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1. Realization of a Desktop Flight Simulation System for Motion-Cueing Studies

Author

Berkay Volkaner, S. Numan Sozen, and V. Emre Omurlu

Subjects
Electronics, TK7800-8360, Electronic computers. Computer science, QA75.5-76.95
Abstract

Parallel robotic mechanisms are generally used in flight simulators with a motion-cueing algorithm to create an unlimited motion feeling of a simulated medium in a bounded workspace of the simulator. A major problem in flight simulators is that the simulation has an unbounded space and the manipulator has a limited one. Using a washout filter in the motion-cueing algorithm overcomes this. In this study, a low-cost six degrees of freedom (DoF) desktop parallel manipulator is used to test a classical motion-cueing algorithm; the algorithm's functionality is confirmed with a Simulink real-time environment. Translational accelerations and angular velocities of the simulated medium obtained from FlightGear flight simulation software are processed through a generated washout filter algorithm and the simulated medium's motion information is transmitted to the desktop parallel robotic mechanism as a set point for each leg. The major issues of this paper are designing a desktop simulation system, controlling the parallel manipulator, communicating between the flight simulation and the platform, designing a motion-cueing algorithm and determining the parameters of the washout filters.

Published
2016
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2. The significance of Rai and Binet clinical staging on the survival of chronic lymphocytic leukemia patients in the Kurdistan region of Iraq

Author

Shlan S Muhammad, Ahmed Khudair Yassin, Rawand P Shamoon, Nawsherwan S Mohammed, Marwa Nadhim Nadhim, Kawa M Hassan, Bryar Sabah Rashid, Shokhan M Mohammad, Ranan karadagh, Ghanim S Numan, Lara Lateef Abdulrahman, Sana D Jalal, Zhala O Ahmed, Hisham A Getta, Tavan I Mahmood, Basil K Abdulla, Dana A Abdullah, Rozh-hat A Yousif, and Zeki A Mohamed

Subjects
binet staging, chronic lymphocytic leukemia, rai staging, survival, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

BACKGROUND: Chronic lymphocytic leukemia is an uncommon type of leukemia in Iraq, although many reported cases of chronic lymphocytic leukemia in the Iraqi Kurdistan region are of high risk stage. Staging of chronic lymphocytic leukemia is essential in treatment planning and for disease prognosis. the aims of this study were to find out the difference in patients' survival with early and late clinical stages, and to evaluate CLL outcome in relation to the Rai and Binet staging. PATIENTS AND METHODS: This retrospective cross-sectional analysis studied 250 patients, 170 male and 80 female, with chronic lymphocytic leukemia who were registered in three hemato-oncology centers in Iraqi Kurdistan for the last 10 years. The diagnosis of the disease was made according to the guideline of the International Workshop Chronic Lymphocytic Leukemia update of the National Cancer Institute. The patients' clinical staging was determined by a senior hematologist based on the clinical and laboratory findings. RESULTS: The mean age of the patients was 63(±11.8) years, 40% were >65 years. The median survival was 27 months. Elderly patients >65 years had significantly lower mean survival. The Rai staging was distributed as follows: stage 0 (24.8%), stage I (12.8%), stage II (30.8%), stage III (9.6%) and stage IV (22%). The median survival was significantly higher among patients with Rai stage 0 comparing to patients with advanced stages (P

Published
2021
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3. The pattern of bone marrow involvement among chronic lymphocytic leukemia patients and its impact on the disease outcome in Kurdistan Region of Iraq

Author

Marwa Nadhim Karam, Kawa M Hasan, Nawsherwan S Mohammed, Ahmed K Yassin, Shokhan Mohammad Mustafa, Lara Lateef Abdulrahman, Ranan K Polis, Ghanim S Numan, Shlan S Mohammed, Rawand P Shamoon, Bryar Sabah Rashid, Sana D Jalal, Rozhhat A Yousif, Zeki A Mohamed, Tavan I Mahmood, Basil K Abdulla, Dana A Abdullah, Zhalla O Ahmed, and Hisham A Getta

Subjects
bone marrow, chronic lymphocytic leukemia, overall survival, progression-free survival, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

OBJECTIVES : There are the variable degrees of bone marrow (BM) infiltration patterns in chronic lymphocytic leukemia (CLL). Four BM patterns: Interstitial, nodular, mixed, and diffuse patterns were identified. The aim of this study is to assess the effects of BM infiltration patterns on the disease outcome among CLL patients in Kurdistan Region of Iraq. METHODS: This study is a cross-sectional, descriptive, retrospective involved 106 patients with CLL disease. The data are collected in the Kurdistan region of Iraq (including Erbil, Sulaymaniyah, and Duhok) cancer centers. Through the period from January 1, 2010 to December 31, 2019. BM histopathology study of all patients was assessed and correlated with the disease outcome. RESULTS: Fifty-three (50.0%) patients had interstitial BM patterns, 17 (16.0%) had nodular BM pattern, 14 (13.2%) had mixed BM patterns, and 22 (20.8%) had diffuse BM pattern. The results showed that patients with interstitial, nodular, and mixed BM patterns had a superior overall survival (OS) and progression-free survival (PFS) rate than diffuse BM pattern. Kaplan–Meier curve illustrates that our CLL patients with interstitial BM patterns had a better mean OS rate (44.0 months) than diffuse BM pattern with a mean of (23.2 months). As well as for PFS, the mean was (35.7 months) for the interstitial BM patterns and (17.6 months) for diffuse BM pattern. CONCLUSIONS: We demonstrate that the BM involvement patterns have a prognostic value in our CLL patients and provide more reliable information regarding the clinical outcome.

Published
2021
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4. Impact of clinical staging and demographic data (age and sex) on response to treatment and survival of chronic lymphocytic leukemia patients in Kurdistan Region of Iraq

Author

Bryar Sabah Rashid, Sana D Jalal, Ahmed K Yassin, Kawa M Hassan, Zeki A Mohamed, Zhala O Ahmed, Tavan I Mahmood, Rawand P Shamoon, Shokhan M Mustafa, Marwa Nadhim Karam, Dana A Abdullah, Shlan S Mohammad, Lara L Abdulrahman, Rozh-hat A Yousif, Basil K Abdulla, Nawsherwan S Mohammed, Hisham A Getta, Ranan K Polus, and Ghanim S Numan

Subjects
binet staging, chronic lymphocytic leukemia, survival, watch and wait, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

BACKGROUND: The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Certain patients go through a brisk illness progression, and others stay alive for quite a long time without requiring treatment. OBJECTIVE: This study was conducted to evaluate the impact of clinical staging, age, gender, and treatment initiation on the survival of CLL patients in Kurdistan-Iraq. MATERIALS AND METHODS: A total of 239 CLL patients from Oncology Centers from Kurdistan-Iraq were enrolled in a retrospective study from January 1, 2010, to December 31, 2020. A standardized questionnaire was used to obtain demographics data, presenting features, blood investigations, and imaging results. The diagnosis and treatment assessment was based on the International Workshop of CLL, and clinical staging was performed using both Rai and Binet classifications. There were two groups of patients (watch and wait) and (treated) groups. RESULTS: The median age at the diagnosis was 64 years old with a male: female ratio of 2.3:1. Eighty-three patients (34.7%) were diagnosed incidentally and about one-third of the patients presented with advanced stage, and also, 62.3% of the patients received therapy throughout the study period. The 3-year overall survival was (81.1%) (95% confidence interval 74.3%–87.9%). Of particular interest to report that advanced age, Binet Stage C, and hemoglobin

Published
2021
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5. Probabilistic seismic hazard assessment for Iraq

Author

Hussein K. Chlaib, Wathiq Abdulnaby, Haydar Al-Shukri, Hanan Mahdi, Najah Abd, Ammar M. Shakir, Rengin Gök, Tuna Onur, Ali Ramthan, Taher H. Ameen, and Nazar M. S. Numan

Subjects
Engineering, 010504 meteorology & atmospheric sciences, business.industry, Seismic loading, Active fault, Induced seismicity, 010502 geochemistry & geophysics, 01 natural sciences, Hazard, Tectonics, Geophysics, Seismic hazard, Geochemistry and Petrology, Building code, Seismic risk, business, Seismology, 0105 earth and related environmental sciences
Abstract

Probabilistic seismic hazard assessments (PSHA) form the basis for calculating seismic loads in most contemporary seismic provisions in building codes around the world. The current building code of Iraq, which was published in 1997, is currently undergoing a significant engineering update. This study was undertaken in order to support the building code update and to satisfy the need in Iraq for a contemporary assessment of seismic hazard in terms of spectral accelerations. Seismic source characterization largely relies on a newly compiled earthquake catalog since sufficiently detailed information is not available on active faulting in the country even though there are numerous known active faults. There is also a lack of locally recorded strong-motion data. As a result, we make use of attenuation tomography studies in the region to compare local attenuation characteristics with that in other parts of the world where ground-motion prediction equations are available for use in PSHA. For most of the country, the attenuation of 1HzLg waves indicates an attenuation rate that is slower than active tectonic regions but faster than stable continental regions. Hence, we use ground-motion prediction equations from active tectonic and stable continental regions, weighted equally. The PSHA results are presented for a 2% chance of being exceeded in 50 years and on a reference ground condition of the National Earthquake Hazards Reduction Program (NEHRP) site class B. The probability level and reference ground conditions were selected to be consistent with the update of Iraq’s building code. The largest hazard, and consequently the design ground motions, is in the northern cities of Sulaymaniyah and Erbil, consistent with the fact that they are the two urban areas closest to major tectonic features to the north and east of Iraq. Additionally, the Badra–Amarah fault zone is a significant contributor to seismic hazard in the country; therefore, urban areas near it exhibit high seismic hazard.

Published
2020
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6. A Comprehensive Earthquake Catalog for Iraq in Terms of Moment Magnitude

Author

Najah Abd, Nazar M. S. Numan, Wathiq Abdulnaby, Tuna Onur, Hanan Mahdi, Rengin Gök, Haydar Al-Shukri, Hussein K. Chlaib, Ammar M. Shakir, and Taher H. Ameen

Subjects
010504 meteorology & atmospheric sciences, Magnitude (mathematics), Moment tensor, Moment magnitude scale, 010502 geochemistry & geophysics, 01 natural sciences, Coda, Earthquake catalog, Moment (mathematics), Geophysics, Geological survey, Seismology, Geology, 0105 earth and related environmental sciences
Abstract

A comprehensive earthquake catalog was compiled for Iraq and neighboring areas as part of a broader probabilistic seismic‐hazard assessment project. The Iraq Seismic Network (ISN) was established in 1976 and became operational in the early 1980s. However, recording and reporting of seismic data has been intermittent in Iraq. Hence, events were collected from various sources, including the ISN when available, International Seismological Centre (ISC), European‐Mediterranean Seismological Centre, U.S. Geological Survey Centennial Catalog, Global Centroid Moment Tensor solutions, and Ambraseys’ extensive work on cataloging of instrumental era earthquakes in the Middle East (e.g., Ambraseys, 1978, 2001, 2009). We supplement these with new direct moment magnitude calculations based on coda calibration technique. For many of the larger events in the catalog, more than one magnitude is available. Directly calculated moment magnitudes ( M w) were favored, followed by body‐wave magnitude ( m b) obtained from the ISC. Where no directly calculated M w was available, other magnitude scales were converted to M w using relationships compatible with the local catalog. The resulting earthquake catalog spans from the year 1900 until the end of 2009, covers the region bounded by 26°–40° N latitudes and 36°–51° E longitudes, and includes more than 18,000 earthquakes, of which roughly 4000 are M w 4.0 or larger.

Published
2017
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7. Does the time between ordering and administering the first dose of antibiotic influences outcome in septic shock patients?

Author

Mohammad S. Numan, Abdullah F. Alotaibi, Ayman Morish, Lama H. Meriky, Haifa Algethamy, and Abeer A Arab

Subjects
business.industry, Septic shock, medicine.drug_class, Mortality rate, Antibiotics, Drug resistance, Critical Care and Intensive Care Medicine, medicine.disease, Intensive care unit, law.invention, Sepsis, Anesthesiology and Pain Medicine, law, Intensive care, Anesthesia, Hospital discharge, Medicine, business
Abstract

Background & Objectives: It is generally believed that significant delay in administering antibiotics in severely septic patients and those with septic shock increases mortality. However, most studies were retrospective and/or of questionable design. Moreover, the starting times from which delays were measured varied and often seemed somewhat amorphous. We assessed the duration of time between antibiotics being ordered and first administered among patients with newly diagnosed septic shock in a Saudi intensive care unit (ICU), and its effects on 30-day mortality and the rate of major complications. We also sought to identify any time threshold at which the mortality rate clearly increased. Methodology: Data were prospectively collected on 96 patients ≥14-years-old (male/ female = 49%; mean age 62.1 y) admitted to our ICU and followed for ≥30 days, or until hospital discharge or death. The time between ordering and administering the first dose of antibiotics after diagnosis of septic shock was recorded and its impact upon survival and major complications analyzed. Results: Fifty of 96 patients died within the ICU. Unexpectedly, mortality rate declined steadily between < one min (60%) and 5 h delay (44%), but rose sharply beyond five hours (p < 0.001). Time delay did not significantly influence the rate of any major complication other than death. Conclusions: Our results call into question recent conclusions that delays administering antibiotics beyond one to two hours result in significantly increased mortality. Further prospective, large scale studies are necessary to clarify this issue. Citation: Algethamy HM, Arab AA, Morish A, Meriky LH, Numan MS, Alotaibi AF. Does the time between ordering and administering the first dose of antibiotic influence outcomes in septic shock patients? Anaesth pain & intensive care 2019;23(3)

Published
2020
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8. Gene-environment interactions in Paget's disease of bone

Author

Nathalie Amiable, Mohamed S Numan, Edith Gagnon, Jacques P. Brown, Mariam Dessay, Laëtitia Michou, and Sonia Jean

Subjects
Adult, Male, medicine.medical_specialty, Protein Data Bank (RCSB PDB), Osteoclasts, medicine.disease_cause, Risk Assessment, Tobacco smoke, Bone resorption, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Rheumatology, Downregulation and upregulation, Osteoclast, Reference Values, Internal medicine, Sequestosome-1 Protein, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Adaptor Proteins, Signal Transducing, 030203 arthritis & rheumatology, Air Pollutants, business.industry, Incidence, RANK Ligand, Age Factors, Quebec, Environmental Exposure, Middle Aged, medicine.disease, Osteitis Deformans, In vitro, Paget's disease of bone, Endocrinology, medicine.anatomical_structure, Cross-Sectional Studies, Logistic Models, Gene Expression Regulation, Multivariate Analysis, Mutation, Female, Gene-Environment Interaction, Tobacco Smoke Pollution, business, Oxidative stress, Cadmium
Abstract

Objectives This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). Methods We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. Results An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients' osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients' osteoclasts were observed. Conclusions Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.

Published
2018

9. Impact of Air Pollutants on Oxidative Stress in Common Autophagy-Mediated Aging Diseases

Author

Jacques P. Brown, Mohamed S Numan, and Laëtitia Michou

Subjects
Pathology, medicine.medical_specialty, autophagy, Health, Toxicology and Mutagenesis, SQSTM1/p62, lcsh:Medicine, Review, Disease, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Air pollutants, medicine, Humans, oxidative stress, neurodegenerative diseases, air pollutants, Amyotrophic lateral sclerosis, 030304 developmental biology, 0303 health sciences, Autophagy, aging, lcsh:R, Public Health, Environmental and Occupational Health, RNA, Paget’s disease of bone, medicine.disease, 3. Good health, Cell biology, Paget's disease of bone, 13. Climate action, cigarettes, tobacco smoke, 030217 neurology & neurosurgery, Oxidative stress, Frontotemporal dementia, wood heating
Abstract

Atmospheric pollution-induced cellular oxidative stress is probably one of the pathogenic mechanisms involved in most of the common autophagy-mediated aging diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, disease, as well as Paget's disease of bone with or without frontotemporal dementia and inclusion body myopathy. Oxidative stress has serious damaging effects on the cellular contents: DNA, RNA, cellular proteins, and cellular organelles. Autophagy has a pivotal role in recycling these damaged non-functional organelles and misfolded or unfolded proteins. In this paper, we highlight, through a narrative review of the literature, that when autophagy processes are impaired during aging, in presence of cumulative air pollution-induced cellular oxidative stress and due to a direct effect on air pollutant, autophagy-mediated aging diseases may occur.

Published
2015

10. “Appropriate” Versus “Inappropriate” Antibiotic Administration, “Prior To” Versus “After” the Diagnosis of Septic Shock. Impact on Patients with Sepsis Admitted to a Saudi Intensive Care Unit

Author

Abdullah F. Alotaibi, Ayman Morish, Mohammad S. Numan, and Haifa Algethamy

Subjects
Original Paper, medicine.medical_specialty, treatment, medicine.drug_class, Septic shock, business.industry, medicine.medical_treatment, Antibiotics, Soft tissue, Disease, medicine.disease, mortality, Intensive care unit, antibiotics, law.invention, sepsis, Sepsis, law, Internal medicine, medicine, septic shock, SOFA score, business, Dialysis
Abstract

Introduction: Delaying broad-spectrum antibiotics beyond 1-2 hours once the septic shock is diagnosed increases patients’ risk of death. However, what is the impact of already being on antibiotics when a septic shock is diagnosed? Aim: We compared demographics, clinical characteristics and outcomes in septic shock patients on antibiotics initiated prior to versus after septic shock was diagnosed; whose initial antibiotics were considered appropriate for the offending organism(s); and who died in versus were discharged from the ICU. Methods: Data were prospectively collected on 161 patients ≥ 14-years-old (female: male=1:1; mean age 61.1yrs) admitted to the ICU for septic shock, and followed for ≥30 days, or until hospital discharge or death. Results: Few inter-group differences were identified. Those treated early were more likely to have a nosocomial infection (p=0.03), skin or soft tissue source of their infection (p=0.01), or a diabetes-related limb amputation (p=0.02); but received fewer antibiotics (p=0.01). Those on appropriate antibiotics were more likely to be female (p=0.048), but less likely to have a skin or soft tissue source of infection (p=0.03). Neither starting antibiotics early, nor being on appropriate antibiotics impacted any outcome measure, including survival. Predictors of mortality were ≥1 co-morbid condition (p=0.03), more versus fewer co-morbid conditions (p=0.009), cardiovascular disease at baseline (p=03), requiring dialysis at baseline (p=0.008), and a higher day#1 SOFA score (p

Published
2020
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11. Tranexamic acid in coronary artery surgery: One-year results of the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial

Author

Paul S. Myles, Julian A. Smith, Jessica Kasza, Brendan Silbert, Mohandas Jayarajah, Thomas Painter, D. James Cooper, Silvana Marasco, John McNeil, Jean S. Bussières, Shay McGuinness, Kelly Byrne, Matthew T.V. Chan, Giovanni Landoni, Sophie Wallace, Andrew Forbes, Paul Myles, Julian Smith, Donald Esmore, Henry Krum, A. Tonkin, B. Buxton, S. Heritier, A. Merry, D. Liew, J. McNeil, A. Forbes, D.J. Cooper, S. Wallace, A. Meehan, P. Myles, W. Galagher, C. Farrington, A. Ditoro, L. Wutzlhofer, D. Story, P. Peyton, S. Baulch, S. Sidiropoulos, D. Potgieter, R.A. Baker, B. Pesudovs, E. O'Loughlin J Wells, P. Coutts, S. Bolsin, C. Osborne, K. Ives, J. Smith, A. Hulley, G. Christie-Taylor, T. Painter, S. Lang, H. Mackay, C. Cokis, S. March, P.G. Bannon, C. Wong, L. Turner, D. Scott, B. Silbert, S. Said, P. Corcoran, L. de Prinse, J.S. Bussières, N. Gagné, A. Lamy, L. Semelhago, M.T.V. Chan, M. Underwood, G.S.Y. Choi, B. Fung, G. Landoni, R. Lembo, F. Monaco, F. Simeone, D. Marianello, G. Alvaro, G. De Vuono, D. van Dijk, J. Dieleman, S. Numan, S. McGuinness, R. Parke, P. Raudkivi, E. Gilder, K. Byrne, J. Dunning, J. Termaat, G. Mans, M. Jayarajah, J. Alderton, D. Waugh, M.J. Platt, A. Pai, A. Sevillano, A. Lal, C. Sinclair, G. Kunst, A. Knighton, G.M. Cubas, P. Saravanan, R. Millner, V. Vasudevan, M. Patteril, E. Lopez, R. Basu, J. Lu, Myles, P, Smith, Ja, Kasza, J, Silbert, B, Jayarajah, M, Painter, T, Cooper, Dj, Marasco, S, Mcneil, J, Bussières, J, Mcguinness, S, Byrne, K, Chan, Mtv, Landoni, G, Wallace, S, Forbes, A, and ATACAS investigators and the ANZCA Clinical Trials, Network

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Time Factors, Antifibrinolytic, medicine.drug_class, Myocardial Infarction, disability-free survival, Hemorrhage, Coronary Artery Disease, anesthesia, 030204 cardiovascular system & hematology, antiplatelet, Coronary artery disease, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Fibrinolytic Agents, Coronary thrombosis, Risk Factors, Activities of Daily Living, medicine, Humans, Myocardial infarction, Coronary Artery Bypass, antifibrinolytic, Stroke, Aged, Aspirin, business.industry, Coronary Thrombosis, Middle Aged, medicine.disease, Antifibrinolytic Agents, Progression-Free Survival, Cardiac surgery, Tranexamic Acid, 030228 respiratory system, major adverse cardiac event, Anesthesia, outcome, Female, Surgery, Cardiology and Cardiovascular Medicine, business, Tranexamic acid, medicine.drug
Abstract

Background Tranexamic acid reduces blood loss and transfusion requirements in cardiac surgery but may increase the risk of coronary graft thrombosis. We previously reported the 30-day results of a trial evaluating tranexamic acid for coronary artery surgery. Here we report the 1-year clinical outcomes. Methods Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score of less than 8. Secondary outcomes included a composite of myocardial infarction, stroke, and death from any cause through to 1 year after surgery. Results The rate of death or disability at 1 year was 3.8% in the tranexamic acid group and 4.4% in the placebo group (relative risk, 0.85; 95% confidence interval, 0.64-1.13; P = .27), and this did not significantly differ according to aspirin exposure at the time of surgery (interaction P = .073). The composite rate of myocardial infarction, stroke, and death up to 1 year after surgery was 14.3% in the tranexamic acid group and 16.4% in the placebo group (relative risk, 0.87; 95% CI, 0.76-1.00; P = .053). Conclusions In this trial of patients having coronary artery surgery, tranexamic acid did not affect death or severe disability through to 1 year after surgery. Further work should be done to explore possible beneficial effects on late cardiovascular events.

Published
2019
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12. Structure and stratigraphy of the Borrowdale Volcanic rocks of the Kentmere area, English Lake District

Author

N. J. Soper and N. M. S. Numan

Subjects
geography, geography.geographical_feature_category, biology, Andesites, Andesite, Geochemistry, Anticline, Geology, Ecological succession, Fold (geology), biology.organism_classification, Volcanic rock, Paleontology, Monocline, Volcano
Abstract

The Borrowdale Volcanic rocks of Kentmere have been reinvestigated. A previous structural interpretation (Mitchell 1929) involving Caledonian isoclines superimposed upon pre-Caradocian NNE trending folds is shown to be incorrect; neither set of structures exist. The geometry of the major structural elements in the area, the Nan Bield Anticline and the Caledonoid cleavage, is described. Evidence is adduced which suggests that the anticline was formed in pre-Caradocian time as a large open fold trending approximately E-W. Its present geometry and that of the Wren Gill Monocline result from the superimposition of the regional end-Silurian cleavage obliquely and inhomogeneously across this pre-existing fold. The volcanic succession is divided into four compositionally and petrographically defined formations. In upward sequence these are the Nan Bield and Wren Gill formations (andesitic lavas and tuffs), Kentmere Formation (mainly dacitic pryoclastic rocks) and the Garbourn Formation (andesites and dacites), totalling over 2800 m. It is thought that much of this succession was deposited subaqueously.

Published
2007
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13. Paget's disease of bone: an osteoimmunological disorder?

Author

Jacques P. Brown, Laëtitia Michou, Nathalie Amiable, and Mohamed S Numan

Subjects
musculoskeletal diseases, Osteoimmunology, Osteoporosis, SQSTM1/p62, Pharmaceutical Science, Review, Bone and Bones, Bone remodeling, Osteoprotegerin, Osteoclast, Drug Discovery, Medicine, Animals, Humans, Immunologic Factors, Molecular Targeted Therapy, Pharmacology, osteoimmunology, biology, business.industry, RANKL, Paget’s disease of bone, medicine.disease, Osteitis Deformans, Prognosis, 3. Good health, Metabolic Bone Disorder, Paget's disease of bone, medicine.anatomical_structure, Immunology, osteoclast, biology.protein, Cytokines, Bone Remodeling, Inflammation Mediators, business, Biomarkers, Signal Transduction
Abstract

Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget’s disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget’s disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget’s disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

Published
2015

15. Decreased expression of ErbB4 and tyrosine hydroxylase mRNA and protein in the ventral midbrain of aged rats

Author

S. Numan, Kerstin H. Lundgren, Ann M. Hemmerle, Kim B. Seroogy, and Jonathan W. Dickerson

Subjects
Male, medicine.medical_specialty, Aging, Receptor, ErbB-4, Tyrosine 3-Monooxygenase, Cell Survival, Dopamine, Down-Regulation, Substantia nigra, Article, Midbrain, Internal medicine, Glial cell line-derived neurotrophic factor, medicine, Animals, RNA, Messenger, biology, Tyrosine hydroxylase, Pars compacta, General Neuroscience, Dopaminergic, Ventral Tegmental Area, Parkinson Disease, Rats, Inbred F344, Rats, Ventral tegmental area, ErbB Receptors, Substantia Nigra, medicine.anatomical_structure, Endocrinology, nervous system, Gene Expression Regulation, Nerve Degeneration, biology.protein, medicine.drug
Abstract

Decreased availability or efficacy of neurotrophic factors may underlie an increased susceptibility of mesencephalic dopaminergic cells to age-related degeneration. Neuregulins (NRGs) are pleotrophic growth factors for many cell types including mesencephalic dopamine cells in culture and in vivo. The functional NRG receptor ErbB4 is expressed by virtually all midbrain dopamine neurons. To determine if levels of the NRG receptor are maintained during aging in the dopaminergic ventral mesencephalon, expression of ErbB4 mRNA and protein was examined in young (3 months), middle-aged (18 months), and old (24–25 months) Brown Norway/Fischer 344 F1 rats. ErbB4 mRNA levels in the substantia nigra pars compacta (SNpc), but not the adjacent ventral tegmental area (VTA) or subtantia nigra pars lateralis (SNl), were significantly reduced in the middle-aged and old animals when compared to young rats. Protein expression of ErbB4 in the ventral midbrain was significantly decreased in the old rats when compared to the young rats. Expression of tyrosine hydroxylase (TH) mRNA levels were significantly reduced in the old rats when compared to young animals in the SNpc, but not in the VTA or SNl. Tyrosine hydroxylase protein levels in the ventral midbrain were also decreased in the old animals when compared to the young animals. These data demonstrate a progressive decline of ErbB4 expression, coinciding with a loss of the dopamine-synthesizing enzyme TH, in the ventral midbrain of aged rats, particularly in the SNpc. These findings may implicate a role for diminished NRG/ErbB4 trophic support in dopamine-related neurodegenerative disorders of aging such as Parkinson’s disease.

Published
2009

16. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology

Author

Shannon L. Macauley, Lamya S. Shihabuddin, Fred H. Gage, Tatyana V. Taksir, J. Clarke, Michael R. Huff, Gregory R. Stewart, Wendy Yang, James Dodge, S. Numan, G. Parsons, and Marco A. Passini

Subjects
Pathology, medicine.medical_specialty, Cell Survival, Biology, Mice, Prosencephalon, In vivo, Cell Movement, Transduction, Genetic, Neurobiology of Disease, medicine, otorhinolaryngologic diseases, Animals, Mice, Knockout, Niemann-Pick Diseases, General Neuroscience, Brain, Neural stem cell, Transplantation, Mice, Inbred C57BL, stomatognathic diseases, Cholesterol, Sphingomyelin Phosphodiesterase, Acid sphingomyelinase, Cholesterol storage, Sphingomyelin, Lysosomes, Immunostaining, Intracellular, medicine.drug, Stem Cell Transplantation
Abstract

Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined).In vitro, gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs.In vivo, transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.

Published
2004

17. Sex differences in the effects of testosterone and its metabolites on vasopressin messenger RNA levels in the bed nucleus of the stria terminalis of rats

Author

N. A. Bullock, Zuoxin Wang, S. Numan, and G. J. De Vries

Subjects
Male, medicine.medical_specialty, Vasopressin, endocrine system, medicine.drug_class, Neuropeptide, Biology, Thalamus, Internal medicine, medicine, Animals, Testosterone, Castration, RNA, Messenger, Sex Characteristics, Estradiol, urogenital system, General Neuroscience, Dihydrotestosterone, Rats, Inbred Strains, Articles, Androgen, Rats, Arginine Vasopressin, Stria terminalis, Drug Combinations, Endocrinology, Estrogen, Female, hormones, hormone substitutes, and hormone antagonists, Hormone, medicine.drug
Abstract

Male rats have about two times as many steroid-responsive vasopressin-immunoreactive (AVP-ir) neurons in the bed nucleus of the stria terminalis (BST) as female rats. This sex difference does not depend on differences in circulating hormone levels, since it persists in males and females that are treated with similar levels of testosterone. To analyze the cellular basis of this sex difference, we compared the effects of testosterone and its metabolites on AVP mRNA expression in the BST of males and females that were gonadectomized at 3 months of age. When rats received implants of Silastic tubing filled with testosterone, males had more cells that were labeled for AVP mRNA and more labeling per cell than females. When, in a second experiment, rats received implants of either empty tubing, or tubing with dihydrotestosterone (DHT), estradiol (E), or E plus DHT, hardly any labeled cells were found in rats with empty implants. E treatment significantly stimulated AVP mRNA expression in both sexes, but significantly more so in males, which had more cells that were labeled for AVP mRNA and more labeling per cell than females. DHT treatment by itself did not stimulate AVP mRNA expression, but when given in combination with E, it significantly increased the number of cells over that of animals treated with E alone. This increase was seen in males only. However, in both sexes, it increased the labeling per cell over that of animals treated with E only, but more so in males than in females. These data suggest that in addition to a sex difference in the number of cells that produce AVP there is also a sex difference in estrogen as well as androgen responsiveness in individual AVP-producing cells in the BST.

Published
1994

20. Long-term survival after fludarabine, cyclophosphamide, and rituximab treatment in previously untreated chronic lymphocytic leukemia patients

Author

Shokhan Mohammad Mustafa, Ahmed Khudair Yassin, Nawsherwan S Mohammed, Rawand P Shamoon, Marwa N Karam, Shlan S Mohammad, Lara Lateef Abdulrahman, Zhalla O Ahmed, Bryar Sabah Rashid, Tavan I Mahmood, Rozhhat A Yousif, Kawa M Hasan, Zeki A Mohamed, Hisham A Getta, Sana D Jalal, Dana A Abdullah, Basil K Abdulla, Ghanim S Numan, and Ranan Karadagh

Subjects
and rituximab, chronic lymphocytic leukemia, complete response, cyclophosphamide, fludarabine, survival, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

BACKGROUND: Chronic lymphocytic leukemia (CLL) is characterized by a lower incidence rate in Iraq and Kurdistan as compared to Western countries. However, a good prognosis of CLL is dependable on diagnosis, risk stratification, and a better choice of an appropriate treatment regimen. AIM OF THE STUDY: To evaluate the effectiveness of fludarabine, cyclophosphamide, and rituximab (FCR) regimen in comparison to other chemotherapy regimens in the management of patients with CLL in Kurdistan region/Iraq. PATIENTS AND METHODS: A retrospective review study carried out in three cancer centers in the Kurdistan region of Iraq for the duration of 10 years through the period from January 1, 2010 to December 31, 2019, on 152 CLL patients. CLL was diagnosed according to the International Workshop on CLL. The treatment of CLL patients was either by FCR chemo-immunotherapy regimen or other chemotherapies. RESULTS: The FCR chemo-immunotherapy was the treatment of 38.8% of CLL patients, while 61.2% of CLL patients were treated by other chemotherapies. There was a significant association between younger age patients and the use FCR chemo-immunotherapy (P = 0.001). There was a significant association between a complete response and treatment by FCR chemo-immunotherapy (P = 0.02). The mean overall survival duration and progression-free survival of CLL patients treated by FCR chemo-immunotherapy were significantly longer than the mean survival time of CLL patients treated by other chemotherapies (P = 0.01). CONCLUSIONS: Complete response and survival of CLL patients treated by FCR chemo-immunotherapy were better than the complete response and survival of CLL patients treated by other chemotherapies.

Published
2021
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21. TELKAİF BÖLGESİNDE YER ALTI SUYU KALİTESİNDE DEĞİŞİKLİKLER MUSUL KUZEYİ, IRAK.

Author

İbrahim S.Al and Nazar M. S. NUMAN

Subjects
Irak, Telkaif bölgesi, yer altı suyu, su kimyası, Travertine, tectonic emplacement, Mineralogy, QE351-399.2
Abstract

Su kaynaklarındaki kıtlık, nüfusu, artan ihtiyaçlarını karşılamak için kendi kuıyularını açmaya ve yer altı suyunu çekmeye zorlamıştır. Çalışma alanı, Irak’ta buğday, arpa, mercimek ve sebze gibi ürünlerin ekildiği ve büyükbaş hayvan yetiştiriciliğinin yapıldığı başlıca zirai alanlardan biridir. Yer altı suyu örneklerinin kimyasal özelliklerinin incelenmesinin önemi, litolojik birimlerin ve suyun karşılıklı etkileşiminin ve, doğal çözülme süreç­leri yüzünden artan doğal çözünmüş tuz konsantrasyonlarının bilinmesi açısından önemlidir. Telkaif bölgesin­den alınan yer altı suyu örneklerinin kimyasal özellikleri, ev içi ve zirai kullanım için özelliklerinin belirlenmesi amacıyla 14 örnekte incelenmiştir. Yeraltı suyu örneklerinin elektrik iletkenliği (Ec), pH, toplam çözünmüş katilar (TDS), Na+, K+, Ca+2, Mg+2, HC03_1, S04-2, N03_1,CM konsantrasyonları ve toplam sertlik (TH) gibi fiziksel ve kimyasal özellikleri belirlenmiştir. Piper diyagramı kullanılarak, yeraltı sularının uygunluğu, türü ve jeokimyasal gelişmelerinin gösterilmesi için grafik olarak hidrokimyasal parametreleri de analiz edilmiştir. Yer altı suyunun sulama için uygunluğunun gösterilmesi için Richard (1954) ve Wilcox (1955) sınıflamaları da kullanılmıştır. Çalışma alanına yayılmış olan kuyulardan Al-Fatha, Injana litolojik birimleri ve Kuvaterner akiferler tanımlanmış ve incelenmiştir. Bölgedeki yer altı suları yağmur sularından ve suyu toplama havzalarına ulaştıran vadilerden beslenmektedir, inceleme alanının yer altı suyu kimyası yeraltı suyu örneklerinin çoğunun CaHC03 and CaS04 türünde sular olduğunu göstermekte; örneklerde toplam sertlik (TH) ve toplam çözünmüş katilar (TDS) yüksek olup bunlar genellikle düşük alkali değerlerine sahiptir

Published
2009

22. Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART-FID.

Author

Nouhravesh N, Garg J, Rockhold FW, De Pasquale CG, O'Meara E, Lewis GD, Butler J, Harrington J, Ezekowitz JA, Ponikowski P, Troughton RW, Wong YW, Blackman N, Numan S, Adamczyk R, Hernandez AF, and Mentz RJ

Abstract

Aims: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM., Methods and Results: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported., Conclusions: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2024
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23. Patient-Reported Outcomes After Ferric Carboxymaltose Treatment for Iron Deficiency Anemia: A Prospective Observational Study.

Author

Kwong WJ, Numan S, Hunter TD, Alves D, Patel A, and Shanbhag S

Abstract

Background: Iron deficiency anemia (IDA) is a common cause of fatigue and impaired quality of life. The present study aimed to evaluate the impact of intravenous iron supplementation with ferric carboxymaltose (FCM) on fatigue, physical function, and general health among patients with IDA attending routine clinical care., Methods: This was a prospective, single arm, observational study of adult patients prescribed with intravenous FCM for the treatment of IDA during routine clinical care. We used Patient-Reported Outcomes Measurement Information System (PROMIS) instruments to evaluate fatigue (PROMIS Short Form v1.0 13a [FACIT-Fatigue]), general health status (PROMIS Scale v1.2), and physical function (PROMIS Short Form v2.0 4a) before and at 3 and 6 months after FCM treatment., Results: A total of 152 patients were enrolled. Mean age was 47.4 ± 16.0 years and 82.2% were female. Mean serum hemoglobin was 10.2 ± 1.4 g/dL at baseline. All patients were treated with at least one FCM dose at baseline, with 77.6% receiving a two-dose treatment course. The mean baseline FACIT-Fatigue score was 61.0 ± 9.0, improving significantly to 50.2 ± 9.5 at 3 months after FCM treatment. A minimum 5-point improvement, pre-defined as clinically meaningful, was seen in the FACIT-Fatigue, PROMIS Global Physical Health, Global Mental Health and PROMIS Physical Function scores for 72.7%, 52.8%, 41.7% and 39.8% of patients at 3 months (p < 0.0001 for each change from baseline), with statistically significant improvement continuing at 6 months. Mean serum hemoglobin was significantly increased at both 3 and 6 months (12.8 g/dL [N = 44] and 12.4 g/dL [N = 54], respectively)., Conclusion: IDA patients attending routine clinical practice reported substantial levels of fatigue and impairments in physical function and global health prior to intravenous iron treatment. Patients experienced significant improvements in fatigue symptoms, physical function, and global health at 3 months after treatment with FCM, which were sustained at 6 months., Competing Interests: Winghan J Kwong is an employee of Daiichi Sankyo, the study sponsor. Syed Numan is an employee of American Regent, a Daiichi Sankyo Group Company. Tina D. Hunter and Dalila Alves are employees of CTI Clinical Trial & Consulting, which is a consultant to Daiichi Sankyo, the study sponsor. Anish Patel is a consultant for AbbVie and a speakers bureau member for Bristol Myers Squibb, Janssen, and Takeda. Satish Shanbhag is a consultant for Beigene and Takeda. The authors report no other conflicts of interest in this work., (© 2023 Kwong et al.)

Published
2023
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24. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile-associated diarrhoea: preclinical and preliminary clinical data.

Author

van Dissel JT, de Groot N, Hensgens CM, Numan S, Kuijper EJ, Veldkamp P, and van 't Wout J

Subjects
Animals, Cattle, Cohort Studies, Cricetinae, Diarrhea immunology, Humans, Pilot Projects, Prospective Studies, Antibodies, Bacterial therapeutic use, Clostridioides difficile immunology, Clostridium Infections prevention & control, Diarrhea prevention & control
Abstract

In a pilot study, the feasibility of immune whey protein concentrate (40%; immune WPC-40) to aid the prevention of relapse of Clostridium difficile diarrhoea was evaluated. Immune WPC-40 was made from milk after immunization of Holstein-Frisian cows with C. difficile-inactivated toxins and killed whole-cell C. difficile. Immune WPC-40 contained a high concentration of specific sIgA antibodies, and was effective in neutralizing the cytotoxic effect of C. difficile toxins in cell assays in vitro. Immune WPC-40 conferred protection from otherwise lethal C. difficile-associated caecitis in hamsters. To obtain preliminary data in humans, 16 patients (10 male; median 57 years) with toxin- and culture-confirmed C. difficile diarrhoea were enrolled in an uncontrolled cohort study. Nine had a history of relapsing C. difficile diarrhoea. After completion of standard antibiotic treatment, the patients received immune WPC-40 TID for 2 weeks; it was well tolerated and no treatment-related adverse effects were observed. In all but one case, C. difficile toxins had disappeared from the faeces upon completion of treatment. During a follow-up period of median 333 days (range 35 days to 1 year), none of the patients had suffered another episode of C. difficile diarrhoea. These preliminary data suggest that immune whey protein concentrate-40 may be of help in the prevention of relapse of C. difficile diarrhoea.

Published
2005
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25. Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology.

Author

Shihabuddin LS, Numan S, Huff MR, Dodge JC, Clarke J, Macauley SL, Yang W, Taksir TV, Parsons G, Passini MA, Gage FH, and Stewart GR

Subjects
Animals, Brain enzymology, Cell Movement, Cell Survival, Cholesterol metabolism, Lysosomes enzymology, Mice, Mice, Inbred C57BL, Mice, Knockout, Niemann-Pick Diseases enzymology, Niemann-Pick Diseases pathology, Prosencephalon cytology, Sphingomyelin Phosphodiesterase genetics, Transduction, Genetic, Brain surgery, Lysosomes pathology, Niemann-Pick Diseases surgery, Sphingomyelin Phosphodiesterase metabolism, Stem Cell Transplantation
Abstract

Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined). In vitro, gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs. In vivo, transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.

Published
2004
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26. Differential regulation of neurotrophin and trk receptor mRNAs in catecholaminergic nuclei during chronic opiate treatment and withdrawal.

Author

Numan S, Lane-Ladd SB, Zhang L, Lundgren KH, Russell DS, Seroogy KB, and Nestler EJ

Subjects
Animals, Brain-Derived Neurotrophic Factor genetics, Drug Administration Schedule, Drug Implants, Locus Coeruleus drug effects, Locus Coeruleus metabolism, Male, Mesencephalon drug effects, Morphine administration & dosage, Nerve Growth Factors genetics, Neurotrophin 3, RNA, Messenger biosynthesis, Rats, Rats, Sprague-Dawley, Receptor Protein-Tyrosine Kinases genetics, Receptor, Ciliary Neurotrophic Factor, Receptor, trkC, Receptors, Nerve Growth Factor genetics, Time Factors, Ventral Tegmental Area drug effects, Ventral Tegmental Area metabolism, Brain-Derived Neurotrophic Factor metabolism, Gene Expression Regulation drug effects, Mesencephalon metabolism, Morphine pharmacology, Nerve Growth Factors metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, Nerve Growth Factor metabolism
Abstract

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their receptors trkB and trkC, respectively, are expressed in the locus coeruleus (LC) and ventral tegmental area (VTA), brain regions known to be involved in opiate addiction. Previously, administration of exogenous neurotrophins has been shown to oppose effects of chronic morphine treatment on LC and VTA neurons. However, the response of endogenous neurotrophins in LC and VTA to opiate treatment is unknown. In this study, BDNF, NT-3, trkB, and trkC mRNAs were analyzed in these regions after chronic morphine treatment and during antagonist precipitated withdrawal. Although chronic morphine exposure resulted in only modest increases in BDNF and NT-3 mRNA expression in LC, precipitated withdrawal led to a marked, rapid, and prolonged increase in BDNF mRNA and a delayed decrease in NT-3 mRNA. Levels of trkB and trkC mRNAs, which were unchanged by chronic morphine treatment, were elevated in LC at 2 and 6 hr of withdrawal. By 20 hr, trkB mRNA levels in LC had returned to control, whereas trkC mRNA levels fell below control values. In contrast to the substantial alterations observed in LC, there was no regulation of the neurotrophins or trk mRNAs within the VTA during chronic opiate treatment or withdrawal, with the exception of an increase in trkB mRNA at 6 hr of withdrawal. These results suggest that neurotrophins and their receptors per se may be involved in opiate-induced plasticity of the LC, whereas other mechanisms would appear to be involved in the VTA.

Published
1998

27. Sex differences in the effects of testosterone and its metabolites on vasopressin messenger RNA levels in the bed nucleus of the stria terminalis of rats.

Author

De Vries GJ, Wang Z, Bullock NA, and Numan S

Subjects
Animals, Castration, Dihydrotestosterone pharmacology, Drug Combinations, Estradiol pharmacology, Female, Male, Rats, Rats, Inbred Strains, Arginine Vasopressin genetics, RNA, Messenger metabolism, Sex Characteristics, Testosterone metabolism, Testosterone pharmacology, Thalamus metabolism
Abstract

Male rats have about two times as many steroid-responsive vasopressin-immunoreactive (AVP-ir) neurons in the bed nucleus of the stria terminalis (BST) as female rats. This sex difference does not depend on differences in circulating hormone levels, since it persists in males and females that are treated with similar levels of testosterone. To analyze the cellular basis of this sex difference, we compared the effects of testosterone and its metabolites on AVP mRNA expression in the BST of males and females that were gonadectomized at 3 months of age. When rats received implants of Silastic tubing filled with testosterone, males had more cells that were labeled for AVP mRNA and more labeling per cell than females. When, in a second experiment, rats received implants of either empty tubing, or tubing with dihydrotestosterone (DHT), estradiol (E), or E plus DHT, hardly any labeled cells were found in rats with empty implants. E treatment significantly stimulated AVP mRNA expression in both sexes, but significantly more so in males, which had more cells that were labeled for AVP mRNA and more labeling per cell than females. DHT treatment by itself did not stimulate AVP mRNA expression, but when given in combination with E, it significantly increased the number of cells over that of animals treated with E alone. This increase was seen in males only. However, in both sexes, it increased the labeling per cell over that of animals treated with E only, but more so in males than in females.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1994

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