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]
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Nuclear factor-kappa beta signaling is required for transforming growth factor Beta-2 induced ocular hypertension.

Sat, 01/11/2020 - 07:31
Related Articles

Nuclear factor-kappa beta signaling is required for transforming growth factor Beta-2 induced ocular hypertension.

Exp Eye Res. 2020 Jan 07;:107920

Authors: Hernandez H, Roberts AL, McDowell CM

Abstract
A major risk for the development of primary open-angle glaucoma (POAG) is elevated intraocular pressure (IOP). Elevated IOP is caused by increased outflow resistance due in part to excessive extracellular matrix (ECM) deposition in the trabecular meshwork (TM). The role of transforming growth factor beta 2 (TGFβ2) in inducing ECM production is well understood. Recent studies suggest that toll-like receptor 4 (TLR4) plays an important role in fibrogenesis. We have previously described a crosstalk between TGFβ2 and TLR4 in the development of ocular hypertension and glaucomatous TM damage. Nuclear factor-kappa beta (NF-κB) is critical for TLR4 signaling. To determine the transactivation of NF-κB, TM cells were stimulated with cellular fibronectin containing the EDA isoform (cFN-EDA), TGFβ2, or lipopolysaccharide (LPS) in combination with a selective TLR4 inhibitor. cFN-EDA, TGFβ2, and LPS all induced transactivation of NF-κB and inhibition of TLR4 blocked the effect of each treatment paradigm. To evaluate the role of NF-κB in IOP regulation, we utilized our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2 in mice harboring a mutation in NF-κB and wild-type controls. IOP was measured over time and eyes accessed by immunohistochemistry for the ECM protein FN and the specific FN-EDA isoform. Ad5.TGFβ2 induced ocular hypertension and expression of FN and FN-EDA in wild-type mice, but mutation in NF-κB blocked the effect. These data suggest that NF-κB is necessary for TGFβ2-induced ECM production and ocular hypertension and the transactivation of NF-κB is dependent on both TGFβ2 and TLR4.

PMID: 31923415 [PubMed - as supplied by publisher]

Two-stage Bayesian GWAS of 9576 individuals identifies SNP regions that are targeted by miRNAs inversely expressed in Alzheimer's and cancer.

Thu, 01/09/2020 - 06:56

Two-stage Bayesian GWAS of 9576 individuals identifies SNP regions that are targeted by miRNAs inversely expressed in Alzheimer's and cancer.

Alzheimers Dement. 2020 Jan;16(1):162-177

Authors: Pathak GA, Zhou Z, Silzer TK, Barber RC, Phillips NR, Alzheimer's Disease Neuroimaging Initiative, Breast and Prostate Cancer Cohort Consortium, and Alzheimer's Disease Genetics Consortium

Abstract
INTRODUCTION: We compared genetic variants between Alzheimer's disease (AD) and two age-related cancers-breast and prostate -to identify single-nucleotide polymorphisms (SNPs) that are associated with inverse comorbidity of AD and cancer.
METHODS: Bayesian multinomial regression was used to compare sex-stratified cases (AD and cancer) against controls in a two-stage study. A ±500 KB region around each replicated hit was imputed and analyzed after merging individuals from the two stages. The microRNAs (miRNAs) that target the genes involving these SNPs were analyzed for miRNA family enrichment.
RESULTS: We identified 137 variants with inverse odds ratios for AD and cancer located on chromosomes 19, 4, and 5. The mapped miRNAs within the network were enriched for miR-17 and miR-515 families.
DISCUSSION: The identified SNPs were rs4298154 (intergenic), within TOMM40/APOE/APOC1, MARK4, CLPTM1, and near the VDAC1/FSTL4 locus. The miRNAs identified in our network have been previously reported to have inverse expression in AD and cancer.

PMID: 31914222 [PubMed - in process]

Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study.

Thu, 01/09/2020 - 06:56

Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study.

Am J Physiol Regul Integr Comp Physiol. 2020 Jan 08;:

Authors: Cushen SC, Sprouse ML, Blessing A, Sun J, Jarvis SS, Okada Y, Fu Q, Romero SA, Phillips NR, Goulopoulou S

Abstract
Mitochondrial DNA (mtDNA) exposed to the extracellular space due to cell death has immunostimulatory properties. Case-control studies reported a positive association between odds of developing preeclampsia and circulating mtDNA. These findings are based on relative quantification protocols that do not allow determination of absolute concentrations of mtDNA and are highly sensitive to nuclear DNA contamination. Furthermore, circulating mtDNA concentrations in response to normal pregnancy, which is an inflammatory state characterized by continuous placental cell apoptosis, have not been established. The main objective of this study was to determine longitudinal changes in circulating mtDNA from preconception to 1st trimester, 3rd trimester, and postpartum in healthy pregnant women. Absolute real-time PCR quantification of mtDNA and nuclear DNA (nDNA) was performed on whole genomic extracts from serum using TaqMan® probes and chemistry. Serum cell-free mtDNA and nDNA concentrations were greater in late pregnancy as compared to early pregnancy and postpartum. Pregnant women carrying neonates at the upper quartile of birth length distribution had higher concentrations of mtDNA in late pregnancy compared to pregnancies carrying neonates at the lower quartile. The correlation between circulating mtDNA and nDNA concentrations varied by sex (i.e. pregnancies carrying female vs. male fetuses). This study is the first to establish temporal patterns of circulating cell-free mtDNA concentrations in normal human pregnancy using absolute DNA quantification techniques. Concentrations of circulating mtDNA in normal pregnancy may be used as reference values for the development of clinical prognostic or diagnostic tests in pregnant women with, or at risk, of developing gestational complications.

PMID: 31913687 [PubMed - as supplied by publisher]

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Wed, 01/08/2020 - 06:45

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Molecules. 2019 Dec 28;25(1):

Authors: Vanden Eynde JJ, Mangoni AA, Rautio J, Leprince J, Azuma YT, García-Sosa AT, Hulme C, Jampilek J, Karaman R, Li W, Gomes PAC, Hadjipavlou-Litina D, Capasso R, Geronikaki A, Cerchia L, Sabatier JM, Ragno R, Tuccinardi T, Trabocchi A, Winum JY, Luque FJ, Prokai-Tatrai K, Spetea M, Gütschow M, Kosalec I, Guillou C, Vasconcelos MH, Kokotos G, Rastelli G, de Sousa ME, Manera C, Gemma S, Mangani S, Siciliano C, Galdiero S, Liu H, Scott PJH, de Los Ríos C, Agrofoglio LA, Collina S, Guedes RC, Muñoz-Torrero D

Abstract
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].

PMID: 31905602 [PubMed - in process]

Circumferential canal surgery: a brief history.

Tue, 01/07/2020 - 06:35

Circumferential canal surgery: a brief history.

Curr Opin Ophthalmol. 2020 Jan 03;:

Authors: Dickerson JE, Brown RH

Abstract
PURPOSE OF REVIEW: Most microinvasive glaucoma surgery (MIGS) procedures bypass outflow resistance residing proximally in the trabecular meshwork and inner wall of Schlemm's canal. A novel procedure combining trabeculotomy with viscodilation adds to this by also addressing distal resistance of the canal and collector channel ostia. This review examines the development and evidence for both trabeculotomy and canaloplasty separately and the combination in a single procedure.
RECENT FINDINGS: Recent aqueous angiography studies have confirmed the segmental nature of outflow through Schlemm's canal highlighting the need to address distal outflow pathway resistance. Combined trabeculotomy and viscodilation ab interno is a novel approach with a new purpose-designed device (OMNI Surgical System) becoming available to surgeons in early 2018. Recent results as both a standalone and combined with cataract procedure demonstrate significant intraocular pressure reductions with an average 41% reduction from baseline in the pseudophakic group.
SUMMARY: Targeting both distal as well as proximal points of outflow resistance in the conventional pathway may prove to be a highly efficacious MIGS modality. Additional large prospective studies are currently ongoing to confirm these preliminary results.

PMID: 31904595 [PubMed - as supplied by publisher]

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Tue, 01/07/2020 - 06:35

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Theranostics. 2020;10(1):74-90

Authors: Zhang LY, Pan J, Mamtilahun M, Zhu Y, Wang L, Venkatesh A, Shi R, Tu X, Jin K, Wang Y, Zhang Z, Yang GY

Abstract
Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.

PMID: 31903107 [PubMed - in process]

Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Tue, 01/07/2020 - 06:35

Intermittent Hypoxia Training for Treating Mild Cognitive Impairment: A Pilot Study.

Am J Alzheimers Dis Other Demen. 2020 Jan-Dec;35:1533317519896725

Authors: Wang H, Shi X, Schenck H, Hall JR, Ross SE, Kline GP, Chen S, Mallet RT, Chen P

Abstract
Although intermittent hypoxia training (IHT) has proven effective against various clinical disorders, its impact on mild cognitive impairment (MCI) is unknown. This pilot study examined IHT's safety and therapeutic efficacy in elderly patients with amnestic MCI (aMCI). Seven patients with aMCI (age 69 ± 3 years) alternately breathed 10% O2 and room-air, each 5 minutes, for 8 cycles/session, 3 sessions/wk for 8 weeks. The patients' resting arterial pressures fell by 5 to 7 mm Hg (P < .05) and cerebral tissue oxygenation increased (P < .05) following IHT. Intermittent hypoxia training enhanced hypoxemia-induced cerebral vasodilation (P < .05) and improved mini-mental state examination and digit span scores from 25.7 ± 0.4 to 27.7 ± 0.6 (P = .038) and from 24.7 ± 1.2 to 26.1 ± 1.3 (P = .047), respectively. California verbal learning test score tended to increase (P = .102), but trail making test-B and controlled oral word association test scores were unchanged. Adaptation to moderate IHT may enhance cerebral oxygenation and hypoxia-induced cerebrovasodilation while improving short-term memory and attention in elderly patients with aMCI.

PMID: 31902230 [PubMed - in process]

Similar Effects of Acute Resistance Exercise on Carotid Stiffness in Males and Females.

Tue, 01/07/2020 - 06:35

Similar Effects of Acute Resistance Exercise on Carotid Stiffness in Males and Females.

Int J Sports Med. 2020 Jan 05;:

Authors: Grigoriadis G, Rosenberg AJ, Lefferts WK, Wee SO, Schroeder EC, Baynard T

Abstract
Sex differences exist in vascular responses to blood pressure perturbations, such as resistance exercise. Increases in aortic stiffness following acute resistance exercise appear different between sexes, with attenuated increases in females vs. males. Whether sex differences exist in carotid stiffness, following resistance exercise is unknown. This study sought to examine sex differences in carotid stiffness, aortic stiffness, and hemodynamics following acute resistance exercise. Thirty-five participants (18 male) completed 3 sets of 10 repetitions of maximal isokinetic knee extension/flexion. Aortic stiffness and hemodynamics were estimated using an automated oscillometric blood pressure monitor at baseline, 5- and 30-min post-exercise. Carotid stiffness was assessed by β-stiffness index, pressure-strain elastic modulus and arterial compliance using ultrasonography. Resistance exercise increased aortic stiffness, mean and systolic pressure at 5-min (p<0.01), and pressure-strain elastic modulus at 5-min in both sexes (p<0.05). Arterial compliance decreased at 5- and 30-min post exercise in both sexes (p<0.01). No interaction effects were detected in carotid stiffness, aortic stiffness, and hemodynamics, indicating similar vascular responses between sexes. Our findings indicate that the large arteries appear to stiffen similarly following resistance exercise in males and females when presented with similar blood pressure responses.

PMID: 31902128 [PubMed - as supplied by publisher]

Metformin and cognition from the perspectives of sex, age, and disease.

Sat, 01/04/2020 - 05:36
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Metformin and cognition from the perspectives of sex, age, and disease.

Geroscience. 2020 Jan 02;:

Authors: Chaudhari K, Reynolds CD, Yang SH

Abstract
Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.

PMID: 31897861 [PubMed - as supplied by publisher]

Insights into the gene expression profiles of active and restricted R/G-HIV+ human astrocytes: Implications for shock or lock therapies in the brain.

Sat, 01/04/2020 - 05:36
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Insights into the gene expression profiles of active and restricted R/G-HIV+ human astrocytes: Implications for shock or lock therapies in the brain.

J Virol. 2020 Jan 02;:

Authors: Edara VV, Ghorpade A, Borgmann K

Abstract
A significant number of people living with human immunodeficiency virus-1 (HIV-1) suffer from HIV-associated neurocognitive disorders (HAND). Many previous studies investigating HIV in astrocytes as a heterogenous population have established the relevance of astrocytes to HIV-associated neuropathogenesis. However, these studies were unable to differentiate the state of infection, i.e. active or latent, or to evaluate how this affects astrocyte biology. In this study a pseudotyped doubly labelled fluorescent reporter R/G-HIV-1 was used to identify and enrich restricted and active populations of HIV+ astrocytes based on the viral promoter activity. Here we report, the majority of human astrocytes restricted R/G-HIV-1 gene expression early during infection and were resistant to reactivation by vorinostat and interleukin 1β. However, actively infected astrocytes were inducible, leading to increased expression of viral proteins upon reactivation. R/G-HIV-1 infection also significantly decreased cell proliferation and glutamate clearance ability of astrocytes, which may contribute to excitotoxicity. Moreover, transcriptome analyses to compare gene expression patterns of astrocyte harboring active vs restricted LTRs revealed that the gene expression patterns were similar, and that the active population demonstrated more widespread and robust changes. Our data suggest that harboring the HIV genome profoundly alters astrocyte biology and strategies that keep the virus latent (e.g. Block and Lock) or those that reactivate the latent virus (e.g. Shock and Kill) would be detrimental to astrocyte function, and possibly augment their contributions to HAND.Importance: More than 36 million people are living with HIV-1 worldwide, and despite antiretroviral therapy 30-50% of the people living with HIV-1 (PLWH) suffer from mild to moderative neurocognitive disorders. HIV-1 reservoirs in the CNS are challenging to address due to low penetration of antiretroviral drugs, lack of resident T cells, and permanent integration of provirus into neural cells such as microglia and astrocytes. Several studies have shown astrocyte dysfunction during HIV-1 infection. However, little is known about how HIV-1 latency affects their function. The significance of our research is in identifying that the majority of HIV+ astrocytes restrict HIV expression and were resistant to reactivation. Further, simply harboring the HIV genome profoundly altered astrocyte biology, resulting in a proinflammatory phenotype and functional changes. In this context, therapeutic strategies to reactivate or silence astrocyte HIV reservoirs, without excising proviral DNA, will likely lead to detrimental neuropathological outcomes during HIV CNS infection.

PMID: 31896591 [PubMed - as supplied by publisher]

Methylenedioxymethamphetamine-like discriminative stimulus effects of seven cathinones in rats.

Fri, 01/03/2020 - 05:14

Methylenedioxymethamphetamine-like discriminative stimulus effects of seven cathinones in rats.

Behav Pharmacol. 2019 Dec 30;:

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
Synthetic cathinone derivatives are commonly considered quasi-legal alternatives for stimulant drugs, such as cocaine and methamphetamine, but some derivatives are increasingly being detected in club drug formulations of Ecstasy or 'Molly' as substitutes for methylenedioxymethamphetamine (±-MDMA). Although several studies have evaluated the psychostimulant-like effects of synthetic cathinones, few cathinone compounds have been assessed for MDMA-like activity. In order to determine their likelihood of interchangeability with entactogenic club drugs, the discriminative stimulus effects of methcathinone, 4-fluoromethcathinone, 4-methylmethcathinone, 4-methylethcathinone, 3-fluoromethcathinone, pentedrone, and ethylone were assessed in Sprague-Dawley rats trained to discriminate 1.5 mg/kg racemic methylenedioxymethamphetamine (±-MDMA) from vehicle. Methamphetamine and the cathinones 4-fluoromethcathinone, 4-methylmethcathinone, 4-methylethcathinone, 3-fluoromethcathinone, pentedrone, and ethylone fully substituted for the discriminative stimulus effects of ±-MDMA. In contrast, methcathinone produced a maximum of only 43% ±-MDMA-appropriate responding and higher doses suppressed responding. Most, but not all of the cathinone compounds tested have discriminative stimulus effects similar to those of MDMA as well as psychostimulant-like effects; however, the potency of MDMA versus psychostimulant substitution varies substantially among the compounds, suggesting that a subset of synthetic cathinones are more MDMA-like than psychostimulant-like. These findings further highlight the highly-variable pharmacology of this class of compounds and suggest that those cathinones with MDMA-like effects may also have increased use as club drugs.

PMID: 31895060 [PubMed - as supplied by publisher]

Inhibition of miR-497 improves functional outcome after ischemic stroke by enhancing neuronal autophagy in young and aged rats.

Fri, 01/03/2020 - 05:14
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Inhibition of miR-497 improves functional outcome after ischemic stroke by enhancing neuronal autophagy in young and aged rats.

Neurochem Int. 2019 07;127:64-72

Authors: Chen X, Lin S, Gu L, Zhu X, Zhang Y, Zhang H, Shao B, Zhuge Q, Jin K

Abstract
Over the years miR-497 has been found to play a vital role in the pathogenesis of neurological diseases, including ischemic stroke. However, its underlying mechanism remains largely unexplored. Here, we used miR-497 agomir (miR-497 agonist), miR-497 antagomir (miR-497 inhibitor) and 3-MA (autophagy inhibitor) to treat ischemic rats (n = 10-12 per group) induced by permanent distal middle cerebral artery occlusion (dMCAO), followed the functional outcome assessment 24 h after dMCAO. We found that treatment of miR-497 antagomir, but not miR-497 angomir, reduced the infarct volume and improved neurological deficits after ischemic stroke, along with upregulation of the autophagy-related protein LC3 expression (mean ± SEM,p < 0.05). While the ischemic rats treated with 3-MA exhibited inhibition of autophagy, which in turn abolished functional recovery as observed in miR-497 antagomir-treated group (p < 0.05). Interestingly, the role of miR-497 in functional recovery in aged ischemic rats was less effective, compared to young adult ischemic rats (p < 0.05). Our data suggest that inhibition of miR-497 could protect cerebral ischemic injury by enhancing autophagy and also age-dependent.

PMID: 30654114 [PubMed - indexed for MEDLINE]

The effect of age, sex and strains on the performance and outcome in animal models of stroke.

Fri, 01/03/2020 - 05:14
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The effect of age, sex and strains on the performance and outcome in animal models of stroke.

Neurochem Int. 2019 07;127:2-11

Authors: Zhang H, Lin S, Chen X, Gu L, Zhu X, Zhang Y, Reyes K, Wang B, Jin K

Abstract
Stroke is one of the leading causes of death worldwide, and the majority of cerebral stroke is caused by occlusion of cerebral circulation, which eventually leads to brain infarction. Although stroke occurs mainly in the aged population, most animal models for experimental stroke in vivo almost universally rely on young-adult rodents for the evaluation of neuropathological, neurological, or behavioral outcomes after stroke due to their greater availability, lower cost, and fewer health problems. However, it is well established that aged animals differ from young animals in terms of physiology, neurochemistry, and behavior. Stroke-induced changes are more pronounced with advancing age. Therefore, the overlooked role of age in animal models of stroke could have an impact on data quality and hinder the translation of rodent models to humans. In addition to aging, other factors also influence functional performance after ischemic stroke. In this article, we summarize the differences between young and aged animals, the impact of age, sex and animal strains on performance and outcome in animal models of stroke and emphasize age as a key factor in preclinical stroke studies.

PMID: 30291954 [PubMed - indexed for MEDLINE]

Single stage bilateral flexible intramedullary fixation of periprosthetic distal femur fractures.

Tue, 12/31/2019 - 07:39
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Single stage bilateral flexible intramedullary fixation of periprosthetic distal femur fractures.

Arthroplast Today. 2019 Dec;5(4):421-426

Authors: Neal DC, Sambhariya V, Rahman SK, Tran A, Wagner RA

Abstract
We present a patient with bilateral Rorabeck II/Su III periprosthetic distal femur fractures treated successfully with bilateral single stage flexible intramedullary fixation. Flexible intramedullary fixation of Rorabeck II/Su III periprosthetic distal femur fractures provides the benefits of shorter operative time, lower blood loss, and preservation of bone stock compared to plate fixation and distal femur replacement. We suggest that for patients with similar injuries flexible intramedullary fixation can be a viable treatment option.

PMID: 31886383 [PubMed]

Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model.

Tue, 12/31/2019 - 07:39
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Treatment and Prevention of Recurrent Clostridium difficile Infection with Functionalized Bovine Antibody-Enriched Whey in a Hamster Primary Infection Model.

Toxins (Basel). 2019 02 06;11(2):

Authors: Heidebrecht HJ, Weiss WJ, Pulse M, Lange A, Gisch K, Kliem H, Mann S, Pfaffl MW, Kulozik U, von Eichel-Streiber C

Abstract
Toxin-induced Clostridium difficile infection (CDI) is a major disease characterized by severe diarrhea and high morbidity rates. The aim with this study was to develop an alternative drug for the treatment of CDI. Cows were repeatedly immunized to establish specific immunoglobulin G and A titers against toxins A (TcdA) and B (TcdB) and against C. difficile cells in mature milk or colostrum. The effect of three different concentrations of anti-C. difficile whey protein isolates (anti-CD-WPI) and the standard of care antibiotic vancomycin were investigated in an animal model of CD infected hamsters (6 groups, with 10 hamsters each). WPI obtained from the milk of exactly the same cows pre-immunization and a vehicle group served as negative controls. The survival of hamsters receiving anti-CD-WPI was 50, 80 and 100% compared to 10 and 0% for the control groups, respectively. Vancomycin suppressed the growth of C. difficile and thus protected the hamsters at the time of administration, but 90% of these hamsters nevertheless died shortly after discontinuation of treatment. In contrast, the surviving hamsters of the anti-CD-WPI groups survived the entire study period, although they were treated for only 75 h. The specific antibodies not only inactivated the toxins for initial suppression of CDI, but also provoked the inhibition of C. difficile growth after discontinuation, thus preventing recurrence. Oral administration of anti-CD-WPI is a functional therapy of CDI in infected hamsters for both primary treatment and prevention of recurrence. Thus, anti-CD-WPI could address the urgent unmet medical need for treating and preventing recurrent CDI in humans.

PMID: 30736358 [PubMed - indexed for MEDLINE]

Nanopore sequencing: An enrichment-free alternative to mitochondrial DNA sequencing.

Tue, 12/31/2019 - 07:39
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Nanopore sequencing: An enrichment-free alternative to mitochondrial DNA sequencing.

Electrophoresis. 2019 01;40(2):272-280

Authors: Zascavage RR, Thorson K, Planz JV

Abstract
Mitochondrial DNA sequence data are often utilized in disease studies, conservation genetics and forensic identification. The current approaches for sequencing the full mtGenome typically require several rounds of PCR enrichment during Sanger or MPS protocols followed by fairly tedious assembly and analysis. Here we describe an efficient approach to sequencing directly from genomic DNA samples without prior enrichment or extensive library preparation steps. A comparison is made between libraries sequenced directly from native DNA and the same samples sequenced from libraries generated with nine overlapping mtDNA amplicons on the Oxford Nanopore MinION™ device. The native and amplicon library preparation methods and alternative base calling strategies were assessed to establish error rates and identify trends of discordance between the two library preparation approaches. For the complete mtGenome, 16 569 nucleotides, an overall error rate of approximately 1.00% was observed. As expected with mtDNA, the majority of error was detected in homopolymeric regions. The use of a modified basecaller that corrects for ambiguous signal in homopolymeric stretches reduced the error rate for both library preparation methods to approximately 0.30%. Our study indicates that direct mtDNA sequencing from native DNA on the MinION™ device provides comparable results to those obtained from common mtDNA sequencing methods and is a reliable alternative to approaches using PCR-enriched libraries.

PMID: 30511783 [PubMed - indexed for MEDLINE]

Motion Preservation in Hallux Rigidus After Failure of Hydrogel Implantation: Treatment Considerations and a Report of 2 Cases.

Sun, 12/29/2019 - 13:14
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Motion Preservation in Hallux Rigidus After Failure of Hydrogel Implantation: Treatment Considerations and a Report of 2 Cases.

J Foot Ankle Surg. 2020 Jan - Feb;59(1):162-168

Authors: Carpenter B, Klemeyer L

Abstract
Hallux rigidus is a common condition treated daily by surgeons worldwide. During the past decade, the standard treatment algorithm has been questioned by both patients and surgeons seeking alternatives to arthrodesis, which was previously considered the gold standard for advanced disease. Patients are living longer, and many have a more active lifestyle; thus, recreating and improving range of motion and achieving pain relief are increasingly desirable. The treatment spectrum and implant options for motion-preserving techniques in the metatarsophalangeal joint has been widened with the recent US Food and Drug Administration approval of a polyvinyl-alcohol hydrogel implant. In the controlled US Food and Drug Administration trial, the 2-year revision rate was 9.2% and all failures were revised to a first metatarsophalangeal arthrodesis. Outcomes comparison of these revisions to primary fusions showed less predictable pain relief and may warrant alternative treatment considerations, preferably those that allow for continuation of motion preservation. Revision of failed hydrogel implants to arthrodesis can be performed through various first metatarsophalangeal fusion techniques or, as introduced in this review, with a fourth-generation threaded hemiarthroplasty. Excellent 10-year results with primary hemiarthroplasty supported its use as revision procedure in 2 failed polyvinyl-alcohol implantations, preserving arthrodesis for future salvage if necessary. The purpose of this report was to outline a motion-preserving technique after failed hydrogel implants and describe preoperative, intraoperative, and postoperative considerations for optimized outcomes.

PMID: 31882138 [PubMed - in process]

Racial and Ethnic Differences in Response to Anticoagulation: A Review of the Literature.

Fri, 12/27/2019 - 06:36
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Racial and Ethnic Differences in Response to Anticoagulation: A Review of the Literature.

J Pharm Pract. 2019 Dec 26;:897190019894142

Authors: Gibson CM, Yuet WC

Abstract
INTRODUCTION: Anticoagulants are among the most frequently prescribed medications in the United States. Racial and ethnic disparities in incidence and outcomes of thrombotic disorders are well-documented, but differences in response to anticoagulation are incompletely understood.
OBJECTIVE: The objective of this review is to describe the impact of race and ethnicity on surrogate and clinical end points related to anticoagulation and discuss racial or ethnic considerations for prescribing anticoagulants.
METHODS: A PubMed and MEDLINE search of clinical trials published between 1950 and May 2018 was conducted using search terms related to anticoagulation, specific anticoagulant drugs, race, and ethnicity. References of identified studies were also reviewed. English-language human studies on safety or efficacy of anticoagulants reporting data for different races or ethnicities were eligible for inclusion.
RESULTS: Seventeen relevant studies were identified. The majority of major trials reviewed for inclusion either did not include representative populations or did not report on the racial breakdown of participants. Racial differences in pharmacokinetics, dosing requirements, drug response, and/or safety end points were identified for unfractionated heparin, enoxaparin, argatroban, warfarin, rivaroxaban, and edoxaban.
CONCLUSIONS: Race appears to influence drug concentrations, dosing, or safety for some but not all direct oral anticoagulants. This information should be considered when selecting anticoagulant therapy for nonwhite individuals.

PMID: 31875763 [PubMed - as supplied by publisher]

A novel phylogenetic approach for de novo discovery of putative nuclear mitochondrial (pNumt) haplotypes.

Fri, 12/27/2019 - 06:36
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A novel phylogenetic approach for de novo discovery of putative nuclear mitochondrial (pNumt) haplotypes.

Forensic Sci Int Genet. 2019 11;43:102146

Authors: Smart U, Budowle B, Ambers A, Soares Moura-Neto R, Silva R, Woerner AE

Abstract
Current approaches for parsing true variation (i.e. signal) from noise, broadly involve estimating a baseline value of the latter, below which all sequence data are ignored. In an effort to deliver a more objective criterion for setting such thresholds, a novel approach based on phylogenetic principles is presented here., Our method deconstructs a special category of noise from true mitochondrial genome data, namely nuclear insertions of mitochondrial DNA (Numts). This bioinformatic approach leverages the relationship of massively parallel sequence reads and is capable of discovering putative Numts (pNumts) in absence of a reference genome. The new method was tested on a whole mitochondrial genome dataset (n = 41 individuals from an admixed population sample from Rio de Janeiro) and led to the discovery of 451 pNumt variants. Comparison of these pNumts haplotypes against an existing Numt database revealed 147 exact matches to previously discovered Numts, while 122 haplotypes differed only by a single base pair and none matched exclusively to the mitochondrial genome. In general, these sequences were considerably more divergent from the mitochondrial genome than from those of the Numt database, supporting that the novel pNumts were probably hitherto uncatalogued variants. Unlike previous techniques, our method appears to be able to detect both polymorphic and fixed Numt sequences. It was also found that the region containing the D-Loop and associated Promoters (DLP) in the human mitochondrial genome, which harbors markers of forensic genetics importance, is the origin of several Numts. Though currently designed for the mitochondrial genome, our novel approach has the potential to be expanded to other scenarios that might require construing signal from noise, including the deconvolution of mixtures, thus significantly improving how analytical thresholds may be established.

PMID: 31446343 [PubMed - indexed for MEDLINE]

The effects of inpatient music therapy on self-reported symptoms at an academic cancer center: a preliminary report.

Fri, 12/27/2019 - 06:36
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The effects of inpatient music therapy on self-reported symptoms at an academic cancer center: a preliminary report.

Support Care Cancer. 2019 Nov;27(11):4207-4212

Authors: Lopez G, Christie AJ, Powers-James C, Bae MS, Dibaj SS, Gomez T, Williams JL, Bruera E

Abstract
PURPOSE: Music therapy has shown benefits for reducing distress in individuals with cancer. We explore the effects of music therapy on self-reported symptoms of patients receiving inpatient care at a comprehensive cancer center.
METHODS: Music therapy was available as part of an inpatient integrative oncology consultation service; we examined interventions and symptoms for consecutive patients treated by a board-certified music therapist from September 2016 to May 2017. Patients completed the Edmonton Symptom Assessment Scale (ESAS, 10 symptoms, scale 0-10, 10 most severe) before and after the intervention. Data was summarized by descriptive statistics. Changes in ESAS symptom and subscale scores (physical distress (PHS), psychological distress (PSS), and global distress (GDS)) were evaluated by Wilcoxon signed rank test.
RESULTS: Data were evaluable for 96 of 100 consecutive initial, unique patient encounters; 55% were women, average age 50, and majority with hematologic malignancies (47%). Reasons for music therapy referral included anxiety/stress (67%), adjustment disorder/coping (28%), and mood elevation/depression (17%). The highest (worst) symptoms at baseline were sleep disturbance (5.7) and well-being (5.5). We observed statistically and clinically significant improvement (means) for anxiety (- 2.3 ± 1.5), drowsiness (- 2.1 ± 2.2), depression (- 2.1 ± 1.9), nausea (- 2.0 ± 2.4), fatigue (- 1.9 ± 1.5), pain (- 1.8 ± 1.4), shortness of breath (- 1.4 ± 2.2), appetite (- 1.1 ± 1.7), and for all ESAS subscales (all ps < 0.02). The highest clinical response rates were observed for anxiety (92%), depression (91%), and pain (89%).
CONCLUSIONS: A single, in-person, tailored music therapy intervention as part of an integrative oncology inpatient consultation service contributed to the significant improvement in global, physical, and psychosocial distress. A randomized controlled trial is justified.

PMID: 30825024 [PubMed - indexed for MEDLINE]

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