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PubMed1991

Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs.

A vascular-supraspinal-myogenic (VSM) model for pain in migraine based on our previous clinical and pathophysiological observations is proposed. According to the model, perceived pain (headache) intensity is determined by the sum of nociception from cephalic arteries and pericranial myofascial tissues converging upon the same neurons and integrated with supraspinal effects (usually facilitating). Vascular input predominates over myofascial input in migraine, whereas significance of supraspinal facilitation is difficult to estimate. The importance of these 3 effects may vary between patients and in the same individual with time. The model is in accordance with recent experimental studies showing convergence of somatovisceral afferents upon n. caudalis neurons. Also, long term potentiation due to nociceptive activation and sensitization of neurons to input from wider areas and non-nociceptive stimuli are relevant to our model. In tension-type headache, nociception is primarily myofascial, but vascular input cannot be disregarded. Supraspinal facilitation probably plays a large, sometimes dominant role (the MSV model). The model explains much of the complexity of the clinical picture of these disorders as well as their tendency to overlap and to change into one another. Also, a number of pathophysiological observations such as why muscles are tender during migraine, why trigger-point injection may cure migraine attacks and why chronic tension-type headache is often associated with episodes of pulsating pain, can be explained. The model gives a rational explanation of empirically developed, internationally accepted, multimodal treatment strategies for migraine and tension-type headache. It may thus serve a useful purpose in explaining the disorder to patients. Finally, the model points to several avenues of future research in animals and man.

Animals↗
PubMed1996

The pathophysiology and development of immunity during long-term subclinical infection with Trichostrongylus colubriformis of sheep receiving different nutritional treatments.

The objective of this study was to investigate the relationship between protein nutrition, the pathophysiology, and acquisition and expression of immunity in long-term subclinical intestinal parasitism in sheep. Growing sheep were either uninfected controls or parasitised for 27 weeks with a daily dose of 2500 larvae of Trichostrongylus colubriformis, whilst they were given access to: (1) a low protein food, (2) a high protein food, or (3) a choice between the two foods, where they were allowed to select their diet. Blood samples were taken weekly for determination of serum albumin, total protein, Ca, P, urea and fructosamine concentrations. At the end of the study all sheep received a single (secondary) challenge infection (30,000 T. colubriformis L3) after treatment with anthelmintic to assess their immune status. The concentrations of sheep-mast cell proteinases (SMCP) in intestinal tissue, the number of circulating eosinophils and the total worm numbers recovered from the intestinal tract were used to investigate the effects of previous nutrition on the acquisition and expression of immunity. From the biochemical variables measured over 27 weeks, only serum fructosamine was affected by the interaction between feeding treatment and parasitism: fructosamine concentrations declined only in the parasitised animals on the low protein food during Weeks 6-15 of infection. This casts doubt on the usefulness of plasma fructosamine levels as an indicator of gastrointestinal parasitism, due to its being influenced by the nutritional environment. Total protein, albumin, calcium and phosphorus concentrations in the serum were affected by parasitism, but independently of feeding treatment. During the period of secondary challenge eosinophil numbers and SMCP concentrations were higher in the parasitised animals, reflecting the animals immune responsiveness. The numbers of worms recovered from the intestine of previously parasitised sheep were low; all three indicators of the development of acquired immunity were unaffected by previous nutritional treatment of the sheep. The results do not support the view that the pathophysiology of long term subclinical intestinal parasitism and the expression of acquired immunity induced by a trickle infection could be affected by the feeding treatment of the sheep (protein nutrition).

Animal Nutritional Physiological Phenomena↗
PubMed1995

Pathophysiology of irradiated skin and breast.

The evolution, time course, and dose response of gross and histologic changes associated with the acute and late changes of the skin are noted and a composite pathophysiologic operational model given. This model focuses the selection of the observations to be "scored" to assess the tolerance and cosmetic response of the skin and breast to different dose and combined therapy studies. Skin scoring, Late effects skin, Late effects breast, Skin irradiation response, Breast radiation response, Pathophysiology of irradiated skin, Dose tolerance of skin, Dose tolerance of breast, Skin functional unit, Microvessel response to irradiation.

Animals↗
PubMed1993

Relation of pathophysiologic mechanisms to outcome in heart failure.

Advances in the treatment of heart failure with angiotensin-converting enzyme inhibitors have been accompanied by an improved understanding of the pathophysiology of heart failure. The inability of the heart to act as a pump is determined in some patients by alterations to the architecture of the heart and changes in the extracellular space, particularly fibrosis. The degree to which the failure of the heart as a pump can be attributed to a reduced ability of the myocyte to contract is contentious. The origin of symptoms is still uncertain but does relate to identified changes in the lung, increased peripheral resistance and atrophy of skeletal muscle. The mechanisms of action of angiotensin-converting enzyme inhibitors are numerous and do not yet account easily for the clinical benefits. Further epidemiologic studies are needed to ascertain the proportion of patients who manifest progressive heart failure rather than deterioration due to further cardiac events. Understanding the pathophysiology of heart failure will allow therapy to be tailored to the requirements of the individual patient.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Radiopharmacological profiles of tracers under pathophysiological conditions. Bone uptake of 99mTc-phytate in vitamin D deficient rats.

The radiopharmaceutical 99mTc-phytate, formed by reacting the phosphatic ligand, myo-inositol hexakisphosphate with a reduced form of 99mTcO4-, is widely employed in diagnostic nuclear medicine for scinti-imaging the RE system. Despite it being a compound derived from a ligand containing phosphatic functional moieties it does not concentrate to a significant extent in the osseous tissue following i.v. injection into animals or humans. Neither has there been any clinical report citing its localization in the skeletal tissue consequent to its i.v. injection into patients with different types of pathophysiological conditions/metabolic bone disorders. In the course of our study of the homing characteristics of radiopharmaceuticals into specific organ systems or secondary target sites we found that 99mTc-phytate could be directed to some extent into the skeletal tissues of experimental rats by altering its physiological milieu--viz. by decreasing blood calcium levels and increasing bone resorption. Such an altered physiologic condition is obtained by experimentally inducing vitamin D deficiency in animals. Our results show that 8-10% of the administered dose could be redirected to the bone matrix but at the expense of the liver. The study also indicates that many so-called organ specific 99mTc-radiopharmaceuticals could have more than one target tissue/organ system for accumulation consequent to being introduced into the systemic circulation. In a number of instances the secondary target may be masked and may be elicited only under certain specific pathophysiologic conditions.

Animals↗
PubMed1991

Hypercalcemia of malignancy: pathophysiology, diagnosis and treatment.

Malignancy is the most frequent cause of hypercalcemia in hospitalized patients. The pathophysiology of hypercalcemia of malignancy (HM) is complex. Increased bone resorption is involved in most cases caused either by extensive local bone destruction or by humoral factors. Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain PTH-like bioactivity. Recently, cDNAs coding for a PTH-related protein (PTH-rP) has been cloned. The N-terminal amino acid sequence of this protein shows a considerable homology with human PTH. However, other bone resorbing factors including prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25-dihydroxyvitamin D may be involved in different types of malignancy. HM is usually progressive with troublesome symptoms and a high mortality. Several treatment alternatives are available including rehydration, bisphosphonates, calcitonin, plicamycin, phosphate, and glucocorticoids. Others are under investigation. Treatment should be individualized taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia and renal failure, and the prognosis related to the malignant disease.

Amino Acid Sequence↗
PubMed2004

Pathophysiology of severe malaria in children.

Over the past decade there has been a growing recognition that the rationalization of severe malaria in children into the two major syndromes of cerebral malaria and severe malaria anaemia is much too simplistic. Indeed, it has become apparent that death from severe malaria may arise from a wider spectrum of pathophysiological disorders with many features in common with the derangements seen in sepsis syndromes. Amongst these derangements acidosis has emerged as a central feature of severe malaria and the major predictor of a fatal outcome. We review the improved understanding of the pathophysiology of severe malaria through a series of clinical scenarios that reflect more accurately the clinical diversity of severe malaria in African children. Current therapeutic challenges are discussed and research priorities are highlighted.

Acidosis↗
PubMed2004

Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award.

OBJECTIVE: Soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), which antagonizes VEGF functions, has been implicated in the pathophysiology of preeclampsia. The purpose of this study was to determine whether preeclampsia is associated with a change in the plasma concentration of sVEGFR-1, and, if so, whether such a change is correlated with the severity of the disease. METHODS: A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in plasma obtained from normal pregnant women (n=61) and patients with preeclampsia (n=61). Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. RESULTS: Preeclampsia had a higher median plasma concentration of sVEGFR-1 than normal pregnancy (P <.001). The median plasma concentration of sVEGFR-1 was higher in early-onset (< or =34 weeks) than late-onset (>34 weeks) preeclampsia (P=.005), and higher in severe than in mild preeclampsia (P=.002). In normal pregnancy, there was a correlation between plasma concentration of sVEGFR-1 and gestational age (r=0.5; P <.001). In contrast, there was a negative correlation between plasma concentration of sVEGFR-1 and gestational age at the onset of preeclampsia (r=-0.5; P <.001). CONCLUSION: Preeclampsia is associated with an increased plasma sVEGFR-1 concentration. The elevation of sVEGFR-1 concentration is correlated with the severity of the disease. These observations suggest the participation of VEGF and its soluble receptor in the pathophysiology of preeclampsia.

Adolescent↗
PubMed2005

Pathophysiologic targets in the early phase of acute heart failure syndromes.

An episode of acute heart failure syndromes (AHFS) can be defined as a rapid or gradual onset of signs and symptoms of heart failure (HF) in hospital admission and can arise from a variety of pathophysiologic mechanisms. This article reviews our current understanding of the pathophysiology of AHFS in order to identify potential therapeutic targets. Most patients with AHFS present with either normal systolic blood pressure or elevated blood pressure. Patients who present with elevated systolic blood pressure usually have pulmonary congestion and a relatively preserved left ventricular ejection fraction (LVEF), and have symptoms that typically develop abruptly, these patients often are elderly women. Patients with normal systolic blood pressure presenting with systemic congestion and reduced LVEF are usually younger, with a history of chronic HF, and have symptoms that develop gradually over days or weeks. Accordingly, most episodes of AHFS can be classified as either "vascular" failure or "cardiac" failure. In addition to the abnormal hemodynamics (increase in pulmonary capillary wedge pressure and/or decrease in cardiac output) that characterize patients with AHFS, myocardial injury--which may be related to a decrease in coronary perfusion and/or further activation of neurohormones and renal dysfunction (ie, the cardiorenal syndrome)--probably contributes to short-term and post-discharge cardiac events. Patients with AHFS also have significant cardiac and non-cardiac underlying conditions that contribute to the pathogenesis of AHFS, including coronary artery disease (ischemia, hibernating myocardium, and endothelial dysfunction), hypertension, atrial fibrillation, and type 2 diabetes mellitus. The goals of therapy for AHFS should be not only to improve symptoms and hemodynamics, but also to preserve or improve renal function and prevent myocardial damage.

Acute Disease↗
PubMed2006

Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology.

Aldosterone is an important mediator of the renin-angiotensin-aldosterone system (RAAS) that plays a major role in the pathophysiology of cardiovascular disease as well as regulation of extracellular fluid volume and potassium. In experimental models, aldosterone has been shown to promote endothelial dysfunction; induce vascular inflammation, myocardial ischemia, and necrosis; increase collagen synthesis in cardiac fibroblasts; contribute to plasminogen activator inhibitor-1 regulation; decrease baroreceptor sensitivity and reflex function; block myocardial uptake of norepinephrine; increase oxidative stress; and stimulate cardiomyocyte apoptosis. A review of animal and human studies with aldosterone blockers reveals improvement in, and in some cases complete reversal of, these pathophysiologic effects of aldosterone on the cardiovascular system.

Aldosterone↗
PubMed2005

Reduced mRNA and protein content of rho guanine nucleotide exchange factor (RhoGEF) in Bartter's and Gitelman's syndromes: relevance for the pathophysiology of hypertension.

BACKGROUND: Activation of RhoA/Rho kinase (ROK) pathway by angiotensin II (Ang II) is involved in the pathophysiology of hypertension and remodeling. In Bartter's and Gitelman's syndrome (BS/GS), the short-term and long-term signaling of Ang II are blunted. The BS/GS have also reduced expression and response on Ang II challenge of ROK, which indicate downregulation of RhoA/ROK pathway. As causes for RhoA/ROK downregulation in BS/GS, we hypothesized an alteration at the level of the upstream regulators of RhoA such as reduced expression of Rho guanine nucleotide exchange factor (RhoGEF), which links activation of G protein-coupled receptors to RhoA/ROK signaling or increased guanine nucleotide dissociation inhibitor (RhoGDI), which inhibits dissociation of GDP from GDI maintaining RhoA in an inactive state. METHODS: In mononuclear cells of 9 BS/GS and 9 healthy controls (C), we looked at gene and protein expression (reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot) of RhoA, RhoGEF, and RhoGDI. RESULTS: In BS/GS RhoA gene and protein expression were not different from C. Also RhoGDI mRNA and protein levels were not different. On the contrary, p115RhoGEF mRNA and protein levels were reduced in BS/GS. CONCLUSIONS: Reduced p115RhoGEF may explain the downregulation of RhoA/ROK pathway in BS/GS. This is the first report of upstream regulators of RhoA level in BS/GS, a human clinical condition characterized by reduced vascular tone regulation. Because BS/GS represent the mirror image of derangements involved in hypertension, the reduced RhoGEF expression in BS/GS underlines a major impact of RhoA/ROK pathway on blood pressure regulation and confirms BS/GS as a good human model for exploring mechanisms involved in the pathophysiology of hypertension and remodeling.

Adult↗
PubMed2004

The pathophysiology of airway dysfunction.

Asthma and chronic obstructive pulmonary disease (COPD) are distinct inflammatory disorders with differing pathophysiologic mechanisms, different clinical courses, and, therefore, distinct treatment strategies. Whereas in asthma airflow limitation is typically episodic and reversible, airflow limitation in COPD is progressive and only partially reversible. In contrast to asthma, which is characterized by an elevated number of eosinophils in the blood and the accumulation of elevated numbers of activated eosinophils, mast cells, and CD4+ T(H)2-lymphocytes in the lungs, the primary inflammatory cells present in the lungs of patients with stable COPD are neutrophils, macrophages, and CD8+ lymphocytes. Bronchoconstriction in COPD is largely regulated by cholinergically mediated vagal tone, and the pathologic processes of COPD further reduce airway patency. Bronchodilators, most notably anticholinergics, are recommended as first-line pharmacologic therapy for COPD. Proper use of inhaled anticholinergic medications has been shown to lead to significant reversibility of acetylcholine-mediated bronchoconstriction during both stable disease and exacerbations of COPD. For patients with asthma, current guidelines recommend anti-inflammatory medications, specifically inhaled corticosteroids and leukotriene-modifiers, as first-line therapy, making these agents the mainstay of asthma therapy. In contrast, the current guidelines for COPD management recommend that inhaled anti-inflammatory agents be tried in patients with COPD only as second-line therapy for patients who have severe to very severe airflow obstruction with frequent exacerbations and who remain symptomatic despite maximized bronchodilation with multiple inhaled bronchodilators. Hence, it is extremely important to understand the differences between the underlying pathogenesis and pathophysiology of COPD and those of asthma, as these differences dictate the implementation of distinctly different treatment options for these 2 diseases.

Asthma↗
PubMed2006

Pathophysiology of overactive bladder.

Overactive bladder (OAB) is a complex of symptoms frequently encountered in the primary care setting. Impediments to optimal management of OAB include inaccurate perceptions on the part of patients and primary care providers, e.g., that the symptoms of OAB represent a natural progression of aging and are beyond the scope of treatment or that diagnosis and treatment are specialist concerns. Complicating the physician's task is the reluctance of many patients to initiate discussion of their OAB symptoms and the fact that patients often develop disruptive coping strategies rather than seek medical treatment, possibly because of a belief that OAB is a normal part of aging rather than an actual medical condition. In most cases, OAB may be managed quite well by the primary care physician who has an understanding of the pathophysiology of OAB. This article reviews normal bladder function and then explores pathophysiologic changes that likely cause the symptoms of OAB.

Aging↗
PubMed2007

From here to eternity: a unified kinetic model for the pathophysiology of atherosclerotic events.

Two operative pathophysiological models underlie the clinical management of ischemic heart disease: a physical model founded on the magnitude of vascular stenosis and a biochemical model founded on the inflammatory processes within the atherosclerotic plaque. Despite their complementary natures, these 2 models are implicitly competitive--the stenotic model supporting the primacy of aggressive interventional procedures and the inflammatory model supporting the primacy of conservative medical management. We unified these alternative perspectives through a kinetic model that characterizes the pathophysiology of cardiovascular events as a network of exponential transitions between the inflammatory and stenotic states. According to this model, the prevalence of the normative (nonstenotic and noninflammatory) state falls exponentially, while the prevalences of the inflammatory and stenotic states rise to a peak and then fall off exponentially. According to this model, event rate increases as a complex function of both myocardial ischemia and vascular inflammation. Although the model has yet to be prospectively validated, it provides a theoretical foundation for predicting the degree to which atherosclerotic events are due to inflammation versus stenosis and the degree to which they can thereby be prevented by treatment strategies directed at plaque stabilization or relief of ischemia.

Coronary Artery Disease↗
PubMed2005

Perinatal asphyxia pathophysiology in pig and human: a review.

In utero fetuses are evidently exposed to several factors that cause an interruption of the oxygen flow through the umbilical cord causing asphyxia leading to hypoxia and metabolic acidosis. These conditions are important causes of intra-partum and neonatal mortality. The main objective of this review is to provide current information regarding the pathophysiology of asphyxia in piglets around parturition; the physiological mechanisms invoked by affected piglets to compensate perinatal hypoxemia are discussed. This review also addresses some similarities and differences of asphyxia between piglets and other mammals, including human neonates. Metabolic acidosis and hypoxia are sequela to asphyxia and can cause profound health effects in postnatal performance because of an abnormal suckling, a reduced absorption of colostrum and inadequate passive transfer of neonatal immunity. Acidosis also cause hypothermia, increased mortality and reduced survival in neonates. One of the first deleterious effects of intrauterine hypoxia is the expulsion of meconium into the amniotic sac leading to meconium staining of the skin, and in severe cases, meconium aspiration into the lungs. Even though there have been technological changes and improvements in husbandry, piglet mortality due to asphyxia remains a major problem. One potential alternative to reduce neonatal mortality in pigs is the monitoring of fetal stress during birth and the implemention of strategies such as the Apgar score, that is often used in human pediatrics. It is also important to consider the physiological, behavioral and biochemical changes that take place during parturition which subsequently impact the vitality, maturity and development of neonatal pigs. Understanding the pathophysiology of fetal hypoxia should help practitioners and farmers implement more effective delivery techniques aimed at reducing neonatal mortality and improving postnatal performance.

Acidosis↗
PubMed2004

Pathophysiology of functional dyspepsia.

Functional dyspepsia is a highly prevalent symptom complex and a heterogeneous disorder. Recent studies showed potential associations between specific pathophysiologic disturbances and dyspeptic symptoms. Delayed gastric emptying reported in about 30% of patients with functional dyspepsia is associated with the symptoms of postprandial fullness, nausea, and vomiting. Impaired gastric accommodation present in 40% of functional dyspepsia patients is found to be associated with early satiety. Hypersensitivity to gastric distension is observed in 37% of functional dyspepsia patients and associated with the symptoms of postprandial pain, belching, and weight loss. Psychosocial factors and altered response to duodenal lipids or acid have also been identified as pathophysiologic mechanisms.

Dyspepsia↗
PubMed2006

The pathophysiology of traumatic brain injury in alpha7 nicotinic cholinergic receptor knockout mice.

The alpha7 nicotinic cholinergic receptor is a ligand-gated ion channel with calcium permeability similar to that of ionotrophic glutamate receptors. Previous studies from our laboratory have implicated changes in expression alpha7 nicotinic cholinergic receptors in the pathophysiology of traumatic brain injury (TBI). In rats, TBI causes a time-dependent and significant decrease in cortical and hippocampal alpha-[(125)I]-bungarotoxin (BTX) binding. We have postulated that deficits in alpha7 expression may contribute to TBI-induced cognitive impairment and that nicotinic receptor agonists can reverse alpha7 binding deficits and result in significant cognitive improvement compared to saline-treated controls. Thus, alpha7 nAChRs could be involved in a form of cholinergically mediated excitotoxicity following brain injury. In the current study, wild-type, heterozygous and null mutant mice were employed to test the hypothesis that genotypic depletion of the alpha7 receptor would render animals less sensitive to tissue loss and brain inflammation following experimental brain injury. Mice were anesthetized and subjected to a 0.5-mm cortical contusion injury of the somatosensory cortex. Brain inflammation, changes in nicotinic receptor expression and cortical tissue sparing were evaluated in wild-type, heterozygous and homozygous mice 1 week following TBI. In wild-type mice, brain injury caused a significant decrease in BTX binding in several hippocampal regions, consistent with what we have measured in rat brain following TBI. However, there were no genotypic differences in cortical tissue sparing or brain inflammation in this experiment. Although the results of this study were largely negative, it is still plausible that changes in the activity/expression of native alpha7 receptors contribute to pathophysiology following TBI. However, when null mutant mice develop in the absence of central alpha7 expression, it is possible that compensatory changes occur that confound the results obtained.

Acetylcholine↗
PubMed2006

Hydroxylation of D-phenylalanine as a novel approach to detect hydroxyl radicals: application to cardiac pathophysiology.

OBJECTIVE: Research in the pathophysiology of ischemia/reperfusion or redox signaling is hindered by lack of simple methodology to measure short-lived oxygen radicals. In the presence of hydroxyl radical ((*)OH), d-phenylalanine (d-Phe) yields para-, meta- and ortho-tyrosine. We have previously demonstrated that d-Phe can accurately detect (*)OH formation in chemical, enzymatic and cellular systems by simple HPLC methodology [Anal Biochem 290:138;2001]. In the present study, we tested whether d-Phe hydroxylation can be used to detect (*)OH formation in intact organs. METHODS: Rat hearts were perfused with buffer containing 5 mM d-Phe and subjected to 30 min of total global ischemia at 37 degrees C followed by 45 min of reperfusion. Quantitative analysis of the three hydroxytyrosine isomers was achieved by HPLC-based electrochemical detection of cardiac venous effluent, with the analytical cells operating in the oxidative mode. The detection limit of this assay was <10 fmol. RESULTS: Under baseline conditions, hydroxytyrosine release from the heart was very low ( congruent with0.8 nmol/min/g). However, a prominent tyrosine burst occurred immediately upon post-ischemic reflow. In cardiac effluent collected 40 s into reperfusion, the hydroxytyrosine concentration was more than 40 times greater than at baseline; hydroxytyrosine concentration then progressively declined, to return to pre-ischemic values by 5 min of reperfusion. In parallel experiments, formation of hydroxytyrosines was markedly reduced in hearts reperfused in the presence of the (*)OH scavenger mannitol. Inclusion of 5 mm d-Phe in the perfusion medium altered neither basal cardiac function nor coronary vascular tone, but it enhanced recovery of myocardial function during post-ischemic reperfusion, consistent with direct reaction with (*)OH. CONCLUSION: Our results demonstrate that d-Phe is a sensitive method for detection of (*)OH generation in the heart. Since d-Phe is not a substrate for endogenous enzymes, it can be exploited as a reliable method to measure (*)OH formation under a variety of pathophysiological conditions.

Animals↗