163,776 research outputs found
[Report to Chief J. E. Curry, by an unknown author #1]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
[Report to Chief J. E. Curry, by an unknown author #2]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
Murder on the mountain: author talk with Peter J. Wosh
No full textAuthor talk by Peter J. Wosh on May 5th, 2022, on his book, "Murder on the Mountain: crime, passion, and punishment in gilded age New Jersey.
Hyperreactive peripheral neutrophils in periodontitis : FCc receptor activation and plasma proteins
No full textIt is now well established that adult and juvenile periodontitis are associated with a hyperreactivity of the peripheral neutrophils when measured as increased generation of free oxygen radicals after stimulation of the Fcgamma-receptors.Aim: The aims of these investigations were to study if the increased radical generation was: 1) located intra- or extracellularly and attributed to a specific oxygen species or various activation pathways, 2) connected with "priming" (pre-stimulation only disclosed by a secondary activation), 3) associated with systemic aberrations in plasma parameters induced by the periodontal disease or cigarette smoking or 4) related to the neutrophil production of the cytokines IL-8 and TNFalpha after stimulation.Patients: All the patients with adult periodontitis had marked tissue destruction and were matched for age, sex and smoking habits. All participants were generally healthy and without medication, which could influence the inflammatory response. Systemic affections of inflammatory parameters in plasma were checked. Only non-smoking subjects were included in the last study.Methods: Total generation of the oxygen species was measured with luminol enhanced chemiluminescence while the extracellular part was measured with iso-luminol enhanced chemiluminescence. The intracellular H2O2 generation with dichloro-fluorescein-diacetate was measured by flow cytometry after simulation with opsonized bacteria (Fcgamma-receptors). The neutrophil response to the cytokines, TN17 (x and IL-8 was measured by release of the two cytokines in the incubation medium after stimulation of the Fcgamma-receptors.Results and discussion: An increased total (extra- plus intracellular) radical generation from the peripheral neutrophils in periodontitis was confirmed, as well as an increased extracellular production, while the intracellular production of H2O2 did not differ between patients and controls. The response to non-specific priming and priming by TNFalpha and LPS did not differ between patients and controls. The inflammatory plasma parameters were normal in patients and controls indicating absence of occasional inflammation, but a slight systemic effect of the periodontitis in the form of increasing CRP and decreasing IgG2 was traced. However, a marked enhancing effect of cigarette smoking was observed on most acute phase parameters in blood. Cigarette smoking also lowered the neutrophil response of IL-8 after stimulation in patients. The generation of oxygen radicals was increased using both FcgammaR, CR3 and PMA activation but the FcgammaR activation was significantly higher in the patients.Conclusions: These studies confirm a hyperreactivity of peripheral neutrophils in periodontitis, measured as an increased, both total and extracellular, generation of oxygen species. This increased generation is in its initial stimulation step most obviously bound to the Fcgamma receptors, and probably not caused by higher neutrophil sensitivity to neither non-specific priming nor TNFalpha or LPS priming. Systemic effects of inflammatory plasma parameters are mainly correlated to cigarette smoking, meaning that pathogenetic studies on periodontitis should be one on well treated, non-smoking subjects. The systemic effects of periodontitis per se are small because of the minor local inflammation. The hyperreactivity of the neutrophils seems to be of a cell bound genetic nature involving Fc-receptors and their signalling pat ways.List of scientific papersI. Fredriksson M, Gustafsson A, Asman B, Bergstrom K (1998). "Hyper-reactive peripheral neutrophils in adult periodontitis: generation of chemiluminescence and intracellular hydrogen peroxide after in vitro priming and FcgammaR-stimulation. " J Clin Periodontol 25(5): 394-8 https://pubmed.ncbi.nlm.nih.gov/9650876II. Fredriksson M, Gustafsson A, Asman B, Bergstrom K (1999). "Periodontitis increases chemiluminescence of the peripheral neutrophils independently of priming by the preparation method" Oral Dis 5(3): 229-33 https://pubmed.ncbi.nlm.nih.gov/10483069III. Fredriksson MI, Figueredo CM, Gustafsson A, Bergstrom KG, Asman BE (1999). "Effect of periodontitis and smoking on blood leukocytes and acute-phase proteins. " J Periodontol 70(11): 1355-60 https://pubmed.ncbi.nlm.nih.gov/10588499IV. Fredriksson M, Bergstrom K, Asman B (2002). "IL-8 and TNFalpha from peripheral neutrophils and acute-phase proteins in periodontitis. Effect of cigarette smoking: a pilot study" J Clin Periodontol 29: (Accepted)V. Fredriksson M, Gustafsson A, Bergstrom K, Asman B (2001). "More oxygen radicals from neutrophils periodontitis." (Submitted)</p
A component-based development framework for supporting functional and non-functional analysis in control system design
No full textMr. Melvin J. Collier, RWWL AUC, June 2011
No full textThis video is a conversation with Mr. Melvin J. Collier. Mr. Collier talks about his book, "From Mississippi to Africa: A Journey of Discovery". Daniel Le, AUC Woodruff Library, is the interviewer
Tracer development and PET studies : labeled proinsulin C-peptide and an EGFR-TK inhibitor
No full textPositron emission tomography (PET), which localizes and quantifies positron decays over time, enables non-invasive in vivo distribution studies of trace amounts of compounds labeled with positron emitters. The use of PET to image disease processes is growing as the number of available tracers increases and, especially, as they become more selective and specific. PET is also increasingly being used in the development of drugs. Since trace amounts of the drug can be administered, distribution and kinetic studies can be performed in humans early in the developmental process to ascertain that the intended biophase is actually reached and to a satisfactory extent and duration.This thesis includes (1) developments for an imaging approach with oncological application, which is based on an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK) and (2) drug development with respect to studying the pharmacokinetics and biodistribution of proinsulin C- peptide, which is being evaluated for treating long-term complications in type 1 diabetes mellitus (DM).The EGFR, normally involved in mitogenic signaling, is over-expressed in many different cancer types, e.g. non-small cell lung, glial cell, head and neck, pancreatic, bladder, prostate and breast cancer. A correlation between the amount of EGFR and poor prognosis has been established in a number of these cancers. A radiotracer selective for the EGFR could therefore be of interest for tumor localization and for treatment selection or evaluation of therapeutic response.Methods to produce a precursor for radiolabeling PD153035 (4-(3-bromoanilino)- 6,7dimethoxyquinazoline), a potent inhibitor selective for the EGFR-TK (Ki~5.2 pM; 1C50~29 pM), were sought. Synthetic strategies for producing 6- or 7- mono-desmethyl and 6,7-didesmethyl PD15305 were identified. Thus different positions for labeling can be selected, which is of potential interest for metabolic studies. [6-Methoxy-11C]PD153035 was produced and its in vivo distribution to normal and proliferating tissue was evaluated in rats. In healthy rat, radioactivity was observed mainly in liver, heart, brain and in the gastrointestinal tract. Tumor radioactivity concentrations, studied in rats implanted with a human neuroblastoma cell line (SH- SY5Y), varied in accordance with differences in tumor size and viability (determined post-mortem). The results motivate further studies to determine the selectivity and specificity of [11C]PD153035 distribution to tumor in order to elucidate whether this tracer has potential for EGFR-TK level imaging with PET.Type 1 (insulin-dependent) DM, characterized by impaired or no insulin production, is accompanied by an increased risk for micro (kidneys, nerves, retina) and macro (heart, brain, extremities) vascular dysfunction. Since insulin is lacking, so is C-peptide, which is normally produced and released in equimolar amounts together with insulin. Studies have demonstrated that administration of C-peptide to IDDM patients results in increased blood flow to skeletal muscle and skin, improved renal function and amelioration of diabetic neuropathy.A multi-step procedure to label human C-peptide with fluorine-18 based on the activated ester N- suceinimidyl-4-[18F]fluorobenzoate ([18F]SFB) to afford N-4-[18F]fluorobenzoyl-C-peptide ([18F]FB-C-peptide) was identified. With the purpose of furthering the knowledge on Cpeptide's in vivo distribution, with special emphasis on the kinetics in the kidneys, [18F]FB-Cpeptide was studied in monkeys and in volunteering type 1 DM patients using PET. Following iv administration of [18F]FB-C-peptide, radioactivity distributed mainly to the kidneys. A tendency, albeit not statistically significant due to the small number of subjects, to slower kinetics in kidney and liver was observed when pharmacological doses of C-peptide were co-administered with the tracer. Low concentrations of radioactivity in skeletal muscle could, due to their large total mass in the body, account for approximately 15% of the administered dose. The distribution findings are consistent with the documented beneficial effects engendered by C-peptide on renal function and on blood flow to skeletal muscle.List of scientific papersI. Synthesis of [methoxy-11C]PD153035, a selective EGF receptor tyrosine kinase inhibitor. (1998). "Johnstrom P, Fredriksson A, Thorell JO, Stone-Elander S" J Labelled Cpd. Radiopharm 41: 623-9II. Fredriksson A, Johnstrom P, Thorell JO, von Heijne G, Hassan M, Eksborg S, Kogner P, Borgstrom P, Ingvar M, Stone-Elander S (1999). "In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants. " Life Sci 65(2): 165-74 https://pubmed.ncbi.nlm.nih.gov/10416822III. Fredriksson A, Stone-Elander S (2002). "Rapid microwave-assisted cleavage of methyl phenyl ethers: New method for synthesizing desmethyl precursors and for removing protecting groups." J Labelled Cpd. Radiopharm 45: 529-38IV. Fredriksson A, Johnstrom P, Stone-Elander S, Jonasson P, Nygren PA, Ekberg K, Johansson BL, Wahren J (2001). "Labelling of human C-peptide by conjugation with N-succinimidyl-4-[18F]fluorobenzoate." J Labelled Cpd. Radiopharm 44: 509-19V. Fredriksson A, Ekberg K, Ingvar M, Johansson BL, Wahren J, Stone-Elander S (2002). "In vivo biodistribution and pharmacokinetics of 18F-labeled human C-peptide: Evaluation in monkeys using positron emission tomography, PET." Life Sci (In Print)VI. Fredriksson A, Ekberg K, Ingvar M, Johansson BL, Wahren J, Stone-Elder S (2002). "In vivo biodistribution of 18F-labeled C-peptide in humans: Evaluation using PET." (Manuscript)VII. Fredriksson A, Thorell JO, Stone-Elander S (supporting data) (2002). "App. till artikel 3: Synthesis of 4-(3-bromoanilino)-7-hydroxy-6-methoxyquinazoline, 7 (7-des-methylPD150335): Preparation of a reference compound."</p
The role of red blood cells in inflammation and remodeling
No full textBesides being carriers of oxygen and carbon dioxide, red blood cells (RBCs) also have a scavenger function, binding inflammatory mediators to surface receptors. Animal and experimental models have suggested a role for RBCs in inflammatory and fibrotic responses and patients with idiopathic pulmonary hemosiderosis, a disease characterized by lung hemorrhage, frequently develop fibrosis. Fibroblasts, the resident cell in the connective tissue, play an active role in tissue remodeling by proliferating and migrating. These cells have the capacity to produce and secrete matrix components, matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases and a variety of cytokines and growth factors. Alteration in these fibroblast functions may lead to impaired repair, resulting in loss in lung function. Given the ability of RBCs to interact with extracellular matrix in lung disorders, the present thesis is based on the hypothesis that RBCs might play a role in repair and progression of fibrosis.We used a model where human lung fibroblasts were cultured in floating three-dimensional collagen gels, a method that reflects the contractile process typical of tissue remodeling. RBCs, hemolyzed RBCs and RBC-conditioned medium (RBC-CM) stimulated fibroblastmediated collagen gel contraction in a time and concentration dependent manner. RBCs and RBC-CM also stimulated fibroblast fibronectin secretion. In addition, transforming growth factor-beta1 was increased in culture supernatants when fibroblasts were co-cultured with RBCs, whereas the concentration of prostaglandin-E2 did not change.Accumulation of neutrophils is a regular feature in many inflammatory and fibrotic lung disorders. Neutrophil elastase, a serine protease released by neutrophils, further augmented RBCinduced fibroblast-mediated collagen gel contraction. Both contraction induced by neutrophil elastase and RBCs was attenuated by a pan-MMP-inhibitor, indicating a role for fibroblastderived MMP in the contractile process. This was supported by increased activity of MMP-1, - 2 and 3 in gel culture supernatants.Both RBCs and RBC-CM were able to stimulate fibroblast release of interleukin-8 (IL-8), a chemoattractant for neutrophils. The pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) also stimulated fibroblast IL-8 secretion and when the cytokines were added together with RBCs, a synergistic stimulatory effect on fibroblast IL-8 secretion was observed. Transwell, an in vitro model for cell migration, showed that supernatants from fibroblasts cultured with IL-1beta/TNF-alpha stimulated neutrophil migration. When RBCs were added, neutrophil migration was further enhanced.Cell proliferation and apoptosis is crucial in order to maintain fibroblast homeostasis. RBCs inhibited fibroblast proliferation measured by three different in vitro methods. In addition, RBCs increased fibroblast susceptibility to staurosporine-induced apoptosis. RBC-CM did not affect fibroblast proliferation and apoptosis, indicating that cell-cell contact is necessary to mediate these effects.We conclude that RBCs can act on several fibroblast functions important in tissue remodeling. Since micro hemorrhage occurs in many inflammatory and fibrotic lung disorders, the present thesis support a role for RBCs in regulating repair mechanisms after injury.List of scientific papersI. Fredriksson K, Lundahl J, Fernvik E, Liu XD, Rennard SI, Skold CM (2002). Red blood cells stimulate fibroblast-mediated contraction of three dimensional collagen gels in co-culture. Inflamm Res. 51(5): 245-51. https://pubmed.ncbi.nlm.nih.gov/12056512II. Fredriksson K, Lundahl J, Palmberg L, Romberger DJ, Liu XD, Rennard SI, Skold CM (2003). Red blood cells stimulate human lung fibroblasts to secrete interleukin-8. Inflammation. 27(2): 71-8. https://pubmed.ncbi.nlm.nih.gov/12797546III. Fredriksson K, Stridh H, Lundahl J, Rennard SI, Skold CM (2004). Red blood cells inhibit proliferation and stimulate apoptosis in human lung fibroblasts in vitro. Scand J Immunol. 59(6): 559-65. https://pubmed.ncbi.nlm.nih.gov/15182251IV. Fredriksson K, Lundahl J, Liu XD, Klominek J, Rennard SI, Skold CM (2004). Red blood cells increase secretion of matrix metalloproteinases (MMPs) from human lung fibroblasts in vitro. [Manuscript]</p
Muscle mitochondria in sepsis
No full textPatients treated in the intensive care unit (ICU) for sepsis induced multiple organ failure often suffer from skeletal muscle fatigue after ICU discharge. Since mitochondria are the main determinants of muscle fatigability, their function in muscle of these patients was the theme of this thesis. Decreased muscle mitochondrial activity has been related to mortality in patients suffering from acute sepsis. The present thesis has two major aims. The first is to describe mitochondrial derangements in muscle from septic patients and the second one was to elucidate the underlying mechanisms for these mitochondrial problems.To describe the mitochondrial derangements in muscle from septic patients, muscle biopsies were obtained from respiratory and leg muscle of mechanically ventilated septic patients and healthy control patients. In both muscle tissues a decreased mitochondrial content was found in comparison to controls. In addition, leg muscle had lower concentrations of energy rich phosphates and an increased lactate concentration. The second study relating to this problem was performed in a human model for studying the very early phase of sepsis. In this study leg muscle biopsies were obtained at baseline and 2 and 4 hours after an intravenous endotoxin injection. Mitochondrial enzyme activities increased 2 hours after endotoxin and went back to baseline at 4 hours. The concentration of ATP did not change between baseline and the two consecutive biopsies, however an increase in activity was found between 2 and 4 hours after endotoxin.The second aim was to characterize underlying mechanisms that may cause mitochondrial derangements in septic patients. The effect of inactivity on muscle mitochondria was evaluated in diaphragm muscle from mechanically ventilated piglets. The mitochondrial enzyme activity of complex IV was significantly decreased after 5 days of mechanical ventilation while the other mitochondrial enzymes and content did not change. In the last study mitochondrial protein turnover and biogenesis were evaluated in leg muscle from septic ICU patients. Mitochondrial protein synthesis and mRNA levels of mitochondrial proteins were not different between patients and controls. Some of the mitochondrial transcription factors increased in mRNA levels, whereas the others did not change in comparison to controls. The mRNA levels of the active subunits of two mitochondrial matrix proteases increased significantly while the membrane bound proteases did not change.In summary, the mitochondrial content is decreased in respiratory and leg muscle from septic ICU patients. In leg the lower mitochondrial content was accompanied by low concentrations of energetic phosphates. A human model of sepsis indicated a biphasic development of mitochondrial derangements were an initial increase in mitochondrial enzyme activity is followed by a decrease. The cause of the decrease in mitochondrial content does not seem to be related to inactivation by mechanical ventilation as evaluated in piglets. Decreased mitochondrial content cannot be explained by a decreased mitochondrial protein synthesis or biogenesis. It is more likely that an increased mitochondrial protein breakdown is responsible for the decreased mitochondrial content in patients with sepsis induced multiple organ failure.List of scientific papersI. Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O (2006). Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Physiol Endocrinol Metab. 291(5): E1044-50. https://pubmed.ncbi.nlm.nih.gov/16803854II. Fredriksson K, Fläring U, Guillet C, Wernerman J, Rooyackers O (2006). Muscle mitochondrial activity and energic status in a human model of sepsis. [Manuscript]III. Fredriksson K, Radell P, Eriksson LI, Hultenby K, Rooyackers O (2005). Effect of prolonged mechanical ventilation on diaphragm muscle mitochondria in piglets. Acta Anaesthesiol Scand. 49(8): 1101-7. https://pubmed.ncbi.nlm.nih.gov/16095451IV. Fredriksson K, Tjäder I, Ahlman B, Scheele C, Wernerman J, Timmons JA, Rooyackers O (2006). Mitochondrial protein turnover in muscle from patients with sepsis induced multiple organ failure. [Manuscript]</p
Local and systemic inflammatory mediators and their relation to pressure-pain threshold and pain of the temporomandibular joint
No full textThe first aim of this investigation was to investigate the validity of TMJ pressure-pain threshold for assessment of pain conditions of inflammatory nature in the TMJ. Pressure-pain threshold was recorded from the palpable lateral pole of the TMJ condyle with a hand-held electronic pressure algometer (Somedic Production AB, Sollentuna, Sweden). TMJ pressure-pain threshold is systemically modulated and not modulated by the investigated inflammatory mediators (5-HT, TNFα, IL-1sRII) in the TMJ synovial fluid. TMJ pressure-pain threshold is therefore not valid as a tool for assessment of intra-articular pain conditions of inflammatory nature.The second aim was to investigate differences in pressure-pain threshold between genders in healthy individuals and RA patients as well as between healthy females and female RA patients with clinical signs of TMJ involvement. TMJ pressure-pain threshold in female RA patients is lower than in male RA patients as well as in healthy females. No difference between healthy females and males was observed.The third aim of was to investigate the influence of synovial fluid and blood levels of 5-HT and TNFα on the effects by intra-articular injections of glucocorticoid regarding pressure-pain threshold and on pain of the TMJ in patients with chronic inflammatory TMJ disorders. The glucocorticoid was injected into the upper joint compartment of the TMJ. TMJ synovial fluid samples were obtained before and after treatment. Patients with detectable pretreatment levels of synovial fluid 5-HT experienced a larger reduction of TMJ pain intensity at rest and on maximum mouth opening after treatment with intra-articular glucocorticoid. Patients with detectable pretreatment levels of synovial fluid TNFα experience a larger reduction of TMJ pain on maximum mouth opening than those without after treatment. Pretreatment presence of TNFα or 5-HT in the synovial fluid predicts reduction of TMJ pain by intra-articular injection of glucocorticoid in patients with chronic inflammatory TMJ disorders.The fourth and final aim was to investigate the relative importance of systemic and local inflammatory mediators (5-HT, TNFα, IL-1sRII) in the modulation of pressurepain threshold and other pain entities in patients with seropositive or seronegative RA involving the TMJ and whether these pain entities are related to each other. TMJ synovial fluid samples were obtained from all patients. TMJ pressure-pain threshold as well as other TMJ pain entities were recorded. The results indicate that TMJ pressure-pain threshold is modulated by systemic rather than local inflammatory mediators and is unrelated or weakly related to other TMJ pain entities in RA patients. TMJ pain intensity at rest is mainly locally modulated but with an additional systemic influence. TMJ movement pain is mainly modulated by systemic mediators in the seropositive patients and mainly by local mediators in the seronegative patients. Tenderness and pain reflex to palpation are modulated mainly by systemic mediators in both groups, where TNFα dominate in seropositive and 5-HT in seronegative patients.List of scientific papersI. Fredriksson L, Alstergren P, Kopp S (2000). Absolute and relative facial pressure-pain thresholds in healthy individuals. J Orofac Pain. 14(2): 98-104. https://pubmed.ncbi.nlm.nih.gov/11203752 II. Fredriksson L, Alstergren P, Kopp S (2003). Pressure pain thresholds in the craniofacial region of female patients with rheumatoid arthritis. J Orofac Pain. 17(4): 326-32. https://pubmed.ncbi.nlm.nih.gov/14737877 III. Fredriksson L, Alstergren P, Kopp S (2005). Serotonergic mechanisms influence the response to glucocorticoid treatment in TMJ arthritis. Mediators Inflamm. 2005(4): 194-201. https://doi.org/10.1155/MI.2005.194 IV. Fredriksson L, Alstergren P, Kopp S (2006). Tumor necrosis factor in temporomandibular joint synovial fluid predicts treatment effect on pain of intra-articular glucocorticoid treatment. Mediators of Inflammation. [Accepted] https://doi.org/10.1155/MI/2006/59425 V. Alstergren P, Fredriksson L, Kopp S (2006). Temporomandibular joint pressure-pain threshold is modulated by systemic inflammatory mechanisms and only weakly related to other temporomandibular joint pain entities in rheumatoid arthritis. [Submitted]</p
- …
