Gibson D. Lewis Library

Recent Research Articles from UNTHSC

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Updated: 2 hours 42 min ago

Improving diabetic patient transition to home healthcare: leading risk factors for 30-day readmission.

Thu, 07/16/2015 - 3:29am
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Improving diabetic patient transition to home healthcare: leading risk factors for 30-day readmission.

Am J Manag Care. 2015 Jun;21(6):440-50

Authors: Chen HF, Popoola T, Radhakrishnan K, Suzuki S, Homan S

Abstract
OBJECTIVES: To identify risk factors of 30-day readmissions due to ambulatory care-sensitive conditions (ACSCs) for diabetic Medicare home healthcare beneficiaries in order to improve transition from hospital-based care to home healthcare.
STUDY DESIGN: We analyzed diabetic Medicare beneficiaries who received home healthcare within 14 days of hospital discharges in 2009. The unit of analysis is the home health episode for post acute care.
METHODS: The conceptual framework was guided by Andersen's Behavioral Model of Health Services. Data sources included: Medicare Beneficiary Summary File, Medicare Provider Analysis Review, Outcome Assessment Information Set, Home Health Agency Research Identifiable File, Hospital Readmissions Reduction Program Supplemental Data File, Provider of Services File, and Area Health Resources File. The dependent variable was time to first 30-day ACSC-related readmission. Proportional hazards regression was used for the statistical analyses.
RESULTS: The 30-day ACSC-related readmission rate was approximately 6% in our study sample, costing the Medicare program about $62 million. Predictors of readmissions due to ACSCs within 30 days of hospital discharge were: being aged 75 to 84 years, being an African American, requiring assistance in medication management, and having 1 or more of the following clinical conditions: congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, renal failure, deficiency anemia, fluid and electrolyte diseases, depression and/or anxiety, and pressure or stasis ulcer. Patients with chronic obstructive pulmonary disease or renal failure had a 40% higher risk of 30-day ACSC-related readmissions than their counterparts.
CONCLUSIONS: Knowing the risk factors identified above, hospital providers can improve care planning and transition of care to the home healthcare providers.

PMID: 26168064 [PubMed - in process]

Delayed-Onset Nodules Secondary to a Smooth Cohesive 20 mg/mL Hyaluronic Acid Filler: Cause and Management.

Thu, 07/16/2015 - 3:29am
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Delayed-Onset Nodules Secondary to a Smooth Cohesive 20 mg/mL Hyaluronic Acid Filler: Cause and Management.

Dermatol Surg. 2015 Jul 8;

Authors: Beleznay K, Carruthers JD, Carruthers A, Mummert ME, Humphrey S

Abstract
BACKGROUND: The shift from 2- to 3-dimensional soft tissue augmentation has allowed the development of hyaluronic acid (HA) fillers, which are long lasting and also reversible. Delayed-onset inflammatory nodules have recently been reported with the use of HA fillers.
OBJECTIVE: The authors document their experience with delayed-onset nodules after 3-dimensional facial injection of Juvéderm Voluma (HA-V) over 68 months.
MATERIALS AND METHODS: The authors conducted a retrospective chart review of patients who were treated with HA-V between February 1, 2009, and September 30, 2014, to evaluate for delayed-onset nodules.
RESULTS: Over 68 months, 4,702 treatments were performed using 11,460 mL of HA-V. Twenty-three patients (0.5%) experienced delayed-onset nodules. The median time from injection to reaction was 4 months, and median time to resolution was 6 weeks. Nine of the 23 (39%) had an identifiable immunologic trigger such as flu-like illness before the nodule onset. In the authors' experience, prednisone, intralesional corticosteroids, and hyaluronidase were effective treatments.
CONCLUSION: Although delayed nodules are uncommon from HA-V (0.5%), it is important to be aware of this adverse effect and have a management protocol in place. It is the authors' opinion from the patients' responses and from the literature that these nodules are immune mediated in nature.

PMID: 26166260 [PubMed - as supplied by publisher]

MicroRNA-940 suppresses prostate cancer migration and invasion by regulating MIEN1.

Thu, 07/16/2015 - 3:29am
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MicroRNA-940 suppresses prostate cancer migration and invasion by regulating MIEN1.

Mol Cancer. 2014;13:250

Authors: Rajendiran S, Parwani AV, Hare RJ, Dasgupta S, Roby RK, Vishwanatha JK

Abstract
BACKGROUND: MicroRNAs (miRNAs) are crucial molecules that regulate gene expression and hence pathways that are key to prostate cancer progression. These non-coding RNAs are highly deregulated in prostate cancer thus facilitating progression of the disease. Among the many genes that have gained importance in this disease, Migration and invasion enhancer 1 (MIEN1), a novel gene located next to HER2/neu in the 17q12 amplicon of the human chromosome, has been shown to enhance prostate cancer cell migration and invasion, two key processes in cancer progression. MIEN1 is differentially expressed between normal and cancer cells and tissues. Understanding the regulation of MIEN1 by microRNA may enable development of better targeting strategies.
METHODS: The miRNAs that could target MIEN1 were predicted by in silico algorithms and microarray analysis. The validation for miRNA expression was performed by qPCR and northern blotting in cells and by in situ hybridization in tissues. MIEN1 and levels of other molecules upon miRNA regulation was determined by Western blotting, qPCR, and immunofluorescence. The functional effects of miRNA on cells were determined by wound healing cell migration, Boyden chamber cell invasion, clonal and colony formation assays. For knockdown or overexpression of the miRNA or overexpression of MIEN1 3'UTR, cells were transfected with the oligomiRs and plasmids, respectively.
RESULTS: A novel miRNA, hsa-miR-940 (miR-940), identified and validated to be highly expressed in immortalized normal cells compared to cancer cells, is a regulator of MIEN1. Analysis of human prostate tumors and their matched normal tissues confirmed that miR-940 is highly expressed in the normal tissues compared to its low to negligible expression in the tumors. While MIEN1 is a direct target of miR-940, miR-940 alters MIEN1 RNA, in a quantity as well as cell dependent context, along with altering its downstream effectors. The miR-940 inhibited migratory and invasive potential of cells, attenuated their anchorage-independent growth ability, and increased E-cadherin expression, implicating its role in mesenchymal-to-epithelial transition (MET).
CONCLUSIONS: These results, for the first time, implicate miR-940, a regulator of MIEN1, as a promising novel diagnostic and prognostic tool for prostate cancer.

PMID: 25406943 [PubMed - indexed for MEDLINE]

Analysis of provider specialties in the treatment of patients with clinically diagnosed back and joint problems.

Thu, 07/16/2015 - 3:29am
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Analysis of provider specialties in the treatment of patients with clinically diagnosed back and joint problems.

J Eval Clin Pract. 2015 Jul 7;

Authors: Wilson FA, Licciardone JC, Kearns CM, Akuoko M

Abstract
RATIONALE, AIMS AND OBJECTIVES: Although several studies have compared patient outcomes by provider specialty in the treatment of back and joint pain, little is known about the cost-effectiveness of improving patient outcomes across specialties. This study uses a large-scale, nationally representative database to evaluate the cost-effectiveness of being treated by specific provider specialists for back and joint pain in the United States.
METHOD: The 2002-2012 Medical Expenditure Panel Surveys were used to examine patients diagnosed with back and/or joint problems seeking treatment from doctors (internal medicine, family/general, osteopathic medicine, orthopaedics, rheumatology, neurology) or other providers (chiropractor, physical therapist, acupuncturist, massage therapist). A total of 16 546 respondents aged 18 to 85 and clinically diagnosed with back/joint pain were examined. Self-reported measures of physical and mental health and general quality of life (measured by the EuroQol-5D) were compared with average total costs of treatment across medical providers.
RESULTS: Total annual treatment costs per person ranged from $397 for family/general doctors to $1205 for rheumatologists. Cost-effectiveness analysis suggests that osteopathic, family/general, internal medicine doctors and chiropractors and massage therapists were more cost-effective than other specialties in improving physical function to back pain patients. For mental health measures, family/general and orthopaedic doctors and physical therapists were more cost-effective compared with other specialties. Similar to results on physical function, family/general, osteopathic and internal medicine doctors dominated other specialties. However, only massage therapy was cost-effective among non-doctor providers in improving quality of life measures.
CONCLUSIONS: Patients seeking care for back and joint-related health problems face a wide range of treatments, costs and outcomes depending on which specialist provider they see. This study provides important insight on the relationship between health care costs and patients' perceived physical and mental health status from receiving treatment for diagnosed back/joint problems.

PMID: 26154344 [PubMed - as supplied by publisher]

Arsenic exposure, hyperuricemia, and gout in US adults.

Thu, 07/16/2015 - 3:29am
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Arsenic exposure, hyperuricemia, and gout in US adults.

Environ Int. 2015 Mar;76:32-40

Authors: Kuo CC, Weaver V, Fadrowski JJ, Lin YS, Guallar E, Navas-Acien A

Abstract
BACKGROUND: There is very limited information on the association between arsenic and serum uric acid levels or gout. The aim of this study was to investigate the association of arsenic with hyperuricemia and gout in US adults.
METHODS: A cross-sectional study was conducted in 5632 adults aged 20years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2010 with determinations of serum uric acid and urine total arsenic and dimethylarsinate (DMA). Hyperuricemia was defined as serum uric acid higher than 7.0mg/dL for men and 6.0mg/dL for women. Gout was defined based on self-reported physician diagnosis and medication use.
RESULTS: After adjustment for sociodemographic factors, comorbidities and arsenobetaine levels, the increase in the geometric means of serum uric acid associated with one interquartile range increase in total arsenic and DMA levels was 3% (95% CI 2-5) and 3% (2-5), respectively, in men and 1% (0-3) and 2% (0-4), respectively, in women. In men, the adjusted odds ratio for hyperuricemia comparing the highest to lowest quartiles of total arsenic was 1.84 (95% CI, 1.26-2.68) and for DMA it was 1.41 (95% CI, 1.01-1.96). The corresponding odds ratios in women were 1.26 (0.77, 2.07) and 1.49 (0.96, 2.31), respectively. The odds ratio for gout comparing the highest to lowest tertiles was 5.46 (95% CI, 1.70-17.6) for total arsenic and 1.98 (0.64-6.15) for DMA among women older than 40years old. Urine arsenic was not associated with gout in men.
CONCLUSION: Low level arsenic exposures may be associated with the risk of hyperuricemia in men and with the prevalence of gout in women. Prospective research focusing on establishing the direction of the relationship among arsenic, hyperuricemia, and gout is needed.

PMID: 25499256 [PubMed - indexed for MEDLINE]

Aberrant histone acetylation promotes mitochondrial respiratory suppression in the brain of alcoholic rats.

Thu, 07/16/2015 - 3:29am
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Aberrant histone acetylation promotes mitochondrial respiratory suppression in the brain of alcoholic rats.

J Pharmacol Exp Ther. 2015 Feb;352(2):258-66

Authors: Jung ME, Metzger DB

Abstract
The acetylation of histone proteins in the core of DNA regulates gene expression, including those affecting mitochondria. Both histone acetylation and mitochondrial deficit have been implicated in neuronal damage associated with drinking problems. Many alcoholics will repeat unsuccessful attempts at abstaining, developing a pattern of repeated drinking and withdrawal. We investigated whether aberrant histone acetylation contributes to mitochondrial and cellular damage induced by repeated ethanol withdrawal (EW). We also investigated whether this effect of histone acetylation involves let-7f, a small noncoding RNA (microRNA). Male rats received two cycles of an ethanol/control diet (7.5%, 4 weeks) and withdrawal. Their prefrontal cortex was collected to measure the mitochondrial respiration and histone acetylation using extracellular flux (XF) real-time respirometry and gold immunostaining, respectively. Separately, HT22 (mouse hippocampal) cells received two cycles of ethanol exposure (100 mM, 20 hours) and withdrawal. Trichostatin A (TSA) as a histone acetylation promoter and let-7f antagomir were applied during withdrawal. The mitochondrial respiration, let-7f level, and cell viability were assessed using XF respirometry, quantitative polymerase chain reaction, TaqMan let-7f primers, and a calcein-acetoxymethyl assay, respectively. Repeated ethanol withdrawn rats showed a more than 2-fold increase in histone acetylation, accompanied by mitochondrial respiratory suppression. EW-induced mitochondrial respiratory suppression was exacerbated by TSA treatment in a manner that was attenuated by let-7f antagomir cotreatment. TSA treatment did not alter the increasing effect of EW on the let-7f level but dramatically exacerbated the cell death induced by EW. These data suggest that the multiple episodes of withdrawal from chronic ethanol impede mitochondrial and cellular integrity through upregulating histone acetylation, independent of or additively with let-7f.

PMID: 25406171 [PubMed - indexed for MEDLINE]

Characterization of a new composite PMMA-HA/Brushite bone cement for spinal augmentation.

Thu, 07/16/2015 - 3:29am
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Characterization of a new composite PMMA-HA/Brushite bone cement for spinal augmentation.

J Biomater Appl. 2014 Nov;29(5):688-98

Authors: Aghyarian S, Rodriguez LC, Chari J, Bentley E, Kosmopoulos V, Lieberman IH, Rodrigues DC

Abstract
Calcium phosphate fillers have been shown to increase cement osteoconductivity, but have caused drawbacks in cement properties. Hydroxyapatite and Brushite were introduced in an acrylic two-solution cement at varying concentrations. Novel composite bone cements were developed and characterized using rheology, injectability, and mechanical tests. It was hypothesized that the ample swelling time allowed by the premixed two-solution cement would enable thorough dispersion of the additives in the solutions, resulting in no detrimental effects after polymerization. The addition of Hydroxyapatite and Brushite both caused an increase in cement viscosity; however, these cements exhibited high shear-thinning, which facilitated injection. In gel point studies, the composite cements showed no detectable change in gel point time compared to an all-acrylic control cement. Hydroxyapatite and Brushite composite cements were observed to have high mechanical strengths even at high loads of calcium phosphate fillers. These cements showed an average compressive strength of 85 MPa and flexural strength of 65 MPa. A calcium phosphate-containing cement exhibiting a combination of high viscosity, pseudoplasticity and high mechanical strength can provide the essential bioactivity factor for osseointegration without sacrificing load-bearing capability.

PMID: 25085810 [PubMed - indexed for MEDLINE]

Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

Thu, 07/16/2015 - 3:29am
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Enhancement of anti-tumor effect of particulate vaccine delivery system by 'bacteriomimetic' CpG functionalization of poly-lactic-co-glycolic acid nanoparticles.

Nanomedicine (Lond). 2015;10(6):915-29

Authors: Kokate RA, Thamake SI, Chaudhary P, Mott B, Raut S, Vishwanatha JK, Jones HP

Abstract
AIM: Low immunogenicity remains a major obstacle in realizing the full potential of cancer vaccines. In this study, we evaluated CpG-coated tumor antigen (Tag)-encapsulating 'bacteriomimetic' nanoparticles (CpG-nanoparticle [NP]-Tag NPs) as an approach to enhance anti-tumor immunity.
MATERIALS & METHODS: CpG-NP-Tag NPs were synthesized, characterized for their physicochemical properties and tested in vivo.
RESULTS: We found CpG predosing followed by intraperitoneal (IP) immunization with CpG-NP-Tag NPs significantly attenuated tumor growth in female BALB/c mice compared with respective controls. Histopathological and Immunofluorescence data revealed CpG-NP-Tag tumors had lower proliferation, higher apoptotic activity, greater CD4(+) and CD8(+) T cell infiltration as well as higher IFN-γ levels as compared with control groups.
CONCLUSION: Our findings suggest CpG-NP-Tag NPs can enhance anti-tumor effect of nanoparticulate tumor vaccination system.

PMID: 25867857 [PubMed - indexed for MEDLINE]

Amiloride and GMQ Allosteric Modulation of the GABA-A ρ1 Receptor: Influences of the Intersubunit Site.

Thu, 07/16/2015 - 3:29am
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Amiloride and GMQ Allosteric Modulation of the GABA-A ρ1 Receptor: Influences of the Intersubunit Site.

J Pharmacol Exp Ther. 2015 Jun;353(3):551-9

Authors: Snell HD, Gonzales EB

Abstract
Amiloride, a diuretic used in the treatment of hypertension and congestive heart failure, and 2-guanidine-4-methylquinazoline (GMQ) are guanidine compounds that modulate acid-sensing ion channels. Both compounds have demonstrated affinity for a variety of membrane proteins, including members of the Cys-loop family of ligand-gated ion channels, such as the heteromeric GABA-A αβγ receptors. The actions of these guanidine compounds on the homomeric GABA-A ρ1 receptor remains unclear, especially in light of how many GABA-A αβγ receptor modulators have different effects in the GABA-A ρ1 receptors. We sought to characterize the influence of amiloride and GMQ on the human GABA-A ρ1 receptors using whole-cell patch-clamp electrophysiology. The diuretic amiloride potentiated the human GABA-A ρ1 GABA-mediated current, whereas GMQ antagonized the receptor. Furthermore, a GABA-A second transmembrane domain site, the intersubunit site, responsible for allosteric modulation in the heteromeric GABA-A receptors mediated amiloride's positive allosteric actions. In contrast, the mutation did not remove GMQ antagonism but only changed the guanidine compound's potency within the human GABA-A ρ1 receptor. Through modeling and introduction of point mutations, we propose that the GABA-A ρ1 intersubunit site plays a role in mediating the allosteric effects of amiloride and GMQ.

PMID: 25829529 [PubMed - indexed for MEDLINE]

Conceptual framework and quantification of population vulnerability for effective emergency response planning.

Sat, 07/11/2015 - 3:32am

Conceptual framework and quantification of population vulnerability for effective emergency response planning.

J Emerg Manag. 2015 May-Jun;13(3):227-238

Authors: Ramisetty-Mikler S, Mikler AR, O'Neill M, Komatz J

Abstract
OBJECTIVE: The study focused on the methodological advancement and analytical approach of using multilevel data to define population vulnerability and risk in bioemergency disaster planning.
METHODS: The authors considered two types of vulnerabilities, transportation vulnerability that stems from lack of access to transportation (public or private) and communication vulnerability that stems from unavailability of needed language-specific communication resources. The authors used Transit Authority general transit feed data and the American Community Survey 5-year estimate data (2006-2010 summary files) to quantify these vulnerabilities. These data were integrated with Topologically Integrated Geographic Encoding and Referencing (TIGER) data for spatial analysis. A response plan was generated for Tarrant County, TX, and deemed feasible before consideration of vulnerable populations.
RESULTS: The results point to the importance of integrating geographical and population demographic features that represent potential barriers to the optimum distribution and utilization of resources into the analysis of response plans. An examination of transportation vulnerabilities indicate that, of those vulnerable in Tarrant County, nearly 23,000 individuals will be at-risk of not being able to reach the Point Of Dispensing (POD) to obtain services as they are beyond walking distance to the POD and lack access to transportation resources. The analysis of language vulnerability depicts an uneven distribution resulting in nonuniform demand at PODs for translation resources. There are more than 11,000 at-risk households in the South East region of Tarrant County alone that are truly in need of translation services.
CONCLUSIONS: The authors demonstrated that multiple vulnerabilities at each POD can be quantified by aggregating the vulnerability at the available granularity (ie, all blocks or block groups) in a given service area. The quantification of vulnerability at each service area facilitates a POD-based at-risk analysis for the response plan. Disparities stemming from social, behavioral, cultural, economic, and health characteristics of diverse subpopulations could induce the need for additional targeted resources to support emergency response efforts.

PMID: 26150366 [PubMed - as supplied by publisher]

Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.

Sat, 07/11/2015 - 3:32am
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Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.

Cell Death Dis. 2014;5:e1457

Authors: Ruan L, Zhang Z, Mu L, Burnley P, Wang L, Coder B, Zhuge Q, Su DM

Abstract
FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOP(flox)-FoxN1 mice, in which over- and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOP(flox) in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOP(flox) mediated by progressive uCreER(T) leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreER(T)-mediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreER(T) activation in juveniles adversely influenced total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Over- and ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development.

PMID: 25299782 [PubMed - indexed for MEDLINE]

Self-Efficacy to Drive While Intoxicated: Insights into the Persistence of Alcohol-Impaired Driving.

Wed, 07/08/2015 - 3:29am

Self-Efficacy to Drive While Intoxicated: Insights into the Persistence of Alcohol-Impaired Driving.

Alcohol Clin Exp Res. 2015 Jul 4;

Authors: Rossheim ME, Weiler RM, Barnett TE, Suzuki S, Walters ST, Barry AE, Cannell B, Pealer LN, Moorhouse MD, Zhang Q, Thombs DL

Abstract
BACKGROUND: Scant research has examined event-level risk factors for impaired driving in natural drinking settings. This study assessed driving self-efficacy among intoxicated individuals to better understand decision-making about alcohol-impaired driving at night after exiting on-premise drinking establishments.
METHODS: Interview and breath test data were collected from bar patrons (n = 512) exiting 2 college bar districts in Florida and Texas.
RESULTS: Results from a multivariable linear regression model indicated that self-efficacy to drive while intoxicated was more strongly associated with situational variables, that is, perceived drunkenness and self-estimated blood alcohol concentration than patron traits, that is, past-year history of drinking, risk proneness, and sex. A large proportion of bar patrons, particularly men, expressed confidence in their ability to drive, despite being highly intoxicated. Moreover, the majority of legally intoxicated patrons who were confident in their ability to drive were aware of their high level of intoxication.
CONCLUSIONS: Emphasis should be placed on the enactment and enforcement of policies and laws to prevent alcohol-impaired driving.

PMID: 26147102 [PubMed - as supplied by publisher]

Cerebral blood velocity regulation during progressive blood loss compared to lower body negative pressure in humans.

Tue, 07/07/2015 - 3:31am

Cerebral blood velocity regulation during progressive blood loss compared to lower body negative pressure in humans.

J Appl Physiol (1985). 2015 Jul 2;:jap.00127.2015

Authors: Rickards CA, Johnson BD, Harvey RE, Convertino VA, Joyner MJ, Barnes JN

Abstract
Lower body negative pressure (LBNP) is often used to simulate blood loss in humans. It is unknown if cerebral blood flow responses to actual blood loss are analogous to simulated blood loss during LBNP. Nine healthy men were studied at baseline, during 3 levels of LBNP (5-min at -15, -30, -45 mmHg), and during 3 levels of blood loss (333, 667, 1000 ml). LBNP and blood loss conditions were randomized. Intra-arterial mean arterial pressure (MAP) was similar during LBNP compared with blood loss (p≥0.42). Central venous pressure (CVP; 2.8±0.7 vs. 4.0±0.8, 1.2±0.6 vs. 3.5±0.8, 0.2±0.9 vs. 2.1±0.9 mmHg for level 1, 2, and 3; p≤0.003) and stroke volume (71±4 vs. 80±3, 60±3 vs. 74±3, 51±2 vs. 68±4 ml for level 1, 2, and 3; p≤0.002) were lower during LBNP compared with blood loss. Despite differences in CVP, middle cerebral artery velocity (MCAv) and cerebrovascular conductance (CVC) were similar between LBNP and blood loss at each level (MCAv at level 3: 62±6 vs. 66±5 cm/s; p=0.37; CVC at level 3: 0.72±0.05 vs. 0.73±0.05 cm/s/mmHg; p=0.53). While the slope of the relationship between MAP and MCAv was slightly different between LBNP and blood loss (LBNP: 0.41 ±0.03 cm/s/mmHg vs. Blood Loss: 0.66 ± 0.04 cm/s/mmHg; P=0.05), time domain gain between MAP and MCAv at maximal LBNP/blood loss (P=0.23), and low frequency MAP-mean MCAv transfer function coherence, gain and phase were similar (P≥0.10). Our results suggest that cerebral hemodynamic responses to LBNP to -45 mmHg and blood loss up to 1000 ml follow a similar trajectory, and the relationship between arterial pressure and cerebral blood velocity are not altered from baseline under these conditions.

PMID: 26139213 [PubMed - as supplied by publisher]

Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials.

Sat, 07/04/2015 - 3:32am
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Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials.

J Surg Res. 2015 Apr;194(2):679-87

Authors: Verhoef C, Singla N, Moneta G, Muir W, Rijken A, Lockstadt H, de Wilt JH, O-Yurvati A, Zuckerman LA, Frohna P, Porte RJ

Abstract
BACKGROUND: Fibrocaps, a ready-to-use, dry-powder fibrin sealant containing human plasma-derived thrombin and fibrinogen, is being developed as an adjunct for surgical hemostasis.
MATERIALS AND METHODS: Safety and efficacy of Fibrocaps applied directly or by spray device, in combination with gelatin sponge, was compared with that of gelatin sponge-alone in two randomized, single-blind controlled trials: FC-002 US (United States) and FC-002 NL (the Netherlands). A total of 126 adult patients were randomized (Fibrocaps: n = 47 [FC-002 US], n = 39 [FC-002 NL]; gelatin sponge alone: n = 23 [FC-002 US], n = 17 [FC-002 NL). One bleeding site was treated during a surgical procedure (n = 125). Time to hemostasis (primary end point) was measured, with a 28-d safety follow-up. Four surgical indications included hepatic resection (n = 58), spinal procedures (n = 37), peripheral vascular procedures (n = 30), and soft tissue dissection (n = 1).
RESULTS: Mean (standard deviation) time to hemostasis was significantly shorter after Fibrocaps treatment than after gelatin sponge alone (FC-002 US: 1.9 [1.3] versus 4.8 min [3.1], P < 0.001; FC-002 NL: 2.2 [1.3] versus 4.4 min [3.1], P = 0.004). The incidence of hemostasis was greater after Fibrocaps compared with that of gelatin sponge alone within 3 min (FC-002 US: 83% versus 35%, P < 0.001; FC-002 NL: 77% versus 53%, P = 0.11), 5 min (94% versus 61%, P = 0.001; 95% versus 71%, P = 0.022), and 10 min (100% versus 78%, P = 0.003; 100% versus 82%, P = 0.025). Adverse events were consistent with surgical procedures performed and patients' underlying diseases and generally similar between treatment arms; most were mild or moderate in severity. Non-neutralizing antithrombin antibodies were detected in 5% of Fibrocaps-treated patients on day 29.
CONCLUSIONS: Fibrocaps had good safety and efficacy profiles, supporting continuing clinical development as a novel fibrin sealant.

PMID: 25586331 [PubMed - indexed for MEDLINE]

Membrane topology of human presenilin-1 in SK-N-SH cells determined by fluorescence correlation spectroscopy and fluorescent energy transfer.

Sat, 07/04/2015 - 3:32am
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Membrane topology of human presenilin-1 in SK-N-SH cells determined by fluorescence correlation spectroscopy and fluorescent energy transfer.

Cell Biochem Biophys. 2014 Nov;70(2):923-32

Authors: Midde K, Rich R, Saxena A, Gryczynski I, Borejdo J, Das HK

Abstract
Presenilin-1 (PS1) protein acts as passive ER Ca(2+) leak channels that facilitate passive Ca(2+) leak across ER membrane. Mutations in the gene encoding PS1 protein cause neurodegeneration in the brains of patients with familial Alzheimer's disease (FAD). FADPS1 mutations abrogate the function of ER Ca(2+) leak channel activity in human neuroblastoma SK-N-SH cells in vitro (Das et al., J Neurochem 122(3):487-500, 2012) and in mouse embryonic fibroblasts. Consequently, genetic deletion or mutations of the PS1 gene cause calcium (Ca(2+)) signaling abnormalities leading to neurodegeneration in FAD patients. By analogy with other known ion channels it has been proposed that the functional PS1 channels in ER may be multimers of several PS1 subunits. To test this hypothesis, we conjugated the human PS1 protein with an NH2-terminal YFP-tag and a COOH-terminal CFP-tag. As expected YFP-PS1, and PS1-CFP were found to be expressed on the plasma membranes by TIRF microscopy, and both these fusion proteins increased ER Ca(2+) leak channel activity similar to PS1 (WT) in SK-N-SH cells, as determined by functional calcium imaging. PS1-CFP was either expressed alone or together with YFP-PS1 into SK-N-SH cell line and the interaction between YFP-PS1 and PS1-CFP was determined by Förster resonance energy transfer analysis. Our results suggest interaction between YFP-PS1 and PS1-CFP confirming the presence of a dimeric or multimeric form of PS1 in SK-N-SH cells. Lateral diffusion of PS1-CFP and YFP-PS1 in the plasma membrane of SK-N-SH cells was measured in the absence or in the presence of glycerol by fluorescence correlation spectroscopy to show that both COOH-terminal and NH2-terminal of human PS1 are located on the cytoplasmic side of the plasma membrane. Therefore, we conclude that both COOH-terminal and NH2-terminal of human PS1 may also be oriented on the cytosolic side of ER membrane.

PMID: 24839116 [PubMed - indexed for MEDLINE]

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Fri, 07/03/2015 - 3:29am

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

Exp Physiol. 2015 Jul 1;

Authors: Jouett NP, Watenpaugh DE, Dunlap ME, Smith ML

Abstract
We hypothesized that simultaneous stimulation of O2 - and CO2 -sensitive chemoreflexes produces synergistic activation of the sympathetic nervous system, and that this effect would be most apparent at low lung volume (expiratory) phases of respiration. Each subject (n = 11) breathed 16 gas mixtures in random order: a 4 × 4 matrix of normoxic to hypoxic (8, 12, 16, 21% O2 ) combined with normocapnic to hypercapnic gases (0, 2, 4 and 6% CO2 ). Tidal volume, arterial pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were measured continuously before and while breathing each gas mixture for 2 min. Changes in MSNA were determined for each gas mixture. MSNA was subdivided into low and high lung volume and respiratory phases to investigate further modulation by components of normal respiratory phase. Both hypoxia and hypercapnia increased mean MSNA independently. Mean and low lung volume MSNA increased exponentially with increasing levels of combined hypoxia and hypercapnia and resulted in a significant interaction (p<0.01). In contrast, MSNA during the high lung volume phase of respiration never increased significantly (P > 0.4). Similar, but less pronounced effects were found for expiratory and inspiratory phases of respiration. These effects created marked respiratory periodicity in MSNA at higher levels of combined hypoxia and hypercapnia. Finally, the response to hypoxia was not affected by hypocapnia, suggesting that the interaction occurs only during excitatory chemosensitive stimuli. These data indicate that hypoxia and hypercapnia interact to elicit synergistic sympathoexcitation, and that withdrawal of sympathoinhibitory effects of lung inflation exaggerates this chemoreflex interaction. This article is protected by copyright. All rights reserved.

PMID: 26132990 [PubMed - as supplied by publisher]

Vestiges of an Ancient Border in the Contemporary Genetic Diversity of North-Eastern Europe.

Fri, 07/03/2015 - 3:29am

Vestiges of an Ancient Border in the Contemporary Genetic Diversity of North-Eastern Europe.

PLoS One. 2015;10(7):e0130331

Authors: Neuvonen AM, Putkonen M, Översti S, Sundell T, Onkamo P, Sajantila A, Palo JU

Abstract
It has previously been demonstrated that the advance of the Neolithic Revolution from the Near East through Europe was decelerated in the northernmost confines of the continent, possibly as a result of space and resource competition with lingering Mesolithic populations. Finland was among the last domains to adopt a farming lifestyle, and is characterized by substructuring in the form of a distinct genetic border dividing the northeastern and southwestern regions of the country. To explore the origins of this divergence, the geographical patterns of mitochondrial and Y-chromosomal haplogroups of Neolithic and Mesolithic ancestry were assessed in Finnish populations. The distribution of these uniparental markers revealed a northeastern bias for hunter-gatherer haplogroups, while haplogroups associated with the farming lifestyle clustered in the southwest. In addition, a correlation could be observed between more ancient mitochondrial haplogroup age and eastern concentration. These results coupled with prior archeological evidence suggest the genetic northeast/southwest division observed in contemporary Finland represents an ancient vestigial border between Mesolithic and Neolithic populations undetectable in most other regions of Europe.

PMID: 26132657 [PubMed - as supplied by publisher]

Estimating sleep from multisensory armband measurements: validity and reliability in teens.

Fri, 07/03/2015 - 3:29am
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Estimating sleep from multisensory armband measurements: validity and reliability in teens.

J Sleep Res. 2015 Jul 1;

Authors: Roane BM, Van Reen E, Hart CN, Wing R, Carskadon MA

Abstract
Given the recognition that sleep may influence obesity risk, there is increasing interest in measuring sleep parameters within obesity studies. The goal of the current analyses was to determine whether the SenseWear(®) Pro3 Armband (armband), typically used to assess physical activity, is reliable at assessing sleep parameters. The armband was compared with the AMI Motionlogger(®) (actigraph), a validated activity monitor for sleep assessment, and with polysomnography, the gold standard for assessing sleep. Participants were 20 adolescents (mean age = 15.5 years) with a mean body mass index percentile of 63.7. All participants wore the armband and actigraph on their non-dominant arm while in-lab during a nocturnal polysomnographic recording (600 min). Epoch-by-epoch sleep/wake data and concordance of sleep parameters were examined. No significant sleep parameter differences were found between the armband and polysomnography; the actigraph tended to overestimate sleep and underestimate wake compared with polysomnography. Both devices showed high sleep sensitivity, but lower wake detection rates. Bland-Altman plots showed large individual differences in armband sleep parameter concordance rates. The armband did well estimating sleep overall, with group results more similar to polysomnography than the actigraph; however, the armband was less accurate at an individual level than the actigraph.

PMID: 26126746 [PubMed - as supplied by publisher]

Assessment of the role of DNA repair in damaged forensic samples.

Fri, 07/03/2015 - 3:29am
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Assessment of the role of DNA repair in damaged forensic samples.

Int J Legal Med. 2014 Nov;128(6):913-21

Authors: Ambers A, Turnbough M, Benjamin R, King J, Budowle B

Abstract
Previous studies on DNA damage and repair have involved in vitro laboratory procedures that induce a single type of lesion in naked templates. Although repair of singular, sequestered types of DNA damage has shown some success, forensic and ancient specimens likely contain a number of different types of lesions. This study sought to (1) develop protocols to damage DNA in its native state, (2) generate a pool of candidate samples for repair that more likely emulate authentic forensic samples, and (3) assess the ability of the PreCR(TM) Repair Mix to repair the resultant lesions. Complexed, native DNA is more difficult to damage than naked DNA. Modified procedures included the use of higher concentrations and longer exposure times. Three types of samples, those that demonstrated damage based on short tandem repeat (STR) profile signals, were selected for repair experiments: environmentally damaged bloodstains, bleach-damaged whole blood, and human skeletal remains. Results showed trends of improved performance of STR profiling of bleach-damaged DNA. However, the repair assay did not improve DNA profiles from environmentally damaged bloodstains or bone, and in some cases resulted in lower RFU values for STR alleles. The extensive spectrum of DNA damage and myriad combinations of lesions that can be present in forensic samples appears to pose a challenge for the in vitro PreCR(TM) assay. The data suggest that the use of PreCR in casework should be considered with caution due to the assay's varied results.

PMID: 24792635 [PubMed - indexed for MEDLINE]

Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.

Thu, 07/02/2015 - 3:29am
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Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study.

Lancet Oncol. 2015 Apr;16(4):465-74

Authors: Pui CH, Pei D, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, Sandlund JT, Ribeiro RC, Rubnitz JE, Inaba H, Bhojwani D, Gruber TA, Leung WH, Downing JR, Evans WE, Relling MV, Campana D

Abstract
BACKGROUND: The level of minimal residual disease during remission induction is the most important prognostic indicator in patients with acute lymphoblastic leukaemia (ALL). We aimed to establish the clinical significance of minimal residual disease in a prospective trial that used sequential minimal residual disease measurements to guide treatment decisions.
METHODS: Between June 7, 2000, and Oct 24, 2007, 498 assessable patients with newly diagnosed ALL were enrolled in a clinical trial at St Jude Children's Research Hospital. We provisionally classified the risk of relapse as low, standard, or high according to patients' baseline clinical and laboratory features. Final risk assignment to establish treatment intensity was based mainly on minimal residual disease levels measured on days 19 and 46 of remission induction, and on week 7 of maintenance treatment. Additional measurements of minimal residual disease were made on weeks 17, 48, and 120 (end of treatment). The primary aim was to establish the association between event-free survival and patients' minimal residual disease levels during remission induction and sequentially post-remission. This trial was registered at ClinicalTrials.gov, number NCT00137111.
FINDINGS: Irrespective of the provisional risk classification, 10-year event-free survival was significantly worse for patients with 1% or greater minimal residual disease levels on day 19 compared with patients with lower minimal residual disease levels (69·2%, 95% CI 49·6-82·4, n=36 vs 95·5%, 91·7-97·5, n=244; p<0·001 for the provisional low-risk group and 65·1%, 50·7-76·2, n=56 vs 82·9%, 75·6-88·2, n=142; p=0·01 for the provisional standard-risk group). 12 patients with provisional low-risk ALL and 1% or higher minimal residual disease levels on day 19 but negative minimal residual disease (<0·01%) on day 46 were treated for standard-risk ALL and had a 10-year event-free survival of 88·9% (43·3-98·4). For the 280 provisional low-risk patients, a minimal residual disease level of less than 1% on day 19 predicted a better outcome, irrespective of the minimal residual disease level on day 46. Of provisional standard-risk patients with minimal residual disease of less than 1% on day 19, the 15 with persistent minimal residual disease on day 46 seemed to have an inferior 10-year event-free survival compared with the 126 with negative minimal residual disease (72·7%, 42·5-88·8 vs 84·0%, 76·3-89·4; p=0·06) after receiving the same post-remission treatment for standard-risk ALL. Of patients attaining negative minimal residual disease status after remission induction, minimal residual disease re-emerged in four of 382 studied on week 7, one of 448 at week 17, and one of 437 at week 48; all but one of these six patients died despite additional treatment. By contrast, relapse occurred in only two of the 11 patients who had decreasing minimal residual disease levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
INTERPRETATION: Minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual disease-guided treatment. Sequential minimal residual disease monitoring after remission induction is warranted for patients with detectable minimal residual disease.
FUNDING: National Institutes of Health and American Lebanese Syrian Associated Charities.

PMID: 25800893 [PubMed - indexed for MEDLINE]

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