Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
Updated: 1 hour 38 min ago

Application of Nanotechnology in Cancer Diagnosis and Therapy - A Mini-Review.

Thu, 11/12/2020 - 12:49
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Application of Nanotechnology in Cancer Diagnosis and Therapy - A Mini-Review.

Int J Med Sci. 2020;17(18):2964-2973

Authors: Jin C, Wang K, Oppong-Gyebi A, Hu J

Abstract
Cancer is a leading cause of death and poor quality of life globally. Even though several strategies are devised to reduce deaths, reduce chronic pain and improve the quality of life, there remains a shortfall in the adequacies of these cancer therapies. Among the cardinal steps towards ensuring optimal cancer treatment are early detection of cancer cells and drug application with high specificity to reduce toxicities. Due to increased systemic toxicities and refractoriness with conventional cancer diagnostic and therapeutic tools, other strategies including nanotechnology are being employed to improve diagnosis and mitigate disease severity. Over the years, immunotherapeutic agents based on nanotechnology have been used for several cancer types to reduce the invasiveness of cancerous cells while sparing healthy cells at the target site. Nanomaterials including carbon nanotubes, polymeric micelles and liposomes have been used in cancer drug design where they have shown considerable pharmacokinetic and pharmacodynamic benefits in cancer diagnosis and treatment. In this review, we outline the commonly used nanomaterials which are employed in cancer diagnosis and therapy. We have highlighted the suitability of these nanomaterials for cancer management based on their physicochemical and biological properties. We further reviewed the challenges that are associated with the various nanomaterials which limit their uses and hamper their translatability into the clinical setting in certain cancer types.

PMID: 33173417 [PubMed - in process]

β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes.

Thu, 11/12/2020 - 12:49
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β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes.

Biomedicines. 2020 Nov 06;8(11):

Authors: Edara VV, Nooka S, Proulx J, Stacy S, Ghorpade A, Borgmann K

Abstract
Reactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/β-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced mediators of the Wnt/β-catenin pathway including β-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of β-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of β-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1β alone and in combination with TNF-α, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by β-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by β-catenin. To better understand this relationship, we examined the crossroads between β-catenin and nuclear factor (NF)-κB pathways. While NF-κB expression was significantly increased by IL-1β and TNF-α, NF-κB levels were not affected by β-catenin knockdown. IL-1β treatment significantly increased glycogen synthase kinase (GSK)-3β phosphorylation, which inhibits β-catenin degradation. Further, pharmacological inhibition of GSK-3β increased nuclear translocation of both β-catenin and NF-κB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, β-catenin and NF-κB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases β-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that β-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.

PMID: 33171974 [PubMed]

3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro.

Thu, 11/12/2020 - 12:49
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3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro.

Int J Mol Sci. 2020 Nov 07;21(21):

Authors: Al-Ghadban S, Pursell IA, Diaz ZT, Herbst KL, Bunnell BA

Abstract
The growth and differentiation of adipose tissue-derived stem cells (ASCs) is stimulated and regulated by the adipose tissue (AT) microenvironment. In lipedema, both inflammation and hypoxia influence the expansion and differentiation of ASCs, resulting in hypertrophic adipocytes and deposition of collagen, a primary component of the extracellular matrix (ECM). The goal of this study was to characterize the adipogenic differentiation potential and assess the levels of expression of ECM-remodeling markers in 3D spheroids derived from ASCs isolated from both lipedema and healthy individuals. The data showed an increase in the expression of the adipogenic genes (ADIPOQ, LPL, PPAR-γ and Glut4), a decrease in matrix metalloproteinases (MMP2, 9 and 11), with no significant changes in the expression of ECM markers (collagen and fibronectin), or integrin A5 in 3D differentiated lipedema spheroids as compared to healthy spheroids. In addition, no statistically significant changes in the levels of expression of inflammatory genes were detected in any of the samples. However, immunofluorescence staining showed a decrease in fibronectin and increase in laminin and Collagen VI expression in the 3D differentiated spheroids in both groups. The use of 3D ASC spheroids provide a functional model to study the cellular and molecular characteristics of lipedema AT.

PMID: 33171717 [PubMed - in process]

Elevated blood urea nitrogen is associated with recurrence of post-operative chronic subdural hematoma.

Wed, 11/11/2020 - 05:27
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Elevated blood urea nitrogen is associated with recurrence of post-operative chronic subdural hematoma.

BMC Neurol. 2020 Nov 10;20(1):411

Authors: Wang N, Hu J, Oppong-Gyebi A, Zhu X, Li Y, Yang J, Ruan L, Zhuge Q, Ye S

Abstract
BACKGROUND: Chronic subdural hematoma (CSDH) is fundamentally treatable with about a 2-31% recurrence rate. Recently, there has been renewed interest in the association between Blood Urea Nitrogen (BUN) and intracranial lesion. Therefore, this paper attempts to show the relationship between BUN and CSDH recurrence.
METHODS: A total of 653 CSDH cases with Burr-hole Irrigation (BHI) were enrolled from December 2014 to April 2019. The analyzed parameters included age, gender, comorbidities, laboratory investigations, medication use and hematoma location. The cases were divided into recurrence and non-recurrence groups while postoperative BUN concentration was further separated into quartiles (Q1 ≤ 4.0 mmol/L, 4.0 < Q2 ≤ 4.9 mmol/L, 4.9 < Q3 ≤ 6.4 mmol/L, Q4 > 6.4 mmol/L). Restricted cubic spline regressions and logistic regression models were performed to estimate the effect of BUN on CSDH recurrence.
RESULTS: CSDH recurrence was observed in 96 (14.7%) cases. Significant distinctions were found between recurrence and non-recurrence groups in postoperative BUN quartiles of cases (P = 0.003). After adjusting for the potential confounders, the odds ratio of recurrence was 3.069 (95%CI =1.488-6.330, p = 0.002) for the highest quartile of BUN compared with the lowest quartile. In multiple-adjusted spline regression, a high BUN level visually showed a significantly high OR value of recurrence risk.
CONCLUSIONS: Elevated BUN at post-operation is significantly associated with the recurrence of CSDH, and it is indicated that high levels of serum BUN after evacuation may serve as a risk factor for CSDH recurrence.

PMID: 33167883 [PubMed - in process]

At the intersection of precision medicine and population health: an implementation-effectiveness study of family health history based systematic risk assessment in primary care.

Tue, 11/10/2020 - 10:48
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At the intersection of precision medicine and population health: an implementation-effectiveness study of family health history based systematic risk assessment in primary care.

BMC Health Serv Res. 2020 Nov 07;20(1):1015

Authors: Orlando LA, Wu RR, Myers RA, Neuner J, McCarty C, Haller IV, Harry M, Fulda KG, Dimmock D, Rakhra-Burris T, Buchanan A, Ginsburg GS

Abstract
BACKGROUND: Risk assessment is a precision medicine technique that can be used to enhance population health when applied to prevention. Several barriers limit the uptake of risk assessment in health care systems; and little is known about the potential impact that adoption of systematic risk assessment for screening and prevention in the primary care population might have. Here we present results of a first of its kind multi-institutional study of a precision medicine tool for systematic risk assessment.
METHODS: We undertook an implementation-effectiveness trial of systematic risk assessment of primary care patients in 19 primary care clinics at four geographically and culturally diverse healthcare systems. All adult English or Spanish speaking patients were invited to enter personal and family health history data into MeTree, a patient-facing family health history driven risk assessment program, for 27 medical conditions. Risk assessment recommendations followed evidence-based guidelines for identifying and managing those at increased disease risk.
RESULTS: One thousand eight hundred eighty-nine participants completed MeTree, entering information on N = 25,967 individuals. Mean relatives entered = 13.7 (SD 7.9), range 7-74. N = 1443 (76.4%) participants received increased risk recommendations: 597 (31.6%) for monogenic hereditary conditions, 508 (26.9%) for familial-level risk, and 1056 (56.1%) for risk of a common chronic disease. There were 6617 recommendations given across the 1443 participants. In multivariate analysis, only the total number of relatives entered was significantly associated with receiving a recommendation.
CONCLUSIONS: A significant percentage of the general primary care population meet criteria for more intensive risk management. In particular 46% for monogenic hereditary and familial level disease risk. Adopting strategies to facilitate systematic risk assessment in primary care could have a significant impact on populations within the U.S. and even beyond.
TRIAL REGISTRATION: Clinicaltrials.gov number NCT01956773 , registered 10/8/2013.

PMID: 33160339 [PubMed - in process]

Spleen is not required for therapeutic effects of 4OH-GTS-21, a selective α7 nAChR agonist, in the sub-acute phase of ischemic stroke in rats.

Tue, 11/10/2020 - 10:48
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Spleen is not required for therapeutic effects of 4OH-GTS-21, a selective α7 nAChR agonist, in the sub-acute phase of ischemic stroke in rats.

Brain Res. 2020 Nov 04;:147196

Authors: Gaidhani N, Kem WR, Uteshev VV

Abstract
Acute ischemic stroke (AIS) causes both central and peripheral inflammation, while activation of α7 nicotinic acetylcholine receptors (nAChRs) provides both central and peripheral anti-inflammatory and anti-apoptotic effects. Here, we provide evidence that 4OH-GTS-21, a selective α7 agonist, produces its therapeutic effects via primarily central sites of action because 4OH-GTS-21 was found equally effective in splenectomized and non-spenectomized rats in the sub-acute phase of ischemic stroke (≤1 week). However, the spleen may boost the therapeutic efficacy of 4OH-GTS-21 in certain behavioral tasks as our data also indicated. In our tests, AIS was modeled by transient middle cerebral artery occlusion (tMCAO). Splenectomy was done 2 weeks before tMCAO. We determined that: 1) Daily 4OH-GTS-21 treatments for 7 days after tMCAO significantly reduced neurological deficits and brain injury in both splenectomized and non-spelenectomized rats demonstrating that the spleen is not required for therapeutic benefits of 4OH-GTS-21; 2) The effects of 4OH-GTS-21 in the adhesive sticker removal test were significantly weaker in splenectomized animals suggesting that the spleen boosts the efficacy of 4OH-GTS-21 in the first week after tMCAO; and 3) Ischemic brain injury was not significantly affected by splenectomy in both vehicle-treated and 4OH-GTS-21-treated animals. These data support the hypothesis that the therapeutic efficacy of sub-chronic (≤1 week) 4OH-GTS-21 primarily originates from central sites of action. These results validate brain availability as a critical factor for developing novel α7 ligands for AIS.

PMID: 33159972 [PubMed - as supplied by publisher]

COVID-19 and TB control in immigrant communities.

Tue, 11/10/2020 - 10:48
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COVID-19 and TB control in immigrant communities.

Int J Tuberc Lung Dis. 2020 Sep 01;24(9):975-977

Authors: Wilson FA, Miller TL, Stimpson JP

PMID: 33156769 [PubMed - in process]

Behavioral effects of four novel synthetic cathinone analogs in rodents.

Tue, 11/10/2020 - 10:48
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Behavioral effects of four novel synthetic cathinone analogs in rodents.

Addict Biol. 2020 Nov 05;:e12987

Authors: Gatch MB, Shetty RA, Sumien N, Forster MJ

Abstract
A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N-ethylhexedrone, 4-chloroethcathinone (4-CEC), and 4'-methyl-α-pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant-like effects to assess their abuse liability. Locomotor activity was assessed in an open-field assay using Swiss-Webster mice to screen for locomotor stimulant effects and to identify behaviorally-active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague-Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N-ethylhexedrone, 4-CEC, and MPHP dose-dependently increased locomotor activity. Dipentylone, N-ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4-CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4-CEC that produced peak effects lasted 2 to 3 h, the peak dose of N-ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4-CEC occurred at doses that substantially decreased response rate. Only 4-CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N-ethylhexedrone, 4-CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

PMID: 33155384 [PubMed - as supplied by publisher]

ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load.

Tue, 11/10/2020 - 10:48
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ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load.

Nat Commun. 2020 11 05;11(1):5594

Authors: Kasetti RB, Patel PD, Maddineni P, Patil S, Kiehlbauch C, Millar JC, Searby CC, Raghunathan V, Sheffield VC, Zode GS

Abstract
The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.

PMID: 33154371 [PubMed - in process]

Fractionation of DNA and protein from individual latent fingerprints for forensic analysis.

Fri, 11/06/2020 - 05:57
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Fractionation of DNA and protein from individual latent fingerprints for forensic analysis.

Forensic Sci Int Genet. 2020 Oct 21;50:102405

Authors: Schulte KQ, Hewitt FC, Manley TE, Reed AJ, Baniasad M, Albright NC, Powals ME, LeSassier DS, Smith AR, Zhang L, Allen LW, Ludolph BC, Weber KL, Woerner AE, Freitas MA, Gardner MW

Abstract
Human touch samples represent a significant portion of forensic DNA casework. Yet, the generally low abundance of genetic material combined with the predominantly extracellular nature of DNA in these samples makes DNA-based forensic analysis exceptionally challenging. Human proteins present in these same touch samples offer an abundant and environmentally-robust alternative. Proteogenomic methods, using protein sequence variants arising from nonsynonymous DNA mutations, have recently been applied to forensic analysis and may represent a viable option looking forward. However, DNA analysis remains the gold standard and any proteomics-based methods would need to consider how DNA could be co-extracted from samples without significant loss. Herein, we describe a simple workflow for the collection, enrichment and fractionation of DNA and protein in latent fingerprint samples. This approach ensures that DNA collected from a latent fingerprint can be analyzed by traditional DNA casework methods, while protein can be proteolytically digested and analyzed via standard liquid chromatography-tandem mass spectrometry-based proteomics methods from the same touch sample. Sample collection from non-porous surfaces (i.e., glass) is performed through the application of an anionic surfactant over the fingermark. The sample is then split into separate DNA and protein fractions following centrifugation to enrich the protein fraction by pelleting skin cells. The results indicate that this workflow permits analysis of DNA within the sample, yet highlights the challenge posed by the trace nature of DNA in touch samples and the potential for DNA to degrade over time. Protein deposited in touch samples does not appear to share this limitation, with robust protein quantities collected across multiple human donors. The quantity and quality of protein remains robust regardless of fingerprint age. The proteomic content of these samples is consistent across individual donors and fingerprint age, supporting the future application of genetically variable peptide (GVP) analysis of touch samples for forensic identification.

PMID: 33152624 [PubMed - as supplied by publisher]

A Review of Development Initiatives for Pharmacy Student and Resident Preceptors.

Fri, 11/06/2020 - 05:57
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A Review of Development Initiatives for Pharmacy Student and Resident Preceptors.

Am J Pharm Educ. 2020 Oct;84(10):ajpe7991

Authors: Howard ML, Yuet WC, Isaacs AN

Abstract
Objective. To review the published literature describing and evaluating pharmacy student and resident preceptor development. Findings. Database searches yielded 32 published articles on pharmacy preceptor development: 22 for experiential preceptors, eight for resident preceptors, and two encompassing both experiential and resident preceptors. The identified articles covered a variety of preceptor development strategies, including live, web-based, and multifaceted approaches, which were disseminated via analytical studies, needs assessment surveys, and descriptive reports. In analytical studies, the evaluation methods most commonly used were preceptor pre- and post-perception surveys. Summary. Preceptor development strategies vary among pharmacy schools and residency programs. The evaluation methods used also varied, and there is a lack of evidence-based practices related to preceptor development. Preceptor development should be tailored based on preceptor type and program needs. An opportunity exists to further evaluate which strategies are most effective for improving precepting techniques, with an ultimate goal of delineating best practices for pharmacy preceptor development.

PMID: 33149330 [PubMed - in process]

Secreted protein acidic and rich in cysteine (SPARC) knockout mice have greater outflow facility.

Thu, 11/05/2020 - 05:16
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Secreted protein acidic and rich in cysteine (SPARC) knockout mice have greater outflow facility.

PLoS One. 2020;15(11):e0241294

Authors: Yu L, Zheng Y, Liu BJ, Kang MH, Millar JC, Rhee DJ

Abstract
PURPOSE: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates intraocular pressure (IOP) by altering extracellular matrix (ECM) homeostasis within the trabecular meshwork (TM). We hypothesized that the lower IOP previously observed in SPARC -/- mice is due to a greater outflow facility.
METHODS: Mouse outflow facility (Clive) was determined by multiple flow rate infusion, and episcleral venous pressure (Pe) was estimated by manometry. The animals were then euthanized, eliminating aqueous formation rate (Fin) and Pe. The C value was determined again (Cdead) while Fin was reduced to zero. Additional mice were euthanized for immunohistochemistry to analyze ECM components of the TM.
RESULTS: The Clive and Cdead of SPARC -/- mice were 0.014 ± 0.002 μL/min/mmHg and 0.015 ± 0.002 μL/min/mmHg, respectively (p = 0.376, N/S). Compared to the Clive = 0.010 ± 0.002 μL/min/mmHg and Cdead = 0.011 ± 0.002 μL/min/mmHg in the WT mice (p = 0.548, N/S), the Clive and Cdead values for the SPARC -/- mice were higher. Pe values were estimated to be 8.0 ± 0.2 mmHg and 8.3 ± 0.7 mmHg in SPARC -/- and WT mice, respectively (p = 0.304, N/S). Uveoscleral outflow (Fu) was 0.019 ± 0.007 μL/min and 0.022 ± 0.006 μL/min for SPARC -/- and WT mice, respectively (p = 0.561, N/S). Fin was 0.114 ± 0.002 μL/min and 0.120 ± 0.016 μL/min for SPARC -/- and WT mice (p = 0.591, N/S). Immunohistochemistry demonstrated decreases of collagen types IV and VI, fibronectin, laminin, PAI-1, and tenascin-C within the TM of SPARC -/- mice (p < 0.05).
CONCLUSIONS: The lower IOP of SPARC -/- mice is due to greater aqueous humor outflow facility through the conventional pathway. Corresponding changes in several matricellular proteins and ECM structural components were noted in the TM of SPARC -/- mice.

PMID: 33147244 [PubMed - as supplied by publisher]

A Computational Modeling Study of COVID-19 in Bangladesh.

Thu, 11/05/2020 - 05:16
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A Computational Modeling Study of COVID-19 in Bangladesh.

Am J Trop Med Hyg. 2020 Nov 02;:

Authors: Khan IM, Haque U, Kaisar S, Rahman MS

Abstract
The COVID-19 pandemic has spread globally. Only three cases in Bangladesh were reported on March 8, 2020. Here, we aim to predict the epidemic progression for 1 year under different scenarios in Bangladesh. We extracted the number of daily confirmed cases from March 8 to July 20, 2020. We considered the suspected-infected-removed (SIR) model and performed a maximum likelihood-based grid search to determine the removal rate (ɣ). The transmission was modeled as a stochastic random walk process, and sequential Monte Carlo simulation was run 100 times with bootstrap fits to infer the transmission rate (β) and R t. According to the simulation, the (real) peak daily incidence of 3,600 would be followed by a steady decline, reaching below 1,000 in late January 2021. Thus, the model predicted that there would still be more than 300 cases/day even after a year. However, with proper interventions, a much steeper decline would be achieved following the peak. If we apply a combined (0.8β, 1.2ɣ) intervention, there would be less than 100 cases by mid-October, only around five odd cases at the beginning of the year 2021, and zero cases in early March 2021. The predicted total number of deaths (in status quo) after 1 year would be 8,533 which would reduce to 3,577 if combined (0.8β, 1.2ɣ) intervention is applied. We have also predicted the ideal number of tests that Bangladesh should perform and based on that redid the whole simulation. The outcome, though worse, would be manageable with interventions according to the simulation.

PMID: 33146109 [PubMed - as supplied by publisher]

Prevalence of Pulmonary Embolism in COVID-19: a Pooled Analysis.

Thu, 11/05/2020 - 05:16
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Prevalence of Pulmonary Embolism in COVID-19: a Pooled Analysis.

SN Compr Clin Med. 2020 Oct 28;:1-4

Authors: Desai R, Gandhi Z, Singh S, Sachdeva S, Manaktala P, Savani S, Desai V, Sachdeva R, Kumar G

Abstract
There remains a high risk of thrombosis in patients affected by the SARS-CoV-2 virus and recent reports have shown pulmonary embolism (PE) as a cause of sudden death in these patients. However, the pooled rate of this deadly and frequently underdiagnosed condition among COVID-19 patients remains largely unknown. Given the frequency with which pulmonary embolism has been reported as a fatal complication of severe coronavirus disease, we sought to ascertain the actual prevalence of this event in COVID-19 patients. Using PubMed/Medline, EMBASE, and SCOPUS, a thorough literature search was performed to identify the studies reporting rate of PE among COVID-19. Random effects models were obtained to perform a meta-analysis, and I 2 statistics were used to measure inter-study heterogeneity. Among 3066 COVID-19 patients included from 9 studies, the pooled prevalence of PE was 15.8% (95% CI (6.0-28.8%), I 2 = 98%). The pooled rate in younger cohort (age < 65 years) showed a higher prevalence of 20.5% (95% CI (17.6-24.8%)) as compared to studies including relatively older cohort (age > 65 years) showing 14.3% (95% CI (2.9-30.1%)) (p < 0.05). Single-center studies showed a prevalence of 12.9% (95% CI 1.0-30.2%), while that of multicenter studies was 19.5% (95% CI 14.9-25.2%) (p < 0.05). Pulmonary embolism is a common complication of severe coronavirus disease and a high degree of clinical suspicion for its diagnosis should be maintained in critically ill patients.

PMID: 33145478 [PubMed - as supplied by publisher]

Transformation of nonencapsulated Streptococcus pneumoniae during systemic infection.

Thu, 11/05/2020 - 05:16
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Transformation of nonencapsulated Streptococcus pneumoniae during systemic infection.

Sci Rep. 2020 Nov 03;10(1):18932

Authors: Bradshaw JL, Rafiqullah IM, Robinson DA, McDaniel LS

Abstract
Streptococcus pneumoniae (pneumococcus) is a principal cause of bacterial middle ear infections, pneumonia, and meningitis. Capsule-targeted pneumococcal vaccines have likely contributed to increased carriage of nonencapsulated S. pneumoniae (NESp). Some NESp lineages are associated with highly efficient DNA uptake and transformation frequencies. However, NESp strains lack capsule that may increase disease severity. We tested the hypothesis that NESp could acquire capsule during systemic infection and transform into more virulent pneumococci. We reveal that NESp strains MNZ67 and MNZ41 are highly transformable and resistant to multiple antibiotics. Natural transformation of NESp when co-administered with heat-killed encapsulated strain WU2 in a murine model of systemic infection resulted in encapsulation of NESp and increased virulence during bacteremia. Functional capsule production increased the pathogenic potential of MNZ67 by significantly decreasing complement deposition on the bacterial surface. However, capsule acquisition did not further decrease complement deposition on the relatively highly pathogenic strain MNZ41. Whole genome sequencing of select transformants demonstrated that recombination of up to 56.7 kbp length occurred at the capsule locus, along with additional recombination occurring at distal sites harboring virulence-associated genes. These findings indicate NESp can compensate for lack of capsule production and rapidly evolve into more virulent strains.

PMID: 33144660 [PubMed - in process]

VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons.

Thu, 11/05/2020 - 05:16
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VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons.

ACS Chem Neurosci. 2020 Nov 04;11(21):3658-3671

Authors: Spitznagel BD, Mishra NM, Qunies AM, Prael FJ, Du Y, Kozek KA, Lazarenko RM, Denton JS, Emmitte KA, Weaver CD

Abstract
Malignant migrating partial seizures of infancy is a rare, devastating form of epilepsy most commonly associated with gain-of-function mutations in the potassium channel, Slack. Not only is this condition almost completely pharmacoresistant, there are not even selective drug-like tools available to evaluate whether inhibition of these overactivated, mutant Slack channels may represent a viable path forward toward new antiepileptic therapies. Therefore, we used a high-throughput thallium flux assay to screen a drug-like, 100 000-compound library in search of inhibitors of both wild-type and a disease-associated mutant Slack channel. Using this approach, we discovered VU0606170, a selective Slack channel inhibitor with low micromolar potency. Critically, VU0606170 also proved effective at significantly decreasing the firing rate in overexcited, spontaneously firing cortical neuron cultures. Taken together, our data provide compelling evidence that selective inhibition of Slack channel activity can be achieved with small molecules and that inhibition of Slack channel activity in neurons produces efficacy consistent with an antiepileptic effect. Thus, the identification of VU0606170 provides a much-needed tool for advancing our understanding of the role of the Slack channel in normal physiology and disease as well as its potential as a target for therapeutic intervention.

PMID: 33143429 [PubMed - in process]

Phylogeography of montane dragons could shed light on the history of forests and diversification processes on Sumatra.

Thu, 11/05/2020 - 05:16
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Phylogeography of montane dragons could shed light on the history of forests and diversification processes on Sumatra.

Mol Phylogenet Evol. 2020 08;149:106840

Authors: Shaney KJ, Maldonado J, Smart U, Thammachoti P, Fujita M, Hamidy A, Kurniawan N, Harvey MB, Smith EN

Abstract
Biogeographical evidence, both, for and against the "regional endemism paradigm" hypothesis has been uncovered across the Greater Sunda Region (Sundaland) of Southeast Asia. Additionally, there are competing hypotheses regarding how Pleistocene forests may have impacted biological patterns and processes in Sumatra. Using montane agamid lizards from Sumatra, we derived and analyzed a phylogenetic dataset, genetic divergence estimates, and contemporary distributional patterns among species. We tested whether (1) Sumatra's highland Draconinae diversification fits the regional endemism paradigm hypothesis and (2) Draconinae phylogeography provides biological evidence for Pleistocene forest extent at various points in history. Our results suggest in situ diversification was the main driver behind montane Draconinae lizard diversification in Sumatra, rejecting the "regional endemism paradigm". Contemporary distribution of endemic species and their genetic relationships may potentially provide biologicalevidence for determining more precise elevational lower limits of montane forests during the Pleistocene epoch. Our data suggests montane forests did not retreat more than 700-750 m during glacial maxima because lower retreating forests would have become interconnected, allowing for widespread dispersal, exchange of gene flow and sympatric distributions contemporarily. To the contrary, our divergence estimates show that cloud forest dragons have been isolated for millions of years, suggesting there may have been a continuous disconnect between some areas, predating the Pleistocene. There may also be other ecological and evolutionary factors that impacted Draconinae distributions, such as competition, making this an excellent system for testing questions regarding montane biogeography. Additionally, we provide the first phylogeny for a wide range of Sundaland agamid species and identify some biogeographic pressures that may have triggered montane Draconinae diversification in Sumatra.

PMID: 32305510 [PubMed - indexed for MEDLINE]

Muscular architecture of the popliteus muscle and the basic science implications.

Wed, 11/04/2020 - 06:54
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Muscular architecture of the popliteus muscle and the basic science implications.

Knee. 2020 Mar;27(2):308-314

Authors: Wood A, Boren M, Dodgen T, Wagner R, Patterson RM

Abstract
BACKGROUND: The function of the popliteus muscle is largely treated as a static stabilizer and has a lack of basic muscular architectural data to enable study of its dynamic function. A large volume of literature supports its static function and the essential need for reconstruction in the posterolateral knee when injured to restore knee stability.
HYPOTHESIS/PURPOSE: We hypothesize that the popliteus muscle is more significant as a dynamic presence in the knee.
METHODS: A collection of popliteus architectural data was collected from 28 cadaver specimens (mean (SD) 76 years (11)). Physiological cross-sectional area of the popliteus and semimembranosus muscles were calculated from muscle volume and fiber length to power future muscle force prediction models. Posterior knee muscle trajectories were measured with respect to the longitudinal axis of the tibia. A 2-tailed T test was performed.
RESULTS: Significant differences between males and females were found for both the popliteus (p = 1.1E-05) and semimembranosus (p = 2.0E-05) muscle volumes. Significant differences between males and females were also found in PCSA for the popliteus (p = 0.005) and semimembranosus (p = 4.1E-05) muscles. There were no significant differences in fiber length, overall muscle length (with tendon removed), age, and orientation.
CONCLUSION: Further consideration should be given to include the popliteus muscle as a dynamic entity in the knee given its mechanical properties, trajectory, and prior biomechanical evidence showing when and how it is activated. The present study provides data that may shape future directions of research and treatment with regard to posterolateral corner injuries and ligamentous balancing of the knee.

PMID: 31954610 [PubMed - indexed for MEDLINE]

Response to Pazopanib in Patients With Relapsed Osteosarcoma.

Wed, 11/04/2020 - 06:54
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Response to Pazopanib in Patients With Relapsed Osteosarcoma.

J Pediatr Hematol Oncol. 2020 05;42(4):e254-e257

Authors: Elete KR, Albritton KH, Akers LJ, Basha R, Ray A

Abstract
Axial skeleton primary tumor, metastatic disease at presentation, incomplete surgical resection, and <90% tumor necrosis have all been known to influence prognosis adversely in osteosarcoma. Relapse of osteosarcoma, typically occurring within the first 18 months of therapy, with an incidence rate of 50% is treated with surgery, chemotherapy, and targeted therapy. Here, we discuss 2 patients treated with pazopanib, a multi-tyrosine kinase inhibitor presently approved to treat renal cell carcinoma and soft tissue sarcomas. Case 1 achieved positive response and remains on pazopanib. Case 2 sustained gastrointestinal toxicity requiring suspension of drug, despite achieving stable disease.

PMID: 30531600 [PubMed - indexed for MEDLINE]

Forensic investigation approaches of searching relatives in DNA databases.

Tue, 11/03/2020 - 05:27
Related Articles

Forensic investigation approaches of searching relatives in DNA databases.

J Forensic Sci. 2020 Nov 02;:

Authors: Ge J, Budowle B

Abstract
There are several indirect database searching approaches to identify the potential source of a forensic biological sample. These DNA-based approaches are familial searching, Y-STR database searching, and investigative genetic genealogy (IGG). The first two strategies use forensic DNA databases managed by the government, and the latter uses databases managed by private citizens or companies. Each of these search strategies relies on DNA testing to identify relatives of the donor of the crime scene sample, provided such profiles reside in the DNA database(s). All three approaches have been successfully used to identify the donor of biological evidence, which assisted in solving criminal cases or identifying unknown human remains. This paper describes and compares these approaches in terms of genotyping technologies, searching methods, database structures, searching efficiency, data quality, data security, and costs, and raises some potential privacy and legal considerations for further discussion by stakeholders and scientists. Y-STR database searching and IGG are advantageous since they are able to assist in more cases than familial searching readily identifying distant relatives. In contrast, familial searching can be performed more readily with existing laboratory systems. Every country or state may have its own unique economic, technical, cultural, and legal considerations and should decide the best approach(es) to fit those circumstances. Regardless of the approach, the ultimate goal should be the same: generate investigative leads and solve active and cold criminal cases to public safety, under stringent policies and security practices designed to protect the privacy of its citizenry.

PMID: 33136341 [PubMed - as supplied by publisher]

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