171 results on '"Donovan, J.."'
Search Results
2. Studies in medical education: the role of cognitive and psychological characteristics as career choice correlates.
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Donovan JC, Salzman LF, and Allen PZ
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- Analysis of Variance, Social Values, Aptitude Tests, Education, Medical, Graduate, Educational Measurement, Medicine, Personality Inventory, Specialization
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- 1972
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3. Studies in medical education: career choice consistency of medical students.
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Donovan JC, Salzman LF, and Allen PZ
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- Curriculum, General Surgery, Gynecology, Internal Medicine, Obstetrics, Pediatrics, Psychiatry, Psychological Tests, United States, Education, Medical, Medicine, Specialization, Students, Medical
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- 1972
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4. Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy.
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Alison M Barnard, Rebecca J Willcocks, Erika L Finanger, Michael J Daniels, William T Triplett, William D Rooney, Donovan J Lott, Sean C Forbes, Dah-Jyuu Wang, Claudia R Senesac, Ann T Harrington, Richard S Finkel, Barry S Russman, Barry J Byrne, Gihan I Tennekoon, Glenn A Walter, H Lee Sweeney, and Krista Vandenborne
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Medicine ,Science - Abstract
OBJECTIVE:To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. METHODS:MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. RESULTS:Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|ρ| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|ρ| = 0.63-0.73) and peroneals (|ρ| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. DISCUSSION:Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials.
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- 2018
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5. Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation
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Jin Dai, Sara Borst, Jean Ann Maguire, Pamela S. Becker, Sylvia Chien, Sioban Keel, Deborah L. French, Michelle C Krutein, Michaela R. DelPriore, Marshall S. Horwitz, Donovan J. Anderson, Matthew R. Hart, Jasmin Jeffery, Paul Gadue, Eirini P. Papapetrou, and Andriana G. Kotini
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Blood Platelets ,Myeloid Neoplasia ,Myeloid ,Chemistry ,Platelet disorder ,Myeloid leukemia ,Hematology ,Protein degradation ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,chemistry.chemical_compound ,Blood Coagulation Disorders, Inherited ,medicine.anatomical_structure ,RUNX1 ,hemic and lymphatic diseases ,Core Binding Factor Alpha 2 Subunit ,embryonic structures ,medicine ,Cancer research ,Humans ,Blood Platelet Disorders ,Induced pluripotent stem cell - Abstract
RUNX1 familial platelet disorder (RUNX1-FPD) is an autosomal dominant disorder caused by a monoallelic mutation of RUNX1, initially resulting in approximately half-normal RUNX1 activity. Clinical features include thrombocytopenia, platelet functional defects, and a predisposition to leukemia. RUNX1 is rapidly degraded through the ubiquitin-proteasome pathway. Moreover, it may autoregulate its expression. A predicted kinetic property of autoregulatory circuits is that transient perturbations of steady-state levels result in continued maintenance of expression at adjusted levels, even after inhibitors of degradation or inducers of transcription are withdrawn, suggesting that transient inhibition of RUNX1 degradation may have prolonged effects. We hypothesized that pharmacological inhibition of RUNX1 protein degradation could normalize RUNX1 protein levels, restore the number of platelets and their function, and potentially delay or prevent malignant transformation. In this study, we evaluated cell lines, induced pluripotent stem cells derived from patients with RUNX1-FPD, RUNX1-FPD primary bone marrow cells, and acute myeloid leukemia blood cells from patients with RUNX1 mutations. The results showed that, in some circumstances, transient expression of exogenous RUNX1 or inhibition of steps leading to RUNX1 ubiquitylation and proteasomal degradation restored RUNX1 levels, thereby advancing megakaryocytic differentiation in vitro. Thus, drugs retarding RUNX1 proteolytic degradation may represent a therapeutic avenue for treating bleeding complications and preventing leukemia in RUNX1-FPD.
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- 2021
6. Safety, feasibility, and efficacy of strengthening exercise in <scp>Duchenne</scp> muscular dystrophy
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Barry J. Byrne, Hyunjun Park, Glenn A. Walter, Donovan J. Lott, Tanja Taivassalo, Zahra Moslemi, Krista Vandenborne, Abhinandan Batra, Korey D. Cooke, and Sean C. Forbes
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Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Duchenne muscular dystrophy ,Hamstring Muscles ,Isometric exercise ,030105 genetics & heredity ,Article ,Quadriceps Muscle ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Stairs ,Physiology (medical) ,medicine ,Humans ,Muscle Strength ,Functional ability ,Child ,Muscle, Skeletal ,Creatine Kinase ,Exercise ,biology ,Knee extensors ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,Exercise Therapy ,Intensity (physics) ,Muscular Dystrophy, Duchenne ,Treatment Outcome ,Ambulatory ,biology.protein ,Physical therapy ,Feasibility Studies ,Creatine kinase ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
INTRODUCTION: This two-part study explored the safety, feasibility, and efficacy of a mild-moderate resistance isometric leg exercise program in ambulatory boys with Duchenne Muscular Dystrophy (DMD). METHODS: First, we used a dose escalation paradigm with varying intensity and frequency of leg isometric exercise to determine the dose response and safety in 10 boys. Second, we examined safety and feasibility of a 12-week in-home, remotely-supervised, mild-moderate intensity strengthening program in 8 boys. Safety measures included T(2) MRI, creatine kinase levels, and pain. Peak strength and function (time to ascend/descend 4 stairs) were also measured. RESULTS: Dose-escalation revealed no signs of muscle damage. Seven of the 8 boys completed the 12-week in-home program with a compliance of 84.9%, no signs of muscle damage, and improvements in strength (knee extensors p < 0.01; knee flexors p < 0.05) and function (descending steps p < 0.05). DISCUSSION: An in-home, mild-moderate intensity leg exercise program is safe with potential to positively impact both strength and function in ambulatory boys with DMD.
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- 2020
7. Effects of dietary iron restriction on kidney mitochondria function and oxidative stress in streptozotocin-diabetic rats
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Donovan J. Peña-Montes, Xóchitl Trujillo, Miguel Huerta, Maribel Huerta-Cervantes, Mónica Ríos-Silva, Alfredo Saavedra-Molina, and Christian Cortés-Rojo
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Male ,0301 basic medicine ,medicine.medical_specialty ,Iron ,Cell Respiration ,Mitochondrion ,medicine.disease_cause ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,parasitic diseases ,medicine ,Animals ,Rats, Wistar ,Respiratory system ,Molecular Biology ,Kidney ,business.industry ,Iron Deficiencies ,Cell Biology ,Glutathione ,Streptozotocin ,medicine.disease ,Mitochondria ,Rats ,Oxidative Stress ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Molecular Medicine ,business ,Iron, Dietary ,030217 neurology & neurosurgery ,Function (biology) ,Oxidative stress ,medicine.drug - Abstract
Diabetes mellitus is characterized by chronic hyperglycemia causing mitochondrial dysfunction and kidney iron overload has been observed during diabetes. We evaluated the effects of an iron-restricted diet (IRD) on mitochondrial function, oxidative stress, and mitochondrial iron levels in the kidneys of Wistar rats with streptozotocin-induced diabetes. IRD ameliorated mitochondrial dysfunction in diabetic rats by restoring mitochondrial respiration and respiratory complex activity, improving oxidative stress and glutathione status in kidney mitochondria. We also observed mitochondrial iron overload. Our data suggest that elevated iron levels were attenuated by IRD, resulting in modulation of oxidative stress and mitochondrial function in the kidney.
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- 2020
8. Eryngium carlinaeEthanol Extract Corrects Lipid Abnormalities in Wistar Rats with Experimental Diabetes
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Miguel Huerta, Rafael Torres-Martínez, Rafael Salgado-Garciglia, Alfredo Saavedra-Molina, Salvador Manzo-Avalos, Ruth Noriega-Cisneros, Donovan J. Peña-Montes, and Maribel Huerta-Cervantes
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0301 basic medicine ,030109 nutrition & dietetics ,Nutrition and Dietetics ,Ethanol ,business.industry ,Cholesterol ,Atorvastatin ,Medicine (miscellaneous) ,Lipid metabolism ,Disease ,Pharmacology ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Diabetes mellitus ,medicine ,business ,Eryngium carlinae ,Experimental diabetes ,medicine.drug - Abstract
Abnormalities in lipid metabolism, associated with increased risk of cardiovascular disease (CVD), frequently occur in people with diabetes. Eryngium carlinae is a plant used in traditional medicin...
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- 2020
9. Magnetic Resonance Imaging Studies in Duchenne Muscular Dystrophy: Linking Findings to the Physical Therapy Clinic
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Glenn A. Walter, Alison M. Barnard, Kirsten L. Zilke, Rebecca J. Willcocks, Kavya S Nair, Claudia R. Senesac, William D. Rooney, Krista Vandenborne, Ann T. Harrington, and Donovan J. Lott
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Male ,musculoskeletal diseases ,medicine.medical_specialty ,Degenerative Disorder ,Duchenne muscular dystrophy ,Physical Therapy, Sports Therapy and Rehabilitation ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Muscle pathology ,medicine ,Humans ,Early childhood ,Child ,Muscle, Skeletal ,Physical Therapy Modalities ,Muscle Weakness ,medicine.diagnostic_test ,business.industry ,Muscle weakness ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Muscular Dystrophy, Duchenne ,Perspective ,Disease Progression ,Physical therapy ,Contracture ,medicine.symptom ,Exercise prescription ,business ,030217 neurology & neurosurgery - Abstract
Duchenne muscular dystrophy (DMD) is a muscle degenerative disorder that manifests in early childhood and results in progressive muscle weakness. Physical therapists have long been an important component of the multidisciplinary team caring for people with DMD, providing expertise in areas of disease assessment, contracture management, assistive device prescription, and exercise prescription. Over the last decade, magnetic resonance imaging of muscles in people with DMD has led to an improved understanding of the muscle pathology underlying the clinical manifestations of DMD. Findings from magnetic resonance imaging (MRI) studies in DMD, paired with the clinical expertise of physical therapists, can help guide research that leads to improved physical therapist care for this unique patient population. The 2 main goals of this perspective article are to (1) summarize muscle pathology and disease progression findings from qualitative and quantitative muscle MRI studies in DMD and (2) link MRI findings of muscle pathology to the clinical manifestations observed by physical therapists with discussion of any potential implications of MRI findings on physical therapy management.
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- 2020
10. Upper and Lower Extremities in Duchenne Muscular Dystrophy Evaluated with Quantitative MRI and Proton MR Spectroscopy in a Multicenter Cohort
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Ann T. Harrington, John F. Brandsema, Glenn A. Walter, Rebecca J. Willcocks, Harneet Arora, Michael J. Daniels, William T. Triplett, Gihan Tennekoon, Krista Vandenborne, Claudia R. Senesac, Erika Finanger, H. Lee Sweeney, Alison M. Barnard, Donovan J. Lott, William D. Rooney, Sean C. Forbes, Dah Jyuu Wang, and Umar Alabasi
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Male ,In vivo magnetic resonance spectroscopy ,Adolescent ,Proton Magnetic Resonance Spectroscopy ,Duchenne muscular dystrophy ,Deltoid curve ,Thigh ,Biceps ,030218 nuclear medicine & medical imaging ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Forearm ,Outcome Assessment, Health Care ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Muscular dystrophy ,Child ,Muscle, Skeletal ,Prospective cohort study ,Original Research ,Leg ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,Muscular Dystrophy, Duchenne ,Cross-Sectional Studies ,medicine.anatomical_structure ,Case-Control Studies ,030220 oncology & carcinogenesis ,Arm ,Disease Progression ,Feasibility Studies ,business ,Nuclear medicine - Abstract
BACKGROUND: Upper extremity MRI and proton MR spectroscopy are increasingly considered to be outcome measures in Duchenne muscular dystrophy (DMD) clinical trials. PURPOSE: To demonstrate the feasibility of acquiring upper extremity MRI and proton ((1)H) MR spectroscopy measures of T2 and fat fraction in a large, multicenter cohort (ImagingDMD) of ambulatory and nonambulatory individuals with DMD; compare upper and lower extremity muscles by using MRI and (1)H MR spectroscopy; and correlate upper extremity MRI and (1)H MR spectroscopy measures to function. MATERIALS AND METHODS: In this prospective cross-sectional study, MRI and (1)H MR spectroscopy and functional assessment data were acquired from participants with DMD and unaffected control participants at three centers (from January 28, 2016, to April 24, 2018). T2 maps of the shoulder, upper arm, forearm, thigh, and calf were generated from a spin-echo sequence (repetition time msec/echo time msec, 3000/20–320). Fat fraction maps were generated from chemical shift-encoded imaging (eight echo times). Fat fraction and (1)H(2)O T2 in the deltoid and biceps brachii were measured from single-voxel (1)H MR spectroscopy (9000/11–243). Groups were compared by using Mann-Whitney test, and relationships between MRI and (1)H MR spectroscopy and arm function were assessed by using Spearman correlation. RESULTS: This study evaluated 119 male participants with DMD (mean age, 12 years ± 3 [standard deviation]) and 38 unaffected male control participants (mean age, 12 years ± 3). Deltoid and biceps brachii muscles were different in participants with DMD versus control participants in all age groups by using quantitative T2 MRI (P < .001) and (1)H MR spectroscopy fat fraction (P < .05). The deltoid, biceps brachii, and triceps brachii were affected to the same extent (P > .05) as the soleus and medial gastrocnemius. Negative correlations were observed between arm function and MRI (T2: range among muscles, ρ = −0.53 to −0.73 [P < .01]; fat fraction, ρ = −0.49 to −0.70 [P < .01]) and (1)H MR spectroscopy fat fraction (ρ = −0.64 to −0.71; P < .01). CONCLUSION: This multicenter study demonstrated early and progressive involvement of upper extremity muscles in Duchenne muscular dystrophy (DMD) and showed the feasibility of MRI and (1)H MR spectroscopy to track disease progression over a wide range of ages in participants with DMD. © RSNA, 2020 Online supplemental material is available for this article.
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- 2020
11. Modeling disease trajectory in Duchenne muscular dystrophy
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William T. Triplett, Sean C. Forbes, Barry S. Russman, Claudia R. Senesac, G. Tennekoon, Harneet Arora, Rebecca J. Willcocks, Erika Finanger, Michael J. Daniels, Dah Jyuu Wang, Richard S. Finkel, William D. Rooney, Yosef A. Berlow, Elliott O'Brien, Donovan J. Lott, Saptarshi Chakraborty, Brendan Moloney, Alison M. Barnard, Krista Vandenborne, H. Lee Sweeney, Ishu Arpan, and Glenn A. Walter
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Male ,0301 basic medicine ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Adolescent ,Duchenne muscular dystrophy ,Population ,Corticosteroid treatment ,Walking ,Article ,03 medical and health sciences ,0302 clinical medicine ,Adrenal Cortex Hormones ,Internal medicine ,medicine ,Humans ,Muscular dystrophy ,Child ,Muscle, Skeletal ,education ,Leg ,education.field_of_study ,medicine.diagnostic_test ,Disease trajectory ,business.industry ,Disease progression ,Therapeutic effect ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,Child, Preschool ,Disease Progression ,Cardiology ,Female ,Neurology (clinical) ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
ObjectiveTo quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles.MethodsMRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach.ResultsMRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (μ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay μ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay.ConclusionsMRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels.ClinicalTrials.gov identifier:NCT01484678.
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- 2020
12. Hypolipidemic and Antioxidant Effects of Guishe Extract from Agave lechuguilla, a Mexican Plant with Biotechnological Potential, on Streptozotocin-Induced Diabetic Male Rats
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Donovan J. Peña-Montes, Zoé P. Morreeuw, Salvador Manzo-Avalos, Edgar R. Esquivel-Gutiérrez, Alfredo Saavedra-Molina, and Ana G. Reyes
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Antioxidant ,Thiobarbituric acid ,medicine.medical_treatment ,Plant Science ,Pharmacology ,medicine.disease_cause ,Article ,chemistry.chemical_compound ,saponins ,medicine ,oxidative stress ,dyslipidemias ,Ecology, Evolution, Behavior and Systematics ,chemistry.chemical_classification ,Ecology ,biology ,diabetes ,Chemistry ,Glutathione peroxidase ,Botany ,Glutathione ,biology.organism_classification ,Blood chemistry ,Catalase ,Agave lechuguilla ,QK1-989 ,flavonoids ,biology.protein ,Oxidative stress - Abstract
In the present study, we used a by-product from Agave lechuguilla (guishe) to test its antidiabetic effect, hypolipidemic activity, and capacity to mitigate the oxidative stress in kidney mitochondria from streptozotocin-induced diabetic rats. Orally, a crude aqueous extract from lyophilized guishe was administered over 5 weeks at different doses. Blood glucose and body weight were monitored. Also, blood chemistry, bilirubin, and alanine aminotransferase were assayed. Furthermore, the activity of catalase, thiobarbituric acid reactive species, mitochondrial superoxide dismutase, glutathione and glutathione peroxidase were determined in isolated kidney mitochondria. Our results show that guishe extracts have no antidiabetic properties at any dose. Nevertheless, it was able to diminish serum triglyceride levels and regulate the oxidative stress observed in isolated kidney mitochondria. These observations indicate that the aqueous extract from guishe can be used to treat abnormalities in serum lipids, as a hypolipidemic, and mitigate the oxidative stress, as an antioxidant, occurring during diabetes.
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- 2021
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13. Characterizing Expiratory Respiratory Muscle Degeneration in Duchenne Muscular Dystrophy Using MRI
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Krista Vandenborne, Rebecca J. Willcocks, Glenn A. Walter, William D. Rooney, Alison M. Barnard, Michael J. Daniels, William T. Triplett, Barbara K. Smith, Abhinandan Batra, Sean C. Forbes, and Donovan J. Lott
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Weakness ,Duchenne muscular dystrophy ,Critical Care and Intensive Care Medicine ,Pulmonary function testing ,FEV1/FVC ratio ,Adrenal Cortex Hormones ,Internal medicine ,medicine ,Respiratory muscle ,Humans ,Respiratory system ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,Respiratory Muscles ,Hypoventilation ,Education and Clinical Practice: Original Research ,Muscular Dystrophy, Duchenne ,medicine.anatomical_structure ,Cough ,Cardiology ,Abdomen ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
BACKGROUND: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF). RESEARCH QUESTION: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function? STUDY DESIGN AND METHODS: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI. RESULTS: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H(2)O and peak cough flows < 270 L/min. INTERPRETATION: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures.
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- 2021
14. Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury
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Mark Fiecas, Bryon A. Mueller, Timothy Hendrickson, Michelle Thai, Donovan J. Roediger, Anna M Parenteau, Thanharat Silamongkol, Zeynep Başgöze, Kathryn R. Cullen, Melinda Westlund Schreiner, Salahudeen A. Mirza, Conner A. Falke, Bonnie Klimes-Dougan, and Dawson Hill
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Suicide attempt ,Adolescent ,Hydrocortisone ,Left amygdala ,Functional connectivity ,Suicide, Attempted ,Right amygdala ,Amygdala ,Psychiatry and Mental health ,medicine.anatomical_structure ,Cross-Sectional Studies ,nervous system ,Developmental and Educational Psychology ,Trier social stress test ,medicine ,Humans ,Female ,Psychology ,Prefrontal cortex ,Self-Injurious Behavior ,Clinical psychology - Abstract
Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala–mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala–mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.
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- 2021
15. Antidiabetic and antioxidant effect of silver nanoparticles synthesized from the aqueous extract of Eryngium carlinae in the brain of streptozotocin‐induced diabetic rats
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Jenaro Lemus‐de la Cruz, Rafael Salgado-Garciglia, Cinthia Itzel Landa Moreno, Gerardo Rosas‐Trejo, Donovan J. Peña-Montes, Rocío Montoya-Pérez, Alfredo Saavedra-Molina, Salvador Manzo-Avalos, Maribel Huerta-Cervantes, Cristian Mitchell Trejo‐Hurtado, and Christian Cortés-Rojo
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Aqueous extract ,Antioxidant ,Chemistry ,medicine.medical_treatment ,Streptozotocin ,Biochemistry ,Silver nanoparticle ,Genetics ,medicine ,Molecular Biology ,Eryngium carlinae ,Biotechnology ,Nuclear chemistry ,medicine.drug - Published
- 2021
16. Antioxidant Activity of the Ethyl Acetate Extract of Potentilla indica on Kidneys of Streptozotocin‐Induced Diabetic Rats
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Cristian Mitchell Trejo‐Hurtado, Cinthia Itzel Landa-Moreno, Rocío Montoya-Pérez, Alfredo Saavedra-Molina, Donovan J. Peña-Montes, Rafael Salgado-Garciglia, Jenaro Lemus‐de la Cruz, Maribel Huerta-Cervantes, and Salvador Manzo-Avalos
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Antioxidant ,Traditional medicine ,medicine.medical_treatment ,Ethyl acetate ,Streptozotocin ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Genetics ,medicine ,Potentilla indica ,Molecular Biology ,Biotechnology ,medicine.drug - Published
- 2021
17. Network topology changes in chronic mild traumatic brain injury (mTBI)
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Carrie Gentz, Donovan J. Roediger, Bryon A. Mueller, Michael T. Armstrong, Mark Fiecas, Timothy Hendrickson, Kelvin O. Lim, Alicia Fenske, Casey S. Gilmore, Randy H. Kardon, and Elias Boroda
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medicine.medical_specialty ,Traumatic brain injury ,Cognitive Neuroscience ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Network topology ,050105 experimental psychology ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,TBI ,medicine ,Humans ,0501 psychology and cognitive sciences ,Radiology, Nuclear Medicine and imaging ,RC346-429 ,Brain Concussion ,Clustering coefficient ,Modularity (networks) ,Brain Mapping ,medicine.diagnostic_test ,business.industry ,Functional connectivity ,05 social sciences ,Diffuse axonal injury ,fMRI ,Brain ,Infant ,Cognition ,Regular Article ,medicine.disease ,Magnetic Resonance Imaging ,Graph theory ,Neurology ,Brain Injuries ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,Functional magnetic resonance imaging ,030217 neurology & neurosurgery - Abstract
Highlights • Brain networks in mTBI remain plastic decades after injury. • Global integration increased over time in mTBI group to the level of Controls. • mTBI networks became more clustered and less segregated into modules over time., Background In mild traumatic brain injury (mTBI), diffuse axonal injury results in disruption of functional networks in the brain and is thought to be a major contributor to cognitive dysfunction even years after trauma. Objective Few studies have assessed longitudinal changes in network topology in chronic mTBI. We utilized a graph theoretical approach to investigate alterations in global network topology based on resting-state functional connectivity in veterans with chronic mTBI. Methods 50 veterans with chronic mTBI (mean of 20.7 yrs. from trauma) and 40 age-matched controls underwent two functional magnetic resonance imaging scans 18 months apart. Graph theory analysis was used to quantify network topology measures (density, clustering coefficient, global efficiency, and modularity). Hierarchical linear mixed models were used to examine longitudinal change in network topology. Results With all network measures, we found a significant group × time interaction. At baseline, brain networks of individuals with mTBI were less clustered (p = 0.03) and more modular (p = 0.02) than those of HC. Over time, the mTBI networks became more densely connected (p = 0.002), with increased clustering (p = 0.001) and reduced modularity (p
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- 2021
18. Antioxidant and Anti‐Inflammatory Activity of the Ethyl Acetate Extract of Eryngium Carlinae on the Liver of Streptozotocin‐Induced Diabetes Rats
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Rafael Salgado-Garciglia, Cinthia Itzel Landa-Moreno, Rocío Montoya-Pérez, Alfredo Saavedra-Molina, Cristian Mitchell Trejo‐Hurtado, Maribel Huerta-Cervantes, Salvador Manzo-Avalos, Jenaro Lemus‐de la Cruz, and Donovan J. Peña-Montes
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Antioxidant ,medicine.drug_class ,medicine.medical_treatment ,Ethyl acetate ,Pharmacology ,medicine.disease ,Streptozotocin ,Biochemistry ,Anti-inflammatory ,chemistry.chemical_compound ,chemistry ,Diabetes mellitus ,Genetics ,medicine ,Molecular Biology ,Eryngium carlinae ,Biotechnology ,medicine.drug - Published
- 2021
19. Imaging respiratory muscle quality and function in Duchenne muscular dystrophy
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Abhinandan Batra, Krista Vandenborne, William T. Triplett, Barbara K. Smith, Glenn A. Walter, Rebecca J. Willcocks, Donovan J. Lott, Samuel L. Riehl, Sean C. Forbes, and Alison M. Barnard
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Diagnostic Imaging ,Thorax ,medicine.medical_specialty ,Movement ,Duchenne muscular dystrophy ,Thoracic Cavity ,Article ,Pulmonary function testing ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Respiratory muscle ,Humans ,Medicine ,Respiratory function ,030212 general & internal medicine ,Respiratory system ,Muscular dystrophy ,business.industry ,medicine.disease ,Magnetic Resonance Imaging ,Respiratory Muscles ,Muscular Dystrophy, Duchenne ,Cross-Sectional Studies ,Neurology ,Breathing ,Cardiology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
OBJECTIVE: Duchenne muscular dystrophy (DMD) is characterized by damage to muscles including the muscles involved in respiration. Dystrophic muscles become weak and infiltrated with fatty tissue, resulting in progressive respiratory impairment. The objective of this study was to assess respiratory muscle quality and function in DMD using magnetic resonance imaging and to determine the relationship to clinical respiratory function. METHODS: Individuals with DMD (n=36) and unaffected controls (n=12) participated in this cross-sectional magnetic resonance imaging study. Participants underwent dynamic imaging of the thorax to assess diaphragm and chest wall mobility and chemical shift-encoded imaging of the chest and abdomen to determine fatty infiltration of the accessory respiratory muscles. Additionally, clinical pulmonary function measures were obtained. RESULTS: Thoracic cavity area was decreased in individuals with DMD compared to controls during tidal and maximal breathing. Individuals with DMD had reduced chest wall movement in the anterior-posterior direction during maximal inspirations and expirations, but diaphragm descent during maximal inspirations (normalized to height) was only decreased in a subset of individuals with maximal inspiratory pressures less than 60% predicted. Muscle fat fraction was elevated in all three expiratory muscles assessed (p
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- 2019
20. Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with Duchenne muscular dystrophy: a multicenter cross sectional study.
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Sean C Forbes, Rebecca J Willcocks, William T Triplett, William D Rooney, Donovan J Lott, Dah-Jyuu Wang, Jim Pollaro, Claudia R Senesac, Michael J Daniels, Richard S Finkel, Barry S Russman, Barry J Byrne, Erika L Finanger, Gihan I Tennekoon, Glenn A Walter, H Lee Sweeney, and Krista Vandenborne
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Medicine ,Science - Abstract
IntroductionDuchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that (1)H2O T2 derived using (1)H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.MethodsMR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1)H2O T2.ResultsMRI-T2, (1)H2O T2, and lipid fraction were greater (pDiscussionOverall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.
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- 2014
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21. Characterization of 475 Novel, Putative Small RNAs (sRNAs) in Carbon-Starved Salmonella enterica Serovar Typhimurium
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Donovan J. Dahmer, Dominika Houserova, Mike E. Zambrano, Meghan A Dean, Aline Crucello, Valeria M. King, Michael P. Spector, Emmaline C Barnhill, Kevin M. Aria, Shivam V Amin, and Glen M. Borchert
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0301 basic medicine ,Microbiology (medical) ,Salmonella ,Biology ,medicine.disease_cause ,Biochemistry ,Microbiology ,Article ,noncoding RNA ,Transcriptome ,03 medical and health sciences ,transcriptomics ,carbon-starvation ,Gene expression ,medicine ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,Gene ,Genetics ,030102 biochemistry & molecular biology ,lcsh:RM1-950 ,starvation-stress ,Non-coding RNA ,biology.organism_classification ,Base pairing with mRNA ,030104 developmental biology ,Infectious Diseases ,lcsh:Therapeutics. Pharmacology ,Salmonella enterica ,Transfer RNA ,sRNA - Abstract
An increasingly apparent role of noncoding RNA (ncRNAs) is to coordinate gene expression during environmental stress. A mounting body of evidence implicates small RNAs (sRNAs) as key drivers of Salmonella stress survival. Generally thought to be 50–500 nucleotides in length and to occur in intergenic regions, sRNAs typically regulate protein expression through base pairing with mRNA targets. In this work, through employing a refined definition of sRNAs allowing for shorter sequences and sRNA loci to overlap with annotated protein-coding gene loci, we have identified 475 previously unannotated sRNAs that are significantly differentially expressed during carbon starvation (C-starvation). Northern blotting and quantitative RT-PCRs confirm the expressions and identities of several of these novel sRNAs, and our computational analyses find the majority to be highly conserved and structurally related to known sRNAs. Importantly, we show that deletion of one of the sRNAs dynamically expressed during C-starvation, sRNA4130247, significantly impairs the Salmonella C-starvation response (CSR), confirming its involvement in the Salmonella CSR. In conclusion, the work presented here provides the first-ever characterization of intragenic sRNAs in Salmonella, experimentally confirms that sRNAs dynamically expressed during the CSR are directly involved in stress survival, and more than doubles the Salmonella enterica sRNAs described to date.
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- 2021
22. Social Behaviors and Gray Matter Volumes of Brain Areas Supporting Social Cognition in Children and Adolescents with Prenatal Alcohol Exposure
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Erik de Water, Alyssa M. Krueger, Christopher J. Boys, Mariah J. Schumacher, Jeffrey R. Wozniak, Sarah N. Mattson, Madeline N. Rockhold, Kelvin O. Lim, Bryon A. Mueller, Donovan J. Roediger, and Kenneth L. Jones
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0301 basic medicine ,animal structures ,Fusiform gyrus ,General Neuroscience ,Precuneus ,Article ,03 medical and health sciences ,Superior temporal gyrus ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Prosocial behavior ,Social cognition ,Posterior cingulate ,medicine ,Orbitofrontal cortex ,Neurology (clinical) ,Psychology ,Molecular Biology ,030217 neurology & neurosurgery ,Developmental Biology ,Clinical psychology ,Social behavior - Abstract
The goal of this study was to examine: 1) differences in parent-reported prosocial and antisocial behaviors between children and adolescents with and without prenatal alcohol exposure (PAE); 2) differences in gray matter volumes of brain areas supporting social cognition between children and adolescents with and without PAE; 3) correlations between gray matter volumes of brain areas supporting social cognition and parent-reported prosocial and antisocial behaviors. Parents of children and adolescents ages 8–16 years completed measures on their prosocial and antisocial behaviors (i.e., Behavior Assessment Scale for Children, Vineland Adaptive Behaviors Scales, and Child Behavior Checklist) (n = 84; 41 with PAE, 43 without PAE). Seventy-nine participants (40 with PAE, 39 without PAE) also completed a structural Magnetic Resonance Imaging (MRI) scan with quality data. Gray matter volumes of seven brain areas supporting social cognitive processes were computed using automated procedures (FreeSurfer 6.0): bilateral fusiform gyrus, superior temporal gyrus, medial orbitofrontal cortex, lateral orbitofrontal cortex, posterior cingulate cortex, precuneus, and temporal pole. Children and adolescents with PAE showed decreased prosocial behaviors and increased antisocial behaviors as well as smaller volumes of the precuneus and lateral orbitofrontal cortex, even when controlling for total intracranial volume. Social brain volumes were not significantly correlated with prosocial or antisocial behaviors. These findings suggest that children and adolescents with PAE show worse social functioning and smaller volumes of brain areas supporting self-awareness, perspective-taking and emotion-regulation than their same-age peers without PAE.
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- 2021
23. Effects of Apocynin on Heart Muscle Oxidative Stress of Rats with Experimental Diabetes: Implications for Mitochondria
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Elizabeth Sánchez-Duarte, Estefanía Bravo-Sánchez, Rocío Montoya-Pérez, Sarai Sánchez-Duarte, Alfredo Saavedra-Molina, and Donovan J. Peña-Montes
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0301 basic medicine ,medicine.medical_specialty ,Antioxidant ,antioxidant ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,apocynin ,Internal medicine ,medicine ,oxidative stress ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,heart mitochondria ,NADPH oxidase ,biology ,diabetes ,Glutathione peroxidase ,lcsh:RM1-950 ,Cell Biology ,Glutathione ,medicine.disease ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,chemistry ,Apocynin ,biology.protein ,cardiovascular system ,Oxidative stress - Abstract
Diabetes mellitus (DM) constitutes one of the public health problems today. It is characterized by hyperglycemia through a defect in the β-cells function and/or decreased insulin sensitivity. Apocynin has been tasted acting directly as an NADPH oxidase inhibitor and reactive oxygen species (ROS) scavenger, exhibiting beneficial effects against diabetic complications. Hence, the present study’s goal was to dissect the possible mechanisms by which apocynin could mediate its cardioprotective effect against DM-induced oxidative stress. Male Wistar rats were assigned into 4 groups: Control (C), control + apocynin (C+A), diabetes (D), diabetes + apocynin (D+A). DM was induced with streptozotocin. Apocynin treatment (3 mg/kg/day) was applied for 5 weeks. Treatment significantly decreased blood glucose levels and insulin resistance in diabetic rats. In cardiac tissue, ROS levels were higher, and catalase enzyme activity was reduced in the D group compared to the C group, the apocynin treatment significantly attenuated these responses. In heart mitochondria, Complexes I and II of the electron transport chain (ETC) were significantly enhanced in the D+A group. Total glutathione, the level of reduced glutathione (GSH) and the GSH/ oxidized glutathione (GSSG) ratio were increased in the D+A group. Superoxide dismutase (SOD) and the glutathione peroxidase (GSH-Px) activities were without change. Apocynin enhances glucose uptake and insulin sensitivity, preserving the antioxidant defense and mitochondrial function.
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- 2021
24. A multi centre randomized open label trial of chloroquine for the treatment of adults with SARS-CoV-2 infection in Vietnam
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Kestelyn, E, Dung, NTP, Lam Minh, Y, Hung, LM, Quan, NM, Dung, NT, Minh, NNQ, Xuan, TC, Phong, NT, Ninh Thi Thanh, V, Donovan, J, Tu, TNH, Nhat, LTH, Truong, NT, Man, DNH, Thao, HP, Ngoc, NM, Lam, VT, Phat, HH, Phuong, PM, Geskus, RB, Ha, VTN, Quang, NN, Tran Tinh, H, Tan, LV, Thwaites, GE, Day, JN, Chau, NVV, and Group, OUCRU COVID-19 Research
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0301 basic medicine ,medicine.medical_specialty ,coronaviruses ,Medicine (miscellaneous) ,Randomised Clinical Trial ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,03 medical and health sciences ,Study Protocol ,0302 clinical medicine ,Randomized controlled trial ,law ,Chloroquine ,Internal medicine ,medicine ,Clinical endpoint ,030212 general & internal medicine ,Nose ,business.industry ,SARS-CoV-2 ,COVID-19 ,Articles ,3. Good health ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Tolerability ,Vietnam ,Chemoprophylaxis ,business ,Viral load ,medicine.drug - Abstract
Background: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. There is currently no vaccine to prevent COVID-19 or therapeutic agent to treat COVID-19. This clinical trial is designed to evaluate chloroquine as a potential therapeutic for the treatment of hospitalised people with COVID-19. We hypothesise that chloroquine slows viral replication in patients with COVID-19, attenuating the infection, and resulting in more rapid decline of viral load in throat/nose swabs. This viral attenuation should be associated with improved patient outcomes. Method: The study will start with a 10-patient prospective observational pilot study following the same entry and exclusion criteria as for the randomized trial and undergoing the same procedures. The main study is an open label, randomised, controlled trial with two parallel arms of standard of care (control arm) versus standard of care with 10 days of chloroquine (intervention arm) with a loading dose over the first 24 hours, followed by 300mg base orally once daily for nine days. The study will recruit patients in three sites in Ho Chi Minh City, Vietnam: the Hospital for Tropical Diseases, the Cu Chi Field Hospital, and the Can Gio COVID hospital. The primary endpoint is the time to viral clearance from throat/nose swab, defined as the time following randomization until the midpoint between the last positive and the first of the negative throat/nose swabs. Viral presence will be determined using RT-PCR to detect SARS-CoV-2 RNA. Discussion: The results of the study will add to the evidence-based guidelines for management of COVID-19. Given the enormous experience of its use in malaria chemoprophylaxis, excellent safety and tolerability profile, and its very low cost, if proved effective then chloroquine would be a readily deployable and affordable treatment for patients with COVID-19. Trial registration: Clinicaltrials.gov NCT04328493 31/03/2020
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- 2021
25. Mitochondrial metabolism in diabetes
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Alfredo Saavedra-Molina, Rocío Montoya-Pérez, Maribel Huerta-Cervantes, Rafael Salgado-Garciglia, Christian Cortés-Rojo, and Donovan J. Peña-Montes
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Kidney ,business.industry ,Metabolic disorder ,Mitochondrion ,medicine.disease ,Bioinformatics ,medicine.disease_cause ,Nephropathy ,medicine.anatomical_structure ,Diabetes mellitus ,Heart failure ,medicine ,Myocardial infarction ,business ,Oxidative stress - Abstract
Diabetes mellitus (DM) is a heterogeneous set of multifactorial pathogenesis syndrome where the common nexus is metabolic disorder, mainly chronic hyperglycemia and alterations in lipid and protein metabolism. The effects of DM, include long-term damage, dysfunction, and failure of various organs. It especially affects eyes, kidneys, muscle, nerves, heart, and blood vessels. The primary goal of diabetes treatment is the prevention of macrovascular complications (e.g., myocardial infarction, heart failure, and ischemic stroke) as well as the microvascular complications (e.g., retinopathy, neuropathy, and nephropathy). Abnormalities in mitochondrial function are common in the pathophysiology of diabetes that include modifications in the redox state and oxidative and nitrosative stress, as well dysregulation of mitochondrial complex activities. Oxidative stress is a factor that contributes to the development of complications in diabetes; however, its effects can be counteracted using exogenous antioxidants that are found in some plants, which is why people turn to traditional medicines in the search for therapeutic treatment. Identification of major compounds in extracts of medicinal plants can contribute to ameliorate hyperglycemia and oxidative stress due to exacerbated mitochondrial dysfunction in diabetes. The growing need to find alternatives for the treatment of diabetes justifies the study of medicinal plants used in traditional medicine. In this study, we aimed to review information related to possible treatments with bioactive compounds from medicinal plants on diabetes that affect several organs, including liver, heart, brain, muscle, and kidney with exacerbated oxidative stress originated mainly in mitochondria.
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- 2021
26. Walking activity in a large cohort of boys with Duchenne muscular dystrophy
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Krista Vandenborne, Gihan Tennekoon, William D. Rooney, Hilary Cunkle, Erika Finanger, Tanja Taivassalo, Ann M. Harrington, Claudia R. Senesac, Catherine Powers, Rebecca J. Willcocks, Kirsten L. Zilke, and Donovan J. Lott
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0301 basic medicine ,Male ,medicine.medical_specialty ,Physiology ,Duchenne muscular dystrophy ,Walking ,030105 genetics & heredity ,Article ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Activity monitoring ,0302 clinical medicine ,Physical medicine and rehabilitation ,Physiology (medical) ,Accelerometry ,Activities of Daily Living ,medicine ,Humans ,Functional ability ,Mobility Limitation ,Child ,Exercise ,Glucocorticoids ,business.industry ,Ambulatory Status ,Walking (activity) ,medicine.disease ,Large cohort ,Clinical trial ,Muscular Dystrophy, Duchenne ,Functional Status ,Case-Control Studies ,Child, Preschool ,Ambulatory ,Disease Progression ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
INTRODUCTION: In this study we explored walking activity in a large cohort of boys with Duchenne muscular dystrophy (DMD). METHODS: Step activity (monitored for 7 days), functional ability, and strength were quantified in ambulatory boys (5-12.9 years of age) with DMD and unaffected boys. Ambulatory status was determined 2 years later. RESULTS: Two to 5 days of activity monitoring predicted weekly step activity (adjusted R(2) = 0.80-0.95). Age comparisons revealed significant declines for step activity with increasing age, and relationships were found between step activity with both function and strength (P < .01). Our regression model predicted 36.5% of the variance in step activity. Those who were still ambulatory after 2 years demonstrated baseline step activity nearly double that of those who were no longer walking 2 years later (P < .01). DISCUSSION: Step activity for DMD is related to and predictive of functional declines, which may be useful for clinical trials.
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- 2020
27. MR biomarkers predict clinical function in Duchenne muscular dystrophy
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Rebecca J. Willcocks, G. Tennekoon, Sean C. Forbes, Krista Vandenborne, Harneet Arora, H. Lee Sweeney, Dah Jyuu Wang, Ann T. Harrington, Alison M. Barnard, Erika Finanger, Glenn A. Walter, Michael J. Daniels, Saptarshi Chakraborty, William D. Rooney, Claudia R. Senesac, William T. Triplett, and Donovan J. Lott
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Duchenne muscular dystrophy ,Magnetic resonance imaging ,medicine.disease ,Biceps ,Article ,030218 nuclear medicine & medical imaging ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ambulatory ,medicine ,Cardiology ,Biomarker (medicine) ,Neurology (clinical) ,Muscular dystrophy ,business ,030217 neurology & neurosurgery ,Natural history study - Abstract
ObjectiveTo investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function.MethodsOne hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T2 biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months.ResultsLongitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T2, and biceps femoris long head MRI T2 were the strongest predictors of future loss of function, including loss of ambulation.ConclusionsThis study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones.ClinicalTrials.gov identifierNCT01484678.
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- 2020
28. Para-limbic Structural Abnormalities Are Associated With Internalizing Symptoms in Children With Prenatal Alcohol Exposure
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Christopher A. Boys, Jeffrey R. Wozniak, Timothy Hendrickson, Donovan J. Roediger, Edward P. Riley, Sarah N. Mattson, Alyssa M. Krueger, Bryon A. Mueller, Kenneth L. Jones, Kelvin O. Lim, and Mariah J. Schumacher
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Male ,Pediatrics ,medicine.medical_specialty ,animal structures ,Adolescent ,Significant group ,030508 substance abuse ,Medicine (miscellaneous) ,Hippocampus ,Anxiety ,Toxicology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Limbic system ,Pregnancy ,Magnetic resonance imaging of the brain ,medicine ,Limbic System ,Humans ,Child ,Depression (differential diagnoses) ,medicine.diagnostic_test ,Ethanol ,business.industry ,Depression ,Putamen ,Central Nervous System Depressants ,Organ Size ,Magnetic Resonance Imaging ,Psychiatry and Mental health ,medicine.anatomical_structure ,Prenatal alcohol exposure ,Prenatal Exposure Delayed Effects ,Female ,medicine.symptom ,Caudate Nucleus ,0305 other medical science ,business ,030217 neurology & neurosurgery - Abstract
Background Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para-limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. Methods Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi-automated procedures (FreeSurfer) were used to derive para-limbic volumes from T1-weighted anatomical images. Results There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend-level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. Conclusions Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE.
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- 2020
29. Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects
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Miguel Ángel López-Vázquez, Xóchitl Trujillo, Maribel Huerta-Cervantes, Alfredo Saavedra-Molina, María Esther Olvera-Cortés, Miguel Huerta, Rocío Montoya-Pérez, and Donovan J. Peña-Montes
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Male ,0301 basic medicine ,hippocampus ,Hippocampus ,Morris water navigation task ,medicine.disease_cause ,Antioxidants ,Open field ,Lipid peroxidation ,chemistry.chemical_compound ,Cognition ,0302 clinical medicine ,Pregnancy ,oxidative stress ,Cerebral Cortex ,Nutrition and Dietetics ,learning ,Brain ,Catalase ,anxiety ,Glutathione ,Memory, Short-Term ,cortex ,Prenatal Exposure Delayed Effects ,Female ,gestational diabetes ,lcsh:Nutrition. Foods and food supply ,medicine.medical_specialty ,Elevated plus maze ,Offspring ,lcsh:TX341-641 ,Biology ,Article ,Superoxide dismutase ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Maze Learning ,Triglycerides ,Superoxide Dismutase ,behavior ,Cholesterol, HDL ,Diabetes, Gestational ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Lipid Peroxidation ,Reactive Oxygen Species ,metabolism ,030217 neurology & neurosurgery ,Oxidative stress ,Food Science - Abstract
Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal stages was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age. Anxiety-like behavior was evaluated using the elevated plus maze and open field maze, spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both ages as they spent less time in the closed arms of the elevated plus maze at adult age ((P = 0.019, d = 1.083 ( size effect)) and spent more time in the open area of an open field (P = 0.0412, d = 0.743) when young and adult age (P = 0.018, d = 0.65). Adult female GD offspring showed a reduced level of anxiety (P = 0.036, d = 0.966), and young female GD offspring showed a deficiency in spatial learning (P = 0.0291 vs. control, d = 3.207). Adult male GD offspring showed a deficiency in short-term memory (P = 0.017, d = 1.795). We found an increase in ROS and lipid peroxidation, a disruption in the glutathione status, and decreased activity of catalase and superoxide dismutase (P <, 0.05 vs. control, d >, 1.0), in the cerebral cortex and hippocampus of male and female GD offspring. GD altered metabolism, male offspring of both ages and adult females showed a high level of triglycerides and a lower level of high-density lipoprotein-cholesterol (P <, 1.0). Young and adult female offspring displayed higher insulin levels (P <, 0.05, d >, 1.0). These results suggest that gestational diabetes modifies oxidative stress and cognitive behavior in an age- and sex-dependent manner.
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- 2020
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30. Skeletal muscle apoptotic signaling predicts thigh muscle volume and gait speed in community-dwelling older persons: an exploratory study.
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Emanuele Marzetti, Hazel A Lees, Todd M Manini, Thomas W Buford, Juan M Aranda, Riccardo Calvani, Giorgio Capuani, Michael Marsiske, Donovan J Lott, Krista Vandenborne, Roberto Bernabei, Marco Pahor, Christiaan Leeuwenburgh, and Stephanie E Wohlgemuth
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Medicine ,Science - Abstract
Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons.Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R(2) = 0.78; Q(2) = 0.61) as well as gait speed (R(2) = 0.81; Q(2) = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume).Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons.
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- 2012
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31. Longitudinal timed function tests in Duchenne muscular dystrophy: ImagingDMD cohort natural history
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Barry J. Byrne, William T. Triplett, Ann T. Harrington, Glenn A. Walter, Krista Vandenborne, Claudia R. Senesac, Rebecca J. Willcocks, Michael J. Daniels, Harneet Arora, Gihan Tennekoon, Barry S. Russman, H. Lee Sweeney, Dandan Xu, Richard S. Finkel, Donovan J. Lott, Kirsten L. Zilke, and Erika Finanger
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0301 basic medicine ,medicine.medical_specialty ,Longitudinal study ,Supine position ,Physiology ,business.industry ,Duchenne muscular dystrophy ,medicine.disease ,Clinical trial ,Natural history ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Physical medicine and rehabilitation ,Physiology (medical) ,Ambulatory ,Cohort ,medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Introduction Tests of ambulatory function are common clinical trial endpoints in Duchenne muscular dystrophy (DMD). Using these tests, the ImagingDMD study has generated a large data set that can describe the contemporary natural history of DMD in 5-12.9-year-olds. Methods Ninety-two corticosteroid-treated boys with DMD and 45 controls participated in this longitudinal study. Participants performed the 6-minute walk test (6MWT) and timed function tests (TFT: 10-m walk/run, climbing 4 stairs, supine to stand). Results Boys with DMD had impaired functional performance even at 5-6.9 years old. Boys older than 7 had significant declines in function over 1 year for 10-m walk/run and 6MWT. Eighty percent of participants could perform all functional tests at 9 years old. TFTs appear to be slightly more responsive and predictive of disease progression than the 6MWT in 7-12.9 year olds. Discussion This study provides insight into the contemporary natural history of key functional endpoints in DMD. Muscle Nerve 58: 631-638, 2018.
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- 2018
32. Effects of Gestational Diabetes in Cognitive Behavior, Oxidative Stress and Metabolism on the Second-Generation Off-Spring of Rats
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Christian Cortés-Rojo, Maribel Huerta-Cervantes, Alfredo Saavedra-Molina, María Esther Olvera-Cortés, Rocío Montoya-Pérez, Donovan J. Peña-Montes, and Miguel Ángel López-Vázquez
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Male ,hippocampus ,medicine.medical_treatment ,Hippocampus ,medicine.disease_cause ,Spatial memory ,0302 clinical medicine ,Pregnancy ,oxidative stress ,TX341-641 ,Nutrition and Dietetics ,Behavior, Animal ,anxiety ,Gestational diabetes ,Memory, Short-Term ,medicine.anatomical_structure ,Cerebral cortex ,Prenatal Exposure Delayed Effects ,cerebral cortex ,Female ,gestational diabetes ,spatial working memory ,medicine.drug ,medicine.medical_specialty ,second-generation ,Offspring ,Spatial Learning ,030209 endocrinology & metabolism ,Biology ,Article ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,offspring ,Nutrition. Foods and food supply ,Insulin ,Maternal Nutritional Physiological Phenomena ,Streptozotocin ,medicine.disease ,Rats ,Diabetes, Gestational ,Disease Models, Animal ,Endocrinology ,Lipid Peroxidation ,metabolism ,Biomarkers ,030217 neurology & neurosurgery ,Oxidative stress ,Food Science - Abstract
Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.
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- 2021
33. Electrical impedance myography in individuals with collagen 6 and laminin α‐2 congenital muscular dystrophy: a cross‐sectional and 2‐year analysis
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Anam Salman, Katherine Keller, M. Waite, Leslie Nelson, James J. Collins, Tanya J. Lehky, Tianxia Wu, Katherine G. Meilleur, M. Leach, Minal S. Jain, Carsten G. Bönnemann, M. McGuire, Anne Rutkowski, Carole Vuillerot, Sandra Donkervoort, Donovan J. Lott, Tina Duong, Jahannaz Dastgir, and Carmel Nichols
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Male ,0301 basic medicine ,Change over time ,medicine.medical_specialty ,Adolescent ,Physiology ,Population ,Collagen Type VI ,Sensitivity and Specificity ,Severity of Illness Index ,Muscular Dystrophies ,Article ,Running ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Disease severity ,Laminin ,Physiology (medical) ,Internal medicine ,Electric Impedance ,medicine ,Humans ,Muscle Strength ,Sensitivity to change ,Child ,education ,Neurologic Examination ,education.field_of_study ,biology ,Electrical impedance myography ,business.industry ,Myography ,medicine.disease ,Cross-Sectional Studies ,030104 developmental biology ,Child, Preschool ,Cohort ,Congenital muscular dystrophy ,Cardiology ,biology.protein ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Introduction Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD). Methods Forty-one patients with CMD, either collagen 6 related disorders (COL6-RD; n = 21) or laminin α-2-related disorders (LAMA2-RD; n = 20), and 21 healthy pediatric controls underwent 2 yearly EIM exams. In the CMD cohorts, EIM was compared with functional and strength measurements. Results Both CMD cohorts exhibited change over time and had correlation with disease severity. The 50-kHZ phase correlated well with function and strength in the COL6-RD cohort but not in the LAMA2-RD cohort. Discussion EIM is a potentially useful measure in clinical studies with CMD because of its sensitivity to change over a 1-year period and correlation with disease severity. For COL6-RD, there were also functional and strength correlations. Muscle Nerve 57: 54-60, 2018.
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- 2017
34. Leg muscle MRI in identical twin boys with duchenne muscular dystrophy
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William T. Triplett, Glenn A. Walter, Sean C. Forbes, Donovan J. Lott, Abhinandan Batra, Rebecca J. Willcocks, Jerry R. Mendell, Krista Vandenborne, and H. Lee Sweeney
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Physiology ,business.industry ,Duchenne muscular dystrophy ,Thigh muscle ,Anatomy ,medicine.disease ,030218 nuclear medicine & medical imaging ,Leg muscle ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Physiology (medical) ,Medicine ,Neurology (clinical) ,business ,Identical twins ,030217 neurology & neurosurgery ,Fat fraction - Published
- 2018
35. Effects of PDE5 inhibition on dystrophic muscle following an acute bout of downhill running and endurance training
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Glenn A. Walter, Abhinandan Batra, Steve M. Chrzanowski, Krista Vandenborne, Ravneet Vohra, Sean C. Forbes, David W. Hammers, and Donovan J. Lott
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0301 basic medicine ,Downhill running ,medicine.medical_specialty ,Physiology ,Duchenne muscular dystrophy ,Sildenafil Citrate ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Sarcolemma ,Endurance training ,Physiology (medical) ,Internal medicine ,Physical Conditioning, Animal ,medicine ,Animals ,Skeletal muscle damage ,Muscle, Skeletal ,medicine.diagnostic_test ,business.industry ,Dystrophic muscle ,Pde5 inhibition ,Magnetic resonance imaging ,Muscular Dystrophy, Animal ,Phosphodiesterase 5 Inhibitors ,medicine.disease ,Mice, Inbred C57BL ,Muscular Dystrophy, Duchenne ,Endurance Training ,030104 developmental biology ,Endocrinology ,Mice, Inbred mdx ,business ,030217 neurology & neurosurgery ,Research Article ,Muscle Contraction - Abstract
Lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ) contributes to muscle damage and fatigue in dystrophic muscle. In this study, we examined the effects of compensating for lack of nNOSμ with a phosphodiesterase type 5 (PDE5) inhibitor in mdx mice following downhill running and endurance training. Dystrophic mice ( mdx) were treated with sildenafil citrate and compared with untreated mdx and wild-type mice after an acute bout of downhill running and during a progressive low-intensity treadmill running program (5 days/wk, 4 wk). Magnetic resonance imaging (MRI) and spectroscopy (MRS) transverse relaxation time constant (T2) of hindlimb and forelimb muscles were measured as a marker of muscle damage after downhill running and throughout training. The MRI blood oxygenation level dependence (BOLD) response and 31phosphorus MRS (31P-MRS) data were acquired after stimulated muscle contractions. After downhill running, the increase in T2 was attenuated ( P < 0.05) in treated mdx and wild-type mice compared with untreated mdx. During training, resting T2 values did not change in wild-type and mdx mice from baseline values; however, the running distance completed during training was greater ( P < 0.05) in treated mdx (>90% of target distance) and wild-type (100%) than untreated mdx (60%). The post-contractile BOLD response was greater ( P < 0.05) in treated mdx that trained than untreated mdx, with no differences in muscle oxidative capacity, as measured by 31P-MRS. Our findings indicate that PDE5 inhibition reduces muscle damage after a single bout of downhill running and improves performance during endurance training in dystrophic mice, possibly because of enhanced microvascular function. NEW & NOTEWORTHY This study examined the combined effects of PDE5 inhibition and exercise in dystrophic muscle using high-resolution magnetic resonance imaging and spectroscopy. Our findings demonstrated that sildenafil citrate reduces muscle damage after a single bout of downhill running, improves endurance-training performance, and enhances microvascular function in dystrophic muscle. Collectively, the results support the combination of exercise and PDE5 inhibition as a therapeutic approach in muscular dystrophies lacking nNOSμ.
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- 2019
36. Knock‐on effects of gestational diabetes in offspring learning and anxiety without influence of oxidative stress: Effects dependent on sex and age
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Alfredo Saavedra-Molina, Miguel Ángel López-Vázquez, Salvador Manzo-Avalos, Maribel Huerta-Cervantes, Donovan J. Peña-Montes, María Esther Olvera-Cortés, and Christian Cortés-Rojo
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medicine.medical_specialty ,business.industry ,Offspring ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gestational diabetes ,Endocrinology ,Internal medicine ,Genetics ,Medicine ,Anxiety ,medicine.symptom ,business ,Molecular Biology ,Oxidative stress ,Biotechnology - Published
- 2019
37. Dietary iron restriction improvement mitochondrial dysfunction and oxidative stress, and iron supplementation increases oxidative damages in kidneys mitochondria of streptozotocin‐diabetic rats
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Alfredo Saavedra-Molina, Rafael Salgado-Garciglia, Xóchitl Trujillo, Christian Cortés-Rojo, Donovan J. Peña-Montes, Maribel Huerta-Cervantes, Miguel Huerta, and Rocío Montoya-Pérez
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medicine.medical_specialty ,Dietary iron ,Chemistry ,Oxidative phosphorylation ,Mitochondrion ,Streptozotocin ,medicine.disease_cause ,Biochemistry ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Iron supplementation ,Molecular Biology ,Oxidative stress ,Biotechnology ,medicine.drug - Published
- 2019
38. Protective Effect of the Hexanic Extract of Eryngium carlinae Inflorescences In Vitro, in Yeast, and in Streptozotocin-Induced Diabetic Male Rats
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Mónica Ríos-Silva, Miguel Huerta, Donovan J. Peña-Montes, Ruth Noriega-Cisneros, Rafael Salgado-Garciglia, Alfredo Saavedra-Molina, Maribel Huerta-Cervantes, and Xóchitl Trujillo
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0301 basic medicine ,Antioxidant ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,antioxidant activity ,Saccharomyces cerevisiae ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Article ,Eryngium carlinae ,Lipid peroxidation ,Terpene ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,oxidative stress ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Chemistry ,lcsh:RM1-950 ,Cell Biology ,Ascorbic acid ,Streptozotocin ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Catalase ,diabetes mellitus ,biology.protein ,030217 neurology & neurosurgery ,Oxidative stress ,medicine.drug - Abstract
In the present study, we investigated the composition and antioxidant activity of the hexanic extract of Eryngium carlinae inflorescences by employing in vitro assays to measure antioxidant capacity and 2,2-diphenyl-1-picrylhydrazyl scavenging activity. We also applied the hexanic extract to Saccharomyces cerevisiae, under hydrogen peroxide-induced stress. Finally, we tested the extract in male Wistar rats with and without streptozotocin-induced diabetes. The compounds in the hexanic extract were analyzed by gas-chromatography-mass spectrometry, which revealed mainly terpenes and sesquiterpenes, including (Z)&beta, farnesene (38.79%), &beta, pinene (17.53%), calamene (13.3%), and &alpha, farnesene (10.38%). In vitro and in S. cerevisiae, the extract possessed antioxidant activity at different concentrations, compared to ascorbic acid (positive control). In normoglycemic and hyperglycemic rats, oral administration of 30 mg/kg of the extract reduced blood glucose levels, lipid peroxidation in liver, kidney and brain, protein carbonylation, and reactive oxygen species (ROS) production. It also increased catalase activity in the brain, kidneys and liver. These findings show that this hexanic extract of E. carlinae inflorescences possessed antioxidant properties.
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- 2019
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39. Lower Extremity Functional Outcome Measures in Duchenne Muscular Dystrophy-A Delphi Survey
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Rebecca J. Willcocks, Claudia R. Senesac, Barbara K. Smith, Tina Duong, and Donovan J. Lott
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0301 basic medicine ,Male ,medicine.medical_specialty ,Neuromuscular disease ,Delphi Technique ,Duchenne muscular dystrophy ,Population ,Delphi method ,Article ,03 medical and health sciences ,Face-to-face ,0302 clinical medicine ,Physical medicine and rehabilitation ,Outcome Assessment, Health Care ,medicine ,Humans ,Muscular dystrophy ,education ,education.field_of_study ,business.industry ,Operational definition ,medicine.disease ,Clinical trial ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,Neurology ,Lower Extremity ,Exercise Test ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Background Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by progressive muscle weakness, multiple system involvement and premature mortality. Effective treatments for DMD through clinical trials and natural history studies are currently underway. Clinical trials in DMD typically include several outcome measures of motor function. Research sites and studies have been found to have slightly different operational definitions for a given functional outcome resulting in different procedures and protocols for these measurements. Objective The goal of this study is to establish agreement among experts in the field around best practices in collecting functional outcome data in DMD providing researchers and clinicians with guidance on best practices. Methods A group of 30 experts in Duchenne Muscular Dystrophy (DMD) with experience in the development and/ or execution of lower extremity outcome measures for this population met face to face to identify incongruences in the collection of this data. This effort was based in the United States (US) and sponsored by Parent Project Muscular Dystrophy. Several discrepancies were categorized for each outcome which included: 6-minute walk test, 10-meter walk/run, supine to stand, ascend 4 stairs, sit to stand, and the NorthStar Ambulatory Assessment. Following this meeting an additional 32 experts in DMD (28 from the United States and 11 international participants) consented to participate in a Delphi Survey to reach consensus on the protocols and execution of lower extremity outcomes. Results Round one: 70 operationally defined questions were surveyed with 45 (64%) reaching >70% consensus. Round two: 27 questions were operational, with 20 (74%) reaching >70% consensus. Those questions that did not reach consensus appear minor. Conclusion With minor modifications in the collection of data across sites, outcomes could potentially be normalized across research studies. This would reduce excessive training for evaluators in trials and produce minimal differences between protocols. Consistency in protocols will promote more efficient study start up, less errors between administration of items across studies, and ultimately improve quality and reliability of the functional outcomes. The authors strongly advocate for the establishment of a "research network library" that could be utilized by all those performing clinical assessments and trials in DMD.
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- 2018
40. Adaptation of the By-Band randomized clinical trial to By-Band-Sleeve to include a new intervention and maintain relevance of the study to practice
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Rogers, C. A., Reeves, B. C., Byrne, J., Donovan, J. L., Mazza, G., Paramasivan, S., Andrews, R. C., Wordsworth, S., Thompson, J., Blazeby, J. M., Welbourn, R., Agrawal, S., Ajaz, S., Koak, Y., Ahmed, A., Fakih, N., Hakky, S., Moorthy, K., Purkayastha, S., Awad, S., Fareed, K., Leeder, P., Balupuri, S., Carr, W., Jennings, N., Small, P., Byrom, R., Davies, N., Carter, N., Knight, B., Somers, S., Charalampakis, V., Daskalakis, M., Nijar, R., Richardson, M., Singhal, R., Super, P., Clarke, M., Cota, A., Finlay, I., Dexter, S., Hayden, J., Mehta, S., Sarela, A., Kelly, J., Mahon, D., and Noble, H.
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medicine.medical_specialty ,Sleeve gastrectomy ,Evidence-based practice ,Gastroplasty ,medicine.medical_treatment ,Psychological intervention ,MEDLINE ,Gastric Bypass ,Gastric Band ,030209 endocrinology & metabolism ,Pilot Projects ,BTC (Bristol Trials Centre) ,law.invention ,adaptive trial design ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Intervention (counseling) ,medicine ,Roux-en-Y Gastric Bypass ,Relevance (law) ,Humans ,030212 general & internal medicine ,Adjustable gastric band ,Practice Patterns, Physicians' ,Randomized Controlled Trials as Topic ,business.industry ,Patient Selection ,By-Band-Sleeve study investigators ,11 Medical And Health Sciences ,Original Articles ,Sleeve Gastrectomy ,3. Good health ,Surgery ,Obesity, Morbid ,Centre for Surgical Research ,Physical therapy ,Original Article ,Severe obesity ,business ,Delivery of Health Care ,RCT - Abstract
Background Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. Methods The By‐Band study was designed in the UK in 2009–2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux‐en‐Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. Results The pilot phase recruited over 13 months in 2013–2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. Conclusion Adaptation of a two‐group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/)., Something to consider
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- 2018
41. Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies
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Angela Kokkinis, M. McGuire, Robert J. Fee, Courtney Fiorini, Ranjani Logaraj, Irene C Chrismer, Leslie Nelson, Peter McGraw, Fatoumata Tounkara, Minal Jain, Allan Glanzman, E.J. Hartnett, Tina Duong, Kristy Rose, Anne Rutkowski, Mark Barton, Monal Punjabi, Katherine G. Meilleur, Payam Mohassel, M. Leach, M. Waite, G. Averion, Melody M. Linton, Eunice S. Kim, Gina Norato, Sandra Donkervoort, Jocelyn Winkert, Joseph A. Fontana, Carmel Nichols, Jahannaz Dastgir, Ruhi Vasavada, Kristen Zukosky, Carole Vuillerot, James C. Collins, Donovan J. Lott, Eunhee Kim, Katherine Keller, Alice B. Schindler, Marion Main, Jeffrey L. Elliott, A. Reghan Foley, Veronica J. Hinton, Diana Bharucha-Goebel, Linda S. Hynan, and Carsten G. Bönnemann
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Male ,Elbow ,Vital Capacity ,Neuromuscular Disorders ,Motor function ,Pediatrics ,Muscular Dystrophies ,Pulmonary function testing ,0302 clinical medicine ,Child Development ,Outcome Assessment, Health Care ,Longitudinal Studies ,Muscular Dystrophy ,Child ,Brain Diseases ,COL6-Related Dystrophies ,Outcome measures ,Respiratory Function Tests ,medicine.anatomical_structure ,LAMA2-Related Dystrophies ,Neurology ,Child, Preschool ,Congenital muscular dystrophy ,Disease Progression ,Female ,Elbow extension ,Range of motion ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Neurosurgery ,Muscle Strength Dynamometer ,03 medical and health sciences ,Young Adult ,Physical medicine and rehabilitation ,Enteral Nutrition ,030225 pediatrics ,medicine ,Humans ,Muscle Strength ,Mobility Limitation ,Sclerosis ,Arthrometry, Articular ,business.industry ,Infant ,medicine.disease ,respiratory tract diseases ,Muscle strength ,Linear Models ,Quality of Life ,Neurology (clinical) ,sense organs ,Nervous System Diseases ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs).MethodsOver the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts.ResultsTotal MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed.ConclusionResults of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.
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- 2018
42. Antioxidant Effects of Eryngium carlinae in Diabetic Rats
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Mónica Silva-Ríos, Rafael Salgado-Garciglia, Ruth Noriega-Cisneros, Diana García-Cerrillo, Donovan J. Peña-Montes, Maribel Huerta-Cervantes, Alfredo Saavedra-Molina, and Rocío Montoya-Pérez
- Subjects
0301 basic medicine ,Antioxidant ,biology ,Thiobarbituric acid ,medicine.medical_treatment ,General Medicine ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,medicine.disease_cause ,Streptozotocin ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Diabetes mellitus ,Diabetic cardiomyopathy ,medicine ,TBARS ,biology.protein ,Oxidative stress ,medicine.drug - Abstract
Metabolic diseases have increased considerably such as diabetes mellitus (DM). Since diabetes is a systemic disease, it implies high cardiovascular risks. It has been widely established that cardiac injury is related to mitochondrial dysfunction through increment of reactive oxygen species (ROS). Synthetic antioxidants can have important side effects; therefore natural sources may represent a better option. Traditional Mexican medicine has been using Eryngium carlinae (EC) for medical treatment. Also our group showed that hexanic extract possesses in vitro antioxidant capacity. Experimental diabetes in Wistar rats was generated by streptozotocin (STZ) and hexanic extract of EC was supplied for 7 weeks (30 mg/kg). Cholesterol, triacylglycerides, glucose, and thiobarbituric acid reactive substances (TBARS) levels were determined in serum. Mitochondria from left ventricle were used in the quantification of TBARS, reduced glutathione, nitric oxide (NO) levels and activity of superoxide dismutase (SOD) enzyme was performed. Biochemical parameters of glucose and triacylglycerides, as well as TBARS levels in serum show a significant reduction in diabetic group supplied with EC hexanic extract. Thus, we can conclude that the EC hexanic extract possesses antioxidant activity in vitro, and in vivo, by reducing glucose and triacylglycerides levels during hyperglycemia, which may eventually reduce the risk of developing diabetic cardiomyopathy.
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- 2018
43. Two-Year Longitudinal changes in lower limb strength and its relation to loss in function in a large cohort of patients with Duchenne Muscular Dystrophy
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William T. Triplett, Krista Vandenborne, Gihan Tennekoon, H. Lee Sweeney, Michael J. Daniels, Rebecca J. Willcocks, Ishu Arpan, Glenn A. Walter, William McGehee, Richard S. Finkel, Barry J. Byrne, Barry S. Russman, William D. Rooney, Jasjit Deol, Claudia R. Senesac, Abhinandan Batra, Ann T. Harrington, Dandan Xu, Donovan J. Lott, Sunita Mathur, Roxanne Bendixen, Erika Finanger, and Sean C. Forbes
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Duchenne muscular dystrophy ,Physical Therapy, Sports Therapy and Rehabilitation ,Walk Test ,Lower limb ,Plantar flexion ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Humans ,Knee ,030212 general & internal medicine ,Longitudinal Studies ,Muscle Strength ,Muscular dystrophy ,Child ,Muscle, Skeletal ,Knee extensors ,business.industry ,Rehabilitation ,Physical Functional Performance ,musculoskeletal system ,medicine.disease ,Large cohort ,Muscular Dystrophy, Duchenne ,Lower Extremity ,Child, Preschool ,Ambulatory ,Female ,business ,human activities ,030217 neurology & neurosurgery ,Cohort study - Abstract
OBJECTIVE The main objective of this study was to examine the effect of disease on strength in two functionally important lower limb muscles for a period of 2 yrs in children with Duchene muscular dystrophy. DESIGN Seventy-seven Duchene muscular dystrophy children participated in this study. Plantar flexors, knee extensors, strength, and performance on timed tests (6-min walk, 4-stairs, 10-m walk, supine-up) were assessed yearly for 2 yrs. Multivariate normal regression was used to assess changes in strength over time in the Duchene muscular dystrophy group. Spearman correlations were computed to examine relationship between strength and function. RESULTS Normalized plantar flexor and knee extensor strength showed a significant decrease (P < 0.05) over 2 yrs, with larger declines in knee extensor. At baseline, knee extensor strongly correlated with performance on timed tests. However, plantar flexor strength was found to be a stronger predictor of loss in ambulatory function. Modest correlations (r = 0.19-0.34) were found between the decline in strength and functional performance over 2 yrs. CONCLUSIONS This study describes the loss of lower limb strength in a large cohort of Duchene muscular dystrophy children for 2 yrs. The findings support that lower limb strength alone cannot account for the decline in performance on functional tests, and the role of other contributing factors, such as compensatory strategies, should be considered.
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- 2018
44. Hippocampal subfield abnormalities and memory functioning in children with fetal alcohol Spectrum disorders
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Kenneth L. Jones, Alyssa M. Krueger, Sarah N. Mattson, Jeffrey R. Wozniak, Timothy Hendrickson, Christopher A. Boys, Donovan J. Roediger, Bryon A. Mueller, Kelvin O. Lim, Mariah J. Schumacher, and Erik de Water
- Subjects
Male ,animal structures ,Adolescent ,Memory, Episodic ,Hippocampus ,Neuroimaging ,NIH Toolbox ,010501 environmental sciences ,Hippocampal formation ,Toxicology ,01 natural sciences ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Fetal alcohol ,0302 clinical medicine ,Developmental Neuroscience ,Memory ,Pregnancy ,Humans ,Medicine ,Child ,CA1 Region, Hippocampal ,Episodic memory ,Spatial Memory ,0105 earth and related environmental sciences ,Human Connectome Project ,Ethanol ,business.industry ,Subiculum ,Organ Size ,Magnetic Resonance Imaging ,nervous system ,Fetal Alcohol Spectrum Disorders ,Case-Control Studies ,Prenatal Exposure Delayed Effects ,Prenatal alcohol exposure ,Dentate Gyrus ,Female ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Prenatal alcohol exposure (PAE) affects early brain development and has been associated with hippocampal damage. Animal models of PAE have suggested that some subfields of the hippocampus may be more susceptible to damage than others. Recent advances in structural MRI processing now allow us to examine the morphology of hippocampal subfields in humans with PAE. Method Structural MRI scans were collected from 40 children with PAE and 39 typically developing children (ages 8–16). The images were processed using the Human Connectome Project Minimal Preprocessing Pipeline (v4.0.1) and the Hippocampal Subfields package (v21) from FreeSurfer. Using a large dataset of typically developing children enrolled in the Human Connectome Project in Development (HCP-D) for normative standards, we computed age-specific volumetric z-scores for our two samples. Using these norm-adjusted hippocampal subfield volumes, comparisons were performed between children with PAE and typically developing children, controlling for total intracranial volume. Lastly, we investigated whether subfield volumes correlated with episodic memory (i.e., Picture Sequence Memory test of the NIH toolbox). Results Five subfields had significantly smaller adjusted volumes in children with PAE than in typically developing controls: CA1, CA4, subiculum, presubiculum, and the hippocampal tail. Subfield volumes were not significantly correlated with episodic memory. Conclusions The results suggest that several regions of the hippocampus may be particularly affected by PAE. The finding of smaller CA1 volumes parallels previous reports in rodent models. The novel findings of decreased volume in the subicular cortex, CA4 and the hippocampal tail suggest avenues for future research.
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- 2021
45. Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort
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Rebecca J. Willcocks, Claudia R. Senesac, Richard S. Finkel, William D. Rooney, Glenn A. Walter, Erika Finanger, Michael J. Daniels, William T. Triplett, Barry J. Byrne, Gihan Tennekoon, Sean C. Forbes, Krista Vandenborne, H. Lee Sweeney, Donovan J. Lott, Ann T. Harrington, Dah Jyuu Wang, and Barry S. Russman
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In vivo magnetic resonance spectroscopy ,medicine.medical_specialty ,Longitudinal study ,medicine.diagnostic_test ,business.industry ,Duchenne muscular dystrophy ,Magnetic resonance imaging ,medicine.disease ,Biceps ,030218 nuclear medicine & medical imaging ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,Internal medicine ,Ambulatory ,Cohort ,medicine ,Cardiology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Rare disease - Abstract
Objective The aim of this study was to describe Duchenne muscular dystrophy (DMD) disease progression in the lower extremity muscles over 12 months using quantitative magnetic resonance (MR) biomarkers, collected across three sites in a large cohort. Methods A total of 109 ambulatory boys with DMD (8.7 ± 2.0 years; range, 5.0–12.9) completed baseline and 1-year follow-up quantitative MR imaging (transverse relaxation time constant; MRI-T2), MR spectroscopy (fat fraction and 1H2O T2), and 6-minute walk test (6MWT) measurements. A subset of boys completed additional measurements after 3 or 6 months. Results MRI-T2 and fat fraction increased significantly over 12 months in all age groups, including in 5- to 6.9-year-old boys. Significant increases in vastus lateralis (VL) fat fraction were observed in 3 and 6 months. Even in boys whose 6MWT performance improved or remained stable over 1 year, significant increases in MRI-T2 and fat fraction were found. Of all the muscles examined, the VL and biceps femoris long head were the most responsive to disease progression in boys with DMD. Interpretation MR biomarkers are responsive to disease progression in 5- to 12.9-year-old boys with DMD and able to detect subclinical disease progression in DMD, even within short (3–6 months) time periods. The measured sensitivity of MR biomarkers in this multicenter study may be critically important to future clinical trials, allowing for smaller sample sizes and/or shorter study windows in this fatal rare disease. Ann Neurol 2016;79:535–547
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- 2016
46. Gestational diabetes affects spatial working memory and lipid metabolism but not oxidative stress biomarkers in second generation offspring rats
- Author
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Christian Cortés-Rojo, María Esther Olvera-Cortés, Rafael Salgado-Garciglia, Maribel Huerta-Cervantes, Miguel Ángel López-Vázquez, Salvador Manzo-Avalos, Alfredo Saavedra-Molina, Rocío Montoya-Pérez, and Donovan J. Peña-Montes
- Subjects
medicine.medical_specialty ,Offspring ,business.industry ,Lipid metabolism ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Spatial memory ,Gestational diabetes ,Endocrinology ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology ,Oxidative stress ,Biotechnology - Published
- 2020
47. Antioxidant activity of the ethyl acetate extract of Justicia spicigera in two periods of the year (spring‐summer and autumn‐winter) in the liver of adult diabetic rats
- Author
-
Marina Murillo-Villicaña, Ruth Noriega-Cisneros, Rafael Salgado-Garciglia, Alfredo Saavedra-Molina, Maribel Huerta-Cervantes, Asdrúbal Aguilera-Méndez, and Donovan J. Peña-Montes
- Subjects
geography ,geography.geographical_feature_category ,Antioxidant ,biology ,medicine.medical_treatment ,Ethyl acetate ,biology.organism_classification ,Biochemistry ,chemistry.chemical_compound ,Horticulture ,chemistry ,Spring (hydrology) ,Genetics ,medicine ,Justicia spicigera ,Molecular Biology ,Biotechnology - Published
- 2020
48. Activating PAX gene family paralogs to complement PAX5 leukemia driver mutations
- Author
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Marshall S. Horwitz, Tobias Neff, Matthew R. Hart, Christopher C. Porter, Donovan J. Anderson, and Michael Levin
- Subjects
0301 basic medicine ,Male ,Cancer Research ,B Cells ,Cellular differentiation ,Paired Box ,Hypertonic Solutions ,Gene Expression ,medicine.disease_cause ,Kidney ,Biochemistry ,Hematologic Cancers and Related Disorders ,White Blood Cells ,Mice ,0302 clinical medicine ,Spectrum Analysis Techniques ,Osmoregulation ,NFAT5 ,immune system diseases ,Animal Cells ,hemic and lymphatic diseases ,Medicine and Health Sciences ,Small interfering RNAs ,RNA, Small Interfering ,Genetics (clinical) ,Mutation ,B-Lymphocytes ,Pax genes ,Cell Differentiation ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Acute Lymphoblastic Leukemia ,Flow Cytometry ,3. Good health ,Cell biology ,Up-Regulation ,Nucleic acids ,Oncology ,Spectrophotometry ,030220 oncology & carcinogenesis ,Lymphoblastic Leukemia ,Female ,Cytophotometry ,Cellular Types ,Research Article ,lcsh:QH426-470 ,Immune Cells ,Immunology ,Primary Cell Culture ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Protein Domains ,Cell Line, Tumor ,Leukemias ,DNA-binding proteins ,medicine ,Genetics ,Animals ,Humans ,Antibody-Producing Cells ,Non-coding RNA ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Blood Cells ,HEK 293 cells ,PAX2 Transcription Factor ,Wild type ,PAX5 Transcription Factor ,Kidney metabolism ,Biology and Life Sciences ,Proteins ,Cancers and Neoplasms ,Cell Biology ,Xenograft Model Antitumor Assays ,Coculture Techniques ,Gene regulation ,Regulatory Proteins ,lcsh:Genetics ,030104 developmental biology ,HEK293 Cells ,RNA ,PAX5 ,Developmental Biology ,Transcription Factors - Abstract
PAX5, one of nine members of the mammalian paired box (PAX) family of transcription factors, plays an important role in B cell development. Approximately one-third of individuals with pre-B acute lymphoblastic leukemia (ALL) acquire heterozygous inactivating mutations of PAX5 in malignant cells, and heterozygous germline loss-of-function PAX5 mutations cause autosomal dominant predisposition to ALL. At least in mice, Pax5 is required for pre-B cell maturation, and leukemic remission occurs when Pax5 expression is restored in a Pax5-deficient mouse model of ALL. Together, these observations indicate that PAX5 deficiency reversibly drives leukemogenesis. PAX5 and its two most closely related paralogs, PAX2 and PAX8, which are not mutated in ALL, exhibit overlapping expression and function redundantly during embryonic development. However, PAX5 alone is expressed in lymphocytes, while PAX2 and PAX8 are predominantly specific to kidney and thyroid, respectively. We show that forced expression of PAX2 or PAX8 complements PAX5 loss-of-function mutation in ALL cells as determined by modulation of PAX5 target genes, restoration of immunophenotypic and morphological differentiation, and, ultimately, reduction of replicative potential. Activation of PAX5 paralogs, PAX2 or PAX8, ordinarily silenced in lymphocytes, may therefore represent a novel approach for treating PAX5-deficient ALL. In pursuit of this strategy, we took advantage of the fact that, in kidney, PAX2 is upregulated by extracellular hyperosmolarity. We found that hyperosmolarity, at potentially clinically achievable levels, transcriptionally activates endogenous PAX2 in ALL cells via a mechanism dependent on NFAT5, a transcription factor coordinating response to hyperosmolarity. We also found that hyperosmolarity upregulates residual wild type PAX5 expression in ALL cells and modulates gene expression, including in PAX5-mutant primary ALL cells. These findings specifically demonstrate that osmosensing pathways may represent a new therapeutic target for ALL and more broadly point toward the possibility of using gene paralogs to rescue mutations driving cancer and other diseases., Author summary Mutations inactivating PAX5 disrupt B cell differentiation and occur frequently in ALL. Others have previously shown that restoring PAX5 expression normalizes B cell differentiation and leads to disease remission in a mouse model of ALL. We found that exogenous expression of PAX5’s intact and closely related gene family members, PAX2 or PAX8, which are ordinarily silent in lymphocytes but expressed in kidney and other tissues, can substitute for PAX5 and restore differentiation in ALL cells. A new approach for treating ALL might therefore be to discover ways to activate expression of PAX2 or PAX8 in leukemic cells. In the kidney, PAX2 expression is activated by changes in extracellular osmolarity. We found that PAX2 retains the capacity for osmotic activation in ALL cells and that wild type PAX5 expression also increases when ALL cells are osmotically stressed. Adjustment of serum osmolarity—or treatment with drugs targeting pathways responding to osmotic stress—may offer a potential new avenue for ALL therapy by elevating expression of PAX gene family members. More generally, our studies point toward a novel strategy of recruiting paralogs to complement mutations in genes responsible for cancer and other diseases.
- Published
- 2018
49. Antioxidant and hypoglycemic effects of Justicia spicigera in kidney from diabetic rats
- Author
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Marina Murillo-Villicaña, Alfredo Saavedra-Molina, Donovan J. Peña-Montes, Rocío Montoya-Pérez, Jorge A. Mejía-Barajas, Rafael Salgado-Garciglia, José A. Martínez-Mora, and Ruth Noriega-Cisneros
- Subjects
Kidney ,Antioxidant ,Traditional medicine ,biology ,business.industry ,medicine.medical_treatment ,biology.organism_classification ,Biochemistry ,medicine.anatomical_structure ,Genetics ,medicine ,Hypoglycemic Effects ,Justicia spicigera ,business ,Molecular Biology ,Biotechnology - Published
- 2018
50. Tracking Drosophila Larval Behavior in Response to Optogenetic Stimulation of Olfactory Neurons
- Author
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Eryn Slankster, America Mathis, Dennis Mathew, Samipya Kafle, Donovan J. Kohler, Seth R. Odell, and David A. Clark
- Subjects
0301 basic medicine ,Olfactory receptor ,General Immunology and Microbiology ,Larval behavior ,Olfactory receptor neuron ,General Chemical Engineering ,General Neuroscience ,fungi ,Stimulation ,Olfaction ,respiratory system ,Biology ,Optogenetics ,Olfactory neuron ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Odor ,medicine ,sense organs ,Neuroscience - Abstract
The ability of insects to navigate toward odor sources is based on the activities of their first-order olfactory receptor neurons (ORNs). While a considerable amount of information has been generated regarding ORN responses to odorants, the role of specific ORNs in driving behavioral responses remains poorly understood. Complications in behavior analyses arise due to different volatilities of odorants that activate individual ORNs, multiple ORNs activated by single odorants, and the difficulty in replicating naturally observed temporal variations in olfactory stimuli using conventional odor-delivery methods in the laboratory. Here, we describe a protocol that analyzes Drosophila larval behavior in response to simultaneous optogenetic stimulation of its ORNs. The optogenetic technology used here allows for specificity of ORN activation and precise control of temporal patterns of ORN activation. Corresponding larval movement is tracked, digitally recorded, and analyzed using custom written software. By replacing odor stimuli with light stimuli, this method allows for a more precise control of individual ORN activation in order to study its impact on larval behavior. Our method could be further extended to study the impact of second-order projection neurons (PNs) as well as local neurons (LNs) on larval behavior. This method will thus enable a comprehensive dissection of olfactory circuit function and complement studies on how olfactory neuron activities translate in to behavior responses.
- Published
- 2018
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