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At least 487 records · Page 27Linked to original sources
PubMed2002

Role of GABA abnormalities in the inferior colliculus pathophysiology - audiogenic seizures.

gamma-Aminobutyric acid (GABA), acting at GABA(A) receptors, mediates inhibition in inferior colliculus (IC) central nucleus (ICc) neurons and plays a prominent role in mediating acoustically evoked non-monotonicity, offset inhibition, and binaural inhibition, and is also important in tonic inhibition. The IC plays an important role in a number of pathophysiological conditions that involve hearing, including tinnitus, age-related hearing loss, and audiogenic seizures (AGS). AGS are a major form of rodent neurological disorder that can be genetically mediated and can also be readily induced in both young and mature animals. A deficit in GABA-mediated inhibition in IC neurons has been shown to be a critical mechanism in genetic and induced forms of AGS. Thus, both endogenously evoked GABA-mediated inhibition and exogenously applied GABA are reduced in efficacy in IC neurons of rats that are susceptible to AGS. GABA-mediated inhibition in IC neurons is significantly more easily blocked by a GABA(A) antagonist in genetic and induced forms of AGS in vivo and in vitro. AGS can be induced in normal animals by treatments that reduce the effectiveness of GABA in the IC. Glutamate-mediated excitation is a critical element of neurotransmission in IC neurons, and excessive activation of glutamate receptors in the IC is also strongly implicated as the other major mechanism in the pathophysiology of AGS. These neurotransmitter abnormalities result in excessive firing of ICc neurons that acts as the critical initiation mechanism for triggering seizures in response to intense acoustic stimuli.

Acoustic Stimulation↗
PubMed1984

Rett syndrome--clinical studies and pathophysiological consideration.

Eleven female patients with Rett syndrome were evaluated for detecting the pathogenesis. Clinical symptoms were characterized by their orderly sequence of occurrence of particular symptoms at particular ages starting from early infancy, and their progression. Increment of head circumference tapered from late infancy, resulting in microcephalus which corresponded with the clinical features. Surface EMG revealed the tremulous rhythmic discharge underlying the characteristic stereotyped movement of the hands. Serial polysomnographical examinations showed abnormalities of the tonic and phasic components of sleep and increment of % REM stage with age. The results of these clinical, laboratory and polysomnographical examinations were discussed, comparing with other neurological diseases and knowledge of animal experiments. From these findings the pathophysiology of Rett syndrome could be explained by the early and progressive lesions in the brain stem nuclei, which influence the maturation and function of particular parts of the higher central nervous system. Serotonergic and catecholaminergic neurons might have important roles in the pathophysiology of this syndrome. However, biochemical and histochemical examinations of the brain are necessary for detecting the pathogenesis and etiology. And the cause of gynecopathy also remains to be clarified.

Ammonia↗
PubMed1987

Pathophysiology of Rett syndrome.

Rett syndrome is a distinct clinical entity with an unknown cause. In previous publications we stressed the age related sequential appearance of pathognomonic symptoms of Rett syndrome and suggested the early central monoaminergic deficiency disorder as the pathophysiology. In this report we present a series of cinefilms made of one patient at different ages which clearly show the age dependent changes of motor disturbances. Furthermore, the record of sleep-wakefulness rhythm and the series of polysomnography of another patient who was on L-DOPS are presented. The results of sleep studies again confirm the early involvement of the noradrenergic and serotonergic systems and relatively early development of postsynaptic supersensitivity of the dopaminergic system. The possibility of the involvement of the cholinergic system is also suggested. The summary of the sensory evoked potentials (SEP) performed on six patients is also presented and the pathomechanism of cortical involvement is discussed. Based on these new and past findings, we confirm our speculation on the pathophysiology. The basic mechanism is probably the deficient states of the monoaminergic systems occurring at a very early developmental stage. These derangements occurring at an early stage cause serious abnormality in the higher centers during development. The striking age dependent clinical manifestations and measurable physiological parameters are the reflexion of the underlying patho-physiology of Rett syndrome.

Age Factors↗
PubMed2001

Definition, classification, and pathophysiology of acute coronary ischemic syndromes.

The acute coronary syndrome (ACS) is now used to describe a spectrum of clinical presentations that share an underlying pathophysiology, replacing the previous nomenclature of ischemic chest pain. The accurate diagnosis and proper management of patients with these entities require the emergency medicine physician to consider the entire spectrum of ACS, with emphasis placed on early diagnosis and rapid treatment. Each of these syndromes has its own prognosis, pathophysiology, and specific management strategy.

Angina, Unstable↗
PubMed2003

Coronary artery disease: new insights into the pathophysiology, prevalence and early detection of a monster menace.

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the United States and industrialized countries. In the undeveloped world a similar epidemic is brewing. A new pathophysiologic paradigm has emerged, which assigns the mediators of inflammation a much larger role in the disease process. This paradigm has helped explain the unpredictable nature of many adverse consequences of CAD. The long latent phase of the disease and often sudden initial presentation make efforts at early detection extremely important. Considerable work has been devoted to identify as well as influence predisposing risk factors for developing arteriosclerosis. Novel markers of inflammation, like C-reactive protein, have been identified and compared to traditional risk factors. In addition, new imaging modalities introduce the possibility of screening for sub-clinical disease. Electron-beam and spiral CT scanners, as well as other techniques, are emerging as powerful tools to detect early disease presence and allow intervention to take place before major clinical events occur. Advances in our understanding of the pathophysiology and our ability to image the stages of silent disease will go hand in hand to revolutionize our approach to prevention and treatment of this deadly disease.

C-Reactive Protein↗
PubMed2003

Stress-induced changes in pathophysiology and interferon gene expression during primary HSV-1 infection.

Herpes simplex viruses (HSV) are the cause of the most common clinically recognized herpesvirus infections. The severity and duration of the primary HSV infection have been correlated with the frequency and severity of subsequent recurrences. Reactivation of latent HSV-1 can occur as a result of physical or emotional stress; however, the effects of stress on the modulation of the clinical pathophysiology of primary HSV-1 infections are not well understood. Although it is known that stress can be immunosuppresive, the immunological mechanisms by which stress modulates early immune responses, such as type I interferon gene expression during a primary HSV-1 infection are still not understood. It was hypothesized that due to suppressed early immune responses, stress would increase the severity of a cutaneous primary HSV-1 infection. In this investigation, a cutaneous HSV-1 model in the SKH-1 mouse was characterized and utilized to study the effect of restraint stress on the modulation of the clinical pathophysiology of primary HSV-1. Despite prolonged viral replication at the site of primary infection, restraint stress decreased the clinical severity of primary HSV-1 in the skin of SKH-1 mice. A decrease in type I and type II IFN expression was found in the skin of acutely infected restrained mice when compared to controls at day 3 post-infection using competitive RT-PCR. Using the glucocorticoid-receptor antagonist RU486, IFN-beta and INF-gamma expression were restored in restrained animals to control levels. Treatment with RU486 also increased the clinical severity of the cutaneous infection to control levels in restrained mice. Thus, RST masked the severity of an HSV-1 infection by decreasing its clinical signs while impairing the ability of the host to control viral replication prolonging the infectious period.

Animals↗
PubMed1997

Pathophysiology and treatment implications of hypertension in the African-American population.

Regardless of the etiology, hypertension remains a major public health problem in African-Americans and is associated with significant morbidity and mortality. Additional data on the pathophysiology of this disease in this population are needed, as are data on the best therapies to decrease the high complication rate. Because many of the large studies on hypertension have included few African-Americans, recruitment of this ethnic group into clinical trials should be promoted. Further studies into the genetic factors in the pathophysiology of racial differences in hypertension may shed more light on this complex issue.

Antihypertensive Agents↗
PubMed2002

Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development.

The development of imatinib as molecularly targeted therapy for GIST represents an important case study of rational drug development. It is a paradigm of how the molecular understanding of a cancer has resulted in a new effective therapy that targets the critical pathway upon which the GIST cells were dependent: the uncontrollably active KIT signaling pathway. Unresectable or metastatic GISTs have traditionally exhibited a rapid and fatal clinical course, with no evidence of benefit from any standard cytotoxic chemotherapy. The identification of KIT activation as a critical factor in the pathogenesis of GIST led to the search for a new type of therapeutic compound to serve as a KIT inhibitor and to interfere with the constitutive phosphorylation of the KIT kinase in GIST cells. Clarification of the molecular genetic pathophysiology of GIST and the role of KIT activation in this disease, therefore, has not only enabled improved diagnosis and differentiation of GIST from other mesenchymal neoplasms but has also been key in identifying new targeted strategies for therapeutic intervention. The improved understanding of the molecular pathophysiology of GIST, a disease that was previously untreatable with any available systemic therapy, has led to the development of imatinib, a well-tolerated agent that can inhibit the dysregulated KIT signaling pathways in GIST. Imatinib represents the first (and currently the only) effective systemic therapy for patients with unresectable GIST. Imatinib therapy can induce objective responses and stabilization of disease and can provide clinical benefit in the majority of GIST patients treated with the drug. Other strategies are beginning to be explored, such as the use of imatinib earlier the in course of GIST (e.g., as adjuvant therapy after definitive surgical resection of early-stage disease). Integration of signal transduction inhibitors into the armamentarium of cancer therapeutics will undoubtedly continue based on this important paradigm of GIST.

Antineoplastic Agents↗
PubMed2003

Disseminated intravascular coagulation current concepts of etiology, pathophysiology, diagnosis, and treatment.

The pathophysiologic mechanisms and clinical and laboratory manifestations of DIC are complex, partly because of inter-relationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiologic inter-relationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often-confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents and agents that can block, blunt, or modify cytokine activity and the activity of vasoactive substances seem to be of value. The complexity and variable degree of clinical expression suggest that therapy should be individualized depending on the nature of DIC, the patient's age, etiology of DIC, site and severity of hemorrhage or thrombosis, and hemodynamics and other appropriate clinical parameters.

Disseminated Intravascular Coagulation↗
PubMed2001

Contribution of sleep physiology to depressive pathophysiology.

Among the best characterized neurobiological changes in mood disorders are specific alterations in electroencephalographic (EEG) sleep, including disinhibited rapid eye movement (REM) sleep and suppressed slow wave sleep. A strong link between mood disorders and sleep is that depressive symptoms are alleviated by one night of sleep deprivation and reoccur after sleeping. Sleep underlies homeostatic and circadian mechanisms that interact in complex ways. These relationships have been formalized in electrophysiological, neurochemical and neuroendocrinological models that extend to the pathophysiology of affective illness. Sleep research as a pathophysiological window to the brain has contributed extensively to the understanding of the neurobiology of depression and has been a substantial guide for the advancement of model-driven clinical and preclinical research. Pharmacological probes of normal and depressed sleep play an important role. It is anticipated that the combination of novel topographical EEG and neuroimaging techniques with traditional experimental methods will provide us with further insight into the neurobiology of sleep and depression.

Acetylcholine↗
PubMed1993

Sickle cell disease pathophysiology.

The primary pathophysiological event in the erythrocytes of individuals with the various sickle syndromes is the intracellular aggregation or polymerization of sickle haemoglobin (HbS). The extent of polymerization is determined by the intracellular haemoglobin composition (% HbS and % HbS A, A2 and F), concentration (MCHC and % of dense cells) and oxygen saturation, as well as minor factors such as intracellular pH and DPG concentration. Intracellular HbS polymerization leads to a marked decrease in the flexibility or rheological properties of the sickle erythrocytes and obstruction in various microcirculatory beds, as well as chronic anaemia. Other abnormalities in the properties of the sickle erythrocytes, including membrane abnormalities, changes in ion fluxes and volume and endothelial adhesion, result from acute and chronic oxygen-linked polymerization events and may, in turn, modify polymerization. However, within a good approximation, many aspects of sickle cell disease pathophysiology--for example variations in anaemia among the different sickle syndromes--can be explained in terms of differences in polymerization tendency. Thus, the effects of alpha-thalassaemia can be explained with reference to changes in MCHC and syndromes with high HbF are understandable in terms of the sparing effect of HbF on polymerization. Recent therapeutic approaches to sickle cell disease focus on attempts to reduce intracellular HbS polymerization by altering the haemoglobin molecules, erythrocyte properties, or the distribution of intracellular haemoglobin species. The last, through pharmacological elevation of HbF, has become the central focus of much laboratory and clinical research in recent years. Agents such as hydroxyurea (with or without recombinant erythropoietin) and butyrate compounds elevate HbF (and reduce HbS) in a majority of sickle erythrocytes, thus decreasing intracellular polymerization. Current prospective protocols are designed to see if these changes cause clinical improvement at acceptable doses. Other treatment strategies, including bone marrow transplantation and possible gene replacement therapies, are also under active clinical or laboratory investigation.

Anemia, Sickle Cell↗
PubMed1989

Pathophysiology of aplastic anaemia.

No single pathophysiological phenomenon--neither the intrinsic defect of haemopoiesis nor any of the described immune effects--explains aplastic anaemia. Since the intrinsic defect is compatible with near normal haemopoietic function, as seen in autologous bone marrow reconstitution, it cannot be the cause of severe pancytopenia. On the other hand, immune mechanisms cannot be the primary cause of the disease, otherwise haemopoietic function would recover to complete normality after immunosuppressive therapy. From these observations we deduce that the intrinsic defect, a premalignant haemopoietic disorder, can either be clinically quiescent by virtue of repair mechanisms, or induce auto-reactivity of the immune system against the abnormal haemopoietic tissue, drugs, chemicals and viruses acting as non-specific triggers or amplifiers. In this sense, aplastic anaemia could be interpreted as an attempt to 'self-cure' from a variant type of preleukaemia. This means that the original concept of aplastic anaemia being a hypoplastic variant of leukaemia may be true. The fact that aplastic anaemia can present either as acute severe bone marrow failure, as chronic mild pancytopenia or as a myelodysplasia-like syndrome does not imply that the underlying pathophysiological mechanisms are basically different. Variations of the clinical course and the response to immunosuppressive treatment could be explained by variations in the balance between the primary defect and the secondary immune reaction; the co-involvement of accessory cells in the primary disease; the relative time course of the two components and the efficiency of repair mechanisms. From repeated in vitro studies in a large group of aplastic anaemia patients at various stages of disease this concept can be applied to the majority of cases, including chloramphenicol- and virus-induced aplastic anaemia. In a small proportion of patients with pancytopenia occurring after exposure to certain drugs other than chloramphenicol, aplastic anaemia is rapidly and completely reversible after withdrawal of the drug. These patients probably have truly benign aplastic anaemia and thus differ from the majority of patients who are left with a permanently fragile bone marrow once they have acquired aplastic anaemia.

Anemia, Aplastic↗
PubMed2003

Pathophysiological roles of vascular 11beta-hydroxysteroid dehydrogenase and aldosterone.

Mineralocorticoid receptor (MR) binding is tightly regulated by the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSDII) which selectively metabolizes glucocorticoids to inactive metabolites, thus allowing for MR activation by aldosterone. To examine whether this enzyme is involved in the pathophysiology of salt-sensitive hypertension, 11beta-HSDII activity and messenger RNA (mRNA) levels were determined in blood vessels of Dahl Iwai salt-sensitive (DS) and salt-resistant (DR) rats. Decreased 11beta-HSDII activity and mRNA levels in mesenteric arteries were observed in 8-week-old DS rats on a high-salt diet, indicating that 11beta-HSDII may play a significant role in salt sensitivity and hypertension. It has been suggested that mineralocorticoids act on blood vessels, leading to increased vasoreactivity and peripheral resistance. We present direct evidence that blood vessels are aldosteronogenic. The production of aldosterone in blood vessels was compared between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. Vascular aldosterone and CYP11B2 mRNA levels were significantly increased in 2-week-old SHRSP versus WKY rats. However, the vascular aldosterone levels in 4- and 9-week-old SHRSP and WKY rats were similar. High sodium intake further increased both blood pressure and vascular aldosterone synthesis in the SHRSPs. Both the local renin-angiotensin-aldosterone system (RAAS) and the vascular 11beta-HSDII level are critically important in the pathophysiology of cardiovascular disorders.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

[Facial, lingual and pharyngeal electromyography in children: a method to study sucking and swallowing disorders and their pathophysiology].

The authors describe an electromyogaphic protocol developed with the aim of evaluating the sucking-swallowing function and of studying the pathophysiology of its disturbances in the newborn and in infants. This protocol consists of associating several techniques. Some of them are traditional: EMG of the facial muscles and nerves and blink reflex, while others are original: EMG of the tongue and hypoglossal nerve, EMG of the velum palatinum, and a dynamic study using a baby bottle, of the sucking and swallowing reflex for a liquid meal. For each technique, practical procedures are described together with normal results observed between birth and 3 years of age. The authors report on abnormalities observed in pathological conditions and discuss their significance in major nosological contexts. They emphasize the value of this EMG protocol in assessing the sucking-swallowing reflex, in revealing anatomo-functional disturbances in the brainstem and in tackling the pathophysiological aspects of aspiration pneumopathies, feeding difficulties and bucco-facial malformations.

Child, Preschool↗
PubMed1995

The effect of pathophysiology on the surgical treatment of ischemic mitral regurgitation: operative and late risks of repair versus replacement.

Operative correction of ischemic mitral regurgitation (IMR) is associated with high risk approach. The objective of this retrospective study was to examine the interaction between the various underlying pathophysiologic mechanisms, the operative procedure, and their influence on short- and long-term outcomes. Over a 10-year period starting January 1984, mitral valve repair or replacement was performed on 150 patients with IMR. The age range was 42-86, mean 67, years; 71 (47%) were females; 139 (93%) were in NYHA functional class III or IV; 23 (15%) were reoperations; and 30 (20%) were in atrial fibrillation. Functional IMR due to annular dilatation or restrictive leaflet motion was present in 106 (71%), and structural IMR due to ruptured chordae or papillary muscle in 44 (29%). Mitral valve repair was performed in 94 (63%) with an annuloplasty ring employed in 80 (85%) patients. Mitral valve replacement was performed in 56 (37%), with 40 (71%) receiving a bioprosthesis (32 Hancock and 8 Carpentier-Edwards valves) and 16 (29%) a St. Jude valve. Coronary artery bypass graft surgery was performed in 139 (93%) patients. The overall operative mortality (OM) was 14/150 (9.3%). The OM for repair was 9.5% compared to 8.9% for replacement (P = NS). There was higher OM in the elderly, particularly in the repair group (P = 0.053), and a trend towards reduced OM in the recent years of the study (P = NS). No predictors of OM were identified by multivariate logistic regression analysis. Long-term follow-up was 98% complete and ranged from 2-120, mean 31.2, months for a total of 935 patient-years. The overall 5-year survival rate was 71 +/- 6%, with 91 +/- 5% for the replacement group compared to 56% +/- 10% for the repair group (P = 0.01). The functional subset of IMR who had a repair had the worse long-term survival (43 +/- 13%) compared to the structural/repair (76 +/- 13%) and structural/replacement groups (89 +/- 8%), and 92 +/- 7% for the functional/replacement group ((P = 0.0049). Multivariate logistic regression analysis identified the functional/repair group (hazards ratio 4.4; +/- 95%, confidence interval 1.6, 11, (P = 0.0031); and earlier years of surgery (hazards ratio 4.7; +/- 95% confidence interval 1.021; (P = 0.046) to be predictors of worse long-term survival. These results suggest that, in IMR, the underlying responsible pathophysiologic mechanisms appear to be the major determinants of survival, rather than the choice of the operative procedure.

Adult↗
PubMed2002

Chronic renal ischemia: pathophysiologic mechanisms of cardiovascular and renal disease.

Chronic renal ischemia caused by renal artery stenosis (RAS) elicits a complex biologic response. Although the traditional pathophysiologic pathways underlying renal ischemia have been well studied, there is emerging evidence that additional mechanisms may be responsible for producing many of the hemodynamic alterations and end-organ injury seen in patients with RAS, including persistent hypertension, renal insufficiency, and cardiac disturbance syndromes. A better understanding of these mechanisms may allow earlier identification of RAS, provide markers to predict the response to revascularization, or allow unique therapeutic targets for drug development. This and a subsequent article will explore the pathophysiologic and clinical implications of chronic renal ischemia.

Cardiovascular Diseases↗
PubMedDate not supplied

Physiology and pathophysiology of K(ATP) channels in the pancreas and cardiovascular system: a review.

K(ATP) channels are present in pancreatic and extrapancreatic tissues such as heart and smooth muscle, and display diverse molecular composition. They contain two different structural subunits: an inwardly rectifying potassium channel subunit (Kir6.x) and a sulfonylurea receptor (SURX). Recent studies on genetically engineered Kir6.2 knockout mice have provided a better understanding of the physiological and pathophysiological roles of Kir6.2-containing K(ATP) channels. Kir6.2/SUR1 has a pivotal role in pancreatic insulin secretion. Kir6.2/SUR2A mediates the effects of K(ATP) channels openers on cardiac excitability and contractility and contributes to ischemic preconditioning. However, controversy remains on the physiological properties of the K(ATP) channels in vascular smooth muscle cells. Kir6.1 knockout mice exhibit sudden cardiac death due to cardiac ischemia, indicating that Kir6.1 rather than Kir6.2 is critical in the regulation of vascular tone. This article summarizes current understanding of the physiology and pathophysiology of Kir6.1- and Kir6.2-containing K(ATP) channels.

ATP-Binding Cassette Transporters↗