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Flanking Variation Influences Rates of Stutter in Simple Repeats.

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Flanking Variation Influences Rates of Stutter in Simple Repeats.

Genes (Basel). 2017 Nov 17;8(11):

Authors: Woerner AE, King JL, Budowle B

Abstract
It has been posited that the longest uninterrupted stretch (LUS) of tandem repeats, as defined by the number of exactly matching repeating motif units, is a better predictor of rates of stutter than the parental allele length (PAL). While there are cases where this hypothesis is likely correct, such as the 9.3 allele in the TH01 locus, there can be situations where it may not apply as well. For example, the PAL may capture flanking indel variations while remaining insensitive to polymorphisms in the repeat, and these haplotypic changes may impact the stutter rate. To address this, rates of stutter were contrasted against the LUS as well as the PAL on different flanking haplotypic backgrounds. This study shows that rates of stutter can vary substantially depending on the flanking haplotype, and while there are cases where the LUS is a better predictor of stutter than the PAL, examples to the contrary are apparent in commonly assayed forensic markers. Further, flanking variation that is 7 bp from the repeat region can impact rates of stutter. These findings suggest that non-proximal effects, such as DNA secondary structure, may be impacting the rates of stutter in common forensic short tandem repeat markers.

PMID: 29149052 [PubMed]

HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFβ2 in the Trabecular Meshwork.

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HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFβ2 in the Trabecular Meshwork.

Invest Ophthalmol Vis Sci. 2016 Jul 01;57(8):3698-707

Authors: Bermudez JY, Webber HC, Patel GC, Liu X, Cheng YQ, Clark AF, Mao W

Abstract
PURPOSE: Elevated intraocular pressure (IOP) in primary open-angle glaucoma (POAG) results from glaucomatous damage to the trabecular meshwork (TM). The glaucoma-associated factor TGFβ2 is increased in aqueous humor and TM of POAG patients. We hypothesize that histone acetylation has a role in dysregulated TGFβ2 expression.
METHODS: Protein acetylation was compared between nonglaucomatous TM (NTM) and glaucomatous TM (GTM) cells using Western immunoblotting (WB). Nonglaucomatous TM cells were treated with 10 nM thailandepsin-A (TDP-A), a potent histone deacetylase inhibitor for 4 days. Total and nuclear proteins, RNA, and nuclear protein-DNA complexes were harvested for WB, quantitative PCR (qPCR), and chromatin immunoprecipitation (ChIP) assays, respectively. Paired bovine eyes were perfused with TDP-A versus DMSO, or TDP-A versus TDP-A plus the TGFβ pathway inhibitor LY364947 for 5 to 9 days. Intraocular pressure, TM, and perfusate proteins were compared.
RESULTS: We found increased acetylated histone 3 and total protein acetylation in the GTM cells and TDP-A treated NTM cells. Chromatin immunoprecipitation assays showed that TDP-A induced histone hyperacetylation associated with the TGFβ2 promoter. This change of acetylation significantly increased TGFβ2 mRNA and protein expression in NTM cells. In perfusion-cultured bovine eyes, TDP-A increased TGFβ2 in the perfusate as well as elevated IOP. Histologic and immunofluorescent analyses showed increased extracellular matrix and cytoskeletal proteins in the TM of TDP-A treated bovine eyes. Cotreatment with the TGFβ pathway inhibitor LY364947 blocked TDP-A-induced ocular hypertension.
CONCLUSIONS: Our results suggest that histone acetylation has an important role in increased expression of the glaucoma-associated factor TGFβ2. Histone hyperacetylation may be the initiator of glaucomatous damage to the TM.

PMID: 27403998 [PubMed - indexed for MEDLINE]

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.

Recent Research Articles from UNTHSC - Fri, 11/17/2017 - 07:52

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model.

J Neurovirol. 2017 Nov 15;:

Authors: Langford D, Oh Kim B, Zou W, Fan Y, Rahimain P, Liu Y, He JJ

Abstract
HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

PMID: 29143286 [PubMed - as supplied by publisher]

Δ(9)-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats.

Recent Research Articles from UNTHSC - Thu, 11/16/2017 - 07:38
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Δ(9)-Tetrahydrocannabinol-like discriminative stimulus effects of five novel synthetic cannabinoids in rats.

Psychopharmacology (Berl). 2017 Nov 14;:

Authors: Gatch MB, Forster MJ

Abstract
RATIONALE AND OBJECTIVES: Novel synthetic cannabinoid compounds continue to appear in the market advertised as legal alternatives to marijuana and the older synthetic cannabinoid compounds which are now controlled substances. Most of these newer compounds have been found to act at CB1 receptors, so the purpose of this study was to study the abuse liability of these compounds.
METHODS: Five of these compounds (BB-22, FUB-PB-22, 5F-AMB, NM2201, and MAB-CHMINACA) were tested for their ability to produce discriminative stimulus effects similar to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in rats. The ability of the CB1 receptor inverse agonist rimonabant to antagonize the discriminative stimulus effects of the five test compounds was also tested.
RESULTS: All five of the test compounds fully substituted for the discriminative stimulus effects of Δ(9)-THC at some dose, although MAB-CHMINACA produced an inverted U-shaped dose effect. Rimonabant fully antagonized the Δ(9)-THC-like discriminative stimulus effects of BB-22, 5F-AMB, NM2201, and MAB-CHMINACA but only reduced the effects of FUB-PB-22 to 40-50 % of Δ(9)-THC-appropriate responding.
CONCLUSIONS: These findings suggest that all five of the test compounds produced Δ(9)-THC-like effects and will likely have abuse liability similar to that of the controlled cannabinoid compounds.

PMID: 29138877 [PubMed - as supplied by publisher]

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion.

Recent Research Articles from UNTHSC - Mon, 11/13/2017 - 07:36

Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion.

Biochem Biophys Res Commun. 2017 Nov 08;:

Authors: Panchoo M, Lacko A

Abstract
Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.

PMID: 29128352 [PubMed - as supplied by publisher]

Direct PCR amplification of DNA from human bloodstains, saliva, and touch samples collected with microFLOQ(®) swabs.

Recent Research Articles from UNTHSC - Sat, 11/11/2017 - 07:44

Direct PCR amplification of DNA from human bloodstains, saliva, and touch samples collected with microFLOQ(®) swabs.

Forensic Sci Int Genet. 2017 Oct 26;32:80-87

Authors: Ambers A, Wiley R, Novroski N, Budowle B

Abstract
Previous studies have shown that nylon flocked swabs outperform traditional fiber swabs in DNA recovery due to their innovative design and lack of internal absorbent core to entrap cellular materials. The microFLOQ(®) Direct swab, a miniaturized version of the 4N6 FLOQSwab(®), has a small swab head that is treated with a lysing agent which allows for direct amplification and DNA profiling from sample collection to final result in less than two hours. Additionally, the microFLOQ(®) system subsamples only a minute portion of a stain and preserves the vast majority of the sample for subsequent testing or re-analysis, if desired. The efficacy of direct amplification of DNA from dilute bloodstains, saliva stains, and touch samples was evaluated using microFLOQ(®) Direct swabs and the GlobalFiler™ Express system. Comparisons were made to traditional methods to assess the robustness of this alternate workflow. Controlled studies with 1:19 and 1:99 dilutions of bloodstains and saliva stains consistently yielded higher STR peak heights than standard methods with 1ng input DNA from the same samples. Touch samples from common items yielded single source and mixed profiles that were consistent with primary users of the objects. With this novel methodology/workflow, no sample loss occurs and therefore more template DNA is available during amplification. This approach may have important implications for analysis of low quantity and/or degraded samples that plague forensic casework.

PMID: 29126000 [PubMed - as supplied by publisher]

Comparison of faculty assessment and students' self-assessment of performance during clinical case discussions in a pharmacotherapy capstone course.

Recent Research Articles from UNTHSC - Fri, 11/10/2017 - 07:39
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Comparison of faculty assessment and students' self-assessment of performance during clinical case discussions in a pharmacotherapy capstone course.

Med Teach. 2017 Nov 09;:1-6

Authors: Wettergreen SA, Brunner J, Linnebur SA, Borgelt LM, Saseen JJ

Abstract
OBJECTIVES: The primary objective of this study was to compare faculty assessment and third year students' self-assessment of performance in clinical case discussions. The secondary objective was to evaluate if student characteristics influence self-assessments.
METHODS: This retrospective analysis compared faculty and student self-assessment scores for two clinical case discussions using Spearman's correlation and Wilcoxon's signed ranks test. Chi-squared test was used to compare frequency of faculty and student self-assessments indicating the highest possible rating for the pooled score and for each individual component. The pooled score included three individual components: level of engagement, quality of contribution, and professionalism.
RESULTS: Pooled faculty and student self-assessments correlated for both the first (r = 0.41, p < 0.001) and second (r = 0.35; p < 0.001) clinical case discussions. The frequency that faculty and student self-assessment ratings were the highest possible pooled score was similar for both the first (51.3% vs. 44.7%, respectively, p = 0.25) and second (58.6% vs. 47.4%, p = 0.05) clinical case discussions. Student characteristics (age, gender, and grade point average at graduation) did not influence self-assessments.
CONCLUSIONS: Students' self-assessment correlated with faculty assessment of performance during clinical case discussions. Increased use of self-assessments for professional development in pharmacy and other healthcare professional curricula should be considered.

PMID: 29117750 [PubMed - as supplied by publisher]

The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

Recent Research Articles from UNTHSC - Fri, 11/10/2017 - 07:39
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The association between comorbid anxiety disorders and the risk of stroke among patients with diabetes: An 11-year population-based retrospective cohort study.

J Affect Disord. 2016 Sep 15;202:178-86

Authors: Tsai MT, Erickson SR, Cohen LJ, Wu CH

Abstract
BACKGROUND: Diabetes and anxiety disorders are independent risk factors for stroke. However, it remains unclear whether the risk of stroke is higher among diabetic patients with comorbid anxiety than without comorbid anxiety. Therefore, the purpose of this study was to investigate the association between comorbid anxiety and the risk of stroke among patients with diabetes.
METHODS: This is a retrospective cohort study. We used the National Health Insurance Research Database in Taiwan to identify a diabetes cohort with a new diagnosis of an anxiety disorder but without a history of stroke. The enrollment period was 2001-2006 with up to 11 years of follow-up data. Comorbid anxiety was defined by both a clinical diagnosis of the DSM-IV (ICD-9-CM) and prescriptions for anxiolytic medications. Propensity score matching was performed to balance the selected confounders between the anxiety-exposed group and anxiety non-exposed group. Cox-propositional hazard regression models were used to evaluate the association between comorbid anxiety and the risk of stroke.
RESULTS: Among patients with diabetes (N=40,846), an estimated 5.8% (N=2374) of patients had comorbid anxiety disorders. Diabetic patients with comorbid anxiety were significantly associated with a higher risk of stroke compared to patients without comorbid anxiety (hazard ratio: 1.33, 95% confidence interval: 1.02-1.72).
LIMITATIONS: The severity of anxiety or diabetes could not be measured from the claims data. Residual confounding may still exist.
CONCLUSION: A significantly elevated risk of stroke was observed in association with comorbid anxiety among patients with diabetes. Psychiatrists should consider routine screening for anxiety disorders to prevent a stroke event among patients with diabetes.

PMID: 27262640 [PubMed - indexed for MEDLINE]

Capacity of tTreg generation is not impaired in the atrophied thymus.

Recent Research Articles from UNTHSC - Thu, 11/09/2017 - 07:43
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Capacity of tTreg generation is not impaired in the atrophied thymus.

PLoS Biol. 2017 Nov 08;15(11):e2003352

Authors: Oh J, Wang W, Thomas R, Su DM

Abstract
Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.

PMID: 29117183 [PubMed - as supplied by publisher]

Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents.

Recent Research Articles from UNTHSC - Thu, 11/09/2017 - 07:43
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Effect of Cromakalim Prodrug 1 (CKLP1) on Aqueous Humor Dynamics and Feasibility of Combination Therapy With Existing Ocular Hypotensive Agents.

Invest Ophthalmol Vis Sci. 2017 Nov 01;58(13):5731-5742

Authors: Roy Chowdhury U, Rinkoski TA, Bahler CK, Millar JC, Bertrand JA, Holman BH, Sherwood JM, Overby DR, Stoltz KL, Dosa PI, Fautsch MP

Abstract
Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents.
Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment. Human anterior segments with no trabecular meshwork were evaluated for effect on pressure following CKLP1 treatment. CKLP1 alone and in combination with latanoprost, timolol, and Rho kinase inhibitor Y27632 were evaluated for effect on intraocular pressure in C57BL/6 mice and Dutch-belted pigmented rabbits.
Results: CKLP1 lowered episcleral venous pressure (control: 8.9 ± 0.1 mm Hg versus treated: 6.2 ± 0.1 mm Hg, P < 0.0001) but had no detectable effect on outflow facility, aqueous humor flow rate, or uveoscleral outflow. Treatment with CKLP1 in human anterior segments without the trabecular meshwork resulted in a 50% ± 9% decrease in pressure, suggesting an effect on the distal portion of the conventional outflow pathway. CKLP1 worked additively with latanoprost, timolol, and Y27632 to lower IOP, presumably owing to combined effects on different aspects of aqueous humor dynamics.
Conclusions: CKLP1 lowered intraocular pressure by reducing episcleral venous pressure and lowering distal outflow resistance in the conventional outflow pathway. Owing to this unique mechanism of action, CKLP1 works in an additive manner to lower intraocular pressure with latanoprost, timolol, and Rho kinase inhibitor Y27632.

PMID: 29114841 [PubMed - in process]

Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents.

Recent Research Articles from UNTHSC - Wed, 11/08/2017 - 07:41
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Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents.

Curr Eye Res. 2017 Nov 07;:1-12

Authors: Stankowska DL, Mueller BH, Oku H, Ikeda T, Dibas A

Abstract
PURPOSE: The purpose of the current study was to assess the potential involvement of acid-sensing ion channel 1 (ASIC1) in retinal ganglion cell (RGC) death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush (ONC).
RESULTS: ASIC1 protein was significantly increased in optic nerve extracts at day 7 following ONC in rats. Activated calpain-1 increased at 2 and 7 days following ONC as evidenced by increased degradation of α-fodrin, known substrate of calpain. Glial fibrillary acidic protein levels increased significantly at 2 and 7 days post-injury. By contrast, glutamine synthetase increased at 2 days while decreased at 7 days. The inhibition of ASICs with amiloride and psalmotoxin-1 significantly increased RGC survival in rats following ONC (p < 0.05, one-way ANOVA). The mean number of surviving RGCs in rats (n = 6) treated with amiloride (100 µM) following ONC was 1477 ± 98 cells/mm(2) compared with ONC (1126 ± 101 cells/mm(2)), where psalmotoxin-1 (1 μM) treated rats (n = 6) and subjected to ONC had 1441 ± 63 RGCs/mm(2) compared with ONC (1065 ± 76 RGCs/mm(2)). Average number of RGCs in control rats (n = 12) was 2092 ± 46 cells/mm(2). Blocking of ASICs also significantly increased RGC survival from ischemic-like insult from 473 ± 80 to 842 ± 49 RGCs/mm(2) (for psalmotoxin-1) and from 628 ± 53 RGCs/mm(2) to 890 ± 55 RGCs/mm(2) (for amiloride) with p ≤ 0.05, using one-way ANOVA. Acidification (a known activator of ASIC1) increased intracellular Ca(2+) ([Ca(2+)]i) in rat primary RGCs, which was statistically blocked by pretreatment with 100 nM psalmotoxin-1.
CONCLUSIONS: ASIC1 up-regulation-induced influx of extracellular calcium may be responsible for activation of calcium-sensitive calpain-1 in the retina. Calpain-1 induced degradation of α-fodrin and leads to morphological changes and eventually neuronal death. Therefore, blockers of ASIC1 can be used as potential therapeutics in the treatment of optic nerve degeneration.
ABBREVIATIONS: 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF); acid-sensing ion channels (ASICs); analysis of variance (ANOVA); bicinchoninic acid (BCA); brain-derived neurotrophic factor (BDNF); central nervous system (CNS); ciliary neurotrophic factor (CNTF); dimethyl sulfoxide (DMSO); endoplasmic reticulum (ER); ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA); ethylenediaminetetraacetic acid (EDTA); Food and Drug Administration (FDA); glial fibrillary acidic protein (GFAP); glutamine synthetase (GS); intraocular pressure (IOP); kilodalton (kDa); Krebs-Ringer Buffer (KRB); optic nerve crush (ONC); phosphate-buffered saline (PBS); plasma membrane (PM); polymerase chain reaction (PCR); retinal ganglion cell (RGC); RNA Binding Protein With Multiple Splicing (RBPMS); room temperature (RT); standard error of the mean (SEM).

PMID: 29111855 [PubMed - as supplied by publisher]

N-terminal truncations in sex steroid receptors and rapid steroid actions.

Recent Research Articles from UNTHSC - Tue, 11/07/2017 - 07:34
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N-terminal truncations in sex steroid receptors and rapid steroid actions.

Steroids. 2017 Nov 02;:

Authors: Schreihofer DA, Duong P, Cunningham RL

Abstract
Sex steroid receptors act as ligand activated nuclear transcription factors throughout the body, including the brain. However, post-translational modification of these receptors can direct them to extranuclear sites, including the plasma membrane, where they are able to initiate rapid signaling. Because of the conserved domain structure of these receptors, alternative exon splicing can result in proteins with altered nuclear and extranuclear actions. Although much attention has focused on internal and C-terminal splice variants, both estrogen and androgen receptors undergo N-terminal truncations, as well. These truncated proteins not only influence the transcriptional activity of the full-length receptors, but also associate with caveolin and initiate signaling at the plasma membrane. Such actions may have important physiological consequences in neuronal, endothelial, and cancer signaling and cell survival.

PMID: 29104096 [PubMed - as supplied by publisher]

A pilot mobile integrated healthcare program for frequent utilizers of emergency department services.

Recent Research Articles from UNTHSC - Tue, 11/07/2017 - 07:34
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A pilot mobile integrated healthcare program for frequent utilizers of emergency department services.

Am J Emerg Med. 2017 Nov;35(11):1702-1705

Authors: Nejtek VA, Aryal S, Talari D, Wang H, O'Neill L

Abstract
PURPOSE: To examine whether or not a mobile integrated health (MIH) program may improve health-related quality of life while reducing emergency department (ED) transports, ED admissions, and inpatient hospital admissions in frequent utilizers of ED services.
METHODS: A small retrospective evaluation assessing pre- and post-program quality of life, ED transports, ED admissions, and inpatient hospital admissions was conducted in patients who frequently used the ED for non-emergent or emergent/primary care treatable conditions.
RESULTS: Pre- and post-program data available on 64 program completers are reported. Of those with mobility problems (n=42), 38% improved; those with problems performing usual activities (N=45), 58% reported improvement; and of those experiencing moderate to extreme pain or discomfort (N=48), 42% reported no pain or discomfort after program completion. Frequency of ED transports decreased (5.34±6.0 vs. 2.08±3.3; p <0.000), as did ED admissions (9.66±10.2 vs. 3.30±4.6; p<0.000), and inpatient hospital admissions (3.11±5.5 vs. 1.38±2.5; p=0.003).
CONCLUSION: Results suggest that MIH participation is associated with improved quality of life, reduced ED transports, ED admissions, and inpatient hospital admissions. The MIH program may have potential to improve health outcomes in patients who are frequent ED users for non-emergent or emergent/primary care treatable conditions by teaching them how to proactively manage their health and adhere to therapeutic regimens. Programmatic reasons for these improvements may include psychosocial bonding with participants who received in-home care, health coaching, and the MIH team's 24/7 availability that provided immediate healthcare access.

PMID: 28495031 [PubMed - indexed for MEDLINE]

Corticotropin-releasing hormone improves survival in pneumococcal pneumonia by reducing pulmonary inflammation.

Recent Research Articles from UNTHSC - Tue, 11/07/2017 - 07:34
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Corticotropin-releasing hormone improves survival in pneumococcal pneumonia by reducing pulmonary inflammation.

Physiol Rep. 2017 Jan;5(1):

Authors: Burnley B, P Jones H

Abstract
The use of glucocorticoids to reduce inflammatory responses is largely based on the knowledge of the physiological action of the endogenous glucocorticoid, cortisol. Corticotropin-releasing hormone (CRH) is a neuropeptide released from the hypothalamic-pituitary-adrenal axis of the central nervous system. This hormone serves as an important mediator of adaptive physiological responses to stress. In addition to its role in inducing downstream cortisol release that in turn regulates immune suppression, CRH has also been found to mediate inflammatory responses in peripheral tissues. Streptococcus pneumoniae is a microorganism commonly present among the commensal microflora along the upper respiratory tract. Transmission of disease stems from the resident asymptomatic pneumococcus along the nasal passages. Glucocorticoids are central mediators of immune suppression and are the primary adjuvant pharmacological treatment used to reduce inflammatory responses in patients with severe bacterial pneumonia. However, controversy exists in the effectiveness of glucocorticoid treatment in reducing mortality rates during S. pneumoniae infection. In this study, we compared the effect of the currently utilized pharmacologic glucocorticoid dexamethasone with CRH. Our results demonstrated that intranasal administration of CRH increases survival associated with a decrease in inflammatory cellular immune responses compared to dexamethasone independent of neutrophils. Thus, providing evidence of its use in the management of immune and inflammatory responses brought on by severe pneumococcal infection that could reduce mortality risks.

PMID: 28057851 [PubMed - indexed for MEDLINE]

Transcription factor ΔFosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia.

Recent Research Articles from UNTHSC - Sun, 11/05/2017 - 07:33
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Transcription factor ΔFosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia.

Am J Physiol Heart Circ Physiol. 2017 Nov 03;:ajpheart.00268.2017

Authors: Wu Q, Cunningham JT, Mifflin SW

Abstract
ΔFosB is a member of the AP-1 family of transcription factors. ΔFosB has low constitutive expression in the central nervous system and is induced following exposure of rodents to intermittent hypoxia (IH), a model of the arterial hypoxemia that accompanies sleep apnea. We hypothesize ΔFosB in the nucleus of solitary tract (NTS) contributes to increased mean arterial pressure (MAP) during IH. The NTS of 11 male Sprague Dawley rats was injected (3 sites, 100nl per site) with a dominant-negative against ΔFosB (ΔJunD) in an adeno-associated viral vector (AAV)-green fluorescent protein (GFP) reporter. The NTS of 10 rats was injected with AAV-GFP as sham controls. Two weeks after NTS injections rats were exposed to IH for 8h/day, 7 days and MAP recorded using telemetry. In the sham group 7 days IH increased MAP from 99.8 ± 1.1 mmHg to 107.3 ± 0.5 mmHg in the day and from 104.4 ± 1.1 mmHg to 109.8 ± 0.6 in the night. In the group receiving ΔJunD, IH increased MAP during the day from 95.9 ± 1.7 mmHg to 101.3 ± 0.4 mmHg; during the dark MAP increased from 100.9 ± 1.7 mmHg to 102.8 ± 0.5 mmHg (both significantly lower than sham p<0.05). Following injection of the dominant-negative construct in the NTS, IH-induced ΔFosB immunoreactivity was decreased in paraventricular nucleus (p < 0.05), however no change was observed in rostral ventrolateral medulla. These data indicate that ΔFosB within the NTS contributes to the increase in MAP induced by IH exposure.

PMID: 29101166 [PubMed - as supplied by publisher]

Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork.

Recent Research Articles from UNTHSC - Sat, 11/04/2017 - 07:54
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Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork.

Sci Rep. 2017 Nov 02;7(1):14951

Authors: Kasetti RB, Maddineni P, Millar JC, Clark AF, Zode GS

Abstract
Increased synthesis and deposition of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) is associated with TM dysfunction and intraocular pressure (IOP) elevation in glaucoma. However, it is not understood how ECM accumulation leads to TM dysfunction and IOP elevation. Using a mouse model of glucocorticoid (GC)-induced glaucoma, primary human TM cells and human post-mortem TM tissues, we show that increased ECM accumulation leads to endoplasmic reticulum (ER) stress in the TM. The potent GC, dexamethasone (Dex) increased the secretory protein load of ECM proteins in the ER of TM cells, inducing ER stress. Reduction of fibronectin, a major regulator of ECM structure, prevented ER stress in Dex-treated TM cells. Overexpression of fibronectin via treatment with cellular fibronectin also induced chronic ER stress in primary human TM cells. Primary human TM cells grown on ECM derived from Dex-treated TM cells induced ER stress markers. TM cells were more prone to ER stress from ECM accumulation compared to other ocular cell types. Moreover, increased co-localization of ECM proteins with ER stress markers was observed in human post-mortem glaucomatous TM tissues. These data indicate that ER stress is associated with increased ECM accumulation in mouse and human glaucomatous TM tissues.

PMID: 29097767 [PubMed - in process]

Zygomaticomaxillary Morphology and Maxillary Sinus Form and Function: How Spatial Constraints Influence Pneumatization Patterns among Modern Humans.

Recent Research Articles from UNTHSC - Sat, 11/04/2017 - 07:54
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Zygomaticomaxillary Morphology and Maxillary Sinus Form and Function: How Spatial Constraints Influence Pneumatization Patterns among Modern Humans.

Anat Rec (Hoboken). 2017 Jan;300(1):209-225

Authors: Maddux SD, Butaric LN

Abstract
Previous research has suggested that the maxillary sinuses may act as "zones of accommodation" for the nasal region, minimizing the impact of climatic-related changes in nasal cavity breadth on surrounding skeletal structures. However, a recent study among modern human crania has identified that, in addition to nasal cavity breadth, sinus morphology also tracks lateral facial form, especially anterior-posterior positioning of the zygomatics. Here, we expand upon this previous study to further investigate these covariation patterns by employing three samples with distinct combinations of nasal and zygomatic morphologies: Northern Asians (n = 28); sub-Saharan Africans (n = 30); and Europeans (n = 29). For each cranium, 30 landmarks were digitized from CT-rendered models and subsequently assigned to either a midfacial or maxillary sinus "block." Two block partial least squares (2B-PLS) analyses indicate that sinus morphology primarily reflects superior-inferior dimensions of the midface, rather than either nasal cavity breadth or zygomatic position. Specifically, individuals with relatively tall midfacial skeletons exhibit more inferiorly and laterally expanded sinuses compared to those with shorter midfaces. Further, separate across-group and within-group 2B-PLS analyses indicate that regional differences between samples primarily build upon a common pattern of midfacial and sinus covariation already present within each regional group. Allometry, while present, only explains a small portion of the midface-sinus covariation pattern. We conclude that previous findings of larger maxillary sinuses among cold-adapted individuals are not predominantly due to possession of relatively narrow nasal cavities, but to greater maxillary and zygomatic heights. Implications for sinus function and midfacial ontogeny are discussed. Anat Rec, 300:209-225, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 28000407 [PubMed - indexed for MEDLINE]

Optimal Measurement Interval for Emergency Department Crowding Estimation Tools.

Recent Research Articles from UNTHSC - Fri, 11/03/2017 - 07:46
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Optimal Measurement Interval for Emergency Department Crowding Estimation Tools.

Ann Emerg Med. 2017 Nov;70(5):632-639.e4

Authors: Wang H, Ojha RP, Robinson RD, Jackson BE, Shaikh SA, Cowden CD, Shyamanand R, Leuck J, Schrader CD, Zenarosa NR

Abstract
STUDY OBJECTIVE: Emergency department (ED) crowding is a barrier to timely care. Several crowding estimation tools have been developed to facilitate early identification of and intervention for crowding. Nevertheless, the ideal frequency is unclear for measuring ED crowding by using these tools. Short intervals may be resource intensive, whereas long ones may not be suitable for early identification. Therefore, we aim to assess whether outcomes vary by measurement interval for 4 crowding estimation tools.
METHODS: Our eligible population included all patients between July 1, 2015, and June 30, 2016, who were admitted to the JPS Health Network ED, which serves an urban population. We generated 1-, 2-, 3-, and 4-hour ED crowding scores for each patient, using 4 crowding estimation tools (National Emergency Department Overcrowding Scale [NEDOCS], Severely Overcrowded, Overcrowded, and Not Overcrowded Estimation Tool [SONET], Emergency Department Work Index [EDWIN], and ED Occupancy Rate). Our outcomes of interest included ED length of stay (minutes) and left without being seen or eloped within 4 hours. We used accelerated failure time models to estimate interval-specific time ratios and corresponding 95% confidence limits for length of stay, in which the 1-hour interval was the reference. In addition, we used binomial regression with a log link to estimate risk ratios (RRs) and corresponding confidence limit for left without being seen.
RESULTS: Our study population comprised 117,442 patients. The time ratios for length of stay were similar across intervals for each crowding estimation tool (time ratio=1.37 to 1.30 for NEDOCS, 1.44 to 1.37 for SONET, 1.32 to 1.27 for EDWIN, and 1.28 to 1.23 for ED Occupancy Rate). The RRs of left without being seen differences were also similar across intervals for each tool (RR=2.92 to 2.56 for NEDOCS, 3.61 to 3.36 for SONET, 2.65 to 2.40 for EDWIN, and 2.44 to 2.14 for ED Occupancy Rate).
CONCLUSION: Our findings suggest limited variation in length of stay or left without being seen between intervals (1 to 4 hours) regardless of which of the 4 crowding estimation tools were used. Consequently, 4 hours may be a reasonable interval for assessing crowding with these tools, which could substantially reduce the burden on ED personnel by requiring less frequent assessment of crowding.

PMID: 28688771 [PubMed - indexed for MEDLINE]

Chest Pain Risk Scores Can Reduce Emergent Cardiac Imaging Test Needs With Low Major Adverse Cardiac Events Occurrence in an Emergency Department Observation Unit.

Recent Research Articles from UNTHSC - Fri, 11/03/2017 - 07:46
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Chest Pain Risk Scores Can Reduce Emergent Cardiac Imaging Test Needs With Low Major Adverse Cardiac Events Occurrence in an Emergency Department Observation Unit.

Crit Pathw Cardiol. 2016 Dec;15(4):145-151

Authors: Wang H, Watson K, Robinson RD, Domanski KH, Umejiego J, Hamblin L, Overstreet SE, Akin AM, Hoang S, Shrivastav M, Collyer M, Krech RN, Schrader CD, Zenarosa NR

Abstract
OBJECTIVE: To compare and evaluate the performance of the HEART, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) scores to predict major adverse cardiac event (MACE) rates after index placement in an emergency department observation unit (EDOU) and to determine the need for observation unit initiation of emergent cardiac imaging tests, that is, noninvasive cardiac stress tests and invasive coronary angiography.
METHODS: A prospective observational single center study was conducted from January 2014 through June 2015. EDOU chest pain patients were included. HEART, GRACE, and TIMI scores were categorized as low (HEART ≤ 3, GRACE ≤ 108, and TIMI ≤1) versus elevated based on thresholds suggested in prior studies. Patients were followed for 6 months postdischarge. The results of emergent cardiac imaging tests, EDOU length of stay (LOS), and MACE occurrences were compared. Student t test was used to compare groups with continuous data, and χ testing was used for categorical data analysis.
RESULTS: Of 986 patients, emergent cardiac imaging tests were performed on 62%. A majority of patients were scored as low risk by all tools (85% by HEART, 81% by GRACE, and 80% by TIMI, P < 0.05). The low-risk patients had few abnormal cardiac imaging test results as compared with patients scored as intermediate to high risk (1% vs. 11% in HEART, 1% vs. 9% in TIMI, and 2% vs. 4% in GRACE, P < 0.05). The average LOS was 33 hours for patients with emergent cardiac imaging tests performed and 25 hours for patients without (P < 0.05). MACE occurrence rate demonstrated no significant difference regardless of whether tests were performed emergently (0.31% vs. 0.97% in HEART, 0.27% vs. 0.95% in TIMI, and 0% vs. 0.81% in GRACE, P > 0.05).
CONCLUSIONS: Chest pain risk stratification via clinical decision tool scores can minimize the need for emergent cardiac imaging tests with less than 1% MACE occurrence, especially when the HEART score is used.

PMID: 27846006 [PubMed - indexed for MEDLINE]

Solvatochromic dye LDS 798 as microviscosity and pH probe.

Recent Research Articles from UNTHSC - Thu, 11/02/2017 - 07:46
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Solvatochromic dye LDS 798 as microviscosity and pH probe.

Phys Chem Chem Phys. 2017 Nov 01;:

Authors: Doan H, Castillo M, Bejjani M, Nurekeyev Z, Dzyuba SV, Gryczynski I, Gryczynski Z, Raut S

Abstract
Styryl dyes, specifically LDS group dyes, are known solvatochromic and electrochromic probes for monitoring mitochondrial potential in cellular environments. However, the ability of these dyes to respond to fluctuations in viscosity, pH and temperature has not been established. In this study, we demonstrated that LDS 798 (also known as Styryl-11) can sense environmental viscosity (via fluorescence lifetime changes) as well as pH changes (ratiometric intensity change) in the absence of polarity variations. Polarity changes can be probed by spectral changes using LDS 798. Therefore, all properties of the media should be considered, when these types of dyes are used as electrochromic/solvatochromic sensors in cellular environments.

PMID: 29090298 [PubMed - as supplied by publisher]

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