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Concussion: the history of clinical and pathophysiological concepts and misconceptions.

Concussion is a well-recognized clinical entity; however, its pathophysiologic basis remains a mystery. One unresolved issue is whether concussion is associated with lesser degrees of diffuse structural change seen in severe traumatic brain injury, or is the mechanism entirely caused by reversible functional changes. This issue is clouded not only by the lack of critical data, but also by confusion in terminology, even in contemporary literature. This confusion began in ancient times when no distinction was made between the transient effects of concussion and severe traumatic brain injury. The first clear separate recognition of concussion was made by the Persian physician, Rhazes, in the 10th century. Lanfrancus subsequently expanded this concept as brain "commotion" in the 13th century, although other Renaissance physicians continued to obscure this concept. By the 18th century, a variety of hypotheses for concussion had emerged. The 19th century discovery of petechial hemorrhagic lesions in severe traumatic brain injury led to these being posited as the basis of concussion, and a similar logic was used later to suggest diffuse axonal injury was responsible. The neuropathology and pathophysiology of concussion has important implications in neurology, sports medicine, medicolegal medicine, and in the understanding of consciousness. Fresh approaches to these questions are needed and modern research tools, including functional imaging and experimental studies of ion-channel function, could help elucidate this puzzle that has evolved over the past 3,000 years.

Brain Concussion↗

Hyponatremia in the neurosurgical patient: epidemiology, pathophysiology, diagnosis, and management.

OBJECTIVE: Hyponatremia is an important and common electrolyte disorder in critically ill neurosurgical patients that has been reported in association with a number of different primary diagnoses. The correct diagnosis of the pathophysiological cause is vital because it dramatically alters the treatment approach. METHODS: We review the epidemiology and presentation of patients with hyponatremia, the pathophysiology of the disorder with respect to sodium and fluid balance, and the diagnostic procedures for determining the correct cause. RESULTS: We then present the various treatment options, including discussion of one of the newest groups of agents, the arginine vasopressin receptor antagonists, currently under study for the treatment of hyponatremia in neurosurgical patients. CONCLUSION: Hyponatremia is a serious comorbidity in neurosurgical patients that requires particular attention as its treatment varies by cause and its consequences can affect neurological outcome.

Antidiuretic Hormone Receptor Antagonists↗

Establishment and pathophysiological characterization of type 2 diabetic mouse model produced by streptozotocin and nicotinamide.

This study was performed in order to establish a mouse model that represents the non-obese type 2 diabetes reflecting a majority of diabetic patients among Asian races and to show its pathophysiological profiles. Streptozotocin (STZ) was administered to C57BL/6J mice with or without nicotinamide (120 or 240 mg/kg, STZ/NA120 or STZ/NA240), twice with an interval of 2 d, and plasma glucose concentration, body weight, water intake, insulin contents and insulin signal-related proteins were monitored. STZ-induced hyperglycemia (fasting and non-fasting), body weight loss and polyposia were significantly depressed by NA dose-dependently. In STZ/NA120 and STZ/NA240 mice, pancreatic insulin content was retained by 28 and 43% of normal control (10.5+/-0.93 microU/ml), respectively, and histological damage of pancreatic beta cells was also less severe than that observed in STZ mice. When given the calorie-controlled high fat diet, the STZ/NA mice caused hyperlipidemia, and significantly increased insulin resistance. These observations suggest that the combined administration of STZ and NA causes partial depletion of pancreatic insulin and that the high fat constituents lead to insulin resistance in this model. The present mouse model, therefore, well exhibits the recent diabetic pathophysiological characteristics of a majority of Asian patients.

Animals↗

Animal models of coronary spasm and the pathophysiological events in regional vascular hypercontraction.

An animal model of coronary spasm was designed 1) to reproduce coronary spasm similar to that seen in patients with variant angina, 2) to determine whether hypercontraction of the vascular smooth muscle occurs at the site of the spasm, 3) to document the relationship between functional and structural changes of the vascular wall and 4) to characterize the pathophysiological features of coronary spasm. After balloon de-endothelialization and feeding of a high cholesterol diet in mongrel dogs and Göttingen miniature pigs, there was evidence of vascular hypercontraction associated with arteriosclerotic changes. Coronary spasm of more than 75% narrowing of the artery was provoked with ischemic signs in miniature swine. These events could be repeatedly provoked by an intracoronary injection of histamine following pretreatment with cimetidine. The site of hypercontraction corresponded well with the site of the de-endothelialization, an area where the basal vascular tone was increased and was related to histamine activity. Thus, the present animal model will shed light on mechanism involved in vasoactive angina pectoris and aid in clarifying the pathophysiology of vascular smooth muscle.

Animals↗

Effect of ammonia on the gastric mucosa in rats: pathophysiological importance of urease in gastric ulcer disease.

We examined the pathophysiological roles of the urea-urease-ammonia system in gastric ulcer disease using rats. Exposure of the stomach to ammonia (0.01-1.0%) decreased the transmucosal potential difference (PD) and histological injury in a concentration-dependent manner. Exposure of the stomach for 20 min to urea (0.025-0.2%) together with urease (100 IU) produced a decrease in PD and microscopic injury similarly, and the lesion was closely associated with the amount of ammonia produced. Urea and urease alone had no effect on the gastric mucosa. These results suggested the pathophysiological importance of urea, urease and ammonia in gastric ulcer disease.

Ammonia↗

[Basics in the pathophysiology of sepsis].

Within the recent years preclinical and clinical investigations to a great extend increased the pathophysiological understanding what is going on in patients with severe sepsis. It became evident, that not the initiating infection by itself is the main reason for the severity and limited prognosis in sepsis. More important is the unbalanced reaction of the patient's organism to this infection, which is reflected in a mainly cytokine driven inflammation, the so called systemic inflammatory response syndrome, with its consequences. In the context of this syndrome released mediators, in part together with toxins from infectious microorganisms, result in a systemic activation of haemostasis. In the centre of our pathophysiologic model are the activations of the monocyte/macrophage-system and of the endothelium. This results in the activation of plasmatic cascades including the coagulation and fibrinolysis systems. The observed activation of haemostasis and inhibition of fibrinolysis in patients with sepsis by themselves interact with leukocytes and endothelium and play an important role in the progressive derangement of microcirculation. This is clinically reflected in organ dysfunctions. Within a single individual patient there is increased fibrin formation, decreases in coagulation factors, inhibitors and platelets, as well as defects of the fibrinolytic system in parallel that may clinically result in disseminated intravascular coagulation with the risk of bleeding complications in addition to organ dysfunctions.

Humans↗

Myelodysplastic syndromes: recent progress in diagnosis and understanding of their pathophysiology.

Myelodysplastic syndromes (MDS) are common malignant disorders with a poor prognosis. MDS are a group of highly heterogeneous disorders but show certain universal findings including a high incidence in the elderly population, cytopenia, dysplastic myeloid cells, and frequent transformation to acute myeloid leukemia. Until recently, the vast majority of MDS patients were treated with supportive therapy alone, such as transfusions. Allogeneic stem cell transplantation (SCT) has the potential for cure, although due to the age and comorbidity of MDS patients, the role of allogeneic SCT in MDS has been limited. Recently, research in MDS has shown substantial advances that have deepened our understanding of MDS pathophysiology and changed our approach to MDS patients. This review touches on some recent developments in the diagnosis and pathophysiology of MDS.

Apoptosis↗

Free and total dopamine in human plasma: effects of posture, age and some pathophysiological conditions.

Although dopamine (DA) has an important role also outside the central nervous system, the physiological significance of DA in the peripheral plasma is not clearly known. In the present study, we assayed the levels of free and total (free plus conjugated) DA in the human plasma to examine the effect of posture, age and some pathophysiological conditions. Nine healthy volunteers were subjected for head up tilt study. For the examination of the effect of age and some pathophysiological conditions, venous blood samples were taken after overnight fast in 64 control subjects who have no obvious disease and patients who had essential hypertension or congestive heart failure (CHF). The plasma free adrenaline (AD), noradrenaline (NA) and DA were determined by a HPLC-diphenylethylenediamine method and total DA was determined by the same HPLC method after acid hydrolysis. After tilting neither free nor total DA changed significantly despite the increased plasma AD and NA levels. Plasma free NA, DA and total DA levels were correlated positively with age in control subjects but not in the hypertensive nor CHF patients. Patients with CHF showed higher levels of plasma free AD, NA and DA and freeDA/totalDA ratio than did in control subjects. We suspect that plasma DA increased with age partially due to change in renal catecholamine handling and cardiac function.

Adolescent↗

Pathophysiological effects of cocaine in humans: review of scientific issues.

Almost all data on pathophysiological abnormalities associated with human cocaine use comes from clinical observation and testing of cocaine abusers seeking treatment. Such data are subject to several confounding factors which preclude drawing definitive conclusions about the pathophysiological mechanism for the observed abnormality, its prevalence and prognosis, and individual differences in susceptibility. Confounding factors include the unknown purity of cocaine used, uncertainty as to quantity and duration of cocaine exposure, effects of other substances frequently used by cocaine users, abnormalities associated with drug route of administration and the drug abuse lifestyle, and selection bias. Future studies can address these issues by employing more sophisticated research designs, such as prospective, longitudinal follow-up of large, representative samples of cocaine users, case-control comparisons of well characterized cocaine users with appropriately matched groups, and experimental administration of cocaine under safe, controlled conditions.

Catecholamines↗

Pathophysiologic characteristics of the activity-stress paradigm in animal models: inhibitory effect of glucose on these responses.

This review provides a discussion of the pathophysiologic significance of animal models of the activity-stress paradigm and the role of plasma glucose level in the appearance of physical stress responses of those models. Many research reports have demonstrated that animal models exposed to activity-stress are useful as a "symptomatic model" of anorexia nervosa and obsessive-compulsive disorder as well as peptic ulcer. Our findings show that a decrease in plasma glucose concentration is an important factor in determining the activity-stress-induced physical responses. Further investigation of the pathophysiology of activity-stressed animal models may contribute to the development of new therapeutics for diseases such as anorexia nervosa and obsessive-compulsive disorder.

Animals↗

Atherothrombosis: epidemiology, pathophysiology, and prevention.

OBJECTIVES: To review the pathophysiology of atherothrombosis (atherosclerosis with superimposed platelet-rich thrombus formation) and the measures that can be taken to prevent its clinical sequelae through lifestyle modifications and pharmacotherapy, with emphasis on the role of antiplatelet agents. DATA SOURCES: Recent (1995-2003) published scientific literature, as identified by the authors through Medline searches using the terms atherothrombosis, pathophysiology, risk factors, prevention, and reviews on treatment. STUDY SELECTION: Recent systematic English-language review articles were screened for relevant material. DATA SYNTHESIS: Atherothrombosis is a generalized and diffuse progressive process affecting multiple vascular beds; its clinical consequences, including acute coronary syndromes (unstable angina, acute myocardial infarction, and sudden cardiac death), ischemic stroke, and peripheral arterial disease, are unpredictable in their time course and potentially life-threatening. Atherothrombosis rather than arterial stenosis appears to account for most of the acute ischemic manifestations of the atherosclerotic process. Interventions that can favorably influence atherosclerotic progression include lifestyle modifications (dietary control, exercise, and smoking cessation) and pharmacotherapy (lipid-lowering, antihypertensive, antiglycemic, and antiplatelet drugs). The pivotal role played by the platelet in thrombus formation provides the rationale for employing antiplatelet drugs with complementary modes of action (e.g., aspirin, clopidogrel) to prevent atherothrombosis. CONCLUSION: Ischemic cerebrovascular, coronary, and peripheral arterial disease can be regarded as diverse manifestations of a common underlying systemic pathology, namely atherothrombosis. Secondary prevention of an ischemic event in an affected arterial bed confers the added benefit of primary prevention against potential ischemic events in other arterial beds.

Angiotensin-Converting Enzyme Inhibitors↗

Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii.

OBJECTIVE: To explain the role of mifepristone in medical abortions that results in fulminant and lethal septic shock due to Clostridium sordellii. DATA SOURCES: MEDLINE, PubMed, and Google Scholar databases were searched (1984-March 2005). Key search terms were mifepristone, RU38486, RU486, Mifeprex, medical abortion, septic shock, innate immune system, cytokines, and Clostridium sordellii. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included for the information related to the development of the understanding of the pathophysiology of mifepristone-induced septic shock due to C. sordellii. DATA SYNTHESIS: The mechanisms of action of mifepristone were incorporated into the pathophysiology of septic shock due to C. sordellii. Mifepristone, by blocking both progesterone and glucocorticoid receptors, interferes with the controlled release and functioning of cortisol and cytokines. Failure of physiologically controlled cortisol and cytokine responses results in an impaired innate immune system that results in disintegration of the body's defense system necessary to prevent the endometrial spread of C. sordellii infection. The abnormal cortisol and cytokine responses due to mifepristone coupled to the release of potent exotoxins and an endotoxin from C. sordellii are the major contributors to the rapid development of lethal septic shock. CONCLUSIONS: Theoretically, it appears that the mechanisms of mifepristone action favor the development of infection that leads to septic shock and intensifies the actions of multiple inflammatory cytokines, resulting in fulminant, lethal septic shock.

Abortifacient Agents↗

Potential pathophysiological role of endothelin-1 in asthma.

Although endothelin-1 (ET-1) was isolated originally from endothelial cells and the ETs were recognized initially for their cardiovascular actions, extensive research since the discovery of ET-1 has uncovered a spectrum of biological activities of the ETs in many systems, including the lung. Several standard criteria for a pathophysiologically relevant mediator must be fulfilled before ET-1 can be considered unequivocally to contribute to the pathogenesis of asthma. These include that: pathways for the synthesis, release and metabolism of ET-1 exist in the lung; ET receptors are located in relevant cells in the pulmonary system; ET-1 mimics several of the features of asthma; ET-1 levels are elevated in patients with asthma, with a correlation between amounts and disease severity; and drugs which inhibit the release and/or antagonize the biological effects of the ET-1 have therapeutic benefit in asthma. Several of these criteria are fulfilled by ET-1. Notwithstanding a lack of clinical data, there are several reports from preclinical studies indicating the effectiveness of ET receptor antagonists in models of asthma. Only after the results of clinical testing of selective ET receptor antagonists or ECE inhibitors in asthma are available will we know definitively whether ET-1 has fulfilled its promise as a significant player in lung pathophysiology.

Journal Article↗

Disseminated intravascular coagulation: diagnosis, treatment and related pathophysiology.

This review presents a current evaluation of disseminated intravascular coagulopathy from approaches involving clinical and differential diagnosis, pharmacological treatment, biological markers, disease effects on various organs, risk factors and related pathophysiological conditions. While the optimal regimens for treatment with blood components and the absolute indications for anticoagulant and antifibrinolytic treatments are unknown, various studies are discussed which offer promising new drugs for the present and the future. Associations between this disease and other pathophysiologies are presented which provoke new perspective and insight into disease occurrence and progression.

Journal Article↗

Pathophysiology of ovine smoke inhalation injury treated with extracorporeal membrane oxygenation.

An ovine model was used to study the pathophysiology of smoke inhalation injury treated with extracorporeal membrane oxygenation (ECMO). Smoke inhalation is characterized by leukocyte-oxygen free-radical mediated acute lung injury. Treatment with ECMO was by extracorporeal venoarterial or venovenous perfusion using a venous drainage reservoir, roller pump, heat exchanger, and membrane lung oxygenator capable of oxygen delivery to and carbon dioxide removal from a patient. Blood-foreign surface interactions are known to occur during ECMO. We examined the effects of ECMO on circulating leukocytes, oxygen free-radical activity, thromboxane release, and gas exchange after smoke inhalation injury. Animals treated with smoke and ECMO had significantly increased circulating thromboxane B2 levels and oxygen free-radical activity compared with sham-treated animals and animals treated with smoke and mechanical ventilation (MV). Likewise, there was a significant increase in lung wet-to-dry weight ratios in animals treated with smoke and ECMO compared with those treated with smoke and MV. These data may account for the initial deterioration in native lung function after the initiation of ECMO and imply that ECMO may potentiate the pathophysiology of smoke inhalation injury.

Animals↗

Alveolar-capillary membrane dysfunction in heart failure: evidence of a pathophysiologic role.

Chronic heart failure (CHF) increases the resistance to gas transfer across the alveolar-capillary interface. Recent reports highlight the pathophysiologic relevance of changes in the lung leading to impaired fluid and gas exchange in the distal airway spaces. Under experimental conditions, an acute pressure or volume overload can injure the alveolar blood-gas barrier. This may disrupt its anatomic configuration, cause the loss of regulation of fluid-flux, and thereby affect alveolar gas conductance properties. These ultrastructural changes have been identified under the term of stress failure of the alveolar-capillary membrane. In the short term, these alterations are reversible due to the reparative properties of the alveolar surface. However, when the alveolar-capillary membrane is chronically challenged, for instance in patients with CHF, by noxious stimuli, such as humoral, cytotoxic, and genetic factors other than by mechanical trauma, remodeling of pathophysiologic and clinical importance may take place. These changes in some respects resemble the remodeling process in the heart. Emerging findings support the view that, in patients with CHF, alveolar-capillary membrane dysfunction may contribute to symptom exacerbation and exercise intolerance, and may be an independent prognosticator of clinical course. Angiotensin-converting enzyme inhibitors ameliorate the alveolar membrane gas conductance abnormality, reflecting improvement in the remodeling process. This article reviews the putative mechanisms involved in the impairment in gas diffusion in CHF patients and provides a link between physiologic changes and clinical findings.

Capillary Permeability↗

Myelin-associated glycoprotein-mediated signaling in central nervous system pathophysiology.

The myelin-associated glycoprotein (MAG) is a type I membrane-spanning protein expressed exclusively in oligodendrocytes and Schwann cells. It has two generally known pathophysiological roles in the central nervous system (CNS): maintenance of myelin integrity and inhibition of CNS axonal regeneration. The subtle CNS phenotype resulting from genetic ablation of MAG expression has made mechanistic analysis of its functional role in these difficult. However, the past few years have brought some major revelations, particularly in terms of mechanisms of MAG signaling through the Nogo-66 receptor (NgR) complex. Although apparently converging through NgR, a readily noticeable fact is that the neuronal growth inhibitory effect of MAG differs from that of Nogo-66. This may result from the influence of coreceptors in the form of gangliosides or from MAG-specific neuronal receptors such as NgR2. MAG has several other neuronal binding partners, and some of these may modulate its interaction with the NgR complex or downstream signaling. This article discusses new findings in MAG-forward and -reverse signaling and its role in CNS pathophysiology.

Animals↗

[Pathophysiology in diabetes after major resection of the pancreas, with special reference to insulin metabolism and glucagon secretion (author's transl)].

Recently, major resection of the pancreas has been carrier out not only to treat pancreatic carcinoma but also for benign pancreatic diseases. Dragstedt reported that the amount of insulin required to control glycosuria after partial pancreatectomy is much greater than that needed after total pancreatectomy. Although it is thought that diabetes after partial pancreatectomy is considerably different from that after total pancreatectomy, these pathophysiological changes have not been investigated in detail. In the present experiment, changes in carbohydrate and insulin metabolism and glucagon secretion were studied in dogs in order to elucidate the pathophysiology in diabetes after major resection of the pancreas. Immediately after resection of 90% or more of the entire pancreas, diabetes occurred with absolute insulin deficiency, being accompanied by decreased function of the anti-insulin system with poor secretion of glucagon and delayed recovery of blood sugar after the insulin load. Moreover, the half-life of insulin in this group was much longer than that in normal dogs and close to that after total pancreatectomy. These results could explain that the dosage of insulin required to control blood sugar after resection of 90% or more of the entire pancreas was close to that after total pancreatectomy. Six weeks or more after resection of 70 to 90% of the entire pancreas, so-called Sandmeyer's diabetes gradually as a consequence of a decrease in insulin secretion and an increase in glucagon secretion from the remnant pancreas. After the insulin load, glucagon secretion markedly increased and recovery of blood sugar from the insulin hypoglycemia was good, showing hyperfunction of the anti-insulin system. Moreover, the half-life of insulin gradually lengthened but was still shorter than that after total pancreatectomy. These results could well explain the fact that the insulin dosage required to control blood sugar in Sandmeyer's diabetes was 3 to 4 times more than that needed after total pancreatectomy. After resection of less than 70% of the entire pancreas, diabetes did not occur throughout a period of post-operative observation of up to 66 weeks. After the insulin load, glucagon secretion and recovery rate of blood sugar from the insulin hypoglycemia were maintained well, showing normal function of the anti-insulin system, and the half-life of insulin was also within the normal range.

Animals↗