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PubMed2002

Pulmonary hypertension in patients with chronic obstructive pulmonary disease: recent advances in pathophysiology and management.

In patients with chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) is associated with a worse prognosis. Recently, information has been increasing concerning the cellular and molecular aspects of the pathophysiology of PH in COPD. The most striking finding is the role of vascular endothelial cells and endogenous mediators released by these cells. Endothelial cell-dependent relaxation is impaired in COPD patients with PH. Moreover, vascular remodelling in these patients is mainly responsible for irreversible PH in advanced COPD. Smoking cessation will slow down the progression of the disease process and may prevent the development of PH in COPD. The timing of initiation of long-term oxygen therapy is important for the effective management of PH in COPD. Research on therapeutic agents for the effective treatment of PH is still needed in the management aspect of patients with COPD. This review focuses on the recent advances in our understanding of the pathophysiology and treatment of PH in COPD.

Cardiac Catheterization↗
PubMed2002

Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations.

Gastro-oesophageal reflux disease (GERD) is common in obese patients. Apart from the physical discomfort and the economic burden, GERD may increase morbidity and mortality through its association with oesophageal carcinoma. The pathophysiology of GERD differs between obese and lean subjects. First, obese subjects are more sensitive to the presence of acid in the oesophagus. Second, hiatal hernia, capable of promoting GERD by several mechanisms, is more prevalent among the obese. Third, obese subjects have increased intra-abdominal pressure that displaces the lower oesophageal sphincter and increases the gastro-oesophageal gradient. Finally, vagal abnormalities associated with obesity may cause a higher output of bile and pancreatic enzymes, which makes the refluxate more toxic to the oesophageal mucosa. The altered body composition associated with obesity affects the pharmacokinetics of drugs. There are no data regarding the efficacy of any of the drugs used for GERD treatment. The dosages of cimetidine and ranitidine should be calculated according to the patient's ideal body weight, not their actual weight. Of the operative procedures used for weight loss, Roux-en-Y gastric bypass was found to be most effective for GERD, while gastric banding was associated with a high prevalence of reflux. This review outlines the pathophysiology and the treatment of GERD in obesity with emphasis on the therapeutic considerations in this population of patients.

Body Composition↗
PubMed1999

Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies.

In this present thesis I have discussed the epidemiology and possible pathophysiological mechanisms of tension-type headache. A population-based study of 1000 subjects randomly selected from a general population, two clinical studies, and a method study of EMG recordings, were conducted. Tension-type headache was the most prevalent form of headache, with a life-time prevalence of 78% in a general adult population. Thirty percent were affected more than 14 days per year and 3% were chronically affected, i.e. had headache at least every other day. Females were more frequently affected than males, and young subjects more frequently affected than older subjects. Females were more sensitive to mechanical pressure pain and revealed more tenderness from pericranial muscles and tendon insertions than males, and young subjects were more pain-sensitive than older subjects. Significantly higher tenderness in pericranial muscles was found in subjects with tension-type headache compared to migraineurs and to subjects without any experience of headache. Tenderness increased significantly with increasing frequency of tension-type headache in both males and females, whereas no such relation was found for mechanical pain thresholds. The applied EMG methodology was fairly reliable and nonpainful, but due to intersubject variability paired studies should be preferred. Subjects with chronic tension-type headache had slightly increased EMG levels during resting conditions and decreased levels during maximal voluntary contraction compared with headache-free subjects, indicating insufficient relaxation at rest and impaired recruitment at maximal activity. In a subsequent clinical, controlled study, the effect of 30 min of sustained tooth clenching was studied. Within 24 h, 69% of patients and 17% of controls developed a tension-type headache. Shortly after clenching, tenderness was increased in the group who subsequently developed headache, whereas tenderness was stable in the group of patients who remained headache-free, indicating that tenderness might be a causative factor of the headache. Likewise, psychophysical and EMG parameters were studied in 28 patients with tension-type headache, both during and outside of a spontaneous episode of tension-type headache. It was concluded that a peripheral mechanism of tension-type headache is most likely in the episodic subform, whereas a secondary, segmental central sensitization and/or an impaired supraspinal modulation of incoming stimuli seems to be involved in subjects with chronic tension-type headache. Prolonged nociceptive stimuli from myofascial tissue may be of importance for the conversion of episodic into chronic tension-type headache. The author emphasizes that tension-type headache is a multifactorial disorder with several concurrent pathophysiological mechanisms, and that extracranial myofascial nociception may constitute only one of them. The present thesis supplements the understanding of the balance between peripheral and central components in tension-type headache, and thereby, hopefully, leads us to a better prevention and treatment of the most prevalent type of headache.

Adult↗
PubMed2000

Central sensitization in tension-type headache--possible pathophysiological mechanisms.

The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin (5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.

Central Nervous System↗
PubMed2000

Amadori-glycated albumin in diabetic nephropathy: pathophysiologic connections.

Amadori-glycated albumin in diabetic nephropathy: Pathophysiologic connections. Nonenzymatic glycation of proteins represents a major mechanism by which hyperglycemia leads to diabetic renal disease. Recent research has shown that Amadori-modified albumin, the principal glycated protein in plasma, elicits pathobiologic effects in cultured renal cells that are identical to those of high ambient glucose. When added to the incubation media of glomerular mesangial and endothelial cells, glycated albumin stimulates protein kinase C (PKC) activity, increases transforming growth factor-beta (TGF-beta) bioactivity, and induces gene overexpression and enhanced production of extracellular matrix proteins. These cellular events, whereby PKC-mediated TGF-beta activation leads to increased matrix expression, are inextricably linked, and they form the central tenets of a pathophysiologic connection between glycated proteins and diabetic nephropathy. In vivo studies further corroborate the role of glycated proteins in the pathogenesis of diabetic nephropathy. Reduction or neutralization of glycated albumin in the db/db mouse model of type 2 diabetes significantly ameliorates the proteinuria, renal insufficiency, mesangial expansion, and overexpression of matrix proteins. In human type 1 diabetes, the plasma-glycated albumin concentration is independently associated with the presence of nephropathy. Abrogating the biologic effects of increased glycated albumin has novel therapeutic potential in the management of renal complications in diabetes.

Animals↗
PubMed1999

Apheresis and the thrombotic thrombocytopenic purpura syndrome: current advances in diagnosis, pathophysiology, and management.

Endeavors to optimize the management of thrombotic thrombocytopenic purpura (TTP) syndrome and improve mortality and relapse rates are hindered by its poorly understood pathophysiology. Variability in the application of therapeutic plasma exchange (TPE), including replacement fluid strategies, desirable endpoints in the platelet count, serum lactate dehydrogenase concentration, and the use of a TPE taper, limit comparisons among published studies. The diversity of adjunctive therapies such as antiplatelet agents, steroids, and splenectomy further clouds comparisons. Recent progress in the diagnosis, pathophysiology, and management of TTP syndrome are summarized. The possible role of occult infection and newly emerging associations such as ticlopidine therapy are discussed. Advances in possible pathogenic mechanisms, the rationale for different replacement fluids including the recently licensed solvent-detergent treated plasma, and progress in the apheresis management of TTP syndrome are presented.

Blood Component Removal↗
PubMed2002

Evolving pathophysiologic models of functional gastrointestinal disorders.

In contrast to most other disorders of the digestive system, functional disorders of the gut continue to be defined by symptom criteria rather than by biological markers. At the same time, animal models of functional gastrointestinal disorders in which to test pathophysiologic hypotheses are lacking. The aim of this report is to critically review recently proposed conceptual as well as animal models of functional gastrointestinal disorders. Converging disease models have been proposed that postulate an enhanced responsiveness of neural, immune, or neuroimmune circuits in the central nervous system or in the gut to exteroceptive (psychosocial) or interoceptive (tissue irritation, inflammation, infection) perturbations of the organism's homeostasis. The enhanced responsiveness results in dysregulation of gut motility, epithelial function (immune, permeability), and visceral hypersensitivity, which in turn produce irritable bowel syndrome symptoms. These conceptual models provide plausible mechanisms for irritable bowel syndrome symptom generation and are consistent with extensive epidemiologic and pathophysiologic data. Several animal models have recently been proposed that mimic key features of these conceptual disease models. They fall into models triggered by centrally targeted stimuli (neonatal stress, post-traumatic stress disorder) or those triggered by peripherally targeted stimuli (infection, inflammation). Depending on the timing of the trigger (neonatal vs. adult), the changes induced in the animal may be permanent or transient. Future development of existing and novel models involves the use of transgenic and knockout animals, as well as the demonstration of predictive validity in terms of responsiveness to candidate drugs.

Animals↗
PubMed2001

Canine idiopathic dilated cardiomyopathy. Part II: pathophysiology and therapy.

Dilated cardiomyopathy (DCM) in dogs is characterized by ventricular and atrial enlargement, and systolic and diastolic dysfunction, with congestive heart failure (CHF) often developing at some stage. With greater understanding of the impact of neuroendocrine stimulation in heart disease, the understanding of the pathophysiology for CHF has changed considerably. It is no longer considered only to be a simple haemodynamic consequence of pump dysfunction, but is now characterized as a complex clinical syndrome with release of many neurohormones, which are believed to have impact on the progression of disease. This change in our understanding of the pathophysiology of CHF has important therapeutic implications. There are strong indications, although not yet proven, that drugs designed to influence the neuroendocrine activity, such as Angiotensin Converting Enzyme (ACE) inhibitors and beta-receptors antagonists, are efficacious as adjunct therapy of heart failure attributable to DCM in dogs. The benefits of drugs designed to influence the myocardial contractile state (positive inotropes) have not been fully evaluated. However, evidence has emerged in recent years indicating that new types of positive inotropes may be beneficial in dogs with DCM. This review focuses on the neuroendocrine aspects of DCM and their possible therapeutic implications and the place for long-term inotropic support in dogs with DCM.

Adrenergic beta-Antagonists↗
PubMed2002

Evaluation of the pathophysiology of odontogenic maxillary sinusitis using bone scintigraphy.

The inflammatory changes in the maxillary sinus mucosa and wall (mucosal and bony lesions) were evaluated to identify the pathophysiology of odontogenic maxillary sinusitis. Out of 80 patients who underwent CT, 32 patients were examined using single photon emission computerized tomography (SPECT) bone scintigraphy (bone SPECT) with 99mTc-hydroxymethylene-diphosphonate. Mucosal and bony lesions were evaluated morphologically on both images. SPECT data were used to assess the bone activity by calculating the count ratios of the causative alveolar process over the cervical vertebrae. The relationships with clinical symptoms, mucosal changes around the maxillary ostium (ostial lesions), and radiolucencies around the causal teeth (periapical lesions) were assessed. Bone SPECT showing the causal site was valuable for aiding a definitive diagnosis. Mucosal lesions tended to exceed bony lesions horizontally and vertically. Bony lesions tended to extend posteriorly and then anteriorly. The vertical extent of mucosal lesions and the horizontal and vertical extent of bony lesions were correlated with the presence of facial symptoms, ostial lesions, and periapical lesions. Bone activity was significantly correlated with the horizontal and vertical extent of mucosal lesions, horizontal extent of bony lesions, and presence of infraorbital symptoms, ostial lesions, and periapical lesions. Bone activity caused by alveolitis affects the pathophysiology of this disease.

Alveolar Process↗
PubMed2002

Circulating levels of interleukin 18 reflect etiologies of heart failure: Th1/Th2 cytokine imbalance exaggerates the pathophysiology of advanced heart failure.

BACKGROUND: Proinflammatory cytokines such as tumor necrosis factor alpha play an important role in the pathophysiology of CHF. However, the mechanisms of immune activation in CHF remain unknown. Interleukin (IL)-18, a newly discovered cytokine with pleiotropic activities, is known to induce proinflammatory cytokines, chemokines, nitric oxide, and prostaglandins. METHODS AND RESULTS: We studied 86 patients with New York Heart Association functional class II-IV heart failure. Mean age was 62 years, 20 were women, and mean left ventricular ejection fraction was 34.8%. Circulating levels of IL-18 and IL-10, high-sensitivity testing for C-reactive protein, and brain natriuretic peptide levels were determined. Serum IL-18 concentrations were significantly higher in patients with NYHA class IV than in patients with classes II and III (P <.001). The serum level of IL-18 and the ratio of IL-18 to IL-10 were greater in patients with ischemic cardiomyopathy than in those with dilated cardiomyopathy. CONCLUSIONS: Th1/Th2 cytokine imbalance exists in patients with advanced CHF according to various etiologies of CHF. The findings suggest an important role for IL-18 in the pathophysiology of CHF and provide a direction for more specific immunomodulating therapy.

Cytokines↗
PubMed2001

Pathophysiology of acute lung injury.

The acute respiratory distress syndrome (ARDS) is a life-threatening syndrome that may occur in any patient without any predisposition and that is mostly triggered by underlying processes such as sepsis, pneumonia, trauma, multiple transfusions, and pancreatitis. ARDS is defined by (1) acute onset, (2) bilateral infiltrates in chest x-rays, (3) absence of left ventricular failure, and (4) severe arterial hypoxemia with a PaO2/FiO2 ratio less than 200 mmHg. Still, ARDS is feared (mortality 30-40%) and relatively frequent (incidence between 13.5 per 100,000 to 75 per 100,000). Acute lung injury (ALI) describes a similar, but less severe, clinical condition, with PaO2/FiO2 values between 200 and 300 mmHg. Despite ongoing and intensive scientific research in this area, the mechanisms underlying ALI/ARDS are still not completely understood, and until recently, there were no studies demonstrating any beneficial effect of a single treatment modality in ARDS. The recent report that a specific approach to ventilatory support can significantly reduce mortality in ARDS underscores the need for better understanding of the pathophysiological events occurring in this syndrome. This review therefore summarizes the current pathophysiological concepts underlying the evolution of acute hypoxemic respiratory failure and focuses on: (1) possible reasons for the development of ALI/ARDS; (2) cellular and humoral mediator responses leading to a sustained and self-perpetuating inflammation of the lung; (3) consequences with regard to fluid balance, pulmonary perfusion, ventilation, and efficiency of gas exchange; and (4) mechanisms underlying the aggravating complications commonly seen in ARDS, especially ventilator-associated lung injury, ventilator-associated pneumonia, and lung fibrosis.

Journal Article↗
PubMed2003

Pathophysiology of atherosclerotic plaque development and rupture: an overview.

Atherosclerosis is predominantly a clinically silent process, and a substantial percentage of patients are first aware of its consequences through the acute and catastrophic event of thrombosis. Extensive basic and clinical research in the 1990s revealed that plaque disruption initiates the majority of thromboses. Furthermore, recent studies indicate that inflammation plays a major role in the pathophysiology, from initiation of the atheroma to the actual thrombosis itself. Attention has now focused on morphological, mechanical, and biochemical characteristics that increase plaque vulnerability, as determination of these features may allow identification of plaques that are most likely to cause symptoms and acute events in the future. This article reviews basic pathophysiologic aspects of atherosclerotic plaque development and rupture to provide the necessary background for understanding the crucial role of inflammation in acute coronary syndromes.

Arteriosclerosis↗
PubMed2004

[Vasoactive intestinal polypeptide in the respiratory tract: physiology and pathophysiology].

Peptidergic neuromediators have gained importance in the field of respiratory physiology and pathophysiology due to the characterisation of numerous pulmonary effects in the past years. With regard to the multitude of mediators, the neuropeptide vasoactive intestinale polypeptide (VIP) plays a special role as it exerts potent anti-inflammatory and immunomodulatory effects. Neurophysiologically the peptide has been attributed to the family of the inhibitory non-adrenergic non-cholinergic (i-NANC) neuromediators of the pulmonary innervation. VIP-containing nerve fibres are localized in the airway and vascular smooth muscle layers of trachea and bronchi in the human respiratory tract. Apart from strong vasodilatory effects, the peptide also shows a high bronchodilatory potency. In a large number of respiratory diseases VIP may play a pathophysiological role. In this respect, increased levels of VIP have been demonstrated for inflammatory diseases of the upper and lower airways and the peptide may also play a role in pulmonary hypertension. Due to its fast enzymatic cleavage, VIP-based therapies have not been used in routine therapy so far. Also, the use of synthetic VIP-agonists did not lead to an improved outcome in patients with bronchial asthma if compared to classical drugs. However, recent data from animal experiments indicate potent immunomodulatory effects which suggest a future use of this mediator and its agonists in the therapy of immune diseases.

Anti-Inflammatory Agents↗
PubMed2005

[Towards a cellular pathophysiology of Meniere's disease].

BACKGROUND: A modest increase in the hydrostatic pressure within the endolymphatic space may induce an endolymphatic hydrops which in turn is typically associated with Meniere's disease. However, there is no convincing pathophysiological model that might explain, on a cellular level, how a pressure increases may cause disturbed functions of vestibular hair cells and vertigo attacks. METHODS: So far, models involve osmotic mechanisms leading to electrolyte imbalances in the endolymphatic space. Alternatively, impaired longitudinal flow in the endolymphatic space is considered important. RESULTS: Recently, a pressure-sensitive potassium current was identified and characterized in vestibular hair cells. CONCLUSIONS: This current may modify the frequency behavior of a cell and may be the "missing link" in a cellular pathophysiology of the hydrops. Ion currents in hair cells offer attractive targets for pharmacological interventions in Meniere's disease.

Calcium↗
PubMed2005

Diabetic retinopathy: a review of the aarhus approach to studies on epidemiology, computerised grading, and the pathophysiology of the disease.

Diabetic retinopathy is one of the leading causes of blindness in the western world (Munier et al 1998). The challenges for improving the visual prognosis in this disease are comprehensive, and involve a multitude of methodological approaches. Thus, ongoing research programmes are aimed at studying as diverse aspects of diabetic retinopathy as epidemiology, genetics, screening, diagnosis, treatment, and understanding of the pathophysiology of the disease. This review presents the scientific approach followed at Aarhus University Hospital in relation to three of these aspects-epidemiology, computerised grading, and elucidation of the pathophysiology of diabetic retinopathy.

Diabetic Retinopathy↗
PubMed2006

[Pathophysiological aspects of brain structural disturbances in patients with Fabry disease: literature review].

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-GAL) enzyme activity. Neutral glycosphingolipides (esp. Gb3) accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. Cerebral manifestations that might be mainly due to progressive cerebrovascular dysfunction, are one major and often life-threatening burden of the disease. We reviewed the present literature concerning brain structural alterations in FD and discuss the possibly relevant underlying pathophysiological aspects of these disturbances. Cerebrovascular events (TIA, stroke) occur in FD at a rather early age. In female FD patients who were considered to be less affected "carriers" for a long time, the prevalence of cerebrovascular events seems to be at last as high as in male patients. In structural imaging white matter lesions (WML) can be found frequently even in young FD patients. In a recent study clinically equally affected men and women with FD showed a comparable severity of WML load. Different pathophysiological aspects of cerebral angiopathy and WML development are discussed against the background of current concepts (e. g. accumulation of Gb3 in vascular endothelium with consecutive cell proliferation and luminal stenosis, acceleration of focal intravasal pressure and disturbances of vascular auto-regulation). Pathological increase of pulvinar signal in T1-weighted MRI has also been described in FD. This finding was assumed to be caused by calcification as a consequence of disturbed local circulation. To enhance our knowledge about the relevant neurobiological processes the authors propose a more sensitive and early detection of brain structural changes in FD. New brain structural MRI methods such as diffusion-tensor imaging could provide a pattern of ultrastructural changes even in young patients without visible WML. This strategy could be as well useful for quantification of possible effects of the enzyme replacement therapy on brain structural alterations in FD. Based on recent data a systematic FD-screening by measuring Gb3 in urine of young patients with cryptogenic stroke should be discussed. Basically in such cases FD should be clinically considered.

Brain↗
PubMed2006

[Physiology and pathophysiology of the respiratory system of children].

Positive pressure ventilation in children is associated with problems similar to those in the adults: development of atelectasis and barotrauma. During anesthesia atelectasis develop in up to 90% of patients, requiring the use of higher inspiratory pressure to recruit the collapsed lung regions. Especially in the preterm, newborn and younger infants, prolonged ventilation disturbs the anatomical structure of the soft and vulnerable immature airways and their subsequent growth and development, leading to tracheomegaly, tracheal collapse, and bronchopulmonary dysplasia and predisposing to bronchial obstruction. On the basis of pathophysiologic knowledge and studies of ventilation in children, protective modes of ventilation have evolved. They allow to reopen atelectatic lung regions without overdistension. Through solid knowledge of the underlying pediatric physiology and pathophysiology, the required ventilation management can be optimally adjusted to the young patients in order to achieve the best long-term outcomes.

Anesthesia↗
PubMed1980

A proposed comprehensive pathophysiology of thrombotic thrombocytopenic purpura with implicit novel tests and therapies.

The first detailed comprehensive hypothesis for the pathophysiology of TTP is proposed which accounts for all of the features of TTP at several levels of reference: clinical, physiologic, biochemical, hematologic, and tissue pathology. From the proposed pathophysiology, by deduction, a number of novel diagnostic tests and several rational, promising therapeutic modalities.

Blood Transfusion↗