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Pathophysiologic Mechanisms (pathophysiologic + mechanism)
Kinds of Pathophysiologic Mechanisms Selected AbstractsPathophysiologic mechanisms of persistent pulmonary hypertension of the newbornPEDIATRIC PULMONOLOGY, Issue 6 2005S. Dakshinamurti MD Abstract Persistent pulmonary hypertension of the newborn (PPHN), among the most rapidly progressive and potentially fatal of vasculopathies, is a disorder of vascular transition from fetal to neonatal circulation, manifesting as hypoxemic respiratory failure. PPHN represents a common pathway of vascular injury activated by numerous perinatal stresses: hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury. As with other multifactorial diseases, a single inciting event may be augmented by multiple concurrent/subsequent phenomena that result in differing courses of disease progression. I review the various mechanisms of vascular injury involved in neonatal pulmonary hypertension: endothelial dysfunction, inflammation, hypoxia, and mechanical strain, in the context of downstream effects on pulmonary vascular endothelial-myocyte interactions and myocyte phenotypic plasticity. © 2005 Wiley-Liss, Inc. [source] Acute and Chronic Oral Magnesium Supplementation: Effects on Endothelial Function, Exercise Capacity, and Quality of Life in Patients With Symptomatic Heart FailureCONGESTIVE HEART FAILURE, Issue 1 2006Johanna C. Fuentes MD Endothelial dysfunction is an important pathophysiologic mechanism in the progression of heart failure. The objective of the present study was to determine the effects of acute and chronic oral magnesium supplementation on endothelial function in patients with symptomatic heart failure. Twenty-two symptomatic chronic heart failure patients were randomized to receive 800 mg oral magnesium oxide daily or placebo for 3 months. Data collected included large and small arterial elasticity/compliance, hemodynamic parameters, exercise capacity, and quality-of-life score at baseline, 1 week, and 3 months. Patients who received magnesium had improved small arterial compliance at 3 months from baseline compared with placebo. This study suggests that chronic supplementation with oral magnesium is well tolerated and could improve endothelial function in symptomatic heart failure patients. [source] Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodelingJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2002Antonio Abbate Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and ,1 -adrenergic-stimulation may be major causes of receptor-mediated apoptosis. Benefits due to treatment with ACE-inhibitors and ,-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss. © 2002 Wiley-Liss, Inc. [source] Decreased Srcasm expression in hyperproliferative cutaneous lesionsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 3 2009Marc C. Meulener Background:, Src-family tyrosine kinases (SFKs) are signaling proteins that regulate keratinocyte proliferation and differentiation. Src-activating and signaling molecule (Srcasm) is a recently identified molecule that downregulates SFK activity and promotes keratinocyte differentiation. To determine if Srcasm expression correlates with keratinocyte differentiation, we characterized the level of Srcasm expression in some cutaneous lesions that exhibit increased keratinocyte proliferation. Methods:, Formalin-fixed sections of randomly selected seborrheic keratoses (SKs) and basal cell carcinomas (BCCs) were analyzed for Srcasm and Ki-67 immunohistochemical staining. Anti-Srcasm and anti-Ki-67 stainings were performed in parallel. Results:, All SKs displayed decreased Srcasm staining in areas comprised of basaloid keratinocytes that exhibited an increased Ki-67 index. Higher Srcasm staining levels were detected near pseudohorn cysts where keratinocytes exhibited a lower Ki-67 index. All multicentric and nodular BCCs displayed a prominent loss of Srcasm staining in association with a marked increase in Ki-67 staining. Conclusions:, Our results support the hypothesis that Srcasm protein levels are decreased in the hyperproliferative keratinocytes found in SKs and BCCs. Increased Srcasm protein levels are detected in keratinocytes undergoing differentiation. Decreased Srcasm levels may be part of the pathophysiologic mechanism in cutaneous lesions, exhibiting keratinocyte hyperproliferation. [source] Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: An experimental study on the autoimmune properties of nucleus pulposusJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2009Andrea Geiss Abstract An autoimmune response to herniated nucleus pulposus has been proposed to constitute a pathophysiologic mechanism for inducing sciatica based on the fact that nucleus pulposus under normal conditions is excluded from the development of immunological tolerance. The manifestation of an autoimmune response comprises different steps starting with antigen capture, continuing with activation of T helper (TH) cells and ending with production of autoantibodies. Activated TH cells differentiate into either TH1 cells, predominately producing proinflammatory cytokines such as interferon , (IFN,) or a TH2 subset mainly producing anti-inflammatory cytokines such as interleukin-4 (IL-4). The aim of the present study was to examine if exposure of autologous nucleus pulposus (NP) to the immune system for 3 weeks is potent enough to prime TH cells to differentiate into TH2 cells. The study was performed in a pig model allowing the exposure of NP to the immune system. To assess the polarization of TH cells the intracellular production of IFN, and IL-4 was measured in T cells by using flow cytometry. The revealed predominant production of IL-4 together with low production of IFN, in T cells after NP exposure to the immune system indicates that nucleus pulposus may prime TH cells to develop into IL-4-producing TH2 cells after being exposed to the immune system, for example, in association with disc herniation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:97,103, 2009 [source] Hypercalcemia in Cats: A Retrospective Study of 71 Cases (1991,1997)JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2000Karine CM. A retrospective study was conducted to characterize the diseases, clinical findings, and clinicopathologic and ultrasonographic findings associated with hypercalcemia (serum calcium concentration >11 mg/dL) in 71 cats presented to North Carolina State University Veterinary Teaching Hospital. The 3 most common diagnoses were neoplasia (n = 21), renal failure (n = 18), and urolithiasis (n = 11). Primary hyperparathyroidism was diagnosed in 4 cats. Lymphoma and squamous cell carcinoma were the most frequently diagnosed tumors. Calcium oxalate uroliths were diagnosed in 8 of 11 cats with urolithiasis. Cats with neoplasia had a higher serum calcium concentration (13.5 ± 2.5 mg/dL) than cats with renal failure or urolithiasis and renal failure (11.5 ± 0.4 mg/dL; P <.03). Serum phosphorus concentration was higher in cats with renal failure than in cats with neoplasia (P < .004). Despite the fact that the majority of cats with uroliths were azotemic, their serum urea nitrogen and creatinine concentrations and urine specific gravity differed from that of cats with renal failure. Additional studies are warranted to determine the underlying disease mechanism in the cats we identified with hypercalcemia and urolithiasis. We also identified a small number of cats with diseases that are not commonly reported with hypercalcemia. Further studies are needed to determine whether an association exists between these diseases and hypercalcemia, as well as to characterize the underlying pathophysiologic mechanism for each disease process. [source] Adiponectin and visfatin concentrations in children treated with valproic acidEPILEPSIA, Issue 2 2008Markus Rauchenzauner Summary Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy. [source] Role of Nitric Oxide in Pentylenetetrazol-Induced Seizures: Age-Dependent Effects in the Immature RatEPILEPSIA, Issue 4 2000Anne Pereira de Vasconcelos Summary: Purpose: Seizure susceptibility and consequences are highly age dependent. To understand the pathophysiologic mechanisms involved in seizures and their consequences during development, we investigated the role of nitric oxide (NO) in severe pentylenetetrazol (PTZ)-induced seizures in immature rats. Methods: Four cortical electrodes were implanted in 10-day-old (P10) and 21-day-old (P21) rats, and seizures were induced on the following day by repetitive injections of subconvulsive doses of PTZ. The effects of NG -nitro- l -arginine methyl ester (l -NAME; 10 mg/kg) and 7-nitroindazole (7NI; 40 mg/kg), two NO synthase (NOS) inhibitors, and l -arginine (l -arg; 300 mg/kg), the NOS substrate, were evaluated regarding the mean PTZ dose, seizure type and duration, and mortality rate. Results: At P10, the postseizure mortality rate increased from 18,29% for the rats receiving PTZ only to 100% and 89% for the rats receiving l -NAME and 7NI, respectively; whereas l -arg had no effect. Conversely, at P21, NOS inhibitors did not affect the 82,89% mortality rate induced by PTZ alone, whereas l -arg decreased the mortality rate to 29%. In addition, all NO-related drugs increased the duration of ictal activity at P10, whereas at P21, L -arg and L -NAME affected the first seizure type, producing clonic seizures with L -arg and tonic seizures with L -NAME. Conclusions: The relative natural protection of very immature rats (P10) against PTZ-induced deaths could be linked to a high availability of L -arg and, hence, endogenous NO. At P21, the modulation of seizure type by NO-related compounds may be related to the maturation of the brain circuitry, in particular the forebrain, which is involved in the expression of clonic seizures. [source] In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve headGLIA, Issue 3 2001Gülgün Tezel Abstract In order to improve understanding of remodeling events in the glaucomatous optic nerve head, the migration of optic nerve head astrocytes was studied in vitro. Since elevated intraocular pressure is an important stress factor identified in glaucomatous eyes, optic nerve head astrocytes were incubated under physical stress created by elevated hydrostatic pressure. In addition, they were incubated in the presence of a chemical stimulus, lipolysaccharide (LPS). Migration of reactivated astrocytes in the presence of these stressors was examined using chambers in which cell migration through extracellular matrix-coated pores is only possible following proteolytic digestion of the matrix. We observed that the migratory ability of optic nerve head astrocytes was approximately 4,6 times greater following exposure to elevated hydrostatic pressure or LPS for up to 48 h. Phosphoinositide 3-kinase, protein kinase C, and tyrosine kinase were found to be involved in the signal transduction for activated migration of optic nerve head astrocytes in response to elevated hydrostatic pressure or LPS. In addition, we observed that the stress-induced migration of optic nerve head astrocytes, which is accompanied by proteolytic degradation, resulted in the formation of culture cavities containing mucopolysaccharides. These in vitro findings provide a clearer understanding of the pathophysiologic mechanisms of characteristic tissue remodeling events that occur, in vivo, in the glaucomatous optic nerve head. GLIA 34:178,189, 2001. © 2001 Wiley-Liss, Inc. [source] Recurrent laryngeal cancer presenting as delayed hypoparathyroidismHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2007Amy K Hsu MD Abstract Background. Endocrine dysfunction following therapy for head and neck cancer has been previously described. Permanent hypoparathyroidism may result from the tumor, surgery, or radiation therapy. However, the incidence and significance of delayed hypoparathyroidism following treatment for laryngeal cancer remains unclear. Methods and Results. We report a patient who had stable serum calcium measurements on serial testing following concurrent chemoradiation and salvage laryngectomy for locally advanced laryngeal cancer. The patient subsequently presented 32 months following salvage laryngectomy with new onset, symptomatic hypocalcemia secondary to hypoparathyroidism. Subsequent evaluation revealed local recurrence. Conclusion. To our knowledge, this case represents the first report of delayed hypoparathyroidism as the presenting manifestation of recurrence following treatment for laryngeal cancer. Possible pathophysiologic mechanisms are discussed. © 2007 Wiley Periodicals, Inc. Head Neck, 2007 [source] New insights into the pathobiology of portal hypertensionHEPATOLOGY RESEARCH, Issue 10 2009Praveen Guturu Portal Hypertension is a frequent complication of cirrhosis and causes significant morbidity and mortality. Increased intrahepatic resistance is the primary factor but portal hypertension is also associated with changes in systemic and porto-sytemic collateral circulation. Cirrhosis is a state of vasoregulatory imbalance with excess vasoconstrictors and less vasodilators in hepatic circulation and the reverse is true for systemic circulation. Multiple pathophysiologic mechanisms including endothelial dysfunction, sinusoidal remodeling and angiogenesis are involved in increasing resistance in hepatic vascular bed. Current evidence suggests that these changes in vasoreactivity contribute to a significant proportion of intrahepatic vascular resistance and that they are reversible, providing an attractive target for therapeutic intervention. [source] Angiotensin-Converting Enzyme Inhibitors in the Treatment of Hypertension: An UpdateJOURNAL OF CLINICAL HYPERTENSION, Issue 11 2007William B. White MD Angiotensin-converting enzyme inhibitors are an important treatment option for hypertension, especially when elevated blood pressure exists in the presence of diabetes mellitus, chronic kidney disease, or congestive heart failure. This article reviews some of the pathophysiologic mechanisms involved in patients with hypertension and these comorbidities and how they relate to the renin-angiotensin system (RAS). Inhibition of the RAS when utilized along with other antihypertensive medications has been particularly effective in hypertensive patients with type 2 diabetes, chronic kidney disease, and vascular disorders; consensus group guidelines have reflected this in their treatment recommendations. Clinical trial data demonstrate that the effectiveness of RAS blockers is enhanced by maximizing the daily dose and combining these medications with thiazide diuretics. [source] Cure of gastric antral vascular ectasia by liver transplantation despite persistent portal hypertension: A clue for pathogenesisLIVER TRANSPLANTATION, Issue 8 2002Catherine Vincent Gastric antral vascular ectasia (GAVE) is a rare cause of chronic bleeding in cirrhotic patients. It has been suggested that these gastric lesions might be related to portal hypertension, hepatic insufficiency, or both parameters. We report two cases of cirrhotic patients in whom GAVE was the source of recurrent bleeding. These patients also had complete portal vein thrombosis. Liver transplantation was performed and an end-to-end cavoportal anastomosis was performed, leaving patients with persistent portal hypertension after surgery. We observed complete disappearance of the antral lesions several weeks after transplantation, which shows that the GAVE is not related to portal hypertension but is rather a direct consequence of liver failure. Possible pathophysiologic mechanisms are discussed. [source] Heparin-induced thrombocytopenia: Current status and diagnostic challenges,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Stavroula A Otis Heparin-induced thrombocytopenia (HIT) is a fairly common and potentially catastrophic complication of heparin therapy. Diagnosing HIT remains a challenge, as the patients at risk often have other reasons for thrombocytopenia and/or thrombosis. HIT is considered a clinicopathologic disorder whose diagnosis is generally made on the basis of both clinical criteria and the presence of "HIT antibodies" in the patient's serum or plasma. There are two basic laboratory approaches to detect HIT antibodies. The immunoassays detect antibodies based on their binding properties, whereas the functional assays detect antibodies based on their platelet-activating properties. Prompt and accurate diagnosis of HIT is imperative, as overdiagnosis exposes patients to alternative anticoagulants and their associated bleeding risks, whereas under- or delayed diagnosis leaves patients vulnerable to the thromboembolic sequelae of HIT, which can be life threatening. A critical interpretation of laboratory results by the clinician is an essential component of diagnosing HIT. This requires a keen understanding of the current concepts in the pathophysiologic mechanisms of the disease, and the application of these concepts when interpreting the results of both the functional and immunoassays. Equally important is an awareness of the strengths and weaknesses, as well as the current lack of standardization and proficiency testing, of these assays. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] The Role of Glia and the Immune System in the Development and Maintenance of Neuropathic PainPAIN PRACTICE, Issue 3 2010Ricardo Vallejo MD Abstract Neuropathic pain refers to a variety of chronic pain conditions with differing underlying pathophysiologic mechanisms and origins. Recent studies indicate a communication between the immune system and the nervous system. A common underlying mechanism of neuropathic pain is the presence of inflammation at the site of the damaged or affected nerve(s). This inflammatory response initiates a cascade of events resulting in the concentration and activation of innate immune cells at the site of tissue injury. The release of immunoactive substances such as cytokines, neurotrophic factors, and chemokines initiate local actions and can result in a more generalized immune response. The resultant neuroinflammatory environment can cause activation of glial cells located in the spinal cord and the brain, which appear to play a prominent role in nociception. Glial cells, also known as neuroglia, are nonconducting cells that modulate neurotransmission at the synaptic level. Glial cells can be subdivided into two primary categories: microglia and macroglia, which include astrocytes and oligodendrocytes. Astrocytes and microglia are known to play a role in the development, spread, and potentiation of neuropathic pain. Following peripheral nociceptive activation via nerve injury, microglia become activated and release pro-inflammatory cytokines such as tumor necrosis factor-,, interleukin-1,, and interleukin-6, thereby initiating the pain process. Microglia propagate the neuroinflammation by recruiting other microglia and eventually activating nearby astrocytes, which prolongs the inflammatory state and leads to a chronic neuropathic pain condition. Our review focuses on the role of glia and the immune system in the development and maintenance of neuropathic pain. [source] Origins and treatment of airway inflammation in childhood asthmaPEDIATRIC PULMONOLOGY, Issue S21 2001Robert F. Lemanske Jr. MD Abstract Several early events and risk factors are associated with the development of childhood asthma. Two significant risk factors are viral lower respiratory tract infections and atopy. Studies suggest that imbalances in TH1/TH2 cytokine responses in relationship to viral infections may play a role in the development of the childhood asthmatic phenotype. Airway inflammation is now recognized to contribute to the inception, persistence, and severity of asthmatic symptoms. The majority of information pertaining to airway inflammation in asthma has been derived from adult studies, but recent evaluations have been done in children. Available data are inconclusive as to the right medication to be used at the inception and during the evolution of the asthmatic phenotype in children. Inhaled corticosteroids (ICS( are not consistently effective in young children for a variety of reasons, including underlying pathophysiologic mechanisms that are unresponsive to the pharmacologic properties of ICS. The leukotriene receptor antagonists (LTRAs), recently approved for children as young as 2 years of age, address the relationship between leukotriene production and airway inflammation or remodeling in asthma. Therapeutic trials using LTRAs in children should prove beneficial. Pediatr Pulmonol. 2001; Supplement 21:17,25. © 2001 Wiley-Liss, Inc. [source] Post-transplant lymphoproliferative disorder following pediatric heart transplantationPEDIATRIC TRANSPLANTATION, Issue 1 2006Fernando Mendoza Abstract:, Immunosuppression after heart transplantation is implicated in development of post-transplant lymphoproliferative disorder (PTLD). Despite a higher prevalence of PTLD in children, there is scarce knowledge about incidence, pathophysiologic mechanisms and risk factors for PTLD in pediatric recipients of cardiac allografts. We examined retrospectively the medical records of all 143 pediatric patients (mean age 9.2 ± 6.1 yr) who received donor allografts between 1984 and 2002 and survived over 30 days. Five children (3.5%) developed PTLD over a mean follow-up period of 41.1 ± 46.0 months. Time from transplant to diagnosis of PTLD ranged from 3.9 to 112 months (mean 48.0 ± 41.9 months). Excluding PTLD, no other malignancies were found in this population. Actuarial freedom from PTLD was 99.2%, 99.2% and 96.2% at 1, 2, and 5 yr, respectively. Children who developed PTLD were more likely (by univariate analysis) to have been Rh negative (p = 0.01), Rh mismatched (p = 0.003), Epstein,Barr virus (EBV) seronegative (p = 0.001) and transplanted for congenital heart disease (p < 0.02). PTLD was associated with significant morbidity and mortality with a mean survival following diagnosis of 21.2 months. PTLD is a serious complicating outcome of cardiac transplantation that occurs in approximately 3.5% of children. Aside of immunosuppression, risk factors in this series for developing PTLD include EBV seronegativity and Rh negative status and mismatch. Non-hematogenous malignancies are rare in light of short allograft half-life. [source] CASE REPORTS: Abnormal Sexual Behavior During SleepTHE JOURNAL OF SEXUAL MEDICINE, Issue 12 2009Giacomo Della Marca MD ABSTRACT Introduction., Automatic, uncontrolled, and unaware sexual behaviors during sleep have occasionally been described. The clinical and polysomnographic features of nocturnal sexual behavior allow it to be considered a distinct parasomnia named "sexsomnia". Recently, abnormal sexual behaviors during sleep have been evaluated in the forensic medical context because violent behaviors can be associated with this parasomnia. Aim., To describe the clinical and polysomnographic findings in three patients who referred to our sleep laboratory for sleep disorders and who reported episodes of sleep-related sexual activation. Main Outcome Measures., We analyzed video-polysomnographic recordings, sleep structure, sleep microstructure, and sleep-related respiratory events. Methods., The patients were three males aged 42, 32, and 46 years. All had unremarkable medical, neurological, and psychiatric histories. All underwent full-night polysomnography. Results., Each patient presented a distinct sleep disorder: one had severe obstructive sleep apnea syndrome (OSAS), one presented clinical and polysomnographic features of non-rapid eye movement (NREM) sleep parasomnia (somnambulism), and the third presented clinical and polysomnographic features of rapid eye movement behavior disorder. Conclusions., In our patients, the clinical and polysomnographic findings suggest that abnormal nocturnal sexual behavior can occur in association with distinct sleep disorders, characterized by different pathophysiologic mechanisms and distinctive treatments. Abnormal sexual behaviors during sleep should be investigated with polysomnography in order to define their pathophysiology and to establish appropriate treatments. Della Marca G, Dittoni S, Frusciante R, Colicchio S, Losurdo A, Testani E, Buccarella C, Modoni A, Mazza S, Mennuni GF, Mariotti P, and Vollono C. Abnormal sexual behavior during sleep. J Sex Med 2009;6:3490,3495. [source] Laboratory Forum: Cavernous Nerve Injury Using Rodent Animal ModelsTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2008Onder Canguven ABSTRACT Introduction., With the advance of the "nerve sparing" technique in radical pelvic surgeries, medically unaided rates of normal erectile function following surgery have improved. Precise determinations of post-surgery erection recovery, however, continue to be problematic and rates of normal erectile function range from 9% to 86%. It is understood that injury to cavernous nerves (CNs) occurs despite modern modifications of the surgery, although the precise pathophysiologic mechanisms of surgical erectile dysfunction are not completely understood. Aim., To describe the experimental models of CN injury in small rodents, including both survival surgery (CN injury) and non-survival surgery (monitoring of intracavernosal pressure and arterial blood pressure) models. We also summarize studies on experimental procedures relating to these CN injury models and critique techniques according to their advantages and disadvantages. Main Outcome Measure., Data from a peer review literature search on the topic of CN injury in rodent models. Methods., A comprehensive review of the literature was performed using PubMed. "Cavernous nerve injury" and "animal model" were used as search terms, and a manual bibliographic review of cross-referenced items was performed. Results., Assorted molecular, morphological, and physiological changes are measurable after CN injury in rodent models. Conclusion., Various models of CN injury have been applied successfully and offer insights regarding erectile function recovery effects. Canguven O, and Burnett A. Cavernous nerve injury using rodent animal models. J Sex Med 2008;5:1776,1785. [source] Chronologic Changes of Nitric Oxide Concentration in the Cochlear Lateral Wall and Its Role in Noise-Induced Permanent Threshold ShiftTHE LARYNGOSCOPE, Issue 5 2008Yuh-Shyang Chen MD Abstract Objective: The objective of this study was to investigate the chronologic changes of nitric oxide (NO) concentration in the cochlear lateral wall and to explore its possible role in permanent threshold shift (PTS) after intense noise exposure. Materials and Methods: Seventeen guinea pigs were subjected to a single continuous exposure to broadband white noise at 105 ± 2 dB sound pressure level (SPL) for 40 hours and were divided into four groups according to various postnoise recovery periods. Another 12 guinea pigs were not exposed to noise and served as controls. The hearing status of all animals was evaluated with auditory brainstem responses (ABR) evoked by condensation "click" sounds. ABR were recorded both prior to noise exposure and immediately before killing the animal. After death, NO concentration in the cochlear lateral wall was directly measured with an NO/ozone chemiluminescence technique. Results: An approximately 1.7-fold increase in NO concentration was observed immediately postnoise exposure, which persisted for up to 28 days. The threshold of ABR elevation (mean, 30 dB SPL) peaked immediately after cessation of noise exposure and gradually resolved to a PTS (mean, 14.5 dB SPL) 56 days after noise exposure when NO concentration had returned to its prenoise exposure level. Conclusion: Noise-induced threshold shift, which resolved to a mild PTS, can be partially attributed to NO elevation in the cochlear lateral wall. Our results revealed a nonlinear correlation between ABR recovery and depletion of NO, indicating that the mechanisms of NO changes in the cochlear lateral wall may be more complicated than previously conceived and that other pathophysiologic mechanisms may also play important roles in noise-induced PTS. [source] Histopathologic Clusters Differentiate Subgroups Within the Nonspecific Diagnoses of CAN or CR: Preliminary Data from the DeKAF StudyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. J. Matas The nonspecific diagnoses ,chronic rejection',CAN', or ,IF/TA' suggest neither identifiable pathophysiologic mechanisms nor possible treatments. As a first step to developing a more useful taxonomy for causes of new-onset late kidney allograft dysfunction, we used cluster analysis of individual Banff score components to define subgroups. In this multicenter study, eligibility included being transplanted prior to October 1, 2005, having a ,baseline' serum creatinine ,2.0 mg/dL before January 1, 2006, and subsequently developing deterioration of graft function leading to a biopsy. Mean time from transplant to biopsy was 7.5 ± 6.1 years. Of the 265 biopsies (all with blinded central pathology interpretation), 240 grouped into six large (n > 13) clusters. There were no major differences between clusters in recipient demographics. The actuarial postbiopsy graft survival varied by cluster (p = 0.002). CAN and CNI toxicity were common diagnoses in each cluster (and did not differentiate clusters). Similarly, C4d and presence of donor specific antibody were frequently observed across clusters. We conclude that for recipients with new-onset late graft dysfunction, cluster analysis of Banff scores distinguishes meaningful subgroups with differing outcomes. [source] Beta2 -glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti,,2 -glycoprotein I autoantibodiesARTHRITIS & RHEUMATISM, Issue 4 2008Soheila Rahgozar Objective Beta2 -glycoprotein I (,2GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that ,2GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of ,2GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-,2GPI antibodies was also examined. Methods HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved ,2GPI and anti-,2GPI antibodies was determined in these systems. Results ,2GPI protected thrombin against inactivation by HCII/heparin. Cleavage of ,2GPI at Lys317,Thr318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-,2GPI antibodies potentiated the procoagulant influence of ,2GPI in this system. Conclusion These novel findings suggest that ,2GPI may regulate thrombin inactivation by HCII/heparin. The observation that anti-,2GPI antibodies potentiate the protective effect of ,2GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS. [source] Association Among Serum Fetuin-A Level, Coronary Artery Calcification, and Bone Mineral Densitometry in Maintenance Hemodialysis PatientsARTIFICIAL ORGANS, Issue 10 2009Alper Kirkpantur Abstract Patients with end-stage renal disease have a very high prevalance and extent of arterial calcification. A number of studies suggest that similar pathophysiologic mechanisms are responsible for development and progression of calcification of atherosclerotic plaque and bone formation. Fetuin-A is a potent calcification inhibitor and is expressed in bone, with not-yet well-defined functions. The aim of this study was to investigate the relation between bone mineral densitometry parameters, coronary artery calcification, and serum fetuin-A levels. In a cross-sectional design, we included 72 maintenance hemodialysis (HD) patients and 30 age- and gender- matched healthy controls. Serum fetuin-A levels were studied both in maintenance HD patients and healthy controls. Maintenance HD patients had radius, hip, and lumbar spine bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry and coronary artery calcification score (CACS) measured by electron-beam computed tomography. The associations between site-specific BMD parameters, CACS, and serum fetuin-A levels were studied in maintenance HD patients. CACS, mass, and volume of plaques in coronary arteries were significantly higher in patients with a T-score below ,2.5 than above in the proximal region of the radius, neck and trochanter of the femur, and the lumbar spine. Mean serum fetuin-A concentration was 0.636 ± 0.118 g/L in maintenance HD patients and it was less than healthy controls (0.829 ± 0.100 g/L, P < 0.0001). CACS, mass, and volume of plaques in coronary arteries correlated significantly with the serum fetuin-A levels. Moreover, significant positive correlations were shown between the serum fetuin-A levels, BMD values, and T-scores of proximal radius, neck, and trochanter of the femur, but not with the lumbar spine. The present study demonstrates an association between serum fetuin-A levels, coronary artery calcification, and bone mineral densities,except for the lumbar spine, in maintenance HD patients. However, the results should be interpreted with caution because of the cross-sectional design of the study. [source] | |||||||||||||||||||||||||