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At least 361 records · Page 20Linked to original sources
PubMed2002

The cholinergic pathology in Alzheimer's disease--discrepancies between clinical experience and pathophysiological findings.

The cholinergic hypothesis of Alzheimer's disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-I), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimer's disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-I's. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy.

Alzheimer Disease↗
PubMed2004

Trigeminal autonomic cephalalgias: from pathophysiology to clinical aspects.

The strictly unilateral headaches, more commonly known as trigeminal autonomic cephalalgias (TACs), are characterised by severe, strictly unilateral pain in the territory of the distribution of the trigeminal nerve, associated with autonomic manifestations. The recent International Headache Society classification lists the strictly unilateral headaches as cluster headache (CH), episodic and chronic paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. CH is the most common and best-defined of the TACs, whose pathophysiologies have not been adequately defined. Convincing proposals for pathophysiologic mechanisms must explain the trigeminal distribution of the pain, the homolateral autonomic manifestations; and, for CH, the usually periodic recurrence of the crises and clusters. With regard to CH, (i) the pain is always located periorbitally-frontally, implicating nociceptive mechanisms involving the trigeminal nerve; (ii) the autonomic manifestations homolateral to the pain seem to be both parasympathetic (lacrimation and rhinorrhoea) and sympathetic (ptosis and miosis); and (iii) the periodicity of the attacks and seasonal recurrence of the cluster periods suggest involvement of a biological clock within hypothalamus.

Autonomic Nervous System Diseases↗
PubMed2006

Pathophysiological mechanisms of neuropathic pain.

It is largely acknowledged that multiple and complex pathophysiological mechanisms may be at play in neuropathic pain. This short review summarises the current understanding of pathophysiology of neuropathic pain and focuses on how symptoms translate in mechanisms.

Humans↗
PubMed2003

Percutaneous closure of patent foramen ovale: pathophysiology, indications, and technique.

The percutaneous closure of patent forame ovale (PFO) is currently performed in patients with cryptogenic stroke or paradoxical systemic embolism. The availability of new user friendly devices and the increase in knowledge of the pathophysiology, epidemiology, and follow-up of these patients has broadened the indications and drastically reduced the morbidity related to the intervention. This review considers the main pathophysiological and epidemiological features of PFO and discusses the indications and results of the intervention.

Cardiac Catheterization↗
PubMed2007

Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation.

Cyclophosphamide (CP) and ifosfamide (IF) are widely used antineoplastic agents, but their side-effect of hemorrhagic cystitis (HC) is still encountered as an important problem. Acrolein is the main molecule responsible of this side-effect and mesna (2-mercaptoethane sulfonate) is the commonly used preventive agent. Mesna binds acrolein and prevent its direct contact with uroepithelium. Current knowledge provides information about the pathophysiological mechanism of HC: several transcription factors and cytokines, free radicals and non-radical reactive molecules, as well as poly(adenosine diphosphate-ribose) polymerase (PARP) activation are now known to take part in its pathogenesis. There is no doubt that HC is an inflammatory process, including when caused by CP. Thus, many cytokines such as tumor necrosis factor (TNF) and the interleukin (IL) family and transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) also play a role in its pathogenesis. When these molecular factors are taken into account, pathogenesis of CP-induced bladder toxicity can be summarized in three steps: (1) acrolein rapidly enters into the uroepithelial cells; (2) it then activates intracellular reactive oxygen species and nitric oxide production (directly or through NF-kappaB and AP-1) leading to peroxynitrite production; (3) finally, the increased peroxynitrite level damages lipids (lipid peroxidation), proteins (protein oxidation) and DNA (strand breaks) leading to activation of PARP, a DNA repair enzyme. DNA damage causes PARP overactivation, resulting in the depletion of oxidized nicotinamide-adenine dinucleotide and adenosine triphosphate, and consequently in necrotic cell death. For more effective prevention against HC, all pathophysiological mechanisms must be taken into consideration.

Acrolein↗
PubMed2006

Pathophysiology and therapy of experimental stroke.

1. Stroke is the neurological evidence of a critical reduction of cerebral blood flow in a circumscribed part of the brain, resulting from the sudden or gradually progressing obstruction of a large brain artery. Treatment of stroke requires the solid understanding of stroke pathophysiology and involves a broad range of hemodynamic and molecular interventions. This review summarizes research that has been carried out in many laboratories over a long period of time, but the main focus will be on own experimental research. 2. The first chapter deals with the hemodynamics of focal ischemia with particular emphasis on the collateral circulation of the brain, the regulation of blood flow and the microcirculation. In the second chapter the penumbra concept of ischemia is discussed, providing a detailed list of the physiological, biochemical and structural viability thresholds of ischemia and examples of how these thresholds can be applied for imaging the penumbra. The third chapter summarizes the pathophysiology of infarct progression, focusing on the role of peri-infarct depolarisation, the multitude of putative molecular injury pathways, brain edema and inflammation. Finally, the fourth chapter provides an overview of currently discussed therapeutic approaches, notably the effect of mechanical or thrombolytic reperfusion, arteriogenesis, pharmacological neuroprotection, ischemic preconditioning and regeneration. 3. The main emphasis of the review is placed on the balanced differentiation between hemodynamic and molecular factors contributing to the manifestation of ischemic injury in order to provide a rational basis for future therapeutic interventions.

Animals↗
PubMed2005

A possible role of GLP-1 in the pathophysiology of early dumping syndrome.

Exaggerated plasma concentrations of GLP-1 precede reactive hypoglycemia after oral glucose in gastrectomy patients, resulting in late dumping syndrome. Recently, we showed that GLP-1 elicits the activation of sympathetic outflow. Because sympathetic activation is thought to be a cause of early dumping, we hypothesized that exaggerated GLP-1 may contribute to the pathophysiology of early dumping syndrome. In 11 patients after gastrectomy and 14 controls, blood pressure, heart rate, and plasma concentrations of norepinephrine, epinephrine, GLP-1, glucagon, insulin, and glucose were measured after oral glucose. In gastrectomy patients, GLP-1, norepinephrine, and heart rate peaked 15 to 30 min after oral glucose. Significant positive correlations were found among GLP-1, norepinephrine, and heart rate at 30 min, and these parameters at 30 min were significantly higher in patients with early dumping syndrome. These results suggest that GLP-1 is involved in the pathophysiology of early dumping syndrome.

Adult↗
PubMed2005

Brain metastases: epidemiology and pathophysiology.

Metastases are the most common tumors of the central nervous system (CNS), but cancer databases are often incomplete leading to underestimation of the incidence of even symptomatic brain metastases. Brain imaging studies are not routinely performed on neurologically asymptomatic cancer patients and autopsy studies are outdated. Furthermore, while incidence rates for cancers are stable and mortality is decreasing due to earlier detection and better therapy, the incidence of brain metastases appears to be increasing. The pathophysiology of brain metastases is a complex multistage process, mediated by molecular mechanisms; from the primary organ, cancer cells must transform, grow and be transported to the CNS where they can lay dormant for various lengths of time before invading and growing further. Understanding the pathophysiology of brain metastases is of great importance, because it may lead to the development of more efficient therapies to combat brain tumor growth or to possibly make the CNS an undesirable environment for tumor progression.

Brain Neoplasms↗
PubMed2004

Refractory chronic rhinosinusitis: pathophysiology and management of chronic rhinosinusitis persisting after endoscopic sinus surgery.

Refractory chronic rhinosinusitis (RCRS) is defined as persistence of signs and symptoms of chronic rhinosinusitis, despite technically adequate endoscopic sinus surgery. Rather than a simple, prolonged bout of acute sinusitis, it instead appears to be secondary to an interaction of a susceptible host with the outside environment. Inflammatory responses to colonizing bacteria appear to be responsible for a significant portion of the pathophysiology. Reduction of bacterial load and inflammation of the mucosa play an important role in controlling the disease. Novel treatment strategies, with an emphasis on topical therapies, seem to offer optimal management. In this review, current concepts on the pathophysiology and current therapies available for RCRS are outlined. A practical management strategy based on the author's personal experience draws upon these concepts, and is detailed in this review of an unusual topic.

Anti-Infective Agents↗
PubMed2000

The role of tumor necrosis factor alpha in the pathophysiology of congestive heart failure.

A variety of clinical and experimental investigations have suggested that tumor necrosis factor alpha (TNF-alpha) may play a role in the pathophysiology of heart failure. Serum levels of TNF-alpha are elevated in patients with heart failure, and both cardiac and infiltrating cells of the myocardium can produce this proinflammatory cytokine. Both cardiac myocytes and nonmyocytes also express receptors for TNF-alpha, and experimental studies on isolated cells, muscles, and transgenic models demonstrate the ability of TNF-alpha to recapitulate functional and biochemical alterations resembling that observed in human congestive heart failure. The intracellular pathways affected by TNF-alpha include production of ceramide and an alteration in calcium metabolism. Recent studies in both animal models and clinical investigations suggest that anti-TNF-alpha therapies may limit the pathophysiologic consequences of congestive heart failure.

Animals↗
PubMed2001

Pathophysiological mechanisms of gastroesophageal reflux disease in children.

Gastroesophageal reflux (GER) is an extremely common pediatric problem, but only in the past few years have we developed a better understanding of its pathophysiology. This is related to the wider use of investigative tools such as flexible endoscopy, 24-hour pH monitoring, and more recently, micromanometric methods and noninvasive breath tests, which have been particularly useful in infants. This paper reviews our current understanding of the esophageal and gastric mechanisms contributing to the pathophysiology of GER. In this context, we also highlight areas where new therapeutic approaches may be beneficial.

Child↗
PubMed2003

Pathophysiology and management of pediatric ascites.

Ascites accumulation is the product of a complex process involving hepatic, renal, systemic, hemodynamic, and neurohormonal factors. The main pathophysiologic theories of ascites formation include the "underfill," "overflow," and peripheral arterial vasodilation hypotheses. These theories are not necessarily mutually exclusive and are linked at some level by a common pathophysiologic thread: The body senses a decreased effective arterial blood volume, leading to stimulation of the sympathetic nervous system, arginine-vasopressin feedback loops, and the renin-angiotensin-aldosterone system. Cornerstones of ascites management include dietary sodium restriction and diuretics. Spironolactone is generally tried initially, with furosemide added if clinical response is suboptimal. More refractory patients require large-volume paracentesis (LVP) accompanied by volume expansion with albumin. Placement of a transjugular intrahepatic portosystemic shunt is reserved for individuals with compensated liver function who require very frequent sessions of LVP. Peritoneovenous shunts are not used in contemporary ascites management. Liver transplantation remains the definitive therapy for refractory ascites. Although treatment of ascites fails to improve survival, it benefits quality of life and limits the development of such complications as spontaneous bacterial peritonitis.

Age Factors↗
PubMed2003

Current insights into the pathophysiology of irritable bowel syndrome.

Recent reports have emphasized the possible role of mucosal immune activation and inflammation in neuropathic changes in the pathophysiology of irritable bowel syndrome (IBS). However, novel findings using functional brain imaging techniques have underlined the importance of altered perception of visceral stimuli to symptom generation in IBS. These new developments have rekindled an old debate on peripheral versus central mechanisms in the pathophysiology of IBS. In this review we discuss the latest findings in light of these two concepts. In addition, we provide evidence for the hypothesis that, in the absence of alterations in endogenous pain modulation systems and changes in visceral perception, chronic inflammatory mucosal changes in the gut are not a plausible mechanism to explain the presence of chronic abdominal pain, a cardinal IBS symptom.

Colonic Diseases, Functional↗
PubMed2005

New insights into the pathophysiology of irritable bowel syndrome: implications for future treatments.

Irritable bowel syndrome (IBS) is a multifactorial disorder characterized by abdominal pain and altered bowel habits. Chronic symptoms may occur due to changes in gastrointestinal motor function, enhanced perception of gut stimuli, and psychosocial factors. Recent data suggest that abnormal processing of afferent signals occurs in IBS patients. A newly recognized causative factor in a subset of IBS patients is post-infectious IBS. Altered transport of intestinal gas and bowel distention may contribute to abdominal discomfort, pain, and bloating. Changes in gut microflora have also been reported, but data remain scant. Advances have been made in our understanding of serotonin signaling and metabolism in IBS patients, in part due to the introduction of specific receptor agonists and antagonists. Finally, exciting data are emerging on genetic alterations that may contribute to the pathophysiology and treatment of IBS. Increasingly novel mechanisms are being identified that should aid in better understanding of the complex pathophysiology of IBS and developing new therapies.

Brain↗
PubMed2005

Hypertension in patients with Cushing's disease: pathophysiology, diagnosis, and management.

Hypertension is a very common comorbidity in patients with Cushing's disease/syndrome, resulting from the interplay of several pathophysiologic mechanisms, including stimulation of mineralocorticoid and glucocorticoid receptors as well as the associated insulin resistance, sleep apnea, and overexpression of renin-angiotensin system. Although treatment of Cushing's disease results in resolution or amelioration of hypertension in these patients, a significant proportion of patients do not achieve complete cure or require a prolonged period of time for complete response to therapy. Therefore, therapeutic strategies for Cushing's-specific hypertension are necessary to decrease morbidity and mortality associated with this disease. In this review, we discuss the pathophysiology of hypertension in patients with Cushing's disease, highlighting the therapeutic options, including the exciting new developments in the role of peroxisome proliferator-activated receptor (PPAR)-g agonists in the management of this patient population.

Adrenalectomy↗
PubMed2003

Male osteoporosis: epidemiology and pathophysiology.

In men, osteoporosis is a prevalent problem that is under-recognized and undertreated. Men 50 years and older have a 13% lifetime risk for fracture. Hip and vertebral fractures are associated with significant functional impairment and increased mortality in men. The morbidity and mortality following a fracture is also greater in men than it is in women. By improving our knowledge on the pathophysiology of osteoporosis in men, better management strategies for this condition may be developed. In recent years, there has been greater awareness of the biomechanic factors that contribute to bone strength, which may explain some of the differences in fracture incidence between men and women. There is also growing evidence to support the key role of estrogens in maintaining bone health in older men, similar to women. This review highlights our current understandings on the epidemiology and pathophysiology of male osteoporosis and its related fractures, with particular focus on the determinants of bone strength and the role of sex hormones on bone metabolism in men.

Absorptiometry, Photon↗
PubMed2000

Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders.

The molecular medicine revolution has resulted in a more complete understanding about the etiology and pathophysiology of a variety of illnesses. This remarkable progress reflects in large part the elucidation of the basic mechanisms of signal transduction, and the application of the powerful tools of molecular biology to the study of human disease. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated signal transduction pathways, in particular the stimulatory guanine nucleotide binding protein (Gs)/cyclic AMP and protein kinase C pathways, in the pathophysiology and treatment of mood disorders. Recent studies have also shown that mood stabilizers exert neurotrophic and neuroprotective effects not only in preclinical paradigms, but also in humans. Together, these studies suggest that mood disorders may be associated with impaired neuroplasticity and cellular resiliency, findings that may have major implications for our understanding of mood disorders, and for the development of improved therapeutics.

Animals↗
PubMed2001

The pathophysiology and treatment of autism.

This article critically reviews research done in the past 2 years concerning the pathophysiology and treatment of autism. Recent research in genetics, neuroimaging, neurochemistry, and pharmacologic treatment has advanced the body of knowledge about the pathophysiology of autism. Relatively new imaging technologies (eg, positron emission tomography) are increasingly being applied to the study of subjects with autism and have produced promising results that await replication. Neurochemical and challenge studies continue to suggest a role for 5-HT dysregulation in autism. Additional research is needed to determine the role of neuroendocrine and autoimmune factors in autism. Significant gains have been made in determining which pharmacologic treatments are efficacious in autism. Additional research is needed on agents that might ameliorate the core and associated symptoms of autism.

Autistic Disorder↗