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PubMed2000

Pathophysiology and pharmacological treatment of insulin resistance.

Diabetes mellitus type 2 is a world-wide growing health problem affecting more than 150 million people at the beginning of the new millennium. It is believed that this number will double in the next 25 yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic beta-cell dysfunction, and increased endogenous glucose production. To reduce the marked increase of cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure, and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of antihyperglycemic pharmacological agents to treat insulin resistance, i.e., a-glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this highly heterogeneous and progressive disease.

Animals↗
PubMed2003

Epidemiology and pathophysiology of minor traumatic brain injury.

This review article presents evidence from the current literature on the epidemiology and pathophysiology of concussion. The recent epidemiologic data for a variety of sports are presented relevant to the general population, and professional, college, and high school athletics. The evidence for the pathophysiology of head injury is presented using a mixture of current animal and human studies. A brief discussion on the benefits and limitations of the evidence is offered for the both the epidemiology and pathophysiology of concussion, and how it relates to current treatment options.

Animals↗
PubMed1991

Physiological and pathophysiological modulation of calcium signaling in myocardial cells.

The relationship between changes in intracellular Ca2+ transients and isometric contractions has been assessed in intact cardiac muscle preparations, superficial cells of which have been microinjected with the Ca(2+)-sensitive bioluminescent protein aequorin. Regulation of myocardial contractility by physiological and pathophysiological intervention is achieved by either (1) modulation of intracellular Ca2+ mobilization, or (2) modulation of Ca2+ sensitivity of myofibrils, or both. Regulation of contractility by changes in heart rate a well established frequency-force relationship that plays an important role in the cardiac pumping function in situ is mainly achieved by mechanism (1), other mechanisms becoming involved depending on the range of frequency of stimulation. The length-dependent regulation of contractility (length-tension relationship in vitro or Frank-Starling's law, or ventricular function curve in situ) is achieved essentially by mechanism (2). Catecholamines promote mechanism (1) through activation of beta- and/or alpha-adrenoceptors, alpha-adrenoceptor stimulation being much less effective than beta-stimulation in this respect. beta-Adrenoceptor stimulation decreases, while alpha-stimulation may increase the Ca(2+)-sensitivity of contractile proteins. Subsequent to exposure of muscle preparations to Ca2+ free solution, a prominent and reversible dissociation of force of contraction from Ca2+ transients was produced when the [Ca2+]0 was gradually returned to the level of the normal Krebs-Henseleit solution [( Ca2+]0 = 2.5 mM). The aequorin-injected multicellular intact myocardial cell preparation provides an excellent experimental paradigm through which to address the physiological, pharmacological and pathophysiological modulation of E-C coupling in mammalian cardiac muscle. The subcellular mechanism involved, especially in the pathophysiological modulation of Ca2+ signaling process in myocardial cells, awaits further study.

Animals↗
PubMed2000

Anterior ocular infections: an overview of pathophysiology and treatment.

OBJECTIVE: To provide a review of the pathophysiology and treatment of anterior ocular infections. DATA SOURCE: A MEDLINE search (from 1970 to October 1998) as well as a review of the tertiary literature was performed to identify pertinent literature on pathophysiology and treatment of ocular infections. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Relevant studies were selected for discussion in the article. DATA SYNTHESIS: Ocular infections are common and vary from self-limiting to sight-threatening. Infections occur in different eye structures; presentation and treatment vary accordingly. Infections can occur when tissues of the eye are exposed to pathogens not normally present, when the eye is damaged, allowing pathogens to overcome the natural defenses of the eye, or in immunosuppressed patients where normal flora may become opportunistic. In deciding on appropriate treatment, both the causative pathogen and the structure(s) affected must be considered. The most likely pathogen can often be determined based on clinical signs and symptoms, patient history, or, in some cases, may need to be determined microbiologically. Differences in drug absorption, penetration, and availability to the various structures of the eye affect treatment decisions. Severity of infection, efficacy and safety of medication, and cost/benefit ratios must be taken into consideration in choosing the proper pharmacologic management of various ocular infections. CONCLUSIONS: Treatment of ocular infections depends on knowledge of the pathophysiology and drug disposition at the site of infection. An understanding of the current concepts surrounding the management of the anterior ocular infections presented will aid in the provision of optimal patient care.

Anterior Chamber↗
PubMed2002

Pathophysiology and first-line treatment of osteoarthritis.

OBJECTIVE: To review the pathophysiology of osteoarthritis (OA) and the various treatment modalities, focusing specifically on acetaminophen (APAP), nonsteroidal antiinflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors as the primary treatment options. DATA SOURCES: Primary literature and tertiary references were identified by a MEDLINE search (1966-March 2001) and through other secondary sources. STUDY SELECTION AND DATA EXTRACTION: After evaluating the articles and references identified from the data sources, all the information that was judged relevant by the reviewers was included in the review article. DATA SYNTHESIS: OA is the most common joint disorder worldwide. Current research suggests that factors such as inflammation and changes in subchondral bone may play a larger role in the pathophysiology than previously thought. With this research and the development of COX-2 inhibitors, selecting the medication of choice for OA has become difficult. CONCLUSIONS: More research needs to be done before the pathophysiology of OA can be clearly determined. In the meantime, treatment should be based on clinical data and patient response. Studies have shown that APAP and NSAIDs have comparable efficacy, as do traditional NSAIDs and COX-2 inhibitors. APAP is associated with fewer toxicities than are the traditional NSAIDs. Due to their mechanism of action, the new COX-2 inhibitors should result in fewer adverse effects compared with traditional NSAIDs, but evidence from clinical trials has not been conclusive. Therefore, APAP should still be considered the drug of choice for OA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk.

This is the first of 2 articles evaluating cardiac events in patients undergoing noncardiac surgery. In this article, we review the magnitude of the problem, the pathophysiology of these events, approaches to risk assessment and communication of risk. The number of patients undergoing noncardiac surgery worldwide is growing, and annually 500,000 to 900,000 of these patients experience perioperative cardiac death, nonfatal myocardial infarction (MI) or nonfatal cardiac arrest. Although the evidence is limited, a substantial proportion of fatal perioperative MIs may not share the same pathophysiology as nonoperative MIs. A clearer understanding of the pathophysiology is needed to direct future research evaluating prophylactic, acute and long-term interventions. Researchers have developed tools to facilitate the estimation of perioperative cardiac risk. Studies suggest that the Lee index is the most accurate generic perioperative cardiac risk index. The limitations of the studies evaluating the ability of noninvasive cardiac tests to predict perioperative cardiac risk reveals considerable uncertainty as to the role of these popular tests. Similarly, there is uncertainty as to the predictive accuracy of the American College of Cardiology/American Heart Association algorithm for cardiac risk assessment. Patients are likely to benefit from improved estimation and communication of cardiac risk because the majority of noncardiac surgeries are elective and accurate risk estimation is important to allow informed patient and physician decision-making.

Communication↗
PubMed1983

Pathophysiology of reversible sudden deafness--epidemiological study.

Many aspects of the etiology and pathophysiology of reversible sudden deafness remain obscure. In order to better understand the pathophysiology of reversible sudden deafness we compared the results of two therapies which have different mechanisms of action. The results of therapy with tranexamic acid alone in 49 cases (57 ears) of sudden deafness were compared with the results of treatment with so-called antisludging agents in 65 cases (69 ears) using the chi square contingency test. The same therapeutic effect was observed in both groups despite the different modes of chemical action of the two therapeutics. A series of processes involving an increase in permeability of vascular walls and related edema, and extravascular red cell oozing due to hypoxia or anoxia leading to tissue damage in the inner ear seem to be important factors in the etiology and pathophysiology of reversible sudden deafness.

Adolescent↗
PubMed2003

CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention.

The pathophysiology of overactive bladder (OAB) syndrome is complex, and involves both peripheral and CNS factors. Several CNS disorders are associated with OAB, e.g. stroke, spinal cord injury, Parkinson's disease and multiple sclerosis, and in each disorder the pathophysiology of OAB can be multifactorial. Irrespective of cause or pathophysiology of OAB, antimuscarinic drugs are the first line of pharmacological treatment. However, adverse effects and limited efficacy makes alternative therapeutic principles desirable. Most alternative drugs used for the treatment of OAB have a peripheral site of action, mainly affecting efferent or afferent neurotransmission or the detrusor muscle itself. New targets for pharmacological intervention may be found in the CNS. Several CNS transmitters/transmitter systems are known to be involved in micturition control, but few drugs with a defined CNS site of action (e.g. baclofen, imipramine and duloxetine) have been used for the treatment of voiding disorders. GABA, glutamate, opioid, serotonin, noradrenaline (norepinephrine), and dopamine receptors and mechanisms are known to influence micturition, and drugs influencing these systems could potentially be developed for the treatment of OAB. Preclinical studies in different animal models have shown that modulation of normal micturition and detrusor overactivity by drugs acting within the spinal cord or supraspinally is possible. Promising results have been obtained in such models, e.g. with drugs interfering with GABA mechanisms, serotonin 5-HT1A receptors, mu-opioid receptors and alpha-adrenoreceptors. However, considering the limited predictability of existing animal models for efficacy in humans, positive proof of concept studies in humans are mandatory. Such studies are scarce and further investigations are needed.

Animals↗
PubMed1999

Advances in the pharmacotherapy of migraine. How knowledge of pathophysiology is guiding drug development.

The pharmacotherapy of migraine has advanced in parallel with our understanding of the pathophysiology of the disease. It is likely that it is the gap in our knowledge of the pathogenesis as opposed to the pathophysiology of migraine which hinders development of preventative agents. This century has seen the shift from the vascular theory of migraine pathophysiology (i.e. that cranial vessels were the prime movers in the disorder and thus vasoconstriction would be the prime treatment) to a more integrated neurovascular theory. The neurovascular theory takes the view that vascular change is secondary to neural activation, so changes such as release of trigeminal neuropeptides is predicted, has been demonstrated and suggests a possible new treatment. Similarly, it may be possible to block trigeminal nociceptive transmission in the trigeminal nucleus which might avoid the vascular adverse effects that, while small, plague current treatments. The future for migraine and cluster headache, the neurovascular headaches, is bright as we unravel their biology and this leads to further therapeutic advances.

Blood Proteins↗
PubMed2004

Axonal ionic pathophysiology in human peripheral neuropathy and motor neuron disease.

Testing the excitability of axons can provide insights into the ionic mechanisms underlying the pathophysiology of axonal dysfunction in human neuropathies and motor neuron diseases. Threshold tracking, which was developed in the 1990's, non-invasively measures a number of axonal excitability indices, which depend on membrane potential and on the Na+ and K+ conductances. This paper reviews recent advances in ionic-pathophysiological studies in human subjects in vivo. Membrane potential of human axons can be estimated, because most of the ion channels expressed on the axolemma are voltage-dependent, and patterns of changes in multiple excitability indices can suggest whether axons are depolarized or hyperpolarized. This has been clearly demonstrated in a single patient with acute hypokalemia (hyperpolarization) and patients with chronic renal failure (depolarization due to hyperkalemia). Muscle cramps/fasciculations arise from hyperexcitability of the motor axons. The enhanced excitability can result from altered ion channel function; an increase in persistent Na+ conductance, a decrease in accommodative K+ conductance, and focal membrane depolarization, all of which increase excitability, have been demonstrated in amyotrophic lateral sclerosis or other disorders affecting lower motor neurons. Patients with demyelinating neuropathy often complain of muscle fatigue. During voluntary contraction, the activation of the electrogenic Na+-K+ pump and resulting membrane hyperpolarization can cause activity-dependent conduction block when the safety factor for impulse transmission is critically reduced. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms is of clinical relevance, because once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option for a variety of neuromuscular diseases.

Animals↗
PubMed2005

Pathophysiology of seroma in breast cancer.

PURPOSE: Seroma is the most common complication of mastectomy. The aim of this systematic review is to clarify the pathophysiology of seroma. MATERIALS AND METHODS: A computer-assisted MEDLINE search was conducted, and additional references were found in the bibliographies of these articles. The reference terms ''breast cancer'', ''mastectomy'', ''seroma'', ''lymphocele'' and ''lymphocyst'' were used as both keyword and subject terms. The search was limited to studies published in English. RESULTS: The definition of seroma was highly variable across studies, but was most commonly a seroma large enough to be noticed by the patient or medical staff and affecting the patient's satisfaction in the immediate or acute postoperative period. So far, only limited data are available on the severity of seroma. With respect to the pathophysiology of seroma, the data indicated that several anatomical factors, especially dead space, likely contribute to seroma formation. However, it was obscure whether seroma was due to lymph-like fluid or exudate. CONCLUSION: There is considerable variability in the way seroma is defined across studies, and its pathophysiology remains uncertain.

Breast Neoplasms↗
PubMed2004

Work-related musculoskeletal disorders of the hand and wrist: epidemiology, pathophysiology, and sensorimotor changes.

The purpose of this commentary is to present recent epidemiological findings regarding work-related musculoskeletal disorders (WMSDs) of the hand and wrist, and to summarize experimental evidence of underlying tissue pathophysiology and sensorimotor changes in WMSDs. Sixty-five percent of the 333 800 newly reported cases of occupational illness in 2001 were attributed to repeated trauma. WMSDs of the hand and wrist are associated with the longest absences from work and are, therefore, associated with greater lost productivity and wages than those of other anatomical regions. Selected epidemiological studies of hand/wrist WMSDs published since 1998 are reviewed and summarized. Results from selected animal studies concerning underlying tissue pathophysiology in response to repetitive movement or tissue loading are reviewed and summarized. To the extent possible, corroborating evidence in human studies for various tissue pathomechanisms suggested in animal models is presented. Repetitive, hand-intensive movements, alone or in combination with other physical, nonphysical, and nonoccupational risk factors, contribute to the development of hand/wrist WMSDs. Possible pathophysiological mechanisms of tissue injury include inflammation followed by repair and/or fibrotic scarring, peripheral nerve injury, and central nervous system reorganization. Clinicians should consider all of these pathomechanisms when examining and treating patients with hand/wrist WMSDs.

Cumulative Trauma Disorders↗
PubMedDate not supplied

Surgical pathophysiology and disease management during the centuries.

During the centuries the pathophysiological concept of illness underwent drastic changes, depending on medical discoveries and religious belief. There is evidences of surgical practice in Mesopotamia, Egypt, and Greece 2000 years B.C., but we have to wait the Roman Empire with Celso, Galeno, and most of all Asclepiade and Temisone to appreciate the endeavor to rationally understand diseases as an alteration among different body constituents and not only as divine will. During the Middle Ages, when medicine was disputed by clergy, Ugo and Teodorico Borgognone perceived by intuition the problem of sepsis in patient recovery. This problem was cleared up six centuries later by Semmelweis with his antisepsis. Discoveries of blood circulation, hemostasis, anesthesia, and antisepsis in the 17th and 19th centuries permitted better disease management and have promoted, since the 1950s, pathophysiology as an autonomous discipline. Now pathophysiological mechanisms are used for comprehension of several diseases, such as gallstone formation, peptic ulcers, cranial trauma, cardiovascular abnormalities, and many others, to suggest to us which are the better surgical or clinical trials to realize, while observing caution about their limits and consequences. By a multidisciplinary approach involving surgeons, physiologists, biologists, and physicians, we are able to facilitate patient recovery and to perform modern, scientific, high-quality disease management.

General Surgery↗
PubMed2004

Pathophysiology of tethered cord syndrome: correlation with symptomatology.

Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord. The mechanical cause of TCS is an inelastic structure anchoring the caudal end of the spinal cord that prevents cephalad movement of the lumbosacral cord. Stretching of the spinal cord occurs in patients either when the spinal column grows faster than the spinal cord or when the spinal cord undergoes forcible flexion and extension. Research in patients and experimental animals suggests that there is a link between the clinical dysfunctions that characterize TCS and putative pathophysiological changes that accompany this syndrome. Among these changes are depression of electrophysiological activity and shifts in the reduction/oxidation ratio of cytochrome oxidase. The latter suggests that there is impairment of oxidative metabolism. These putative pathophysiological changes in TCS occur mainly within the lumbosacral cord under excessive tension. The authors discuss the pathophysiology of TCS and examine related symptoms.

Action Potentials↗
PubMed1997

Pathophysiology of hyponatremia after transsphenoidal pituitary surgery.

Hyponatremia after pituitary surgery is presumed to be due to antidiuresis; however, detailed prospective investigations of water balance that would define its pathophysiology and true incidence have not been established. In this prospective study, the authors documented water balance in patients for 10 days after surgery, monitored any sodium dysregulation, further characterized the pathophysiology of hyponatremia, and correlated the degree of intraoperative stalk and posterior pituitary damage with water balance dysfunction. Ninety-two patients who underwent transsphenoidal pituitary surgery were studied. To evaluate posterior pituitary damage, a questionnaire was completed immediately after surgery in 61 patients. To examine the osmotic regulation of vasopressin secretion in normonatremic patients, water loads were administered 7 days after surgery. Patients were categorized on the basis of postoperative plasma sodium patterns. After pituitary surgery, 25% of the patients developed spontaneous isolated hyponatremia (Day 7 +/- 0.4). Twenty percent of the patients developed diabetes insipidus and 46% remained normonatremic. Plasma arginine vasopressin (AVP) was not suppressed in hyponatremic patients during hypoosmolality or in two-thirds of the normonatremic patients after water-load testing. Only one-third of the normonatremic patients excreted the water load and suppressed AVP normally. Hyponatremic patients were more natriuretic, had lower dietary sodium intake, and had similar fluid intake and cortisol and atrial natriuretic peptide (ANP) levels compared with normonatremic patients. Normnonatremia, hyponatremia, and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery. The pathophysiology of hyponatremia after transsphenoidal surgery is complex. It is initiated by pituitary damage that produces AVP secretion and dysfunctional osmoregulation in most surgically treated patients. Additional events that act together to promote the clinical expression of hyponatremia include nonatrial natriuretic peptide-related excess natriuresis, inappropriately normal fluid intake and thirst, as well as low dietary sodium intake. Patients should be monitored closely for plasma sodium, plentiful dietary sodium replacement, mild fluid restriction, and attention to symptoms of hyponatremia during the first 2 weeks after transsphenoidal surgery.

Adult↗
PubMed2005

[The pathophysiology and defense mechanism against superficial and subcutaneous fungal infection].

To determine the pathophysiology of the fungal infection and defense mechanisms against superficial dermatomycosis, two series of experimental infections of Trychophyton mentagrophytes were made on the forearm of a male volunteer. One series was applied topical steroid ointment, the other the vehicle alone. The infected sites were biopsied from each row weekly up to the 4th week, and the set of sites were studied and compared clinically, histopathologically and immunohistochemically. For the study against subcutaneous fungal infection, the same experiments were studied using the subcutaneous inoculation of Sporothrix schenckii. The pathophysiology of the superficial dermatophytosis was thought to be the same as those of the contact (allergic) dermatitis, including the physiodynamics of CD-1 cells. The principal mechanism of the defense lay in the removal of the foreign materials (fungi) together with keratinocytes whose turnover increased because of the eczematous reaction. It was proved that the topical application of steroid ointment suppressed the immune reactions locally, thus forming a paradoxical feature with little inflammatory reaction and abundant fungal elements (so-called atypical tinea). The pathophysiology of the subcutaneous fungal infection was thought to be a suppurative granulomatous reaction and pathologically showed a mixed cell granuloma. The neutrophils and macrophages engulfed and digested the fungi in the forefront, but the circumference was surrounded by epithelioid cells and/or foreign body granuloma. Transepithelial elimination also played some role in the defense. It was proved that when the defense mechanism was weakened by the topically applied steroid ointment, not only the clinical symptoms but also the fungicidal tissue reaction were subdued, and histocytes only engulfed fungi to protect them from dispersion. The trichophytin reaction turned positive on the 14th day, and the sporotrichin reaction on the 7th day.

Dermatitis, Contact↗
PubMed2004

[Strategy and approaches of pathological and pathophysiological research in integrated traditional Chinese and western medicine].

Pathology and pathophysiology are sciences studying the laws and mechanisms of the occurrence and development of diseases, linking up the preclinical and clinical medicine. Owing to the different perspectives and ways of thinking, the western medicine and the traditional Chinese medicine developed respectively their independent theoretical, diagnostic and therapeutic systems. Integrative medicine, combining the theories and treatments of both western medicine and traditional Chinese medicine, has become the developing trend of medicine along with the social development. For this reason, pathological and pathophysiological research in integrated traditional Chinese and western medicine is highly significant for revealing the internal relations between the clinical manifestation and the pathological changes, for expounding the causes, conditions, mechanisms and laws of the occurrence and development of diseases. In doing related research, we should combine the disease and the syndrome, combine the macro-level and the micro-level, combine the part and the whole. We should manage to systematize the clinical research, to establish animal models of the syndromes, and to integrate the animal models of syndromes with the clinical characteristics of diseases. We should apply the theories of traditional Chinese medicine to the pathological and pathophysiological research of modern medicine.

Biomedical Research↗
PubMed2000

Pathophysiology of heparin-induced thrombocytopenia. Clinical and diagnostic implications--a review.

OBJECTIVE: This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. DATA SOURCES AND STUDY SELECTION: Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin->platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a "superactive" heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. CONCLUSIONS: The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

Heparin↗