100 results on '"J. Gerloff"'
Search Results
52. Feeding the dry cow to avoid metabolic disease
- Author
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Brian J. Gerloff
- Subjects
Vitamin ,Cattle Diseases ,Biology ,chemistry.chemical_compound ,Animal science ,Nutrient ,Food Animals ,Pregnancy ,Lactation ,Parturient Paresis ,medicine ,Animals ,Dry matter ,Food science ,Dairy cattle ,food and beverages ,General Medicine ,Ketosis ,medicine.disease ,Fatty Liver ,medicine.anatomical_structure ,chemistry ,Animal Nutritional Physiological Phenomena ,Cattle ,Female ,Acidosis ,Niacin - Abstract
The nonlactating period should be regarded as a preparatory phase for the next lactation, rather than a rest phase from the preceding one. During the early dry period, a diet should be provided that meets nutrient requirements for energy, protein, calcium, phosphorus, selenium, vitamins, and other minerals. This can usually be accomplished by feeding a blend of roughages with little or no grain and providing a vitamin and mineral supplement. The diet during the late dry period, or transitional stage, should provide increased energy (an additional 3 to 4 Mcal), and a PP preventive regimen can be instituted at this time. Five to six pounds of concentrate containing 200 gm of an ammonium sulfate and chloride mixture and 6 gm of niacin can be added to the diet to aid in the transition to lactation. Feeding of high-calcium, lactating-cow grain mix should be avoided until after parturition. Stress should be minimized at and after parturition, and a quiet maternity area should be available. The normal depression in dry matter intake at parturition should be minimized; feeding high-quality roughages at this time is beneficial. Concentrate consumption should be increased gradually following parturition, and careful attention to the soluble and undegradable protein fractions of the diet is warranted. In group feeding situations, introduction to the energy-dense, high-lactation ration should probably be avoided for the first 10 to 14 days postpartum, until the cow is acclimated to the forage mix. Body overconditioning should be avoided. However, attempts to manipulate body condition during the dry period tend to be unrewarding and counterproductive. Following these guidelines should reduce the incidence of metabolic diseases in high-producing dairy cattle.
- Published
- 1988
53. Prevention of dog serum-induced aggregation of pig platelets
- Author
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J. Gerloff and K. N. von Kaulla
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Male ,Swine ,Pharmacology ,Polysaccharide ,General Biochemistry, Genetics and Molecular Biology ,In vitro model ,Dogs ,Platelet Adhesiveness ,Fibrinolytic Agents ,Polysaccharides ,Transplantation Immunology ,Platelet adhesiveness ,medicine ,Animals ,Platelet ,Cellulose ,chemistry.chemical_classification ,Chemistry ,Heparin ,Common denominator ,Complement System Proteins ,Flufenamic Acid ,Flufenamic acid ,Blood ,Biochemistry ,Sulfonic Acids ,Fibrinolytic agent ,medicine.drug - Abstract
SummaryDog serum-induced aggregation of pig platelets in plasma has been considered to be an in vitro model for xenograft rejection. In this paper it is shown that this aggregation can be reduced or totally prevented by pretreatment of the dog serum with certain synthetic fibrinolytic agents or pentosane polysulfo esters or by adding the latter to pig plasma. The common denominator of these compounds is their complement suppressing activity.
- Published
- 1972
54. [In-vitro inhibition of thrombocyte aggregation induced by xenogenic serum]
- Author
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K N, von Kaulla and J, Gerloff
- Subjects
Dogs ,Platelet Adhesiveness ,Fibrinolytic Agents ,Heparinoids ,Heparin ,Polysaccharides ,Swine ,Immune Sera ,Complement Fixation Tests ,Methods ,Animals ,Female ,In Vitro Techniques - Published
- 1972
55. [Biotin]
- Author
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J, GERLOFF
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Folic Acid ,Vitamin B Complex - Published
- 1950
56. The dual sample aggregometer. A new instrument adapted for serial testing of antiaggregating agents
- Author
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J, Gerloff and K N, von Kaulla
- Subjects
Dogs ,Platelet Adhesiveness ,Swine ,Animals ,Humans ,Blood Coagulation Tests - Published
- 1972
57. ASSOCIATION OF MODERATE AND SEVERE HEPATIC LIPIDOSIS IN CATTLE WITH DIFFERING REPRODUCTIVE PERFORMANCE
- Author
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B. J. Gerloff, R. S. Emery, and T. H. Herdt
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medicine.medical_specialty ,chemistry.chemical_compound ,Endocrinology ,Food Animals ,Triglyceride ,chemistry ,Internal medicine ,medicine ,Animal Science and Zoology ,Hepatic lipidosis ,Liver triglyceride ,Biology ,Preliminary analysis - Abstract
Liver biopsies obtained from cattle over the penpartum period were assayed for triglyceride. Subsequent reproductive performance was measured as days open. Preliminary analysis suggests a relationship between liver triglyceride and days open. Factors increasing hepatic fat postpartum may be related to reproductive performance. Key words: Hepatic lipidosis, days open, cattle
- Published
- 1984
58. SALT-RESISTANT TRIGLYCERIDE LIPASE RELATED TO POSTPARTUM DISEASE
- Author
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B. J. Gerloff, R. S. Emery, T. H. Herdt, and J. Liesman
- Subjects
medicine.medical_specialty ,Triglyceride lipase ,Lipoprotein lipase ,biology ,Chemistry ,Fatty liver ,Blood lipids ,medicine.disease ,Postheparin plasma ,Endocrinology ,Food Animals ,Internal medicine ,Liver fat ,biology.protein ,medicine ,Animal Science and Zoology ,Lipase - Abstract
Salt-resistant postheparin plasma lipase in recently parturient cows increased with increasing serum lipids and faster recovery from surgery. This lipase activity was decreased by fasting and excess liver fat. It seemed predominantly extrahepatic although a lipase with characteristics similar to hepatic triglyceride lipase was detected. Key words: Postheparin lipase, lipoprotein lipase, fatty liver, serum lipids
- Published
- 1984
59. (396) Vorschlag zur Konservierung des Gattungsnamens Sphaerozosma Ralfs (1848) gegen Sphaerozosma Corda (1842)
- Author
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J. Gerloff
- Subjects
Plant Science ,Biology ,Ecology, Evolution, Behavior and Systematics - Published
- 1976
60. Hustedt Memorial Volume
- Author
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J. Gerloff and B. J. Cholncky
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Volume (thermodynamics) ,Plant Science ,Anatomy ,Ecology, Evolution, Behavior and Systematics ,Geology - Published
- 1970
61. Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
- Author
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Sundar IK, Rashid K, Gerloff J, Rangel-Moreno J, Li D, and Rahman I
- Subjects
- Animals, DNA Damage genetics, Epithelial Cells pathology, Female, Male, Mice, Inbred C57BL, Mice, Knockout, Oxidative Stress genetics, Smoke adverse effects, Smoking adverse effects, Cellular Senescence genetics, Histone Deacetylase 2 genetics, Lung pathology, Pulmonary Disease, Chronic Obstructive etiology, Pulmonary Emphysema genetics
- Abstract
Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell-specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated β-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS-induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
- Published
- 2018
- Full Text
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62. Genetic Ablation of p16 INK4a Does Not Protect against Cellular Senescence in Mouse Models of Chronic Obstructive Pulmonary Disease/Emphysema.
- Author
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Sundar IK, Rashid K, Gerloff J, Li D, and Rahman I
- Subjects
- Animals, Disease Models, Animal, Mice, Transgenic, Oxidative Stress, Pulmonary Emphysema genetics, Smoking adverse effects, Cellular Senescence genetics, DNA Damage genetics, Epithelial Cells pathology, Lung pathology, Pulmonary Emphysema pathology
- Abstract
Cigarette smoke (CS) affects DNA damage and cellular senescence signaling pathways in the pathogenesis of chronic obstructive pulmonary disease (COPD). p16
INK4a (p16: a cyclin-dependent kinase inhibitor) is a key marker of cellular senescence, which is induced by CS in lung cells. It is thought that removal of p16 attenuates premature aging by removing senesced cells. However, the role of p16 in CS-induced stress-induced premature senescence (SIPS) and senescence-associated secretory phenotype (SASP) during the development of COPD/emphysema is not known. We hypothesize that p16 regulates cellular senescence and DNA damage/repair molecular signaling targets during chronic CS-induced inflammation and airspace enlargement in mouse models of COPD. We used p16 global knockout (KO) and p16 lung epithelial cell-specific KO (p16CreCC10 ) mice to determine whether p16 removal in lung epithelium augments or protects against cellular senescence (SIPS and SASP) in chronic CS- and elastase-induced development of COPD/emphysema in mice. p16 KO mice exposed to chronic CS and p16 lung epithelial cell-specific KO mice exposed to elastase did not show attenuation of lung inflammation, altered lung function, or airspace enlargement. p16 KO and p16CreCC10 exposed to CS and elastase showed increases in lung senescence-associated β-galactosidase activity. Thus, removal of p16-positive cells did not protect against airspace enlargement and decline in lung function induced in COPD mouse models. Our findings suggest that p16 is not the only key player associated with CS-induced cellular senescence phenotypes (SIPS and SASP), decline in lung function, and airspace enlargement in COPD/emphysema.- Published
- 2018
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63. Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema.
- Author
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Rashid K, Sundar IK, Gerloff J, Li D, and Rahman I
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- Animals, Cellular Senescence drug effects, Cellular Senescence genetics, Disease Models, Animal, Female, Gene Expression Regulation drug effects, Inflammation chemically induced, Inflammation genetics, Inflammation physiopathology, Lung drug effects, Lung pathology, Male, Mice, Inbred C57BL, Pulmonary Disease, Chronic Obstructive chemically induced, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Emphysema chemically induced, Pulmonary Emphysema genetics, Smoke, Tobacco Products toxicity, Aging, Cellular Senescence physiology, Lung physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Emphysema physiopathology
- Abstract
Cigarette smoke (CS) induces lung cellular senescence that plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How aging influences cellular senescence and other molecular hallmarks, and increases the risk of CS-induced damage remains unknown. We hypothesized that aging-associated changes in lungs worsen the COPD/emphysema by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls. CS caused a decline in lung function and affected the lung structure of both groups of mice. No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation. Aging per se increased lung cellular senescence and significant changes in damage-associated molecular patterns marker S100A8. Gene transcript analysis using the nanoString nCounter showed a significant upregulation of key pro-senescence targets by CS (Mmp12, Ccl2, Cdkn2a, Tert, Wrn, and Bub1b). Aging independently influenced lung function and structure, as well as increased susceptibility to CS-induced inflammation in emphysema, but had a negligible effect on cellular senescence. Thus, aging solely does not contribute to the induction of cellular senescence by CS in a mouse model of COPD/emphysema.
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- 2018
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64. Inflammatory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavoring Chemicals and Flavored e-Liquids without Nicotine.
- Author
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Muthumalage T, Prinz M, Ansah KO, Gerloff J, Sundar IK, and Rahman I
- Abstract
Background: The respiratory health effects of inhalation exposure to e-cigarette flavoring chemicals are not well understood. We focused our study on the immuno-toxicological and the oxidative stress effects by these e-cigarette flavoring chemicals on two types of human monocytic cell lines, Mono Mac 6 (MM6) and U937. The potential to cause oxidative stress by these flavoring chemicals was assessed by measuring the production of reactive oxygen species (ROS). We hypothesized that the flavoring chemicals used in e-juices/e-liquids induce an inflammatory response, cellular toxicity, and ROS production. Methods: Two monocytic cell types, MM6 and U937 were exposed to commonly used e-cigarette flavoring chemicals; diacetyl, cinnamaldehyde, acetoin, pentanedione, o-vanillin, maltol and coumarin at different doses between 10 and 1,000 μM. Cell viability and the concentrations of the secreted inflammatory cytokine interleukin 8 (IL-8) were measured in the conditioned media. Cell-free ROS produced by these commonly used flavoring chemicals were also measured using a 2',7'dichlorofluorescein diacetate probe. These DCF fluorescence data were expressed as hydrogen peroxide (H
2 O2 ) equivalents. Cytotoxicity due to the exposure to selected e-liquids was assessed by cell viability and the IL-8 inflammatory cytokine response in the conditioned media. Results: Treatment of the cells with flavoring chemicals and flavored e-liquid without nicotine caused cytotoxicity dose-dependently. The exposed monocytic cells secreted interleukin 8 (IL-8) chemokine in a dose-dependent manner compared to the unexposed cell groups depicting a biologically significant inflammatory response. The measurement of cell-free ROS by the flavoring chemicals and e-liquids showed significantly increased levels of H2 O2 equivalents in a dose-dependent manner compared to the control reagents. Mixing a variety of flavors resulted in greater cytotoxicity and cell-free ROS levels compared to the treatments with individual flavors, suggesting that mixing of multiple flavors of e-liquids are more harmful to the users. Conclusions: Our data suggest that the flavorings used in e-juices can trigger an inflammatory response in monocytes, mediated by ROS production, providing insights into potential pulmonary toxicity and tissue damage in e-cigarette users.- Published
- 2018
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65. Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas Chromatography-Mass Spectrometry in e-Liquids and e-Vapors on Human Lung Epithelial Cells and Fibroblasts.
- Author
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Gerloff J, Sundar IK, Freter R, Sekera ER, Friedman AE, Robinson R, Pagano T, and Rahman I
- Abstract
Recent studies suggest that electronic cigarette (e-cig) flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The potential inflammatory response by lung epithelial cells and fibroblasts exposed to e-cig flavoring chemicals in addition to other risk-anticipated flavor enhancers inhaled by e-cig users is not known. The goal of this study was to evaluate the release of the proinflammatory cytokine (interleukin-8 [IL-8]) and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography-mass spectrometry analysis. Flavorings, such as acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde in comparison with tumor necrosis factor alpha (TNFα), were used in this study. Human bronchial epithelial cells (Beas2B), human mucoepidermoid carcinoma epithelial cells (H292), and human lung fibroblasts (HFL-1) were treated with each flavoring chemical for 24 hours. The cells and conditioned media were then collected and analyzed for toxicity (viability %), lung epithelial barrier function, and proinflammatory cytokine IL-8 release. Cell viability was not significantly affected by any of the flavoring chemicals tested at a concentration of 10 μM to 1 mM. Acetoin and diacetyl treatment induced IL-8 release in Beas2B cells. Acetoin- and pentanedione-treated HFL-1 cells produced a differential, but significant response for IL-8 release compared to controls and TNFα. Flavorings, such as ortho-vanillin and maltol, induced IL-8 release in Beas2B cells, but not in H292 cells. Of all the flavoring chemicals tested, acetoin and maltol were more potent inducers of IL-8 release than TNFα in Beas2B and HFL-1 cells. Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells (16-HBE) as measured by electric cell surface impedance sensing. Our findings suggest that some of the e-cig liquids/aerosols containing flavoring chemicals can cause significant loss of epithelial barrier function and proinflammatory response in lung cells., Competing Interests: No competing financial interests exist.
- Published
- 2017
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66. Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease.
- Author
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Ahmad T, Sundar IK, Tormos AM, Lerner CA, Gerloff J, Yao H, and Rahman I
- Subjects
- Acetylation, Animals, Cells, Cultured, DNA Damage, Epithelial Cells metabolism, Epithelial Cells pathology, Fibroblasts metabolism, Fibroblasts pathology, Humans, Lung metabolism, Lung pathology, Mice, Mice, Inbred C57BL, Protein Binding, Pulmonary Emphysema metabolism, Pulmonary Emphysema pathology, Smoking adverse effects, Cellular Senescence, DNA-Binding Proteins metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Shelterin Complex metabolism, Sirtuin 1 metabolism, Telomere metabolism, Telomere-Binding Proteins metabolism
- Abstract
Lung cellular senescence and inflammatory response are the key events in the pathogenesis of chronic obstructive pulmonary disease (COPD) when cigarette smoke (CS) is the main etiological factor. Telomere dysfunction is induced by either critical shortening or disruption of the shelterin complex, leading to cellular senescence. However, it remains unknown whether disruption of the shelterin complex is responsible for CS-induced lung cellular senescence. Here we show that telomere protection protein 1 (TPP1) levels are reduced on telomeres in lungs from mice with emphysema, as well as in lungs from smokers and from patients with COPD. This is associated with persistent telomeric DNA damage, leading to cellular senescence. CS disrupts the interaction of TPP1 with the Sirtuin 1 (Sirt1) complex, leading to increased TPP1 acetylation and degradation. Lung fibroblasts deficient in Sirt1 or treated with a selective Sirt1 inhibitor exhibit increased cellular senescence and decreased TPP1 levels, whereas Sirt1 overexpression and pharmacological activation protect against CS-induced TPP1 reduction and telomeric DNA damage. Our findings support an essential role of TPP1 in protecting CS-induced telomeric DNA damage and cellular senescence, and therefore provide a rationale for a potential therapy for COPD, on the basis of the shelterin complex, in attenuating cellular senescence.
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- 2017
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67. Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease.
- Author
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Yao H, Sundar IK, Huang Y, Gerloff J, Sellix MT, Sime PJ, and Rahman I
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- Aged, Cells, Cultured, Circadian Clocks, Cytokines biosynthesis, Female, Humans, Leukocytes, Mononuclear enzymology, Leukocytes, Mononuclear immunology, Lipopolysaccharides pharmacology, Lung enzymology, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive immunology, Smoking immunology, Smoking metabolism, Pulmonary Disease, Chronic Obstructive enzymology, Sirtuin 1 physiology
- Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBβ, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.
- Published
- 2015
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68. Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease.
- Author
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Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H, and Rahman I
- Subjects
- Animals, Antioxidants pharmacology, Case-Control Studies, Cells, Cultured, DNA Damage, Fibroblasts metabolism, Fibroblasts pathology, Humans, Lung metabolism, Lung pathology, Mice, Mice, Inbred C57BL, Organophosphorus Compounds pharmacology, Piperidines pharmacology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Reactive Oxygen Species metabolism, Respiratory Mucosa metabolism, Respiratory Mucosa pathology, Smoking metabolism, Smoking pathology, Ubiquitin-Protein Ligases metabolism, Cellular Senescence drug effects, Mitophagy drug effects, Pulmonary Disease, Chronic Obstructive etiology, Smoking adverse effects
- Abstract
Cigarette smoke (CS)-induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The molecular mechanism by which CS induces cellular senescence is unknown. Here, we show that CS stress (exposure of primary lung cells to CS extract 0.2-0.75% with a half-maximal inhibitory concentration of ∼0.5%) led to impaired mitophagy and perinuclear accumulation of damaged mitochondria associated with cellular senescence in both human lung fibroblasts and small airway epithelial cells (SAECs). Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin. Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m(3)) as well as in lungs of chronic smokers and patients with COPD. Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling. Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells. In conclusion, defective mitophagy leads to CS stress-induced lung cellular senescence, and restoring mitophagy delays cellular senescence, which provides a promising therapeutic intervention in chronic airway diseases., (© FASEB.)
- Published
- 2015
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69. Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD.
- Author
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Sundar IK, Ahmad T, Yao H, Hwang JW, Gerloff J, Lawrence BP, Sellix MT, and Rahman I
- Subjects
- ARNTL Transcription Factors deficiency, ARNTL Transcription Factors genetics, Animals, CLOCK Proteins genetics, CLOCK Proteins metabolism, Disease Models, Animal, Emphysema etiology, Emphysema mortality, Emphysema virology, Gene Expression Profiling, Gene Expression Regulation, Humans, Influenza A virus pathogenicity, Lung metabolism, Lung pathology, Lung virology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections mortality, Orthomyxoviridae Infections pathology, Orthomyxoviridae Infections virology, Pulmonary Disease, Chronic Obstructive etiology, Pulmonary Disease, Chronic Obstructive mortality, Pulmonary Disease, Chronic Obstructive virology, Pulmonary Fibrosis etiology, Pulmonary Fibrosis mortality, Pulmonary Fibrosis virology, Respiratory Function Tests, Smoke adverse effects, Survival Analysis, Nicotiana adverse effects, Circadian Clocks genetics, Circadian Rhythm genetics, Emphysema genetics, Influenza A virus physiology, Orthomyxoviridae Infections genetics, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Fibrosis genetics
- Abstract
Daily oscillations of pulmonary function depend on the rhythmic activity of the circadian timing system. Environmental tobacco/cigarette smoke (CS) disrupts circadian clock leading to enhanced inflammatory responses. Infection with influenza A virus (IAV) increases hospitalization rates and death in susceptible individuals, including patients with Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that molecular clock disruption is enhanced by IAV infection, altering cellular and lung function, leading to severity in airway disease phenotypes. C57BL/6J mice exposed to chronic CS, BMAL1 knockout (KO) mice and wild-type littermates were infected with IAV. Following infection, we measured diurnal rhythms of clock gene expression in the lung, locomotor activity, pulmonary function, inflammatory, pro-fibrotic and emphysematous responses. Chronic CS exposure combined with IAV infection altered the timing of clock gene expression and reduced locomotor activity in parallel with increased lung inflammation, disrupted rhythms of pulmonary function, and emphysema. BMAL1 KO mice infected with IAV showed pronounced detriments in behavior and survival, and increased lung inflammatory and pro-fibrotic responses. This suggests that remodeling of lung clock function following IAV infection alters clock-dependent gene expression and normal rhythms of lung function, enhanced emphysematous and injurious responses. This may have implications for the pathobiology of respiratory virus-induced airway disease severity and exacerbations.
- Published
- 2015
- Full Text
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70. Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung.
- Author
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Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, Robinson R, and Rahman I
- Subjects
- Aerosols adverse effects, Animals, Bronchoalveolar Lavage, Cell Line, Cotinine blood, Flow Cytometry, Humans, Mice, Nicotine administration & dosage, Solutions administration & dosage, Solutions toxicity, Volatilization, Electronic Nicotine Delivery Systems adverse effects, Nicotine toxicity, Oxidative Stress drug effects, Pneumonia chemically induced, Respiratory Mucosa drug effects
- Abstract
Oxidative stress and inflammatory response are the key events in the pathogenesis of chronic airway diseases. The consumption of electronic cigarettes (e-cigs) with a variety of e-liquids/e-juices is alarmingly increasing without the unrealized potential harmful health effects. We hypothesized that electronic nicotine delivery systems (ENDS)/e-cigs pose health concerns due to oxidative toxicity and inflammatory response in lung cells exposed to their aerosols. The aerosols produced by vaporizing ENDS e-liquids exhibit oxidant reactivity suggesting oxidants or reactive oxygen species (OX/ROS) may be inhaled directly into the lung during a "vaping" session. These OX/ROS are generated through activation of the heating element which is affected by heating element status (new versus used), and occurs during the process of e-liquid vaporization. Unvaporized e-liquids were oxidative in a manner dependent on flavor additives, while flavors containing sweet or fruit flavors were stronger oxidizers than tobacco flavors. In light of OX/ROS generated in ENDS e-liquids and aerosols, the effects of ENDS aerosols on tissues and cells of the lung were measured. Exposure of human airway epithelial cells (H292) in an air-liquid interface to ENDS aerosols from a popular device resulted in increased secretion of inflammatory cytokines, such as IL-6 and IL-8. Furthermore, human lung fibroblasts exhibited stress and morphological change in response to treatment with ENDS/e-liquids. These cells also secrete increased IL-8 in response to a cinnamon flavored e-liquid and are susceptible to loss of cell viability by ENDS e-liquids. Finally, exposure of wild type C57BL/6J mice to aerosols produced from a popular e-cig increase pro-inflammatory cytokines and diminished lung glutathione levels which are critical in maintaining cellular redox balance. Thus, exposure to e-cig aerosols/juices incurs measurable oxidative and inflammatory responses in lung cells and tissues that could lead to unrealized health consequences.
- Published
- 2015
- Full Text
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71. SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism.
- Author
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Yao H, Sundar IK, Ahmad T, Lerner C, Gerloff J, Friedman AE, Phipps RP, Sime PJ, McBurney MW, Guarente L, and Rahman I
- Subjects
- Animals, Antioxidants metabolism, Blotting, Western, Female, Forkhead Box Protein O3, Forkhead Transcription Factors genetics, Humans, Lipid Peroxidation drug effects, Lung Diseases chemically induced, Lung Diseases pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, NF-E2-Related Factor 2 physiology, Protein Carbonylation drug effects, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Forkhead Transcription Factors metabolism, Lung Diseases prevention & control, Oxidative Stress, Sirtuin 1 physiology, Smoke adverse effects
- Abstract
Oxidative and carbonyl stress is increased in lungs of smokers and patients with chronic obstructive pulmonary disease (COPD), as well as in cigarette smoke (CS)-exposed rodent lungs. We previously showed that sirtuin1 (SIRT1), an antiaging protein, is reduced in lungs of CS-exposed mice and patients with COPD and that SIRT1 attenuates CS-induced lung inflammation and injury. It is not clear whether SIRT1 protects against CS-induced lung oxidative stress. Therefore, we determined the effect of SIRT1 on lung oxidative stress and antioxidants in response to CS exposure using loss- and gain-of-function approaches, as well as a pharmacological SIRT1 activation by SRT1720. We found that CS exposure increased protein oxidation and lipid peroxidation in lungs of wild-type (WT) mice, which was further augmented in SIRT1-deficient mice. Furthermore, both SIRT1 genetic overexpression and SRT1720 treatment significantly decreased oxidative stress induced by CS exposure. FOXO3 deletion augmented lipid peroxidation products but reduced antioxidants in response to CS exposure, which was not affected by SRT1720. Interestingly, SRT1720 treatment exhibited a similar effect on lipid peroxidation and antioxidants (i.e., manganese superoxide dismutase, heme oxygenase-1, and NADPH quinone oxidoreductase-1) in WT and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-deficient mice in response to CS exposure. This indicates that SIRT1 protects against CS-induced oxidative stress, which is mediated by FOXO3, but is independent of Nrf2. Overall, these findings reveal a novel function of SIRT1, which is to reduce CS-induced oxidative stress, and this may contribute to its protective effects against lung inflammation and subsequent development of COPD.
- Published
- 2014
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72. A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting αv integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy.
- Author
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Wirth M, Heidenreich A, Gschwend JE, Gil T, Zastrow S, Laniado M, Gerloff J, Zühlsdorf M, Mordenti G, Uhl W, and Lannert H
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized pharmacokinetics, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Bone Neoplasms blood, Bone Neoplasms secondary, Disease-Free Survival, Drug Eruptions etiology, Humans, Integrin alphaV immunology, Male, Middle Aged, Pain Measurement, Prostate-Specific Antigen blood, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant pathology, Sepsis chemically induced, gamma-Glutamyltransferase blood, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Bone Neoplasms drug therapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis., Objective: Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments., Design, Setting, and Participants: A phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥ 18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values., Intervention: Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500 mg every 2 wk)., Outcome Measurements and Statistical Analysis: Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used., Results and Limitations: Patients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥ 18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials., Conclusions: No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500 mg every 3 wk were chosen., Trial Registration: NCT00958477 (EMR 62242-002)., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2014
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73. PKU patients on a relaxed diet may be at risk for micronutrient deficiencies.
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Rohde C, von Teeffelen-Heithoff A, Thiele AG, Arelin M, Mütze U, Kiener C, Gerloff J, Baerwald C, Schultz S, Heller C, Müller AS, Kiess W, and Beblo S
- Subjects
- Adolescent, Adult, Amino Acids administration & dosage, Body Weight, Child, Cross-Sectional Studies, Diet Records, Dietary Proteins administration & dosage, Humans, Middle Aged, Young Adult, Diet, Dietary Supplements, Micronutrients administration & dosage, Micronutrients deficiency, Phenylalanine administration & dosage, Phenylketonurias diet therapy
- Abstract
Objective: To investigate micronutrient supply in phenylketonuria (PKU) patients on a relaxed diet., Subjects/methods: Sixty-seven patients (6-45 years) with a phenylalanine tolerance ≥ 600 mg/day were included in the study. From a 3-day diet record, protein supply as well as consumption of essential amino acids and several micronutrients were assessed and compared with the current recommendations and data for the healthy population., Results: Protein supply and consumption of all essential amino acids were sufficient in all patients. Supply of micronutrients depended on dietary regime. Patients with a total protein supply of 120% or more of the recommended amount and at least 0.5 g protein per kg body weight from amino-acid mixture (AAM) were sufficiently supplied with all investigated micronutrients. All patients without AAM supplement showed severe micronutrient deficiencies in their diet records., Conclusion: PKU patients under a relaxed diet are at risk of an insufficient nutrient supply, if they have first no substitution with AAM, second a protein supply less than 0.5 g per kg body weight from AAM or third a total protein supply less than 120% of the recommendations. Therefore, close monitoring, specific dietary counseling and potential supplementation is mandatory to prevent micronutrient deficiencies in PKU patients.
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- 2014
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74. Role of Axl in early kidney inflammation and progression of salt-dependent hypertension.
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Batchu SN, Hughson A, Gerloff J, Fowell DJ, and Korshunov VA
- Subjects
- Animals, Cell Movement, Chemokines immunology, Cytokines genetics, Disease Progression, Hypertension pathology, Intercellular Signaling Peptides and Proteins physiology, Kidney immunology, Kidney pathology, Leukocytes physiology, Male, Mice, Axl Receptor Tyrosine Kinase, Desoxycorticosterone pharmacology, Hypertension complications, Nephritis etiology, Proto-Oncogene Proteins physiology, Receptor Protein-Tyrosine Kinases physiology
- Abstract
The Gas6/Axl pathway regulates many cell functions and is implicated in hypertension. In this study, we aimed to investigate the role of Axl in immune cells on initiation and progression of salt-dependent hypertension. Deoxycorticosterone acetate (75 mg/60 days release)-salt hypertension was induced for 1 week or 6 weeks in Axl chimeras generated by bone marrow transplant to restrict Axl deficiency to hematopoietic or nonhematopoietic compartments. Depletion of Axl in hematopoietic cells (Axl(-/-) →Axl(+/+)) reduced (133 ± 2 mm Hg) increase in systolic blood pressure compared with other Axl chimeras (≈150 mm Hg) 1 week after deoxycorticosterone acetate-salt. Urine protein and renal oxidative stress were lowest in Axl(-/-) →Axl(+/+) at 1 week after deoxycorticosterone acetate-salt. Compensatory increase in Gas6 in kidneys of recipient Axl(-/-) may affect kidney function and blood pressure in early phase of hypertension. Flow cytometry on kidneys from Axl(-/-) →Axl(+/+) showed increase in total leukocytes, B, and dendritic cells and decrease in macrophages compared with Axl(+/+) →Axl(+/+). These immune changes were associated with decrease in proinflammatory gene expression, in particular interferon γ. Systolic blood pressure returned to baseline in Axl(-/-) →Axl(+/+) and Axl(-/-) →Axl(-/-) but remained increased in Axl(+/+) →Axl(+/+) and Axl(+/+) →Axl(-/-) chimeras after 6 weeks of deoxycorticosterone acetate-salt. Vascular apoptosis was increased in the global Axl(-/-) chimeras in the late phase of hypertension. In summary, we found that expression of Axl in hematopoietic cells is critical for kidney pathology in early phase of salt-dependent hypertension. However, Axl in both hematopoietic and nonhematopoietic lineages contributes to the late phase of hypertension.
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- 2013
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75. Ribosomal protein L17, RpL17, is an inhibitor of vascular smooth muscle growth and carotid intima formation.
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Smolock EM, Korshunov VA, Glazko G, Qiu X, Gerloff J, and Berk BC
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- Animals, Cell Cycle physiology, Cells, Cultured, Computational Biology, G1 Phase physiology, Humans, Male, Mice, Mice, Inbred C3H, Mice, Inbred Strains, Microarray Analysis, Rats, Resting Phase, Cell Cycle physiology, S Phase physiology, Tunica Intima physiology, Tunica Media cytology, Tunica Media physiology, Carotid Arteries cytology, Carotid Arteries physiology, Cell Proliferation, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular physiology, Ribosomal Proteins physiology, Tunica Intima cytology
- Abstract
Background: Carotid intima-media thickening is associated with increased cardiovascular risk in humans. We discovered that intima formation and cell proliferation in response to carotid injury is greater in SJL/J (SJL) in comparison with C3HeB/FeJ (C3H/F) mice. The purpose of this study was to identify candidate genes contributing to intima formation., Methods and Results: We performed microarray and bioinformatic analyses of carotid arteries from C3H/F and SJL mice. Kyoto Encyclopedia of Genes and Genomes analysis showed that the ribosome pathway was significantly up-regulated in C3H/F in comparison with SJL mice. Expression of a ribosomal protein, RpL17, was >40-fold higher in C3H/F carotids in comparison with SJL. Aortic vascular smooth muscle cells from C3H/F grew slower in comparison to SJL. To determine the role of RpL17 in vascular smooth muscle cell growth regulation, we analyzed the relationship between RpL17 expression and cell cycle progression. Cultured vascular smooth muscle cells from mice, rats, and humans showed that RpL17 expression inversely correlated with growth as shown by decreased cells in S phase and increased cells in G(0)/G(1). To prove that RpL17 acted as a growth inhibitor in vivo, we used pluronic gel delivery of RpL17 small interfering RNA to C3H/F carotid arteries. This resulted in an 8-fold increase in the number of proliferating cells. Furthermore, following partial carotid ligation in SJL mice, RpL17 expression in the intima and media decreased, but the number of proliferating cells increased., Conclusions: RpL17 acts as a vascular smooth muscle cell growth inhibitor (akin to a tumor suppressor) and represents a potential therapeutic target to limit carotid intima-media thickening.
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- 2012
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76. Genetic locus on mouse chromosome 7 controls elevated heart rate.
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Smolock EM, Ilyushkina IA, Ghazalpour A, Gerloff J, Murashev AN, Lusis AJ, and Korshunov VA
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- Animals, Crosses, Genetic, Female, Genome, Genome-Wide Association Study, Genotype, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Chromosomes, Mammalian genetics, Genetic Loci, Heart Rate genetics, Mice genetics, Quantitative Trait Loci
- Abstract
Elevated heart rate (HR) is a risk factor for cardiovascular diseases. The goal of the study was to map HR trait in mice using quantitative trait locus (QTL) analysis followed by genome-wide association (GWA) analysis. The first approach provides mapping power and the second increases genome resolution. QTL analyses were performed in a C3HeB×SJL backcross. HR and systolic blood pressure (SBP) were measured by the tail-cuff plethysmography. HR was ∼80 beats/min higher in SJL compared with C3HeB. There was a wide distribution of the HR (536-763 beats/min) in N2 mice. We discovered a highly significant QTL (logarithm of odds = 6.7, P < 0.001) on chromosome 7 (41 cM) for HR in the C3HeB×SJL backcross. In the Hybrid Mouse Diversity Panel (58 strains, n = 5-6/strain) we found that HR (beats/min) ranged from 546 ± 12 in C58/J to 717 ± 7 in MA/MyJ mice. SBP (mmHg) ranged from 99 ± 6 in strain I/LnJ to 151 ± 4 in strain BXA4/PgnJ. GWA analyses were done using the HMDP, which revealed a locus (64.2-65.1 Mb) on chromosome 7 that colocalized with the QTL for elevated HR found in the C3HeB×SJL backcross. The peak association was observed for 17 SNPs that are localized within three GABA(A) receptor genes. In summary, we used a combined genetic approach to fine map a novel elevated HR locus on mouse chromosome 7.
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- 2012
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77. Immune modulation of vascular resident cells by Axl orchestrates carotid intima-media thickening.
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Gerloff J and Korshunov VA
- Subjects
- Animals, Bone Marrow Cells metabolism, Bone Marrow Transplantation, Cells, Cultured, Chemokines metabolism, Collagen metabolism, Cytokines biosynthesis, Extracellular Matrix metabolism, Genotype, Inflammation Mediators metabolism, Leukocytes immunology, Male, Mice, Mice, Knockout, Muscle, Smooth, Vascular immunology, Peptide Fragments metabolism, Proto-Oncogene Proteins deficiency, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases deficiency, Receptor Protein-Tyrosine Kinases genetics, Transplantation Chimera, Tunica Intima immunology, Axl Receptor Tyrosine Kinase, Carotid Arteries immunology, Carotid Intima-Media Thickness, Proto-Oncogene Proteins immunology, Receptor Protein-Tyrosine Kinases immunology
- Abstract
Cellular mechanisms of carotid intima-media thickening (IMT) are largely unknown. The receptor tyrosine kinase Axl is essential for function of both bone marrow (BM) and non-BM cells. We studied the mechanisms by which Axl expression in BM-derived cells (compared with non-BM-derived cells) mediates carotid IMT. Partial ligation of the left carotid artery resulted in a similar carotid blood flow reduction in Axl chimeras. Neither irradiation nor bone marrow transplantation had any effect on the 40% difference in carotid IMT between Axl genotypes. Axl-dependent survival is very important for intimal leukocytes; however, Axl expression in BM cells contributes to <30% of carotid IMT. Axl in non-BM cells has a greater effect on carotid remodeling. Expression of Axl in non-BM cells is crucial for the up-regulation of several key proinflammatory signals (eg, IL-1) in the carotid. We found that Axl is involved in immune activation of cultured smooth muscle cells and in immune heterogeneity of medial cells (measured by major histocompatibility complex class II) after carotid injury. Finally, a lack of Axl in non-BM cells increased collagen Iα expression, which may play a critical role in carotid remodeling. Our data suggest that Axl contributes to carotid remodeling not only by inhibition of apoptosis but also via regulation of immune heterogeneity of vascular cells, cytokine/chemokine expression, and extracellular matrix remodeling., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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78. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 4th communication: drops (without ethanol).
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Lintz W, Becker R, Gerloff J, and Terlinden R
- Subjects
- Administration, Oral, Adult, Analgesics, Opioid administration & dosage, Area Under Curve, Biological Availability, Chromatography, Gas, Cross-Over Studies, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism, Female, Half-Life, Humans, Infusions, Intravenous, Male, Models, Biological, Pharmaceutical Solutions, Phenotype, Sex Characteristics, Tramadol administration & dosage, Analgesics, Opioid pharmacokinetics, Tramadol pharmacokinetics
- Abstract
In a balanced two-period cross-over study with 12 (6 male, 6 female) healthy young subjects the pharmacokinetics and absolute bioavailability of tramadol (tramadol hydrochloride, CAS 36282-47-0) after oral administration of Tramal drops (without ethanol) were to be determined in comparison with a 30-min i.v. infusion. Each fasting volunteer received the two single doses of 50 mg tramadol-HCl each in the morning; the time interval between the administrations was one week. Serum and urine concentrations of tramadol were analysed by gas chromatography. The pharmacokinetic evaluation was carried out model-dependently after previous selection of the optimal model by means of the Akaike information criterion; solely the extent of bioavailability was calculated model-independently. The study population results were presented descriptively as geometric means with standard deviation [xg (SDg)] or as medians with range [x (min, max)]. Model-dependently and model-independently calculated areas under the serum concentration curves (AUC and AUC, resp.) differed only minimally. The extent of the absolute bioavailability (F) of tramadol in the drops, based on AUC data, was 70.6 (1.13)% with a 90% confidence interval of 65.9-75.6% (ANOVAlog). The p.o. serum concentration peaks were reached after tmax = 1.2 (0.74, 1.5) h and amounted to Cmax = 136 (1.33) ng/ml, the half-life of absorption was t1/2,ka = 0.23 (1.89) h and the lag time t0 = 0.23 (0.20, 0.49) h. The dose-normalised p.o. and i.v. results for all pharmacokinetic parameters agreed well with those of a previous study with ethanol-containing drops. In summary, it may be concluded that the active ingredient is rapidly absorbed after oral administration of the drops without ethanol. Rate and extent of the absolute bioavailability of tramadol in drops without ethanol were about the same as after administration of drops with ethanol. The results of this study gave no indication of a therapeutically relevant gender difference in the pharmacokinetics of tramadol.
- Published
- 2000
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79. Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion.
- Author
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Lintz W, Beier H, and Gerloff J
- Subjects
- Adult, Analgesics, Opioid administration & dosage, Analgesics, Opioid blood, Analysis of Variance, Area Under Curve, Biological Availability, Half-Life, Humans, Injections, Intramuscular, Injections, Intravenous, Male, Phenotype, Saliva chemistry, Tramadol administration & dosage, Tramadol blood, Analgesics, Opioid pharmacokinetics, Tramadol pharmacokinetics
- Abstract
Objectives and Methods: The bioavailability of tramadol after i.m. injection of tramadol-HCl was determined from serum concentration data in a balanced two-period crossover study with 12 healthy male subjects in comparison to the 30-min i.v. infusion. Additionally, the tramadol concentrations in saliva and urine samples were measured. The subjects received single doses of 50 mg after an overnight fast, the washout period was one week. Serum, saliva and urine concentrations of tramadol were analyzed by gas chromatography, and pharmacokinetic (PK) evaluation was carried out model-independently. Descriptive statistical evaluation was performed by calculating geometric means with standard deviations (x(g) (SDg)) or medians with ranges (x (min, max)) and the extent of systemic availability (F) was tested for bioequivalence using the ANOVAlog-based 90% confidence interval (CI)., Results: Retrospective sparteine phenotyping revealed two of the subjects as poor metabolizers (PM). Nevertheless, all subjects were considered on statistical evaluation since the PM results were within the range of the extensive metabolizers (EM). The 90% CI of F = AUCi.m./AUCi.v. was 92.9 - 105.4% (x(g) = 99.0%) and was thus within the range of 80 - 125% generally accepted for a positive bioequivalence decision. After i.m. injection the serum concentration peaks were reached after t(max) = 0.75 (0.25, 1.50) h and amounted to c(max) = 166 (1.24) ng/ml; the corresponding results after i.v. infusion were t(max) = 0.50 (0.33, 1.50) h and c(max) = 293 (1.35) ng/ml. Thus, the results reflect the different invasion kinetics of the two modes of administration. However, the observed difference is not therapeutically relevant since in both cases minimal effective serum concentrations are already reached after a few minutes and are maintained for 9 - 10 h on the average. The i.v. results for all PK parameters agreed well with those of previous studies. Tramadol concentrations in saliva and urine were considerably higher than in serum. Therefore, saliva and urine samples are very suitable for the qualitative proof of tramadol intake in therapeutic drug monitoring and forensic toxicology., Conclusions: Tramadol is rapidly and almost completely absorbed after i.m. injection. The i.m. injection and the 30-min i.v. infusion are bioequivalent with respect to the extent of systemic availability. The differences in the times of onset and duration of action to be expected due to a slightly slower invasion after i.m. injection are small and probably therapeutically irrelevant.
- Published
- 1999
80. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol.
- Author
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Paar WD, Poche S, Gerloff J, and Dengler HJ
- Subjects
- Adult, Cytochrome P-450 CYP2D6 physiology, Dealkylation, Female, Humans, Male, Middle Aged, Sparteine metabolism, Analgesics, Opioid metabolism, Cytochrome P-450 CYP2D6 genetics, Polymorphism, Genetic, Tramadol metabolism
- Abstract
Objective: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism., Methods: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O- and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe., Results and Conclusion: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (rs = 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.
- Published
- 1997
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81. Optimization of methods and models in clinical pharmacology.
- Author
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Gerloff J
- Subjects
- Animals, Humans, Models, Biological, Pharmacology, Clinical methods
- Abstract
Utilization of methods and models undoubtedly has its merits in the evaluation and interpretation of data in clinical pharmacology, but it is a process that ought to follow rigorous scientific rules and thoughts. For a discussion about optimization-a word concerning the quality of a procedure-the meaning and extent of the terms, methods, and models are defined, and different types of models are identified. In drug development, many steps can be improved, some within the pharmaceutical companies, some in the interaction with other organizations. This situation requires good organization and scientific sincerity. Some of the pitfalls encountered in daily work are described.
- Published
- 1997
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82. Radiofrequency ablation of idiopathic ventricular tachycardia.
- Author
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Vohra J, Shah A, Hua W, Gerloff J, and Riters A
- Subjects
- Adolescent, Adult, Chest Pain etiology, Electrocardiography, Electrophysiology, Female, Humans, Male, Middle Aged, Postoperative Complications, Tachycardia classification, Tachycardia physiopathology, Tachycardia, Ventricular diagnosis, Tachycardia, Ventricular physiopathology, Catheter Ablation, Tachycardia, Ventricular surgery
- Abstract
Background: Radiofrequency ablation (RFA) has been shown to be very effective in the treatment of supraventricular tachycardias and has replaced surgical ablation. Only a few reports of RFA for idiopathic ventricular tachycardia (VT) have appeared in the literature during the last two years., Aim: This paper presents our experience with RFA for idiopathic VT in 19 patients., Material: The age range of patients was 22-60, with a mean of 37.9 years. Twelve out of 19 were females, two patients had cardiac failure due to almost incessant VT while the rest had normal left ventricular function. Twelve patients had VT arising from the right ventricle (RV); of these, nine were from the outflow tract, two from the RV apex, and one from the mid-anterior RV. Seven patients had VT arising from the left ventricle (LV); of these, five were from the inferobasal portion of the septum and two were from the anterolateral area., Methods: In all patients the diagnostic study and therapeutic RFA were combined in a single procedure. Pacemapping was used to guide the site of RFA in patients with VT arising from the RV. Local activation time (LAT), Purkinje potentials (PP) and pacemapping were used to guide RFA in those patients with LV septal tachycardias., Results: A total of 21 RF procedures were performed in 19 patients and 15 out of 19 patients had successful VT ablation. Ten of the 12 patients with RV tachycardias and all five patients with LV septal (left axis, right bundle branch block) tachycardias were successfully ablated. One patient with mid anterior RV VT required two attempts for successful ablation. One patient with RV outflow tract (RVOT) VT could not be ablated despite two attempts. Two patients with LV tachycardias arising from the antero-lateral LV could also not be ablated. During a follow up period of two to 16 months none of the successful patients had recurrence of VT. The number of RF applications was one to 27, mean 10; fluoroscopy times were four to 75, mean 26.9 minutes., Conclusion: Idiopathic VT frequently arises from the RVOT and inferobasal portion of the LV septum. These tachycardias can be diagnosed on clinical and ECG grounds. RFA for idiopathic VT arising from these areas has a high success rate and this mode of treatment should be considered as a nonpharmacological curative treatment for symptomatic patients.
- Published
- 1996
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83. Pharmacokinetics and absolute bioavailability of lansoprazole.
- Author
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Gerloff J, Mignot A, Barth H, and Heintze K
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles, Administration, Oral, Adult, Analysis of Variance, Anti-Ulcer Agents administration & dosage, Anti-Ulcer Agents blood, Biological Availability, Cross-Over Studies, Humans, Injections, Intravenous, Lansoprazole, Male, Middle Aged, Omeprazole administration & dosage, Omeprazole blood, Omeprazole pharmacokinetics, Phenotype, Tablets, Enteric-Coated, Anti-Ulcer Agents pharmacokinetics, Omeprazole analogs & derivatives
- Abstract
Objective: In a crossover study 12 healthy volunteers received lansoprazole 15 mg or 30 mg orally, or 15 mg intravenously in randomized order as a single dose. Blood samples were taken and plasma levels of lansoprazole were determined using an HPLC method. The volunteers were phenotyped for the debrisoquine/sparteine and mephenytoin polymorphisms., Results: The total clearance was 517 ml.min-1, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in Cmax and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose.
- Published
- 1996
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84. Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase.
- Author
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van Griensven JM, Burggraaf KJ, Gerloff J, Günzler WA, Beier H, Kroon R, Huisman LG, Schoemaker RC, Kluft K, and Cohen AF
- Subjects
- Adult, Enzyme Precursors pharmacokinetics, Fibrinolytic Agents pharmacokinetics, Humans, Liver diagnostic imaging, Male, Recombinant Proteins pharmacokinetics, Recombinant Proteins pharmacology, Reference Values, Ultrasonography, Doppler, Pulsed, Urokinase-Type Plasminogen Activator pharmacokinetics, Enzyme Precursors pharmacology, Exercise physiology, Fibrinolytic Agents pharmacology, Food, Liver Circulation physiology, Urokinase-Type Plasminogen Activator pharmacology
- Abstract
Objective: To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator., Methods: This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography., Results: The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics., Conclusions: u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.
- Published
- 1995
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85. Biochemical markers in early diagnosis of acute myocardial infarction.
- Author
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Gerloff J and Hoeschen K
- Subjects
- Humans, Myocardial Infarction metabolism, Sensitivity and Specificity, Biomarkers analysis, Myocardial Infarction diagnosis
- Published
- 1995
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86. Pharmacokinetics of saruplase, a recombinant unglycosylated human single-chain urokinase-type plasminogen activator and its effects on fibrinolytic and haemostatic parameters in healthy male subjects.
- Author
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de Boer A, Kluft C, Gerloff J, Dooijewaard G, Günzler WA, Beier H, van der Meer FJ, and Cohen AF
- Subjects
- Adult, Amino Acid Sequence, Dose-Response Relationship, Drug, Double-Blind Method, Humans, Male, Metabolic Clearance Rate, Molecular Sequence Data, Partial Thromboplastin Time, Plasminogen Activator Inhibitor 1 analysis, Platelet Function Tests, Recombinant Proteins pharmacokinetics, Recombinant Proteins pharmacology, Urokinase-Type Plasminogen Activator pharmacokinetics, Fibrinolysis drug effects, Hemostasis drug effects, Urokinase-Type Plasminogen Activator pharmacology
- Abstract
Pharmacokinetics of two doses of the recombinant single-chain urokinase-type plasminogen activator (r-scu-PA) saruplase (40 and 20 mg) and its effect on fibrinolytic and haemostatic parameters were studied in six healthy male subjects using a randomized, double-blind, placebo-controlled, cross-over study. Special precautions were taken to prevent artefactual in vitro effects on fibrinolytic activity. The clearance of saruplase ranged from 310 to 862 ml/min and the apparent volume of distribution of the central compartment was about 8 1. Both doses of saruplase caused alpha 2-antiplasmin consumption, indicating some systemic fibrinolytic activation. However, the 20 mg dose caused no detectable fibrinogen breakdown and only a small increase in total fibrin/fibrinogen degradation products (TDP) (from 0.16 microgram/ml [range 0.14 to 0.19] to 0.78 microgram/ml [range 0.56 to 1.26]), while the 40 mg dose produce a fibrinogen breakdown to an average value of 44% (range 19 to 60%) and TDP increased from 0.12 microgram/ml (range 0.11-0.12) to 2.29 micrograms/ml (range 0.45 to 5.55). The breakdown of fibrinogen was related to the quantity of saruplase converted to active two-chain u-PA (tcu-PA) in vivo (6 to 22% conversion). There were no important effects of saruplase on overall blood coagulation (activated partial thromboplastin time) and platelet function (collagen induced platelet aggregation, urinary [2,3-dinor]-thromboxane B2 excretion and plasminogen activator inhibitor 1 [PAI-1] release from platelets). Saruplase is cleared rapidly from the plasma and a variable amount is converted to tcu-PA. This two-chain form of u-PA probably causes the dose-dependent systemic fibrinolytic activation.
- Published
- 1993
87. Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia: a report of 135 procedures.
- Author
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Sathe S, Vohra J, Chan W, Wong J, Gerloff J, Riters A, Hall R, and Hunt D
- Subjects
- Adult, Electrocardiography, Female, Follow-Up Studies, Humans, Male, Tachycardia, Paroxysmal diagnosis, Tachycardia, Paroxysmal epidemiology, Tachycardia, Supraventricular diagnosis, Tachycardia, Supraventricular epidemiology, Time Factors, Catheter Ablation, Heart Conduction System surgery, Tachycardia, Paroxysmal surgery, Tachycardia, Supraventricular surgery
- Abstract
Background: Paroxysmal Supraventricular Tachycardia (PSVT) is a common condition which until recently has been treated with anti-arrhythmic drugs or surgery. Radiofrequency (RF) catheter ablation is a new mode of treatment which provides a cure of this condition., Aims: To present our early experience of RF catheter ablation for PSVT., Methods: One hundred and thirty-five procedures were performed in 117 patients. The diagnostic study and therapeutic catheter ablation were performed as a combined electrophysiological procedure in 74 patients (63%). In 58 patients (50%), PSVT was due to Atrio-ventricular junctional (nodal) re-entrant tachycardia (AVJRT). Twenty-five of the 58 patients underwent a fast pathway ablation while 33 had ablation of their slow pathway. The mean number of radiofrequency pulses delivered was ten for a mean duration of 25 seconds. Radiofrequency ablation of accessory pathways was attempted in 58 patients; pathways were left-sided in 29 patients, postero-septal in 21, midseptal in five, Mahaim connection in two, antero-septal in one and right free wall in one patient. One patient with incessant automatic atrial tachycardia also underwent a successful RF ablation., Results: Using RF ablation cure of PSVT was achieved in 90% of patients. Cure of AVJRT was achieved in 95% (55/58) of patients using either fast or slow pathway ablation. Only one patient required permanent pacemaker implantation for Mobitz type I AV block following fast pathway ablation. The overall success rate for ablation of accessory pathways was 85%. There is an operator learning curve for this procedure suggested by the fact that the success rate for accessory pathway ablation at first attempt was 63% in the first 29 patients and 93% in the remaining 29. There was no significant morbidity or mortality during or after the procedure. In a mean follow-up of nine months in the patients with successful ablation only two patients with AVJRT had a recurrence of documented PSVT. Both these patients had successful repeat RF ablation. Catheter ablation using radiofrequency energy is an effective and safe therapeutic option for patients with symptomatic PSVT.
- Published
- 1993
- Full Text
- View/download PDF
88. [Oxidation of cyclic aromatic amines (author's transl)].
- Author
-
Möhrle H and Gerloff J
- Subjects
- Oxidation-Reduction, Amines
- Published
- 1978
- Full Text
- View/download PDF
89. [Intestinal absorption and metabolism of lanatoside C].
- Author
-
Bodem G, Grube E, Ochs HR, and Gerloff J
- Subjects
- Humans, Intestinal Absorption, Lanatosides metabolism
- Published
- 1978
90. Assessment of cardiac risk 10 days after uncomplicated myocardial infarction.
- Author
-
Jelinek VM, McDonald IG, Ryan WF, Ziffer RW, Clemens A, and Gerloff J
- Subjects
- Exercise Test, Follow-Up Studies, Humans, Middle Aged, Myocardial Infarction mortality, Myocardial Infarction rehabilitation, Prognosis, Recurrence, Risk, Time Factors, Myocardial Infarction diagnosis
- Abstract
A total of 188 patients with uncomplicated acute myocardial infarction (long-term Norris prognostic index 3.2) were rapidly mobilised, underwent a symptom-limited exercise test around the day of discharge from hospital (day 10), and returned to work at a median of six weeks after the acute event. The incidence of cardiac death six months, one year, and three years after infarction was 2.7%, 4.5%, and 7.3% respectively, and the corresponding figures for recurrent heart attacks were 3.4%, 8.2%, and 18.5% respectively. The risk of recurrence of heart attack was predicted by three variables assessed at discharge--namely, a history of classical effort angina (p less than 0.01), radiological heart failure (p less than 0.05), and angina induced by the exercise test (p less than 0.05). The presence of any of these risk factors defined a group of patients with a sevenfold risk of recurrent heart attacks within six months of the initial acute infarct. It is concluded that these risk factors identify a group of patients with a high risk of recurrence early after infarction, in whom vigorous secondary prophylaxis is desirable.
- Published
- 1982
- Full Text
- View/download PDF
91. Nifedipine: kinetics and dynamics after single oral doses.
- Author
-
Ochs HR, Rämsch KD, Verburg-Ochs B, Greenblatt DJ, and Gerloff J
- Subjects
- Administration, Oral, Adult, Blood Pressure drug effects, Clinical Trials as Topic, Eating, Fasting, Female, Heart Rate drug effects, Humans, Kinetics, Male, Myocardial Contraction drug effects, Nifedipine blood, Hemodynamics drug effects, Nifedipine administration & dosage
- Abstract
Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.
- Published
- 1984
- Full Text
- View/download PDF
92. [Mechanocardiographic and pharmacokinetic studies with a new cardiac glycoside in man].
- Author
-
Bodem G and Gerloff J
- Subjects
- Acrylonitrile analogs & derivatives, Acrylonitrile metabolism, Acrylonitrile pharmacology, Cardiac Output drug effects, Clinical Trials as Topic, Digoxin metabolism, Digoxin pharmacology, Drug Evaluation, Half-Life, Heart Rate drug effects, Humans, Protein Binding, Digoxin analogs & derivatives, Heart drug effects
- Published
- 1977
93. [Therapy of a refractory idiopathic thrombocytopenic purpura by vinblastine-loaded thrombocytes (author's transl)].
- Author
-
Budde U, Schmidt R, Gerloff J, and Etzel F
- Subjects
- Adolescent, Humans, Male, Vinblastine administration & dosage, Vinblastine adverse effects, Blood Platelets, Purpura, Thrombocytopenic drug therapy, Vinblastine therapeutic use
- Abstract
A 15-year-old patient with ITP which was refractory to corticosteroids, splenectomy, and immunosuppressive therapy with vincristine was twice treated with platelets loaded with vinblastine. Five days after the application of the platelets vinblastine complex the platelets began to rise up to 600 X 10(9)/l. The remission has lasted until now for more than 15 weeks. The therapy showed no major side effects except for a transient granulocytopenia.
- Published
- 1979
- Full Text
- View/download PDF
94. [Tricyclic benzimidazole derivatives (author's transl)].
- Author
-
Möhrle H and Gerloff J
- Subjects
- Chemical Phenomena, Chemistry, Benzimidazoles chemical synthesis
- Published
- 1978
- Full Text
- View/download PDF
95. [Comparative studies on the bioequivalency of digoxin (Lanoxin) and of beta-methyldigoxin (Lanitop) in patients with cardiac insufficiency].
- Author
-
Otten H, Gerloff J, and Bodem G
- Subjects
- Adult, Aged, Biological Availability, Digoxin therapeutic use, Humans, Middle Aged, Digoxin analogs & derivatives, Digoxin metabolism, Heart Diseases drug therapy
- Published
- 1977
96. Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility.
- Author
-
Ochs HR, Greenblatt DJ, Abernethy DR, Arendt RM, Gerloff J, Eichelkraut W, and Hahn N
- Subjects
- Animals, Dogs, Half-Life, Kinetics, Lipids, Pharmaceutical Preparations metabolism, Solubility, Pharmaceutical Preparations cerebrospinal fluid
- Abstract
In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.
- Published
- 1985
- Full Text
- View/download PDF
97. The dual sample aggregometer. A new instrument adapted for serial testing of antiaggregating agents.
- Author
-
Gerloff J and von Kaulla KN
- Subjects
- Animals, Dogs, Humans, Swine, Blood Coagulation Tests instrumentation, Platelet Adhesiveness
- Published
- 1972
98. Prevention of dog serum-induced aggregation of pig platelets.
- Author
-
Gerloff J and Von Kaulla KN
- Subjects
- Animals, Cellulose pharmacology, Complement System Proteins, Dogs, Fibrinolytic Agents pharmacology, Flufenamic Acid pharmacology, Heparin pharmacology, Male, Polysaccharides pharmacology, Sulfonic Acids pharmacology, Swine, Blood, Platelet Adhesiveness drug effects, Transplantation Immunology
- Published
- 1972
- Full Text
- View/download PDF
99. [Biotin].
- Author
-
GERLOFF J
- Subjects
- Folic Acid, Vitamin B Complex
- Published
- 1950
100. [In-vitro inhibition of thrombocyte aggregation induced by xenogenic serum].
- Author
-
von Kaulla KN and Gerloff J
- Subjects
- Animals, Complement Fixation Tests, Dogs, Female, Heparin pharmacology, In Vitro Techniques, Methods, Polysaccharides pharmacology, Swine, Fibrinolytic Agents pharmacology, Heparinoids pharmacology, Immune Sera pharmacology, Platelet Adhesiveness drug effects
- Published
- 1972
- Full Text
- View/download PDF
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