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PubMed2006

Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies.

A functional vascular supply is critical for the continued growth and development of solid tumors. It also plays a major role in metastatic spread of tumor cells. This importance has led to the concept of targeting the vasculature of the tumor as a form of cancer therapy. Two major types of vascular-targeting agent (VTA) have now emerged: those that prevent the angiogenic development of the neovasculature of the tumor and those that specifically damage the already established tumor vascular supply. When used alone neither approach readily leads to tumor control, and so, for VTAs to be most successful in the clinic they will need to be combined with more conventional therapies. However, by affecting the tumor vascular supply, these VTAs should induce pathophysiologic changes in variables, such as blood flow, pH, and oxygenation. Such changes could have negative or positive influences on the tumor response to more conventional therapies. This review aims to discuss the pathophysiologic changes induced by VTAs and the implications of these effects on the potential use of VTAs in combined modality therapy.

Angiogenesis Inhibitors↗

PubMed2000

Pathophysiology and pharmacological treatment of gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in a gastroenterologist's practice. Gastroesophageal reflux describes the retrograde movement of gastric contents through the lower esophageal sphincter (LES) to the esophagus. It is a common, normal phenomenon which may occur with or without accompanying symptoms. Symptoms associated with GERD include heartburn, acid regurgitation, noncardiac chest pain, dysphagia, globus pharyngitis, chronic cough, asthma, hoarseness, laryngitis, chronic sinusitis and dental erosions. The introduction of fiberoptic instruments and ambulatory devices for continuous monitoring of esophageal pH (24-hour pH monitoring) has led to great improvement in the ability to diagnose reflux disease and reflux-associated complications. The development of pathological reflux and GERD can be attributed to many factors. Pathophysiology of GERD includes incompetent LES because of a decreased LES pressure, transient lower esophageal sphincter relaxations (TLESRs) and deficient or delayed esophageal acid clearance. Uncomplicated GER may be treated by modification of life style and eating habits in an early stage of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H(2) blockers, prokinetics and proton pump inhibitors. Although these drugs are effective, they do not necessarily influence the underlying causes of the disease by improving the esophageal clearance, increasing the LESP or reducing the frequency of TLESRs. The following article gives an overview regarding current concepts of the pathophysiology and pharmacological treatment of GERD.

Antacids↗

PubMed2000

Pathophysiology of lower urinary tract symptoms in aged men without bladder outlet obstruction.

OBJECTIVE: To assess the pathophysiology of lower urinary tract symptoms (LUTS) in aged men without bladder outlet obstruction in a videourodynamic study. METHODS: In a videourodynamic study of 324 consecutive men with moderate to severe LUTS suggestive for bladder outlet obstruction, 112 were found to be urodynamically nonobstructed. International prostatic symptom score (IPSS), uroflowmetry and transrectal sonography of the prostate were assessed before videourodynamic study. The pressure flow expression and the obstructive parameters were compared between the 212 obstructed and 112 nonobstructed men. RESULTS: Of the 112 nonobstructed men investigated, 25 had a normal bladder and urethral trace (22.3%), 5 had detrusor instability (4.5%), 17 had a hypersensitive bladder and a normal urethra (15.2%), 3 had detrusor underactivity and a normal urethra (2.7%), while 61 were found to have a poorly relaxed external sphincter and low detrusor contractility (54.5%). Most of the patients in the normal and hypersensitive groups had normal voiding pressure and high flow (NPHF) tracings, whereas men with detrusor underactivity or a poorly relaxed external sphincter had normal voiding pressure and low flow (NPLF) tracings. Only the maximal flow rate and voided volume were significantly higher in patients with NPHF than in patients with NPLF tracings. However, both groups showed a significantly lower IPSS, less residual urine, and a smaller transition zone index than the obstructive group. After medical treatment, 78 patients (69.6%) had satisfactorily improved, 31 patients (27.6%) remained stationary, while 3 (2.7%) worsened. CONCLUSION: Nonobstructed men with LUTS have various pathophysiologies other than benign prostatic obstruction. In this study 54.5% of these patients had poorly relaxed external sphincter on videourodynamic study. Identification of the underlying pathology can not only prevent unnecessary prostate surgery but can also enable proper medical treatment to be selected.

Aged↗

PubMed2002

Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short- and long-term prognosis. This review focusses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver-support strategies to enhance the recovery process.

Animals↗

PubMed2001

Pathophysiology of sodium and water retention in heart failure.

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.

Adrenergic beta-Antagonists↗

PubMed2001

Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Recent advances in prevention and management.

AIM: To summarize the most common etiologic factors and describe the pathophysiology in the formation of peritoneal adhesions, to outline their clinical significance and consequences, and to evaluate the pharmacologic, mechanical, and surgical adjuvant strategies to minimize peritoneal adhesion formation. METHODS: We performed an extensive MEDLINE search of the internationally published English literature of all medical and epidemiological journal articles, textbooks, scientific reports, and scientific journals from 1940 to 1997. We also reviewed reference lists in all the articles retrieved in the search as well as those of major texts regarding intraperitoneal postsurgical adhesion formation. All sources identified were reviewed with particular attention to risk factors, pathophysiology, clinical manifestations, various methods, and innovative techniques for effectively and safely reducing the formation of postsurgical adhesions. RESULTS: The formation of postoperative peritoneal adhesions is an important complication following gynecological and general abdominal surgery, leading to clinical and significant economical consequences. Adhesion occur in more than 90% of the patients following major abdominal surgery and in 55-100% of the women undergoing pelvic surgery. Small-bowel obstruction, infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery are the most common consequences of peritoneal adhesions. Despite elaborate efforts to develop effective strategies to reduce or prevent adhesions, their formation remains a frequent occurrence after abdominal surgery. CONCLUSIONS: Until additional information and findings from future clinical investigations exist, only a meticulous surgical technique can be advocated in order to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery.

Abdomen↗

PubMedDate not supplied

Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are distinct but related aspects of the same dynamic disease process known as venous thromboembolism (VTE). An estimated 200,000 new cases occur in the United States every year, including 94,000 with PE, resulting in an incidence of 23 per 100,000 patients per year-cases. Without treatment, pulmonary embolism is associated with a mortality rate of approximately 30%, causing nearly 50,000 deaths per year. Moreover, based on post-mortem studies, two-thirds of the patients with pulmonary emboli remain undiagnosed. Clinically, PE may present as (1) isolated dyspnea, (2) pleuritic pain and/or hemoptysis, and (3) circulatory collapse. However, clinical history and examination can be notoriously misleading in reaching a diagnosis. A number of acquired etiologic risk factors (predispositions) are associated with a tendency to develop VTE. These include increasing age, immobilization, surgery, trauma, hospital or nursing home confinement, malignancy, neurologic disease with extremity paresis, as well as certain types of oral contraception and hormone replacement therapy. In addition, a variety of genetic risk factors, such as factor V Leiden, protein S or C deficiency have also been identified. However, in at least half of the instances, no predisposing factors can be identified (idiopathic PE). In the majority of cases thromboemboli originate in the deep veins of the calf or pelvis. The pathogenic conditions for VTE comprise a triad of factors and include (1) venous stasis, (2) hypercoagulable states, and (3) vascular endothelium injury. Occlusion of pulmonary arteries has variable and transient clinical and pathophysiologic consequences, involving both mechanical and reflex effects of vascular occlusion with a consecutive perfusion defect as well as the release of vasoactive and other inflammatory mediators. The objectives of this article are to present an overview of the etiologic and pathogenic factors promoting VTE as well as the pathophysiologic and inflammatory processes following PE.

Comorbidity↗

PubMed2003

Renal cyclooxygenase-2 (COX-2). Physiological, pathophysiological, and clinical implications.

BACKGROUND/AIMS: The role of COX-2 for renal function during renal development, for physiology and pathophysiology of renal diseases and the side effects of available COX-2 inhibitors, has gained increasing interest. We aimed therefore to review the respective role of renal COX-2. METHODS: Review of relevant recent publications in the field, and in addition of in part unpublished data obtained in our laboratories. RESULTS: COX-2 is 'constitutively' localized in the kidney i.e. in macula densa, TALH, interstitial cells, and is of utmost importance for normal renal development. Renal COX-2 is regulated by for example sodium and volume intake, angiotensin II, glucocorticoids often involving specific COX-2 promotor response elements. COX-2 derived prostanoids are required for preservation of renal blood flow and glomerular filtration especially in states of fluid deficit, they promote natriuresis, and furthermore may stimulate renin secretion during low-sodium intake/loop diuretic use. Conversely, COX-2 inhibitors decrease glomerular filtration, and renal perfusion, sometimes even causing acute renal failure. In addition, COX-2 inhibitors cause sodium retention, edema formation, cardiac failure and hypertension. The role of COX-2 derived prostanoids in renal inflammation or failure including diabetic nephropathy and renal transplantation remains at present controversial. CONCLUSION: COX-2 is one of the major players in renal physiology and pathophysiology. One focus of future work should be placed on COX-2 in primary renal diseases.

Animals↗

PubMed2004

Genetics and pathophysiology of hyperinsulinism in infancy.

Hyperinsulinism in infancy (HI) is a condition of neonates and early childhood. For many years the pathophysiology of this potentially lethal disorder was unknown. Advances in the genetics, histopathology and molecular physiology of this disease have now provided insights into the causes of beta-cell dysfunction and revealed levels of diversity far in excess of our previous knowledge. These include defects in ion channel subunit genes and mutations in several enzymes associated with beta-cell metabolism and anaplerosis. In most cases, beta-cell pathophysiology leads to an alteration in the function of ATP-sensitive K(+) channels. This can manifest as 'channelopathies' of K(ATP) channels through gene defects in ABCC8 and KCNJ11 (Ch.11p15); or as a result of 'metabolopathies' through defects in the genes encoding glucokinase (GCK, Ch.7p15-p13), glutamate dehydrogenase (GLUD1, Ch.10q23.3) and short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHSC, Ch.4q22-q26). This review focuses upon the relationship between the causes of HI and therapeutic options.

Adenosine Triphosphate↗

PubMed2005

Recent highlights in the pathophysiology of atopic eczema.

Atopic eczema (AE) belongs to the group of atopic diseases that have become increasingly prevalent over the last decades. The pathophysiology of AE has long remained enigmatic, but much scientific effort has been invested in elucidating the genetic background and the immunological mechanisms underlying AE, leading to a better understanding of this complex disease and to new therapeutic strategies. This review provides an update on the scientific progress that has been achieved in clarifying the pathophysiological mechanisms of AE.

Dermatitis, Atopic↗

PubMed2005

Pathophysiological role of vascular endothelial growth factor in the remnant kidney.

BACKGROUND: Subtotal renal ablation is characterized by initial glomerular hypertrophy, followed by progressive development of glomerulosclerosis and interstitial fibrosis. Vascular endothelial growth factor (VEGF) is involved in glomerular hypertrophy and dysfunction in several pathophysiological conditions. On the other hand, progressive glomerulosclerosis and tubulo-interstitial fibrosis in the remnant kidney have been associated with loss of VEGF expression. METHODS: To explore the pathophysiological role of VEGF in the development of glomerular hypertrophy and renal damage in the remnant kidney model, we examined the effect of a neutralizing VEGF antibody on glomerular volume and kidney function in rats after subtotal nephrectomy or sham operation. Erythropoietin was administered to exclude a confounding effect of anaemia. RESULTS: Six weeks after subtotal nephrectomy, plasma urea and creatinine concentrations, urinary albumin excretion, and mean glomerular volume were elevated in the placebo-treated uraemic rats as compared with the sham-operated rats. Inhibition of VEGF partially prevented the glomerular hypertrophy and largely prevented the rise in urinary albumin excretion, but did not affect creatinine clearance in uraemic rats. CONCLUSIONS: VEGF is a mediator of glomerular hypertrophy after subtotal renal ablation. In view of glomerular hypertrophy as the initial deleterious event ultimately leading to progressive glomerulosclerosis, agents that block this glomerular growth could be useful in preventing scarring in progressive renal disease.

Animals↗

PubMed2005

Pathophysiology of stroke rehabilitation: temporal aspects of neuro-functional recovery.

Stroke almost always causes an impairment of motor activity and function. Clinical recovery, though usually incomplete, is often highly dynamic and reflects the ability of the neuronal network to adapt. Mechanisms that underlie neuro-functional plasticity are now beginning to be understood. Albeit the enormous efforts undertaken to support the natural course of re-convalescence through rehabilitation, little has been done to relate possible effects of these therapeutic approaches to mechanisms of adaptive pathophysiology. The review presented here focuses on these mechanisms during the course of recovery post stroke. Next to an unmasking of latent network representations, other adaptive processes, such as excitatory metabolic stress, an imbalance in activating and inhibiting transmission, leading to salient hyperexcitability or mechanisms that consolidate novel connections prime the system's plastic capabilities. These pathophysiological processes potentially interact with rehabilitative interventions. They therefore form the foundation of positive, but possibly also negative recuperation under therapy.

Brain↗

PubMed2006

Migraine and patent foramen ovale: A residual coincidence or a pathophysiological intrigue?

Migraine is one of the most common neurological disorders and one of the most frequent primary headaches. It imposes a significant burden on the affected individuals, society and health care system. As the etiology and pathophysiology of migraine are not well understood, treatment is largely symptomatic. Patent foramen ovale is a remnant of a fetal circulation and is highly prevalent in the general population. Its presence was linked to several disorders including migraine. The aim of this review was to search in the available data the answer to the question whether the link between migraine and patent foramen ovale is coincidental or whether they represent a pathophysiological entity.

Cardiac Catheterization↗

PubMed2006

Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets.

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery.

Animals↗

PubMedDate not supplied

Localization of interleukin-1 beta converting enzyme mRNA in rat brain vasculature: evidence that the genes encoding the interleukin-1 system are constitutively expressed in brain blood vessels. Pathophysiological implications.

Interleukin (IL)-1 beta-converting enzyme (ICE) cleaves the biologically inactive precursor form of IL-1 beta into mature, bioactive IL-1 beta. Because of the potent effects of IL-1 in blood vessels, we conducted an in situ hybridization study to determine whether ICE mRNA is constitutively expressed in adult rat brain vasculature. Using in situ hybridization histochemistry, we were able to demonstrate that mRNA in blood vessels scattered throughout the brain. In a second set experiments, we found that the genes encoding not only ICE, but also IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), and the IL-1 type I receptor are expressed in brain vasculature. To our knowledge this is the first report documenting the expression of the genes encoding all of the functional elements of the IL-1 system in the same tissue. Our findings have three pathophysiological implications. First, they indicate a possible site where peripheral IL-1 may act in the brain. The vascular IL-1 system stimulates the production of nitric oxide and prostanoids, which could act as mediators of the effects of peripheral IL-1 in the central nervous system. Additionally, vascular IL-1 is known to activate adhesion molecules; our data that the genes encoding the IL-1 system are expressed in brain vasculature further support the concept that IL-1 is implicated in the pathophysiology of atherosclerosis and stroke. Finally, in the context of previous studies documenting that IL-1ra inhibits the effects of IL-1 on endothelial cells, our findings of endogenous IL-1ra mRNA in brain vasculature indicate that IL-1ra might be an endogenous vascular protective agent.

Animals↗

PubMed1990

Experimental pathophysiological correlates of clinical symptomatology in peripheral neuropathic pain syndromes.

Recent advances in the study of nerve pathophysiology in experimental models of nerve and spinal root injury indicate a striking parallel between the abnormal electrical behavior of sensory axons and clinical symptomatology. In conjunction with central pain processes, these pathophysiological mechanisms can account for many of the major features of neuropathic pain syndromes.

Animals↗

PubMed1996

A comparison of pathophysiological changes during hypobaric and normobaric hypoxia in rats.

Littermate male Wistar specific pathogen-free rats were divided into three groups at 28 days of age. The pathophysiological effects seen in rats exposed to normobaric hypoxia (NB) at 10% O2 were compared with those seen in animals exposed to hypobaric hypoxia (HB) at 500 mbar, equivalent to an inspired O2 concentration of 10%, and controls after periods of 5, 10 and 14 days. 5 days' exposure to a low oxygen environment resulted in less weight gain, the development of right ventricular hypertrophy and double elastic laminae in the pulmonary arterioles and an increase in haematocrit and plasma levels of atrial natriuretic peptide (ANP) in both the HB and NB animals compared to controls. There was no significant difference in these values between the two hypoxic groups. After 10 days' exposure to a low oxygen environment, body weight, ventricular ratio, plasma ANP levels and double elastic laminae were higher than the levels seen after 5 days in both NB and HB groups of rats. At day 14 only body weight and haematocrit were greater when compared to day 10 values in NB and HB groups. In conclusion the stress of this hypobaric environment caused no additional changes in the pathophysiological variables studied, compared with the changes seen in NB.

Animals↗

PubMed1988

Gastric ulcer and stomach aging: pathophysiology and clinical implications.

138 consecutive patients with endoscopically and histologically confirmed benign gastric ulcer were investigated in order to evaluate the relationship between aging and parameters relating to gastric ulcer pathophysiology and natural history: prevalence in dyspeptic patients referred to an endoscopic unit, recurrences, gastric acid secretory capacity, peptic activity, incidence of precancerous and neoplastic changes. On the basis of our results, different populations of gastric ulcer patients seem to be identifiable: (1) young patients (aged under 40), with low prevalence and recurrence rates, with acid capacity above normal range, high peptic activity and no risk for precancerous or neoplastic changes, (2) middleaged subjects (41-50), with high prevalence and recurrence rates, high peptic activity and acid activity within the normal range, atrophic gastritis, intestinal metaplasia, dysplasia and low incidence of cancer, and (3) elderly patients (aged over 50), with lower prevalence and recurrence rates, frequent association with chronic atrophic gastritis, impaired acid and peptic secretion, in whom one may observe either an association of the ulceration with cancer or evolution of dysplasia into neoplasia. These observations confirm that elderly and middle-aged gastric ulcer patients should undergo routine follow-up, and that pathophysiological data should be taken into account before deciding upon antiulcer therapy.

Adult↗