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PubMed2002

Extracorporeal treatment in fulminant hepatic failure: pathophysiologic considerations.

Fulminant hepatic failure is a life-threatening clinical syndrome following severe hepatic injury leading to cerebral edema and brainstem herniation. Excessive mortality can be currently reduced only by timely orthotopic liver transplantation. Due to the shortage of donor organs, a considerable proportion of patients develop irreversible neurological damage, multiorgan failure or death while waiting for transplantation. Consequently, alternatives to orthotopic liver transplantation and methods of stabilizing patients on the waiting list including extracorporeal detoxification treatment are currently investigated. Recent advances in the pathophysiology of cerebral edema have challenged some of the traditional assumptions on which many blood detoxification systems are based. This article aims to integrate pathophysiology of hepatic encephalopathy and cerebral edema into a proposed future concept of liver support.

Ammonia↗
PubMed2004

Contrast nephropathy, pathophysiology and prevention.

Contrast nephropathy is a common cause of iatrogenic acute renal failure. Its incidence rises with the growing use of intra-arterial contrast in diagnostic and interventional procedures. Aim of the present review is to summarize the knowledge about pathophysiology and prevention. Nephrotoxicity is related to osmolality, dose and route of the contrast and only occurs in synergy with other factors, such as previous renal impairment and cardiovascular disease. With an interplay of these factors, contrast nephropathy has an impact on morbidity and mortality. Pathophysiological mechanisms are intrarenal vasoconstriction, leading to medullary ischemia, direct cytotoxicity, oxidative tissue damage and apoptosis. Several measures are of proven benefit in patients at risk. Among them are discontinuation of potentially nephrotoxic drugs, hydration, preferably with isotonic sodium bicarbonate, use of low osmolal contrast, oral or intravenous N-acetylcysteine and intravenous theophylline. In patients with severe cardiac and renal dysfunction undergoing cardiac interventions, periprocedural hemofiltration may be considered.

Acute Kidney Injury↗
PubMed2003

Magnetic resonance imaging findings in infantile spasms: etiologic and pathophysiologic aspects.

An etiologic evaluation of 86 patients with infantile spasms is presented and the place of cranial magnetic resonance imaging (MRI) findings within this spectrum is discussed. A total of 103 cranial MRIs, performed between 4 and 72 months of age, were analyzed and classified according to the etiologic and pathophysiologic aspects. Ninety-one percent of cases were diagnosed as symptomatic infantile spasms, and hypoxic-ischemic encephalopathy was the primary cause (30%). The most common involvement was thinning of the corpus callosum in 43 patients (50%), followed by dilation of cerebral ventricles in 32 (36%), delayed myelination in 23 (26.7%), lesions of diencephalic deep gray matter in 17 (19.7%), and enlargement of the subarachnoid space in 12 (14%). Thin corpus callosum and diffuse atrophy were changes mainly associated with hypoxic-ischemic encephalopathy, whereas delayed myelination seemed to be independent from a specific etiology. The results showed that cranial MRI may provide considerable information regarding not only the etiology but also the pathophysiology of infantile spasms.

Brain↗
PubMed1998

Alternating hemiplegia of childhood: insights into its pathophysiology.

Alternating hemiplegia of childhood is a rare disorder characterized by episodic paroxysmal attacks of neurologic dysfunction and has historically been thought to represent a migraine equivalent, an unusual form of epilepsy, or a movement disorder. Medical treatment with a variety of anticonvulsants and migraine agents is largely unsuccessful, and progressive mental deterioration is universally expected. Despite extensive laboratory studies, the pathophysiologic basis of this condition has thus far eluded identification. Recently, an international workshop was held to generate testable hypotheses regarding the pathophysiology of alternating hemiplegia of childhood. This paper summarizes the major proceedings of that workshop, and hopes to stimulate further interest in elucidating the molecular and cellular mechanisms underlying this unusual disorder.

Brain↗
PubMedDate not supplied

Cardiovascular manifestations of acute intracranial lesions: pathophysiology, manifestations, and treatment.

The objective of this article was to review the effects of acute intracranial lesions on myocardial function. The authors reviewed scientific and clinical literature retrieved from a computerized MEDLINE search from January 1965 through January 2002. Pertinent literature was referenced, including clinical and laboratory investigations, to demonstrate the effects of acute intracranial lesions on the cardiovascular system. The literature was reviewed to summarize the mechanisms of cardiac damage and clinical manifestations and treatment of cardiovascular dysfunction caused by acute intracranial lesions. Myocardial damage and rhythm disturbances were shown to occur with acute intracranial neurological disease. The subgroup of patients used in this study formed a substantial pool of cardiac donors for cardiac transplantation. The pathophysiology of myocardial dysfunction and the optimal management continues to be a source of debate. In this article, the authors will review the anatomy, the available evidence of the pathophysiology, and the management of this complex group of patients. They will also discuss areas that need to be further investigated. Cardiovascular effects of acute intracranial lesions are common and contribute to increased morbidity and mortality.

Acute Disease↗
PubMedDate not supplied

Implication of the subthalamic nucleus in the pathophysiology and pathogenesis of Parkinson's disease.

The subthalamic nucleus (STN) has been shown to play an important role in the control of movement and has been considered as a key structure in the functional organization of the basal ganglia. Several studies postulated that the STN plays a critical role in the pathophysiology of Parkinson's disease and that its inhibition or its lesioning can reverse the cardinal motor symptoms. Nevertheless, the beneficial effect was accompanied by dyskinetic abnormal movements. In order to avoid unpleasant and irreversible side effects we used high-frequency stimulation (HFS) of the STN instead of lesions. We have shown that parkinsonian motor symptoms, akinesia, rigidity, and tremor can be alleviated by HFS of the STN in the nonhuman primate model. Side effects were controllable and appeared only at intensities higher than that inducing the improvement of motor symptoms. In severe parkinsonian patients, bilateral STN-HFS greatly improved parkinsonian motor symptoms. Motor fluctuations were attenuated and patients became independent in most activities of daily living. It appears that STN-HFS mimics the effects of lesions by inhibiting its neuronal activity. In a rat model of parkinsonism, we studied the implication of the STN in the excitotoxicity of nigral dopamine cells. We showed that kainic acid lesioning of the STN can protect nigral dopaminergic cells against 6-hydroxydopamine-induced toxicity. The evidence reviewed in the present article clearly demonstrates that the STN is implicated in the pathophysiology and pathogenesis of Parkinson's disease.

Animals↗
PubMedDate not supplied

Pleural effusions: pathophysiology and management.

OBJECTIVE: To review the pathophysiology and management of pleural effusions, including available agents for pleural sclerosis. DATA SOURCES: A MEDLINE search (1966 to present) was performed that included clinical studies in the English language involving the pathophysiology and management of pleural effusions; references used in those articles were screened for additional published information. STUDY SELECTION: All clinical trials were considered for potential inclusion in the review. DATA SYNTHESIS: Pleural effusion is an accumulation of fluid in the pleural space that results when homeostatic forces that control the flow into and out of the area are disrupted. The management of transudative pleural effusions is primarily directed at treatment of the underlying disease. There are several treatment options for pleural effusions, including chemical pleurodesis. Many of the trials that examine the use of talc, bleomycin, and doxycycline have poorly described study designs and end points, with inconsistent evaluation of patients. Each agent is considered to be generally effective and safe, with fever and pain as the most frequently reported adverse effects. The use of talc requires sterilization, and many clinicians use general anesthesia with instillation, which increases the risk associated with the procedure. Bleomycin is generally safe; however, it should not be used in doses exceeding 40 mg/m2. Only uncontrolled trials support the use of doxycycline; however, it provides an effective, safe, and relatively inexpensive alternative. CONCLUSIONS: Pleural effusions are defined as an accumulation of fluid in the pleural space. Treatment is generally palliative. Intrapleural administration of talc, bleomycin, and doxycycline are effective sclerosing agents for treatment of recurrent, symptomatic pleural effusions. Although the most cost-effective agent has not been determined, doxycycline is an inexpensive alternative to bleomycin, and may have fewer adverse effects than talc.

Bleomycin↗
PubMed1996

Pathophysiology and management of the serotonin syndrome.

OBJECTIVE: To review the symptoms, pathophysiology, and treatment of the serotonin syndrome (SS). DATA SOURCES: A MEDLINE search (1957-1995) of the English-language literature pertaining to the SS was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA SYNTHESIS: The SS, an occasionally fatal disorder, is characterized by symptoms such as mental status changes, seizures, myoclonus, and blood dyscrasias. Both the central and peripheral serotonergic systems and several serotonin receptor types are involved in the symptomatology of the SS. The pathogenesis of SS may be due to endogenous as well as iatrogenic deficits in peripheral serotonin metabolism, a stimulus for release of serotonin, and interactions with other neurotransmitter systems. Lorazepam, serotonin-blockers, and nitroglycerin have been used successfully to treat SS. CONCLUSIONS: The SS is increasingly recognized and reported in the literature. Clinical and basic science research have increased our understanding of the pathophysiology, conditions, and agents that may predispose to the development of the syndrome. Newer treatment strategies are discussed.

Animals↗
PubMed1996

Syncope: pathophysiology, diagnosis, and pharmacotherapy.

OBJECTIVE: To review the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SOURCES: A MEDLINE search (1980-1995) using the term syncope and cross-referencing selected articles. STUDY SELECTION: Articles selected were those considered to assist in providing the reader with a basic introduction the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SYNTHESIS: Syncope is a common disorder with many different etiologies. The patient's history and physical examination are extremely important in making the diagnosis. The recent availability of head-upright tilt testing and electrophysiologic studies of the myocardium have helped define the etiology in many patients in whom an etiology would not have been found in the past. When the cause of syncope has been diagnosed, the appropriate therapy to prevent future attacks will be defined in many instances. One form of syncope, known as neurocardiogenic syncope, can be difficult to treat. Recent trials have suggests the use of beta-blockers, fludrocortisone, disopyramide, or selective serotonin reuptake inhibitors may be helpful in some patients.

Adrenergic beta-Antagonists↗
PubMed2002

Disseminated intravascular coagulation: a review of etiology, pathophysiology, diagnosis, and management: guidelines for care.

The pathophysiologic mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiologic interrelationships 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 appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters. At present, treatment of the triggering event, low-dose heparin or antithrombin concentrate and wise choice of components when indicated appear to be the most effective modes of therapy.

Adult↗
PubMed2004

The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology.

It is widely accepted that vascular mechanisms are involved in the genesis of many neurological disorders. In particular, blood-brain barrier (BBB) dysfunction has been related to the severity of Alzheimer's disease, encephalopathy due to meningitis, multiple sclerosis, HIV-associated encephalopathy, epilepsy, gliomas and metastatic brain tumors. The BBB may constitute an important therapeutic target to protect neurons after CNS diseases. Both in vivo and in vitro, the functional phenotype of vascular endothelium is dynamically responsive to circulating cytokines, growth factors and puslatile blood flow (shear stress). Shear stress can play a critical role in vascular homeostasis and pathophysiology; it is a major regulator of remodeling in developed blood vessels and in blood vessels affected by atherosclerotic lesions. The physiological fluid mechanic stimulus, shear stress, could be considered to be an important 'differentiative' stimulus capable of modulating endothelial phenotype in vivo. Endothelial cells undergo cell cycle arrest after exposure to physiological levels of shear stress. As for mature endothelial cells, in which flow mediated shear stress may play a role in the induction, progression and/or prevention of atherosclerosis by changing their function, stress may play a role in endothelial cell differentiation from hemopoietic stem cells and/or from embryonic stem cells. Stem cells may be used to repair vascular damage, including loss of EC, due to a variety of diseases (e.g. myocardial neovascularization by adult bone marrow derived angioblasts). In the brain, it was proposed that neuron-producing stem cells may be used to treat Alzheimer's disease, paralysis, etc. Surprisingly, very few investigators are exploring the use of endothelial precursors to revert or prevent cerebrovascular disease. This review summarizes the most recent data related to cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in blood-brain barrier homeostasis and pathophysiology.

Animals↗
PubMed2005

Pathophysiology of beta thalassemia--a guide to molecular therapies.

The central mechanism underlying the pathophysiology of the beta thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the alpha/non-alpha globin chains leads to an excess of unmatched alpha globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the alpha/non-alpha chain imbalance. They include inheritance of the milder forms of beta thalassemia, co-inheritance of alpha thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing gamma globin expression. Currently, the most promising molecular therapeutic approaches include increasing beta globin gene expression by stem cell gene therapy and increasing gamma globin expression using pharmacological agents or by transduction of the gamma globin genes.

Erythropoiesis↗
PubMed2003

High-altitude pulmonary hypertension: a pathophysiological entity to different diseases.

Pulmonary hypertension is a hallmark of high-altitude pulmonary oedema (HAPE) and of congestive right heart failure in subacute mountain sickness (SMS) and chronic mountain sickness (CMS) in the Himalayas and in the end-stage of CMS (Monge's disease) in the Andes. There are studies to suggest that transmission of excessively elevated pulmonary artery pressure and/or flow to the pulmonary capillaries leading to alveolar haemorrhage is the pathophysiological mechanism of HAPE. In the Himalayas, HAPE was successfully prevented by extending the acclimatisation period from a few days to 5 weeks, however, this did not prevent the occurrence of congestive right heart failure after several weeks of stay at 6,000 m. This leads to the concept that rapid remodelling of the small precapillary arteries prevents HAPE but not the development of right heart failure in SMS and CMS. Unresponsiveness of pulmonary hypertension to oxygen at high altitude and its complete resolution only after weeks of stay at low altitude suggest that structural rather than functional changes are its pathophysiological mechanism. Since pulmonary hypertension at high altitude is the driving force leading to high-altitude pulmonary oedema and "high-altitude right heart failure" in newcomers and residents of high altitude, the authors propose to adjust current terminology accordingly.

Altitude Sickness↗
PubMed1995

Pathophysiology of obstructive sleep apnoea.

The pathophysiology of obstructive sleep apnoea (OSA) is complex and incompletely understood. A narrowed upper airway is very common among OSA patients, and is usually in adults due to nonspecific factors such as fat deposition in the neck, or abnormal bony morphology of the upper airway. Functional impairment of the upper airway dilating muscles is particularly important in the development of OSA, and patients have a reduction both in tonic and phasic contraction of these muscles during sleep when compared to normals. A variety of defective respiratory control mechanisms are found in OSA, including impaired chemical drive, defective inspiratory load responses, and abnormal upper airway protective reflexes. These defects may play an important role in the abnormal upper airway muscle responses found among patients with OSA. Local upper airway reflexes mediated by surface receptors sensitive to intrapharyngeal pressure changes appear to be important in this respect. Arousal plays an important role in the termination of each apnoea, but may also contribute to the development of further apnoea, because of reduction in respiratory drive related to the hypocapnia which results from postapnoeic hyperventilation. A cyclical pattern of repetitive obstructive apnoeas may result. A better understanding of the integrated pathophysiology of OSA should help in the development of new therapeutic techniques.

Adult↗
PubMed2001

How antidepressants work: new perspectives on the pathophysiology of depressive disorder.

BACKGROUND: New research in animals is beginning to change radically our understanding of the biology of stress and the effects of antidepressant agents. AIMS: To relate recent findings from the basic neurosciences to the pathophysiology of depressive disorder. METHOD: Drawing together findings from molecular and physiological studies in rats, social studies in primates and neuropsychological studies in humans, we review the neurotrophic and neuroplastic effects of antidepressants and stress. RESULTS: Stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects. CONCLUSIONS: We propose a central role for the regulation of synaptic connectivity in the pathophysiology of depressive disorder.

Animals↗
PubMed2003

Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system.

There is increasing evidence from a variety of sources that mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamatergic system--which is known to play a major role in neuronal plasticity and cellular resilience--may be involved in the pathophysiology and treatment of mood disorders. Preclinical studies have shown that the glutamatergic system represents targets (often indirect) for the actions of antidepressants and mood stabilizers. There are a number of glutamatergic "plasticity enhancing" strategies that may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, inhibitors of glutamate-release agents, and AMPA potentiators; this research progress holds much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.

Animals↗
PubMed2006

The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology.

Voltage-gated calcium (CaV) channels are ubiquitously expressed in various cell types throughout the body. In principle, the molecular identity, biophysical profile, and pharmacological property of CaV channels are independent of the cell type where they reside, whereas these channels execute unique functions in different cell types, such as muscle contraction, neurotransmitter release, and hormone secretion. At least six CaValpha1 subunits, including CaV1.2, CaV1.3, CaV2.1, CaV2.2, CaV2.3, and CaV3.1, have been identified in pancreatic beta-cells. These pore-forming subunits complex with certain auxiliary subunits to conduct L-, P/Q-, N-, R-, and T-type CaV currents, respectively. beta-Cell CaV channels take center stage in insulin secretion and play an important role in beta-cell physiology and pathophysiology. CaV3 channels become expressed in diabetes-prone mouse beta-cells. Point mutation in the human CaV1.2 gene results in excessive insulin secretion. Trinucleotide expansion in the human CaV1.3 and CaV2.1 gene is revealed in a subgroup of patients with type 2 diabetes. beta-Cell CaV channels are regulated by a wide range of mechanisms, either shared by other cell types or specific to beta-cells, to always guarantee a satisfactory concentration of Ca2+. Inappropriate regulation of beta-cell CaV channels causes beta-cell dysfunction and even death manifested in both type 1 and type 2 diabetes. This review summarizes current knowledge of CaV channels in beta-cell physiology and pathophysiology.

Alternative Splicing↗
PubMed2006

Small vessel abnormalities in alternating hemiplegia of childhood: pathophysiologic implications.

BACKGROUND: The pathophysiology of alternating hemiplegia of childhood (AHC) is unclear. The authors evaluated the skin and muscle biopsies from patients with AHC for vascular abnormalities. METHODS: Skin biopsy specimens from four patients ages 18 months, 8 years, 9 years, and 18 years and muscle biopsies from two of these patients were examined by electron microscopy and compared with healthy controls. RESULTS: Vascular abnormalities were found in both skin and muscle. Skin biopsies showed similar abnormalities in all four patients. Vacuoles were visible in the endothelium. The most striking abnormality was the presence in the tunica media of small and unevenly shaped vascular smooth muscle cells (VSMCs) containing intracytoplasmic vacuoles and, occasionally, apoptotic nuclei, with variations according to patient age. Moreover, most VSMCs had lost junctions with neighboring cells, and some were completely isolated. In vessels from muscle biopsies, the VSMCs showed vacuoles, residual osmiophilic deposits, and myofilament loss with substitution by vacuoles. CONCLUSIONS: The vascular abnormalities in our patients suggest a primary or secondary vascular pathophysiology to alternating hemiplegia of childhood. The vascular smooth muscle cells may be the initial target of the disease process.

Adolescent↗