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PubMedDate not supplied

The pathophysiology of osteoporotic vertebral fractures.

Osteoporosis is an increasingly prevalent chronic metabolic bone disease, characterized by low bone mass that subsequently leads to bone fractures. Vertebral fractures are the most common and the most debilitating of osteoporotic fractures. People with osteoporotic vertebral fractures present a unique challenge to rehabilitation nurses. A better understanding of the complex pathophysiological processes that contribute to this disability will help nurses provide more comprehensive care and education to this growing segment of the population. This article presents an overview of normal physiology and a discussion of the pathophysiological changes that occur in the skeletal, endocrine, and neurological systems throughout the development of osteoporotic vertebral fractures.

Aged↗
PubMed2000

Cytokines associated with the pathophysiology of aggressive fibromatosis.

The rare benign extra-abdominal desmoid tumor is characterized by aggressive invasion of normal tissue. Treatment is complicated by its recurrence, invasiveness, and persistence. The etiology is unknown and the pathophysiology is obscure. Because of exuberant fibroblastic proliferation with collagenous tissue being the primary tissue component, this desmoid tumor has been compared with keloids arising from excessive scar formation in healing wounds. Numerous cytokines are associated with signaling for growth and maintenance of mesenchymal cells. Altered expression of these proteins is associated with many pathologic conditions. It has been proposed that the enhanced expression of platelet-derived growth factor and its receptor characterize desmoid tumors. We tested the hypothesis that the exuberant fibrosis of desmoid tumors may have resulted from the initiation of the cascade of molecular events producing increased expression of cytokines. We used immunohistochemical analysis of cytokines in desmoid tumors compared with keloids and skin to localize the expression of cytokines. The results showed localized increased expression of the cytokines epidermal growth factor, transforming growth factor-beta, tumor necrosis factor-alpha, vascular endothelial growth factor, interleukin-1beta, and interleukin-6 in the endothelial cells of blood vessels in the tumors. Production of tumor necrosis factor-alpha and interleukin-1beta in tumor tissue was increased, but we did not find increased expression of platelet-derived growth factor. We concluded that the increased expression of cytokines associated with angiogenesis usually found in wound healing and invasive tumors may contribute to the pathophysiology of the desmoid tumor.

Adolescent↗
PubMed2006

Pathophysiological advantages of rinsing-suction-reaming (RSR) in a pig model for intramedullary nailing.

Although reamed intramedullary nailing has been one of the greatest advances in modern fracture care, the concomitant increase in medullary cavity pressure leads to intravasation of bone marrow content into the blood stream, an effect that can evoke serious systemic reactions. A newly developed rinsing-suction-reamer (RSR) was able to substantially reduce the pressure and bone marrow intravasation content during experimental femoral nailing. We investigated the pathophysiological effects using the RSR, testing the hypothesis that by reducing marrow fat embolization, RSR would also reduce the activation of coagulation compared with the universal AO-Reamer (AOR) and comparable to external fixation. Twenty-two pigs were treated with either simulated external fixation or reamed femoral nailing using AOR or RSR. During surgery, the intramedullary pressure was measured and intravasation of medullary material was quantified. After surgery, the pigs were kept anaesthetised and monitored for 6 h. At defined intervals, serological, hematological, and hemodynamic parameters were evaluated. The RSR was significantly superior when compared to AOR with regard to the generation of intramedullary pressure and fat embolization; however, with external fixation the values were even lower. The evaluation of other parameters revealed no clear differences between the two reamers and the external fixator. The pig model showed that RSR led to a significant reduction of the intramedullary increase in pressure and fat intravasation compared to AOR. Although the reduction of fat embolism by RSR is not associated with pathophysiological changes, RSR can have advantages for the treatment of femoral fractures.

Animals↗
PubMed1990

A hypothesis on the pathophysiological mechanisms that underlie levodopa- or dopamine agonist-induced dyskinesia in Parkinson's disease: implications for future strategies in treatment.

Long-term treatment of human Parkinson's disease with levodopa or dopamine agonists is often complicated by the appearance of abnormal involuntary movements (dyskinesias) that are extremely difficult to control. Little is known of the cause, pathophysiological mechanisms, or possible strategies for amelioration of this manifestation of dyskinesia. A hypothesis is set forth on the neural mechanisms that mediate levodopa- or dopamine agonist-induced dyskinesia (in particular chorea) as a side effect of the treatment of parkinsonism. Evidence is drawn from both clinical observations and experimental studies in a spectrum of movement disorders ranging from ballism through chorea to parkinsonism. It is proposed that (a) All forms of chorea, whatever their origin, share a common underlying neural mechanism. (b) Disordered activity of the subthalamic nucleus is central to the generation of choreic movements. In levodopa- or dopamine agonist-induced dyskinesia, (c) The site of action of dopaminergic agents in causing chorea is the putamen. (d) The specific pathophysiological state conducive to the appearance of chorea is brought about by the long-term exposure of the dopamine-depleted (parkinsonian) putamen to exogenous dopaminergic agents. (e) Long-term exposure to dopaminergic agents causes (either directly or indirectly) preferential inhibition of the subpopulation of putaminal neurones that project specifically to the lateral segment of the globus pallidus. This causes disinhibition of lateral pallidal neurones, which become overactive and physiologically inhibit the subthalamic nucleus. (f) The hypothesis suggests a number of possible strategies that might be useful for the alleviation of levodopa-induced dyskinesia.

Brain↗
PubMed2004

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation.

Animals↗
PubMed1990

Resealed fiber segments for the study of the pathophysiology of human skeletal muscle.

The usefulness of long fiber segments for the study of the pathophysiology of human skeletal muscle was evaluated. Immediately after biopsy, the fiber segments were depolarized. Within 3 hours the cut ends resealed, and if the segments were greater than or equal to 2.5 cm long they regained normal resting membrane potentials (i.e., negative to -80 mV). Miniature endplate potentials, endplate potentials, action potentials, the current-voltage relationship, and the resting intracellular Ca2+ concentration of the resealed fiber segments were similar to those in fibers that were intact from tendon to tendon. In addition, specific properties of intact fibers obtained from patients with various neuromuscular diseases were preserved in the resealed fiber segments prepared from the same patients or patients with the same diseases. These segments are easily obtained as a routine muscle biopsy performed under local anesthesia; they provide valuable preparations for the study of the pathophysiology of human skeletal muscle as well as for in vitro pharmacological tests.

Action Potentials↗
PubMed2004

Sonographic findings in acute urinary retention secondary to retroverted gravid uterus: pathophysiology and preventive measures.

OBJECTIVES: To explore the pathophysiology of acute urinary retention in women with a retroverted gravid uterus and to suggest measures to prevent its recurrence. METHODS: In five women with a retroverted gravid uterus and acute urinary retention necessitating catheterization, the morphology of the genitourinary system was assessed by using transabdominal, transvaginal and introital sonography. RESULTS: In the supine resting position, the cervix was displaced superiorly and anteriorly by the impacted and retroverted uterus so that it compressed the lower bladder, leading to obstruction of the internal urethral orifice. The upper bladder extended superiorly and overlay the uterus. During straining, urethral motion was not limited and there was an average rotational angle of the bladder neck of 32 degrees, ranging from 21 degrees to 44 degrees. Increasing abdominal pressure further compressed the lower bladder. Measures suggested to the women for the prevention of urinary retention included limiting fluid intake before sleep, changing from the supine to the prone position before getting up and avoiding a Valsalva maneuver but performing a Credé maneuver during voiding. In all except one case these measures successfully prevented recurrence. CONCLUSIONS: Acute urinary retention secondary to a retroverted gravid uterus is caused by a displaced cervix compressing the lower bladder and interfering with drainage to the urethra. The urethra itself is not compressed or distorted. Understanding the pathophysiology of the lower urinary tract may allow maneuvers which prevent acute urinary retention.

Acute Disease↗
PubMed1998

Pathophysiological appraisal of a rat model of total hepatic ischemia with an extracorporeal portosystemic shunt.

BACKGROUND: Animal models of total hepatic ischemia (THI) and reperfusion injury are restricted by concomitant splanchnic congestion. This study was performed to determine the requirement suitable for an extracorporeal portosystemic shunt (PSS) to maintain the intestinal integrity in a rat model of THI. MATERIALS AND METHODS: Using a polyethylene tube (0.86 or 1 mm i.d.), PSS was placed between the mesenteric and jugular veins. Comparison was done between THI models with or without PSS and a partial ischemia model with hepatectomy of the nonischemic lobes. Well-tolerated hepatic ischemic period, portal pressure after 10 min of hepatic ischemia, portal endotoxin levels at 1 h after reperfusion, histological features of the small bowel just before reperfusion, and local jejunal and ileal blood hemoglobin oxygen saturation index (ISO2) were compared among the models. RESULTS: Animals without PSS poorly tolerated 30 min of THI. Animals receiving THI with PSS or partial hepatic ischemia tolerated a longer ischemic period (60 min) with a significantly higher small bowel ISO2, lower portal pressure and endotoxin levels (P < 0.01), and less histological damage of the small bowel when compared to those receiving THI without PSS. Portal endotoxin levels after THI with PSS using a 1-mm i.d. tube as well as partial hepatic ischemia were significantly lower than those after THI with PSS using a 0.86-mm i.d. tube. CONCLUSIONS: THI with PSS using a 1-mm i.d. tube was strikingly similar to partial hepatic ischemia in the pathophysiological profile during hepatic ischemia. PSS with a tube 1 mm or more in inner diameter offers pathophysiological advantages in experiments on THI and reperfusion.

Animals↗
PubMed1993

Pathophysiological characteristics of cutaneous microcirculation in patients with liver cirrhosis: relationships to cardiovascular hemodynamics and plasma neurohormonal factors.

To elucidate pathophysiological characteristics of the peripheral circulation in liver cirrhosis, cutaneous microcirculation was analyzed at the finger, palm, toe, and arch of the foot using laser Doppler spectroscopy in 19 patients with liver cirrhosis, and the results were correlated with cardiovascular hemodynamics (n = 10) and plasma neurohormonal factors (n = 8). Cutaneous blood flow at each area was all significantly reduced (P < 0.001, < 0.05, < 0.01, < 0.001, respectively) in patients with liver cirrhosis compared to those in normals (n = 20). Cutaneous blood mass was also significantly reduced (P < 0.05, < 0.01, < 0.001, respectively) except at the arch of foot in patients with liver cirrhosis. There were significant correlations between finger cutaneous blood flow and systemic vascular resistance (r = -0.73, P < 0.05), plasma norepinephrine level (r = -0.84, P < 0.01), plasma renin activity (r = -0.77, P < 0.01), plasma concentrations of aldosterone (r = -0.76, P < 0.05) and angiotensin II (r = -0.76, P < 0.05), between palm blood flow and plasma vasoactive intestinal polypeptide concentration (r = 0.83, P < 0.05). From these results and our previous data demonstrating increased forearm muscular blood flow in patients with liver cirrhosis, increases in arteriovenous anastomotic flow and the contribution of neurohormonal factors will represent pathophysiological mechanisms for these changes.

Adult↗
PubMed2002

Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABA(A) receptor-mediated chloride currents with an EC(50) of 167 microM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC(50) of 15.1 microM. Furthermore, GAA acted as a partial agonist at heterologously expressed GABA(A) but not GABA(B) receptors. The interaction of GAA with neuronal GABA(A) receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.

Animals↗
PubMed2000

Hypoxia, HIF-1, and the pathophysiology of common human diseases.

Hypoxia plays a fundamental role in the pathophysiology of common causes of mortality, including ischemic heart disease, stroke, cancer, chronic lung disease, and congestive heart failure. In these disease states, hypoxia induces changes in gene expression in target organs that either fail to result in adequate adaptation or directly contribute to disease pathogenesis. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that is expressed in response to cellular hypoxia and mediates multiple cellular and systemic homeostatic responses to hypoxia. Recent studies have provided evidence that important pathophysiological responses to hypoxia in pulmonary hypertension, myocardial ischemia, and cancer are mediated by HIF-1. Pharmacologic and gene therapy strategies designed to modulate HIF-1 activity may represent a novel and effective therapeutic approach to these common disorders.

Animals↗
PubMed2005

Microdialysis in traumatic brain injury--methodology and pathophysiology.

The application of clinical microdialysis to monitor changes in cerebral extracellular chemistry is now well established in several neurosurgical units worldwide. In neuro-intensive care the technique has been predominantly applied to patients with traumatic brain injury and subarachnoid haemorrhage. There is no doubt that microdialysis has increased and continues to increase our understanding of the pathophysiology of these conditions. Current studies are addressing the potential role of microdialysis as a clinical monitoring technique assisting in the management of patients on an intention to treat basis. This involves establishing the relationship between microdialysis and outcome, and the effect of therapeutic manoeuvres on the chemistry. This manuscript describes the place of microdialysis in traumatic brain injury in terms of the fundamental principles, methodology, pathophysiology and clinical application.

Biomarkers↗
PubMed1999

High altitude cerebral edema and acute mountain sickness. A pathophysiology update.

The diagnosis, treatment and prevention of high altitude cerebral edema (HACE) are fairly well established. The major unresolved issues are 1) the pathophysiology, 2) the individual susceptibility, and 3) the relationship of HACE to acute mountain sickness (AMS) and to high altitude pulmonary edema (HAPE). In the context of the two types of cerebral edema, cytotoxic (intracellular) and vasogenic, a leaking of proteins and water through the blood-brain barrier (BBB), a recent MRI study in persons ill with HACE (16) suggested a predominantly vasogenic mechanism. Causes of increased BBB permeability might include mechanical factors (loss of autoregulation and increased capillary pressure), ischemia, neurogenic influences (adrenergic and cholinergic activation), and a host of permeability mediators. Once vasogenic edema develops, cytotoxic edema generally follows, and although likely in HACE, this is still unproven. Symptoms of HACE are related to increased intracranial pressure (ICP), and death is from brain herniation. Treatment is directed both to lowering ICP by reducing the volume of intracranial contents, and to stopping the vasogenic leak. Evidence is accumulating that established moderate to severe AMS is due to cerebral edema, but whether this is true for early AMS (headache) is unclear. New work suggests that the brain swells on ascent to altitude, but that this is unrelated to AMS. Preliminary data showing that those with less cerebrospinal fluid volume (a tighter fit of the brain in the cranium) were more likely to develop AMS supports the hypothesis of Ross that those with less ability to accommodate the increased brain volume are the ones that suffer AMS. The blood-brain barrier and intracranial hemodynamics are the two key elements in the pathophysiology of HACE and AMS.

Altitude↗
PubMed1991

Role of histamine in pathophysiology of heat stress in rats.

Role of histamine in pathophysiology of heat stress (HS) was examined using a pharmacological approach. Subjection of young animals (6-7 wks old) to HS at 38 degrees C for 4 in a B.O.D. incubator resulted in a profound increase in blood-brain barrier (BBB) permeability to Evans blue albumin (EBA) and 131I-sodium by 375% and 478% from the control values respectively. At this time period, the brain water content showed a 3.6% increase from the control. Pretreatment with histamine H2 receptor antagonist cimetidine significantly reduced the extravasation of both the tracers and thwarted the increase of brain water content as compared to the untreated group. On the other hand, pretreatment with histamine H1 antagonist mepyramine failed to reduce these parameters. On the contrary, there was a significantly higher permeation of the tracers in brain along with a greater accumulation of brain water content as compared to the untreated group. These results point out a beneficial effect of histamine H2 receptor antagonists in the pathophysiology of HS.

Animals↗
PubMed1987

The pathophysiological role of renal dopamine, kallikrein kinin and prostaglandin systems in essential hypertension.

In order to clarify the relationship and the pathophysiological role of renal dopamine, kallikrein-kinin and prostaglandin systems in essential hypertensives, the effects of dopamine on these systems and renal sodium handling were investigated. Basal levels of kallikrein, kinin and prostaglandin E2 in essential hypertensives were significantly lower than those in normotensives. Those of kallikrein and kinin were obviously more suppressed in the low renin group than in the normal renin group, but no significant difference in prostaglandin E2 was found in either subgroup. Urinary dopamine excretion was significantly lower in the low renin essential hypertensives, while no significant difference was found between normotensives and normal renin essential hypertensives. Kallikrein activity and prostaglandin E2 were significantly increased in essential hypertensives by dopamine infusion, and no significant difference was found in kallikrein-quantity and kinin between normotensives and essential hypertensives after the infusion. These increases of kallikrein and kinin were significantly higher in the low renin group than in normal renin group, but those of prostaglandin E2 were not. Urine volume, urinary sodium excretion and fractional excretions of sodium and inorganic phosphorus were all increased in both normotensives and essential hypertensives after dopamine infusion. The increases of these were significantly greater in essential hypertensives than in normotensives, and greater in the low renin group than the normal renin group. From these results, it was suggested that the dopamine, kallikrein-kinin and prostaglandin E2 system have a close relationship with each other, and the suppression of these systems may contribute to the pathophysiology of essential hypertension, especially in the low renin group.

Dinoprostone↗
PubMed2007

Conditional mouse models to study developmental and pathophysiological gene function in muscle.

This chapter will review conditional mouse model systems that have been developed to study gene function in skeletal, cardiac, and vascular smooth muscle cells in vivo with an emphasis on the utility of these models for investigating developmental and pathophysiological gene function in muscle. In general, these systems have utilized muscle-specific/selective promoter-enhancers in conjunction with site-specific DNA recombinases, e.g., Cre-loxP, and fusion proteins with these recombinases that confer temporal control, such as tamoxifen-inducible CreER systems. A major focus of this chapter will be to discuss unique challenges of studying Cre-mediated mutagenesis/gene targeting in these muscle types during development and in the adult animal, some of which are inherent of the muscle cell type being studied. For example, unlike cardiac and skeletal muscle cells, the vascular SMC is extremely plastic and able to undergo rapid phenotypic modulation to various environmental cues in vivo. Thus, employing SMC marker gene promoter enhancers for conditional gene targeting in SMCs must take into account the possibility and/or certainty that the particular SMC promoter enhancers used may or may not be transcriptionally active in SMCs of a vessel wall under normal and some pathophysiological conditions. Moreover, individual floxed loci within the same muscle cell type and tissue have different degrees of sensitivity to Cre, most likely dependent on the chromatin state of that particular gene, i.e., closed/condensed state or open/active state. Thus, Cre recombination may be ineffective for specific floxed gene DNA. Lastly, rigorous efforts must be made to confirm the degree of recombination in a tissue, taking into full account the multicellularity of the tissue, to understand the extent of the physiological effect in that organ.

Animals↗
PubMed2003

Non-invasive imaging methods for the characterization of the pathophysiology of brain ischemia.

Non-invasive imaging methods are increasingly used to study the evolution and therapy of brain diseases under both clinical and experimental conditions. In the animal experiment, these methods can be supplemented by invasive tissue assays to allow precise characterization of the underlying pathophysiology. Based on such an approach, this review evaluates the importance of in vivo nuclear magnetic resonance (NMR) and positron emission tomography (PET) for the understanding of the pathophysiology of brain ischemia.

Animals↗
PubMed1998

Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

Animals↗