CD31(-) cells. After treatment with a mixture of mAbs for CCL2 and IL-10, the culture fluids of lineage(-)CD34(+)CD31(+) cells did not show any inhibitory activities on HBD-1 production by NHEK. Lineage(-)CD34(+)CD31(+) cells that appear in association with burn injuries play a role on the inhibition of antimicrobial peptide production by skin keratinocytes through the production of CCL2 and IL-10.

PMID: 24498256 [PubMed - in process]

Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras.

Tue, 02/11/2014 - 4:24am

Effect of glycyrrhizin on pseudomonal skin infections in human-mouse chimeras.

PLoS One. 2014 Jan 3;9(1):e83747

Authors: Yoshida S, Lee JO, Nakamura K, Suzuki S, Hendon DN, Kobayashi M, Suzuki F

Abstract
In our previous studies, peripheral blood lineage(-)CD34(+)CD31(+) cells (CD31(+) IMC) appearing in severely burned patients have been characterized as inhibitor cells for the production of β-defensins (HBDs) by human epidermal keratinocytes (NHEK). In this study, the effect of glycyrrhizin on pseudomonal skin infections was studied in a chimera model of thermal injury. Two different chimera models were utilized. Patient chimeras were created in murine antimicrobial peptide-depleted NOD-SCID IL-2rγ(null) mice that were grafted with unburned skin tissues of severely burned patients and inoculated with the same patient peripheral blood CD31(+) IMC. Patient chimera substitutes were created in the same mice that were grafted with NHEK and inoculated with experimentally induced CD31(+) IMC. In the results, both groups of chimeras treated with glycyrrhizin resisted a 20 LD50 dose of P. aeruginosa skin infection, while all chimeras in both groups treated with saline died within 3 days of the infection. Human antimicrobial peptides were detected from the grafted site tissues of both groups of chimeras treated with glycyrrhizin, while the peptides were not detected in the same area tissues of controls. HBD-1 was produced by keratinocytes in transwell-cultures performed with CD31(+) IMC and glycyrrhizin. Also, inhibitors (IL-10 and CCL2) of HBD-1 production by keratinocytes were not detected in cultures of patient CD31(+) IMC treated with glycyrrhizin. These results indicate that sepsis stemming from pseudomonal grafted site infections in a chimera model of burn injury is controllable by glycyrrhizin. Impaired antimicrobial peptide production at the infection site of severely burned patients may be restored after treatment with glycyrrhizin.

PMID: 24497916 [PubMed - in process]

Oxidative Stress, Testosterone, and Cognition among Caucasian and Mexican-American Men with and without Alzheimer's Disease.

Tue, 02/11/2014 - 4:24am

Oxidative Stress, Testosterone, and Cognition among Caucasian and Mexican-American Men with and without Alzheimer's Disease.

J Alzheimers Dis. 2014 Feb 4;

Authors: Cunningham RL, Singh M, O'Bryant SE, Hall JR, Barber RC

Abstract
Background: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal. Objective: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone's neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. Methods: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer's Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican-American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone. Results: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 μM), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. Conclusion: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST.

PMID: 24496073 [PubMed - as supplied by publisher]

Preliminary assessment of microbiome changes following blood-feeding and survivorship in the Amblyomma americanum nymph-to-adult transition using semiconductor sequencing.

Thu, 02/06/2014 - 4:20am
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Preliminary assessment of microbiome changes following blood-feeding and survivorship in the Amblyomma americanum nymph-to-adult transition using semiconductor sequencing.

PLoS One. 2013;8(6):e67129

Authors: Menchaca AC, Visi DK, Strey OF, Teel PD, Kalinowski K, Allen MS, Williamson PC

Abstract
The physiology of ticks supports a diverse community of non-pathogenic and pathogenic organisms. This study aims to initially characterize the microbial community present within colony-reared Amblyomma americanum using PCR of the variable region 5 of the 16S rRNA gene followed by semiconductor sequencing and classification of sequence data using the Ribosomal Database Project and MG-RAST analysis tools. Comparison of amplicon library datasets revealed changes in the microbiomes in newly engorged nymphs, newly-molted adults, and aged adults, as well as ticks exposed to different environmental conditions. These preliminary data support the concept that microbe survivorship and diversity are partially dependent upon environmental variables and the sequence of blood feeding, molting, and aging. The maintenance and/or emergence of pathogens in ticks may be dependent in part on temporal changes in the microbial community of the tick microbiome.

PMID: 23826210 [PubMed - indexed for MEDLINE]

CS1 (SLAMF7) inhibits production of proinflammatory cytokines by activated monocytes.

Thu, 02/06/2014 - 4:20am
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CS1 (SLAMF7) inhibits production of proinflammatory cytokines by activated monocytes.

Inflamm Res. 2013 Aug;62(8):765-72

Authors: Kim JR, Horton NC, Mathew SO, Mathew PA

Abstract
OBJECTIVE AND DESIGN: CS1 (CRACC, CD319, SLAMF7) is a member of the Signaling Lymphocyte Activation Molecule family expressed on immune cells mediating host defense. CS1 is a self-ligand and has both activating and inhibitory functions in Natural Killer cells. However, the function of CS1 in human monocytes is currently unknown. The objective of this study was to evaluate the control of CS1 surface expression in activated monocytes and to assess the effect of CS1 triggering on proinflammatory cytokine production by monocytes.
MATERIAL, METHODS AND TREATMENT: Human monocytes were isolated from PBMC of healthy volunteers by magnetic depletion method or FACS sorting. The monocytes were cultured with or without LPS (1 μg/ml) in the presence or absence of various pharmacological inhibitors to inhibit NF-кB and PI3K signaling pathways. The cells were stimulated with anti-CS1 antibody or isotype control. Total RNA was extracted and RT-PCR was performed using specific primers for CS1 and EAT-2. Cell supernatants were collected and cytokine levels (TNF-α and IL-12p70) were determined by sandwich ELISA.
RESULTS: Our study revealed that adherent or LPS-activated monocytes express CS1, and CS1 induction is via NF-кB and PI3K pathways. Importantly, cross-linking CS1 resulted in reduced production of proinflammatory cytokines TNF-α and IL-12p70 by LPS-activated monocytes.
CONCLUSIONS: Our study demonstrated that CS1 plays an inhibitory role in human monocytes to control proinflammatory immune responses.

PMID: 23695528 [PubMed - indexed for MEDLINE]

Letter to the Editor regarding the importance of residency programs.

Thu, 02/06/2014 - 4:20am
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Letter to the Editor regarding the importance of residency programs.

J Surg Res. 2013 Oct;184(2):1214

Authors: O-Yurvati AH

PMID: 23673164 [PubMed - indexed for MEDLINE]

Total knee arthroplasty with concurrent femoral and tibial osteotomies in osteogenesis imperfecta.

Wed, 02/05/2014 - 5:19am

Total knee arthroplasty with concurrent femoral and tibial osteotomies in osteogenesis imperfecta.

Am J Orthop (Belle Mead NJ). 2014 Jan;43(1):37-42

Authors: Wagner R, Luedke C

Abstract
Three total knee arthroplasties (TKA) with concurrent femoral and/or tibial osteotomies in 2 patients with osteogenesis imperfecta were performed from 2004 to 2009. The 2 patients were followed for a mean of 6 years. One patient with concurrent TKA, and femoral and tibial osteotomies developed a nonunion of the tibial site that responded to open reduction and internal fixation with iliac crest bone graft. The second patient underwent right TKA with bi-level tibial osteotomies, which healed uneventfully, allowing pain free, unassisted ambulation. The same patient then elected to undergo left TKA with bi-level tibial osteotomies. Intraoperatively he sustained a minor tibial plateau fracture requiring the use of a stemmed component and postoperatively, he developed a nonunion at the proximal site and valgus malunion of the distal site. Revision of fixation was performed at both osteotomy sites, and both healed within 3 months. Both patients are now pain free and ambulate without assistance.

PMID: 24490185 [PubMed - in process]

Evidence for the exclusive expression of functional homomeric α7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats.

Wed, 02/05/2014 - 5:19am

Evidence for the exclusive expression of functional homomeric α7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats.

Neurosci Lett. 2014 Jan 30;

Authors: Tischkau S, Mhaskar Y, Uteshev VV

Abstract
Hypothalamic histaminergic tuberomammillary (TM) neurons in rats express high densities of nicotinic acetylcholine receptors (nAChRs) whose Ca(2+) permeability, kinetic and pharmacological properties are similar to those of heterologous homomeric α7 nAChRs. However, native α7 nAChR subunits can co-assemble with β or α5 nAChR subunits to form functional heteromeric α7-containing α7β or α7α5 nAChRs with kinetics and pharmacology similar to those of α7 homomers. Therefore, although TM nAChRs have been used as an ex vivo model of functional α7 homomers, the molecular makeup of TM nAChRs has not been determined and the expression of functional α7-containing heteromers in TM neurons has not been excluded. To determine the profile of TM nAChR subunit transcripts, we have conducted single-cell qRT-PCR experiments using acutely dissociated TM neurons in rats. TM neurons were found to express transcripts of only principal α3, α6 and α7 nAChR subunits. Transcripts of other known mammalian neuronal subunits (α2, α4-5, α9-10, β2-4) were not detected. In the absence of β and α5 subunits, the expression of functional α7-containing heteromers in TM neurons is highly unlikely because principal α3, α6 and α7 nAChR subunits alone are not known to form functional heteromeric nAChRs. These results support the exclusive expression of native functional α7 homomers in rat TM neurons and introduce these neurons as a unique reliable source of native functional homomeric α7 nAChRs suitable for ex vivo and in vitro pharmacological assays in developing selective α7 nAChR agents.

PMID: 24486841 [PubMed - as supplied by publisher]

Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

Tue, 02/04/2014 - 5:21am
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Efficacy and safety of crofelemer for noninfectious diarrhea in HIV-seropositive individuals (ADVENT trial): a randomized, double-blind, placebo-controlled, two-stage study.

HIV Clin Trials. 2013 Nov-Dec;14(6):261-73

Authors: Macarthur RD, Hawkins TN, Brown SJ, Lamarca A, Clay PG, Barrett AC, Bortey E, Paterson C, Golden PL, Forbes WP

Abstract
BACKGROUND: HIV-associated diarrhea remains a significant concern with limited treatment options.
OBJECTIVE: To determine the optimal dose, efficacy, and safety of crofelemer for noninfectious diarrhea.
METHODS: This randomized, double-blind, phase 3 trial used a 2-stage design. Both stages included 2-week screening, 4-week placebo-controlled treatment, and 20-week placebo-free (open-label) extension phases. In stage I, 196 HIV-seropositive patients with chronic diarrhea were randomized to crofelemer 125 mg, 250 mg, or 500 mg or placebo twice daily. Using a prospective analysis, the 125-mg twice-daily dose was selected for stage II. In stage II, 180 new patients were randomized to crofelemer 125 mg twice daily or placebo for 4 weeks. Primary efficacy analysis was the percentage of patients (stages I/II combined) who achieved clinical response (defined as ≤2 watery stools/week during ≥2 of 4 weeks). During the placebo-free extension phase, response (≤2 watery stools) was assessed weekly.
RESULTS: Significantly more patients receiving crofelemer 125 mg achieved clinical response versus placebo (17.6% vs 8.0%; one-sided, P = .01). Crofelemer 125 mg resulted in a greater change from baseline in number of daily watery bowel movements (P = .04) and daily stool consistency score (P = .02) versus placebo. During the placebo-free extension phase, percentages of weekly responders ranged from 40% to 56% at weeks 11 to 24. Crofelemer was minimally absorbed, well tolerated, did not negatively impact clinical immune parameters, and had a safety profile comparable to placebo.
CONCLUSIONS: In HIV-seropositive patients taking stable antiretroviral therapy, crofelemer provided significant improvement in diarrhea with a favorable safety profile.

PMID: 24334179 [PubMed - indexed for MEDLINE]

Long lived BSA Au clusters as a time gated intensity imaging probe.

Fri, 01/31/2014 - 11:32am

Long lived BSA Au clusters as a time gated intensity imaging probe.

Nanoscale. 2014 Jan 27;

Authors: Raut SL, Fudala R, Rich R, Kokate RA, Chib R, Gryczynski Z, Gryczynski I

Abstract
The work presented here reports the use of long lifetime (>1 μs) BSA Au clusters as a cellular/tissue, time gated, intensity imaging probe. By collecting the emission signal 50 ns post excitation, one can off-gate the intense auto-fluorescence background, thereby greatly enhancing the clarity/specificity in fluorescence imaging.

PMID: 24469148 [PubMed - as supplied by publisher]

Osteopathic manual treatment in patients with diabetes mellitus and comorbid chronic low back pain: subgroup results from the OSTEOPATHIC Trial.

Fri, 01/31/2014 - 11:32am
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Osteopathic manual treatment in patients with diabetes mellitus and comorbid chronic low back pain: subgroup results from the OSTEOPATHIC Trial.

J Am Osteopath Assoc. 2013 Jun;113(6):468-78

Authors: Licciardone JC, Kearns CM, Hodge LM, Minotti DE

Abstract
CONTEXT: Chronic pain is often present in patients with diabetes mellitus.
OBJECTIVE: To assess the effects of osteopathic manual treatment (OMT) in patients with diabetes mellitus and comorbid chronic low back pain (LBP).
DESIGN: Randomized, double-blind, sham-controlled, 2×2 factorial trial, including OMT and ultrasound therapy (UST) interventions.
SETTING: University-based study in Dallas-Fort Worth, Texas.
PATIENTS: A subgroup of 34 patients (7%) with diabetes mellitus within 455 adult patients with nonspecific chronic LBP enrolled in the OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial.
MAIN STUDY MEASURES: The Outpatient Osteopathic SOAP Note Form was used to measure somatic dysfunction at baseline. A 100-mm visual analog scale was used to measure LBP severity over 12 weeks from randomization to study exit. Paired serum concentrations of tumor-necrosis factor (TNF)-α obtained at baseline and study exit were available for 6 subgroup patients.
RESULTS: Key osteopathic lesions were observed in 27 patients (79%) with diabetes mellitus vs 243 patients (58%) without diabetes mellitus (P=.01). The reduction in LBP severity over 12 weeks was significantly greater in 19 patients with diabetes mellitus who received OMT than in 15 patients with diabetes mellitus who received sham OMT (mean between-group difference in changes in the visual analog scale pain score, -17 mm; 95% confidence interval [CI], -32 mm to -1 mm; P=.04). This difference was clinically relevant (Cohen d=0.7). A corresponding significantly greater reduction in TNF-α serum concentration was noted in patients with diabetes mellitus who received OMT, compared with those who received sham OMT (mean between-group difference, -6.6 pg/mL; 95% CI, -12.4 to -0.8 pg/mL; P=.03). This reduction was also clinically relevant (Cohen d=2.7). No significant changes in LBP severity or TNF-α serum concentration were associated with UST during the 12-week period.
CONCLUSION: Severe somatic dysfunction was present significantly more often in patients with diabetes mellitus than in patients without diabetes mellitus. Patients with diabetes mellitus who received OMT had significant reductions in LBP severity during the 12-week period. Decreased circulating levels of TNF-α may represent a possible mechanism for OMT effects in patients with diabetes mellitus. A larger clinical trial of patients with diabetes mellitus and comorbid chronic LBP is warranted to more definitively assess the efficacy and mechanisms of action of OMT in this population.

PMID: 23739758 [PubMed - indexed for MEDLINE]

Blood pressure regulation XI: overview and future research directions.

Wed, 01/29/2014 - 4:41am

Blood pressure regulation XI: overview and future research directions.

Eur J Appl Physiol. 2014 Jan 28;

Authors: Raven PB, Chapleau MW

Abstract
While the importance of regulating arterial blood pressure within a 'normal' range is widely appreciated, the definition of 'normal' and the means by which humans and other species regulate blood pressure under various conditions remain hotly debated. The effects of diverse physiological, pathological and environmental challenges on blood pressure and the mechanisms that attempt to maintain it at an optimal level are reviewed and critically analyzed in a series of articles published in this themed issue of the European Journal of Applied Physiology. We summarize here the major points made in these reviews, with emphasis on unifying concepts of regulatory mechanisms and future directions for research.

PMID: 24463603 [PubMed - as supplied by publisher]

Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: A multiplex real-time PCR assay.

Wed, 01/29/2014 - 4:41am

Simultaneous quantification of mitochondrial DNA copy number and deletion ratio: A multiplex real-time PCR assay.

Sci Rep. 2014;4:3887

Authors: Phillips NR, Sprouse ML, Roby RK

Abstract
Mitochondrial dysfunction is implicated in a vast array of diseases and conditions, such as Alzheimer's disease, cancer, and aging. Alterations in mitochondrial DNA (mtDNA) may provide insight into the processes that either initiate or propagate this dysfunction. Here, we describe a unique multiplex assay which simultaneously provides assessments of mtDNA copy number and the proportion of genomes with common large deletions by targeting two mitochondrial sites and one nuclear locus. This probe-based, single-tube multiplex provides high specificity while eliminating well-to-well variability that results from assaying nuclear and mitochondrial targets individually.

PMID: 24463429 [PubMed - in process]

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Tue, 01/28/2014 - 5:20am

Pre-Clinical Evaluation of rHDL Encapsulated Retinoids for the Treatment of Neuroblastoma.

Front Pediatr. 2013 Mar 21;1:6

Authors: Sabnis N, Pratap S, Akopova I, Bowman PW, Lacko AG

Abstract
Despite major advances in pediatric cancer research, there has been only modest progress in the survival of children with high risk neuroblastoma (NB) (HRNB). The long term survival rates of HRNB in the United States are still only 30-50%. Due to resistance that often develops during therapy, development of new effective strategies is essential to improve the survival and overcome the tendency of HRNB patients to relapse subsequent to initial treatment. Current chemotherapy regimens also have a serious limitation due to off target toxicity. In the present work, we evaluated the potential application of reconstituted high density lipoprotein (rHDL) containing fenretinide (FR) nanoparticles as a novel approach to current NB therapeutics. The characterization and stability studies of rHDL-FR nanoparticles showed small size (<40 nm) and high encapsulation efficiency. The cytotoxicity studies of free FR vs. rHDL/FR toward the NB cell lines SK-N-SH and SMS-KCNR showed 2.8- and 2-fold lower IC50 values for the rHDL encapsulated FR vs. free FR. More importantly, the IC50 value for retinal pigment epithelial cells (ARPE-19), a recipient of off target toxicity during FR therapy, was over 40 times higher for the rHDL/FR as compared to that of free FR. The overall improvement in in vitro selective therapeutic efficiency was thus about 100-fold upon encapsulation of the drug into the rHDL nanoparticles. These studies support the potential value of this novel drug delivery platform for treating pediatric cancers in general, and NB in particular.

PMID: 24459664 [PubMed]

Telehealth Personalized Cancer Risk Communication to Motivate Colonoscopy in Relatives of Patients With Colorectal Cancer: The Family CARE Randomized Controlled Trial.

Sat, 01/25/2014 - 5:31am

Telehealth Personalized Cancer Risk Communication to Motivate Colonoscopy in Relatives of Patients With Colorectal Cancer: The Family CARE Randomized Controlled Trial.

J Clin Oncol. 2014 Jan 21;

Authors: Kinney AY, Boonyasiriwat W, Walters ST, Pappas LM, Stroup AM, Schwartz MD, Edwards SL, Rogers A, Kohlmann WK, Boucher KM, Vernon SW, Simmons RG, Lowery JT, Flores K, Wiggins CL, Hill DA, Burt RW, Williams MS, Higginbotham JC

Abstract
PURPOSE: The rate of adherence to regular colonoscopy screening in individuals at increased familial risk of colorectal cancer (CRC) is suboptimal, especially among rural and other geographically underserved populations. Remote interventions may overcome geographic and system-level barriers. We compared the efficacy of a telehealth-based personalized risk assessment and communication intervention with a mailed educational brochure for improving colonoscopy screening among at-risk relatives of patients with CRC.
METHODS: Eligible individuals age 30 to 74 years who were not up-to-date with risk-appropriate screening and were not candidates for genetic testing were recruited after contacting patients with CRC or their next of kin in five states. Enrollees were randomly assigned as family units to either an active, personalized intervention that incorporated evidence-based risk communication and behavior change techniques, or a mailed educational brochure. The primary outcome was medically verified colonoscopy within 9 months of the intervention.
RESULTS: Of the 481 eligible and randomly assigned at-risk relatives, 79.8% completed the outcome assessments within 9 months; 35.4% of those in the personalized intervention group and 15.7% of those in the comparison group obtained a colonoscopy. In an intent-to-treat analysis, the telehealth group was almost three times as likely to get screened as the low-intensity comparison group (odds ratio, 2.83; 95% CI, 1.87 to 4.28; P < .001). Persons residing in rural areas and those with lower incomes benefitted at the same level as did urban residents.
CONCLUSION: Remote personalized interventions that consider family history and incorporate evidence-based risk communication and behavior change strategies may promote risk-appropriate screening in close relatives of patients with CRC.

PMID: 24449229 [PubMed - as supplied by publisher]

Metabolic Dysfunction of Astrocyte: An Initiating Factor in Beta-amyloid Pathology?

Thu, 01/23/2014 - 7:18am

Metabolic Dysfunction of Astrocyte: An Initiating Factor in Beta-amyloid Pathology?

Aging Neurodegener. 2013 Aug;1(1):7-14

Authors: Yan LJ, Xiao M, Chen R, Cai Z

Abstract
Astrocytes, the most important energy regulator in the brain, support brain energy needs. In the meantime, numerous studies have demonstrated that impaired brain glucose metabolism is closely linked to abnormal astrocytic metabolism in AD. Indeed, the interaction between amyloid plaques and perturbed astrocytic homeostasis contributes to AD pathogenesis and astrocytic metabolic dysfunction is thought to be a trigger for Aβ pathology through oxidative stress and neuroinflammation Moreover, astrocytic metabolic dysfunction may regulate Aβ generation via modulating proteolytic processing of amyloid precursor protein (APP) by β-secretase, γ-secretase, and α-secretase, and may also modulate APP post-translational modifications such as glycosylation, phosphorylation, and tyrosine sulfation. While it is known that metabolic dysfunction of astrocytes contributes to the failure of Aβ clearance, it has also been reported that such dysfunction has neuroprotective property and exhibits no detrimental outcomes. Therefore, the exact role of astrocytic metabolic dysfunction in Aβ pathology remains to be further investigated.

PMID: 24443714 [PubMed - as supplied by publisher]

Involvement of p38 Mapk in reactive astrogliosis induced by ischemic stroke.

Thu, 01/23/2014 - 7:18am

Involvement of p38 Mapk in reactive astrogliosis induced by ischemic stroke.

Brain Res. 2014 Jan 16;

Authors: Choudhury GR, Ryou MG, Poteet E, Wen Y, He R, Sun F, Yuan F, Jin K, Yang SH

Abstract
Reactive astrogliosis is an essential feature of astrocytic response to all forms of central nervous system (CNS) injury and disease, which may benefit or harm surrounding neural and non-neural cells. Despite extensive study, its molecular triggers remain largely unknown in term of ischemic stroke. In the current study we investigated the role p38 mitogen-activated protein kinase (MAPK) in astrogliosis both in vitro and in vivo. In a mouse model of middle cerebral artery occlusion (MCAO), p38 MAPK activation was observed in the glia scar area, along with increased glial fibrillary acidic protein (GFAP) expression. In primary astrocyte cultures, hypoxia and scratch injury-induced astrogliosis was attenuated by both p38 inhibition and knockout of p38 MAPK. In addition, both knockout and inhibition of p38 MAPK also reduced astrocyte migration, but did not affect astrocyte proliferation. In a mouse model of permanent MCAO, no significant difference in motor function recovery and lesion volume was observed between conditional GFAP/p38 MAPK knockout mice and littermates. While a significant reduction of astrogliosis was observed in the GFAP/p38 knockout mice compared with the littermates. Our findings suggest that p38 MAPK signaling pathway plays an important role in the ischemic stroke-induced astrogliosis and thus may serve as a novel target to control glial scar formation.

PMID: 24440774 [PubMed - as supplied by publisher]

An unlikely marriage: life as a wrist surgeon and career officer in the u.s. Navy.

Tue, 01/21/2014 - 5:20am

An unlikely marriage: life as a wrist surgeon and career officer in the u.s. Navy.

J Wrist Surg. 2013 Nov;2(4):288-93

Authors: Lichtman DM

PMID: 24436831 [PubMed]