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PubMed1994

Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern.

Adequate tumour models are a prerequisite in experimental cancer research. The purpose of the present work was to establish and assess the validity of four new orthotopic human melanoma xenograft model systems (A-07, D-12, R-18, U-25). Permanent cell lines were established in monolayer culture from subcutaneous metastases of four different melanoma patients by using an in vivo-in vitro procedure, and cells from these lines were inoculated intradermally in Balb/c nu/nu mice to form tumours. Individual xenografted tumours of the same line differed substantially in growth and pathophysiological parameters, probably as a consequence of differences between inoculation sites in host factors which influence tumour angiogenesis. Nevertheless, xenografted tumours of different lines showed distinctly different biological characteristics. Several biological characteristics of the donor patients' tumours were retained in the xenografted tumours, including angiogenic potential; growth, histopathological and pathophysiological parameters; and sensitivity to radiation, heat and dacarbazine treatment. Moreover, the organ-specific metastatic pattern of the xenografted tumours reflected the pattern of distant metastases in the donor patients. The organs of preference for distant metastases were lungs (A-07, D-12), lymph nodes (R-18) and brain (U-25). R-18 lymph node metastases and U-25 brain metastases developed in the absence of lung involvement. The four orthotopic human melanoma xenograft model systems show great promise for future studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern.

Adult↗
PubMed2006

Pathophysiologically based treatment interventions in schizophrenia.

Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex, are a major determinant of functional outcome in schizophrenia. Here we consider the contributions of disturbances in glutamate, dopamine and GABA neurotransmission to the pathophysiology of working memory impairments in schizophrenia, suggest a cascade of molecular events that might link these disturbances, and argue that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development.

Dopamine↗
PubMed2003

New developments in the pathophysiology of gastro-oesophageal reflux disease (GERD): implications for patient management.

The spectrum of gastro-oesophageal reflux disease (GERD) has expanded; indeed the majority of individuals with symptomatic GERD do not have erosive reflux disease (ERD); this group has been referred to as nonerosive or negative-endoscopy reflux disease (NERD). There may be important differences between NERD and ERD in terms of pathophysiology and management. Thus, NERD patients appear relatively resistant to proton pump inhibitors and may not be good surgical candidates. The clinician caring for patients with GERD must therefore be aware of the full spectrum of GERD and of the pathophysiological and therapeutic implications of NERD. Recent twin studies have revealed that genetic factors play a role in GERD and form the basis for future studies on the role of inheritance in the various manifestations of GERD. Several recent investigations have reaffirmed the primacy of acid reflux in the pathogenesis of GERD and have also provided insights into the pathophysiology of postprandial heartburn. Transient lower oesophageal sphincter relaxations and hiatal hernias have emerged as major and interacting factors in the genesis of reflux events and in the potentiation of acid exposure; the former are attracting considerable attention as a potential therapeutic target. Nocturnal acid breakthrough, which has been implicated in the failure of some patients to respond to high doses of proton pump inhibitors, appears, on further examination, to be a gastric rather than an oesophageal phenomenon, and may not be of clinical or therapeutic importance.

Esophagogastric Junction↗
PubMed1998

New model of renal warm ischaemia-reperfusion injury for comparative functional, morphological and pathophysiological studies.

BACKGROUND: Renal warm ischaemia-reperfusion injury is pertinent to vascular and transplant surgery. While established models provide functional and morphological data the authors wanted to be able to correlate this with the underlying pathophysiology at any chosen time point, thus allowing future interventional effects on reperfusion injury to be evaluated. METHODS: In a rodent model bilateral renal warm ischaemia (15-60 min) and then reperfusion (20 or 80 min) before nephrectomy allowed for analysis of early reperfusion pathophysiology. The remaining kidney provided functional data (glomerular filtration rate (GFR)) at days 2 and 7 before nephrectomy for late analysis and morphology using a new grading system. RESULTS: Acceptable survival rate (ten of 12 animals) was seen with up to 45 min of warm ischaemia. Renal function was impaired at day 2 following 30-60 min of warm ischaemia (P< 0.01) and day 7 in the 45- and 60-min groups (P < 0.05 and P < 0.01 respectively). Strong correlation existed between duration of ischaemia and GFR at day 2 (r2=0.88) and day 7 (r2=0.95). Histological damage in the cortical tubules was evident in the 45- and 60-min groups (P< 0.01). CONCLUSION: This new model allowed comparative functional, morphological and pathophysiological studies while minimizing the number of animals required. Overall 45 min of warm ischaemia gave significant, recoverable injury and is recommended for investigating renal reperfusion injury.

Animals↗
PubMed1999

Pathophysiology of venous ulcers: surgical implications, review, and update.

BACKGROUND: Ambulatory venous hypertension has long been accepted as the principal and sole factor underlying the development of venous ulcers of the leg. This concept is now being seriously challenged as other factors emerge as important in the pathophysiology of venous ulcers. OBJECTIVE: This study was undertaken in order to review and update the current thinking concerning the pathophysiology of venous ulcers of the leg. METHOD: A review of the current medical literature. RESULTS: The prevailing current thinking about the pathophysiology of venous ulcers of the leg reveals that ambulatory venous pressure is the initiating factor. Over time this causes endothelial damage by the activation of leukocytes with subsequent release of proteolytic enzymes along with free oxygen radicals, leading to tissue damage which over time may cause ulceration. CONCLUSIONS: The production of venous ulcers of the leg is more complex than what was first thought. Although it is most likely that inflammatory factors are involved in its production, the cascade of inflammatory events postulated to occur need further investigation and clarification.

Female↗
PubMed2003

Brain tumor and seizures: pathophysiology and its implications for treatment revisited.

Seizures affect approximately 50% of patients with primary and metastatic brain tumors. Partial seizures have the highest incidence, followed by secondarily generalized, depending on histologic subtype, location, and tumor extent. The underlying pathophysiologic mechanisms of tumor-associated seizures are poorly understood and include theories of altered peritumoral amino acids, regional metabolism, pH, neuronal or glial enzyme and protein expression, as well as immunologic activity. An involvement of changed distribution and function of N-methyl-d-aspartate subclass of glutamate receptors also has been suggested. The often unpredictable responses to seizures after surgical tumor removal add substantial evidence that multiple factors are involved. The therapy of tumor-related seizures is far from perfect. Several factors contribute to these treatment difficulties, such as tumor growth and drug interactions; however, one of the main reasons for poor seizure control may result from the insufficient or even absent influence of the currently available antiepileptic drugs (AEDs) on most of the pathophysiologic mechanisms of tumor-related seizures. Studies are needed to elucidate more clearly the pathophysiologic mechanisms of tumor-related seizures and to identify and develop the optimal AEDs.

Animals↗
PubMedDate not supplied

The clinical evaluations of pathophysiology for congenital middle ear cholesteatoma.

PURPOSE: Congenital middle ear cholesteatoma (CMEC) is less common than the acquired variety. Many theories have been put forward to explain the pathophysiology of CMEC; however, none of them have been convincingly proven thus far. This clinical study was performed to analyze the case reviews; assess the characteristic features of CMEC, and evaluate the correlation between those features and the pathophysiology of CMEC. METHODS: The medical records of patients who underwent otologic procedures at the hospitals of the Catholic University, Seoul, Korea, from January 1993 to November 1998 have been reviewed. RESULTS: Of the 14 patients, 3 had cystic lesions isolated to the anterosuperior quadrant of the mesotympanum. The lesions were easy to remove and did not affect the patients' hearing. Eleven patients had more extensive disease with posterior mesotympanum involvement; the lesions were large, were often too extensive to indicate a formative site, and caused ossicular damage. CONCLUSION: CMEC manifests in 2 distinctive forms according to the formation site. This distinctive formation site suggests that the pathophysiology of posterior lesions may be different from that of anterior ones. For early diagnosis of CMEC, a screening program should be established for children to prevent more extensive disease.

Adolescent↗
PubMed2002

[Sudeck's atrophy: pathophysiology and treatment of a complex pain syndrome].

UNLABELLED: Sudeck's atrophy: pathophysiology and treatment of a complex pain syndrome. SUMMARY: The "Morbus Sudeck" or Complex Regional Pain Syndrome (CRPS) forms a typical triad of motor, sensory and autonomic symptoms. It is clinically characterized by spontaneous pain and hyperalgesia not limited to a single nerve territory and disproportionate to the inciting event. An underlying pathophysiology which could explain the whole symptomatology of CRPS is still unknown. Therefore, nowadays therapy is still symptomatic. However, recent research led to a better understanding of the disease and to the beginning of a pathophysiologically orientated therapy.

Afferent Pathways↗
PubMed2004

[Stroke MRI: pathophysiology, potential and perspectives].

Magnetic resonance imaging (MRI) is increasingly utilized as the primary imaging modality in major stroke centers. The ability to depict several aspects of individual pathophysiology makes the use of MRI in stroke both attractive and complex. Profound knowledge of the pathophysiology of the imaging findings is crucial for a rational diagnostic workup. The pathophysiology of MRI in stroke will be reviewed considering recent experiences in clinical application, and the potential of stroke MRI will be assessed. Further perspectives like application of "blood oxygen level dependent" (BOLD) and the use of multiparametric prediction maps will be discussed.

Acute Disease↗
PubMed2006

Pathophysiology of migraine.

The cause and pathophysiology of migraine are not well understood. Over the years research into migraine pathophysiology has focused on the physiology and pharmacology of the headache, the changes in cerebral cortex associated with the symptoms of the aura, and more recently the genetics underlying the migraine syndromes. In this discussion, the neuroanatomical structures activated during migraine attacks, the traditional theories of migraine that serve as the foundation for current research, and the essential findings from current migraine pathophysiological research will be reviewed. Investigations in migraine can be divided into those related to the brain events initiating a migraine attack, those examining the mechanisms of activation and transmission within trigeminal afferent neurons, and those focused on the effect of and the modulation of nociception trigeminal input within the central nervous system.

Blood Vessels↗
PubMed1984

Quantitative investigation of hepatic genomic response to hormonal and pathophysiological stimuli by multivariate analysis of two-dimensional mRNA activity profiles.

We have applied techniques of multivariate analysis to the characterization and comparison of the effects of various pathophysiological and hormonal stimuli on the expression of the rat hepatic genome at a pretranslational level. In vitro translated products were resolved by two-dimensional gel electrophoresis. We analyzed 10 pathophysiological states brought about by variation in thyroidal status, starvation, administration of high carbohydrate diet, and the production of experimentally induced diabetes mellitus. Each state differed significantly from every other state in the two-dimensional electrophoretic profiles. The set consisting of the minimal number of products necessary for maintaining the distinctive patterns was identified. The analysis also defined those clusters of products that behaved in a coordinate fashion in response to the various stimuli. Lastly, the similarity and dissimilarity of hepatic mRNA activity profiles to each other could be geometrically represented in three-dimensional space. Our finding that the hepatic mRNA activity profile could distinguish reliably between closely related hormonal and pathophysiological stimuli indicates the specificity of hepatic genomic expression. A systematic analysis of such profiles may be useful as an overall index of the biologic response at the hepatocellular level.

Animals↗
PubMed1987

Treatment of congestive heart failure. Pathophysiologic and pharmacologic concepts.

Congestive heart failure is a serious health problem in Western society. Understanding of both the basic pathophysiology and the design of rational and effective treatment of this syndrome has increased dramatically in the last ten years. However, congestive heart failure remains a highly lethal disease, which kills at a rate exceeding that of most cancers. Prevention is therefore of the utmost importance and has to come primarily from a reduction in the incidence and damage done from myocardial infarction. Improved understanding of the pathophysiology of idiopathic dilated cardiomyopathy is also needed. Through understanding of pathophysiologic principles, effective therapy based on interference with known mechanisms that are operative in the disease is now available but can be refined in the future.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Pathophysiological characteristics of long- and short-segment Barrett's oesophagus.

BACKGROUND: Depending on the length of the segment of columnar epithelium in the distal oesophagus, Barrett's oesophagus can be divided into long-segment and short-segment Barrett's oesophagus. This article describes the pathophysiological characteristics of both forms of Barrett's oesophagus. METHODS: Review of the literature. RESULTS: Although there is some disagreement, ours and most other studies suggest that long-segment columnar-lined oesophagus is causally linked to chronic gastro-oesophageal reflux and that this from of Barrett's oesophagus is characterized by lower oesophageal sphincter tone, reduced oesophageal contractility and increased acid reflux. Short-segment Barrett's oesophagus is also associated with acid reflux, but the degree of oesophageal acid exposure and the level of other pathophysiological alterations seem to be lower. CONCLUSION: Pathophysiological abnormalities appear to be more prominent in long-segment Barrett's oesophagus than in short-segment Barrett's oesophagus.

Barrett Esophagus↗
PubMed2000

The effects of chronic nitric oxide synthase suppression on glioma pathophysiology.

Nitric oxide synthase (NOS) is strongly expressed in glioma and has an important role in tumour blood flow (TBF) regulation. Whether manipulation of NOS function within a tumour can have any therapeutic effect is unknown. This study therefore evaluated the pathophysiological effects of chronic systemic NOS inhibition on experimental rodent glioma blood flow, growth and necrosis. To determine the duration and pathophysiological effects of systemic NOS inhibition, Ng-nitro-L-arginine methyl ester (L-NAME) was given to rats bearing C6 glioma acutely (single dose i.v., 30 mg kg) or for either 4 or 7 days (i.p. 75 mg kg day) prior to study. TBF and local cerebral blood flow (LCBF) were measured using C14-iodoantipyrine quantitative autoradiography. Tumour volume, tumoural necrosis and tumoural NOS were measured using conventional neuropathology and immunocytochemistry. Acute and 4-day L-NAME administration produced significant TBF reductions (-48 and -39%, respectively) with less marked changes in LCBF (-35 and -15%, respectively). Seven-day L-NAME administration reduced tumour volume (p = 0.12), increased tumoural necrosis (p < 0.05), but immunohistochemistry showed no difference in tumoural NOS expression. These results confirm that NOS has a significant role in the pathophysiology of experimental glioma, and that in this glioma model the effects of chronic systemic NOS inhibition are, for the period under study, predominately anti-tumoural. Whether chronic NOS inhibition is useful as an adjunct in glioma therapy or provides the opportunity for novel therapeutic approaches requires further study.

Animals↗
PubMed2002

Wound pathophysiology, infection and therapeutic options.

Wound healing is a complex and highly regulated process that can be compromised by both endogenous factors (pathophysiological) and exogenous factors (micro-organisms). Microbial colonisation of both acute and chronic wounds is inevitable, and in most situations endogenous bacteria predominate, many of which are potentially pathogenic in the wound environment. The risk of wound infection increases as local conditions favour bacterial growth rather than host defence. Consequently a primary objective in wound management is to redress the host-bacterial balance, and this is most effectively achieved by ensuring that the wound is cleared of devitalised tissue and foreign bodies, the bacterial load and inflammation are controlled, and that adequate tissue perfusion is maintained. Although surgical debridement is the most rapid and effective technique for removing devitalised tissue, topical enzymes, moisture-retentive dressings, biosurgical therapy and vacuum therapy have been used as alternative approaches to wound cleansing and preparation. Topical antimicrobial agents continue to be used widely for preventing wound infection and current interest is focused on alternatives to antibiotics, such as antimicrobial moisture-retentive dressings, honey, essential oils and cationic peptides. In addition to the need to control wound microflora, unregulated inflammation caused by both micro-organisms and underlying abnormal pathophysiological conditions is a major factor associated with poor healing in chronic wounds. Consequently, therapeutic strategies that target chronic inflammatory processes are critical to wound progression. The success of future therapies will be dependent on a growing understanding of the pathophysiological processes and the host-bacterial interactions that significantly influence wound healing.

Acute Disease↗
PubMed1999

Endogenous nitric oxide synthesis: biological functions and pathophysiology.

Modern molecular biology has revealed vast numbers of large and complex proteins and genes that regulate body function. By contrast, discoveries over the past ten years indicate that crucial features of neuronal communication, blood vessel modulation and immune response are mediated by a remarkably simple chemical, nitric oxide (NO). Endogenous NO is generated from arginine by a family of three distinct calmodulin- dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOS use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline. The highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions NO functions as a major non-adrenergic non-cholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital and respiratory tracts. Dysregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions including migraine headache, hypertrophic pyloric stenosis and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy. NO signalling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signalling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, and this affords long-lasting changes in tissue NO levels. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form an even more potent oxidant, peroxynitrite. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Animals↗
PubMed2004

Pathophysiologic role of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure.

PURPOSE: The pathophysiology of heart failure is reviewed, with particular focus on the role of abnormal neurohormonal activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis in the pathophysiology of this syndrome. SUMMARY: Events preceding myocardial infarction and heart failure are driven in part by norepinephrine, angiotensin II, and aldosterone. The sympathetic nervous system likely evolved to mediate acute regulation of the cardiovascular system, not the sustained activation that is seen in heart failure. Overexpression of beta1-receptors in animal models results in decreased left ventricular ejection fraction and ventricular remodeling. In patients with systolic dysfunction, beta-blockade has improved left ventricular function and decreased the risk of sudden death. Chronic exposure to excess angiotensin II produces eccentric ventricular hypertrophy, vasoconstriction, and sodium retention. Angiotensin-converting enzyme (ACE) inhibition causes only a transient depression of aldosterone concentrations; the chronic benefit from ACE inhibition in patients with heart failure likely results from augmentation of bradykinin and not from the inhibition of angiotensin II production. Administration of eplerenone, a selective mineralocorticoid receptor antagonist, following induction of ischemic injury in animals, blocked the progressive ventricular dilatation and reduction in systolic function observed in control animals; clinical studies indicate that those findings can be translated to human cardiovascular disease. Overactivity of the mineralocorticoid receptor in cardiomyocytes could be important even in the absence of excessive levels of aldosterone. Clinical studies demonstrated that strategies of neurohormonal blockade using an ACE inhibitor, angiotensin II receptor antagonist, and beta-blocker are ineffective in reducing circulating aldosterone in patients with heart failure caused by left ventricular systolic dysfunction. CONCLUSION: Aldosterone is a key deleterious hormone influencing all forms of cardiovascular disease, including hypertension, myocardial infarction, and heart failure. Treatment of many cardiovascular diseases should include specific antagonism of the adverse pathophysiologic consequences of aldosterone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Pathophysiological mechanisms of oropharyngeal dysphagia in amyotrophic lateral sclerosis.

We investigated the pathophysiological mechanisms of dysphagia in amyotrophic lateral sclerosis. Forty-three patients with sporadic amyotrophic lateral sclerosis were examined by clinical and electrophysiological methods that objectively measured the oropharyngeal phase of voluntarily initiated swallowing, and these results were compared with those obtained from 50 age-matched control subjects. Laryngeal movements were detected by a piezoelectric sensor and EMG of submental muscles, and needle EMG of the cricopharyngeal muscle of the upper oesophageal sphincter of both the amyotrophic lateral sclerosis and control groups was recorded during swallowing. Amyotrophic lateral sclerosis patients with dysphagia displayed the following abnormal findings. (i) Submental muscle activity of the laryngeal elevators, which produce reflex upward deflection of the larynx during wet swallowing, was significantly prolonged whereas the laryngeal relocation time of the swallowing reflex remained within normal limits. (ii) The cricopharyngeal sphincter muscle EMG demonstrated severe abnormalities during voluntarily initiated swallows. The opening of the sphincter was delayed and/or the closure occurred prematurely, the total duration of opening was shortened and, at times, unexpected motor unit bursts appeared during this period. (iii) During voluntarily initiated swallows there was significant lack of co-ordination between the laryngeal elevator muscles and the cricopharyngeal sphincter muscle. These results point to two pathophysiological mechanisms that operate to cause dysphagia in amyotrophic lateral sclerosis patients. (i) The triggering of the swallowing reflex for the voluntarily initiated swallow is delayed and eventually abolished, whereas the spontaneous reflexive swallows are preserved until the preterminal stage of amyotrophic lateral sclerosis. (ii) The cricopharyngeal sphincter muscle of the upper oesophageal sphincter becomes hyper-reflexic and hypertonic. As a result, the laryngeal protective system and the bolus transport system of deglutition lose their co-ordination during voluntarily initiated swallowing. We conclude that these pathophysiological changes are related mainly to the progressive degeneration of the excitatory and inhibitory corticobulbar pyramidal fibres.

Adult↗