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Pathophysiological heterogeneity of conduction blocks in multifocal motor neuropathy.

The pathophysiological mechanisms responsible for conduction block in multifocal motor neuropathy (MMN) are still unclear. To clarify the physiological abnormalities at the site of the block, we tested the effects induced by polarizing direct currents on motor conduction along forearm nerves in 25 normal nerves (13 subjects), and at the site of conduction block in six nerves (five patients) with MMN. In healthy controls, whereas nerve depolarization failed to change the conditioned compound muscle action potential (CMAP), hyperpolarization elicited a significant, charge-dependent, decrease in the conditioned CMAP size. Hyperpolarization with 4 mC elicited CMAPs that were 86.76 +/- 5.22% (mean +/- SEM) of the control unconditioned response (P < 0.05). Analysis of individual MMN nerves showed that polarizing currents elicited markedly heterogeneous effects: depending on the nerve tested, depolarization or hyperpolarization in most cases significantly improved conduction along motor fibres across the conduction block. In three MMN nerves, pathophysiological abnormalities were consistent with a hyperpolarizing block, in two with a depolarizing block, and in one with a mixed block. Our observations indicate that the pathophysiological abnormalities at the site of conduction block in MMN may arise from depolarization or hyperpolarization, probably depending on the course of disease.

Action Potentials↗

Involvement of ovarian kinin-kallikrein system in the pathophysiology of ovarian hyperstimulation syndrome: studies in a rat model.

The purpose of the present study was to investigate a possible participation of the kinin-kallikrein system (KKS) in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). Symptoms of hyperstimulation were produced in immature female rats using equine chorionic gonadotrophin followed by human chorionic gonadotrophin (HCG). At 48 h after the HCG injection, rats were injected s.c. with 100 microg/kg of HOE140, bradykinin-2 receptor antagonist. Capillary permeability was evaluated using peritoneal Evans blue dye (EB) concentrations 30 min after the i.v. injections. The EB concentrations in the hyperstimulated rats were significantly reduced 4 and 6 h after the HOE140 injection, compared with those injected with the vehicle as a control (4.58+/-0.80 versus 8.22+/-0.87 and 4.32+/-0.74 versus 8.35+/-1.03 microg respectively; P < 0.03), indicating the involvement of kinin in the pathophysiology of OHSS in this model. The administration of 10 IU aprotinin significantly reduced the peritoneal EB concentration when compared with the control (4.13+/-0.53 versus 7.95+/-1.06 microg; P < 0.01), implicating a possible role of kallikrein. Furthermore, pretreatment with RU486 (5 or 10 mg/kg) resulted in a significant reduction of ovarian kinin concentrations 48 h after the HCG injection, compared with the control (1.22+/-0.07 or 1.43+/-0.07 versus 1.94+/-0.10 pg/mg; P < 0.005 and P < 0.05 respectively). Similar results were obtained in the peritoneal EB concentrations. In addition, a significant correlation between the ovarian kinin and peritoneal EB concentrations was observed (P < 0.001, r = 0.539). Thus it was suggested that ovarian KKS plays an intermediary role in the progesterone-induced augmentation of capillary permeability in this experimental model, indicating the involvement of KKS in the pathophysiology of OHSS.

Animals↗

Pathophysiology of cutaneous lupus erythematosus--novel aspects.

The pathophysiology of cutaneous lupus erythematosus (CLE) has been investigated in numerous studies demonstrating that the combination of specific cellular and molecular events is leading to inflammation and tissue damage in this disease. However, a complete understanding of the diverse pathophysiological mechanisms and interactions does not exist. Various environmental factors influence the clinical expression of CLE and a striking relationship has emerged between sunlight exposure and the various subtypes of this disease. In the past years, photoprovocation tests with different ultraviolet (UV) wavelengths have been approved to be an optimal way to evaluate photosensitivity in patients with CLE. Furthermore, research on the pathogenetic mechanisms of UV-induced skin lesions has become an increasingly dynamic field and several new aspects of this disease could be identified. In this review, the impact of UV exposure that contributes to the manifestations of CLE is discussed and recently reported mechanisms in the pathophysiology of this disease are considered including the clearance of apoptotic cells, expression of inducible nitric oxide synthase, function of CD4(+)CD25(+) regulatory T cells, and the role of chemokines for lymphocyte recruitment. Elucidation of the relevant factors might lead to future development of effective strategies to prevent abnormal reactivity in patients with CLE.

Apoptosis↗

Neuronal apoptosis following cerebral ischaemia: pathophysiology and possible therapeutic implications.

PURPOSE OF REVIEW: Neuronal apoptosis following cerebral ischaemia has become an issue of extraordinary scientific interest in the past decade. Besides necrosis, this highly relevant pathomechanism has been shown to be markedly involved in the pathogenesis of delayed postischaemic neuronal damage. As a result, a variety of possible neuroprotective strategies and therapeutic options subsequent to cerebral ischaemia have emerged. This article provides an overview of the pathophysiologic mechanisms underlying delayed neuronal apoptotic degeneration after cerebral ischaemia. Based on these facts, selected therapeutic implications are discussed in detail. RECENT FINDINGS: Recent findings from experimental studies have demonstrated a new therapeutic neuroprotective potential of pharmaceutical blockade of death-inducing ligands (e.g. Fas/CD95 ligand), enhancement of survival signal transduction with endogenous ligands (e.g. erythropoietin) and therapeutically modulating the balance between intracellular anti- and proapoptotic Bcl proteins with intriguing molecular techniques after cerebral ischaemia. SUMMARY: Neuronal apoptosis is highly relevant in the pathophysiology of neurodegenerative disorders, neurotrauma and cerebral ischaemia/reperfusion. Within the past few years, a variety of therapeutic strategies have emerged based on our increasing knowledge of the pathophysiology of apoptosis. Whereas inhibition of single factors in apoptotic cascades (e.g. proteases) has produced rather unsatisfying results, new opportunities have emerged at the molecular level due to advances in molecular medicine. These approaches offer promising opportunities for neuroprotective therapeutic strategies subsequent to cerebral ischaemia. It is tempting to speculate that a combination ('cocktail') of these antiapoptotic interventions might even increase their neuroprotective potential.

Journal Article↗

The pathophysiology of chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting is a major debilitating side effect of oncology treatment despite recent advances in pharmaceutical management. Nurses who provide care to patients experiencing nausea and vomiting are often only marginally aware of the pathophysiological processes involved in the treatment. A better understanding of the science behind current interventions to reduce nausea and vomiting may help nurses use those interventions more effectively. This article reviews current knowledge about the pathophysiology of chemotherapy-induced nausea and vomiting. By understanding the pathophysiology behind this patient experience, gastroenterology nurses can develop a better understanding of the common symptoms of nausea and vomiting in general. When a nurse understands the complexity of factors causing nausea and vomiting, he or she will be better able to provide appropriate interventions to reduce these symptoms.

Antiemetics↗

Restless legs syndrome: a review of clinical and pathophysiologic features.

Restless legs syndrome (RLS), although long ignored and still much underdiagnosed, disrupts the life and sleep considerably of those who have it. Recent clinical and basic research provides for better definition and pathophysiologic understanding of the disorder. The body of knowledge about this disorder has been expanding rapidly during the past decade and it has altered our concepts of this disorder. This review of RLS covers history, diagnosis, morbidity of sleep disturbance, relation to periodic limb movements in both sleep and waking, secondary causes, severity assessment methods, phenotypes for possible genetic patterns, epidemiology, pathophysiology, and medical treatment considerations. The emphasis on pathophysiology includes consideration of central nervous system localization, neurotransmitter and other systems involved, and the role of iron metabolism. Studies to date support the authors' recently advanced iron-dopamine model of RLS.

Anemia, Iron-Deficiency↗

Vasoactive diadenosine polyphosphates in human placenta: possible candidates in the pathophysiology of pre-eclampsia?

BACKGROUND: One hypothesis of the pathophysiology of pre-eclampsia is that placentally derived, yet unidentified, vasoactive factors are released into the maternal circulation, causing hypertension. OBJECTIVE: To determine if diadenosine polyphosphates, new potent vasoconstrictors, are present in human placenta. METHODS AND RESULTS: Human placental tissue was homogenated and fractionated by size-exclusion chromatography, affinity chromatography, anion-exchange chromatography and reversed-phase chromatography. In fractions purified to homogeneity, diadenosine diphosphate, diadenosine triphosphate, diadenosine tetraphosphate, diadenosine pentaphosphate, diadenosine hexaphosphate and diadenosine heptaphosphate were identified by matrix-assisted laser desorption/ionization mass spectrometry, retention-time comparison and enzymatic cleavage analysis. CONCLUSIONS: The presence of diadenosine polyphosphates in human placenta makes them possible candidates for involvement in the pathophysiology of pre-eclampsia. However, their contribution to the pathophysiology of eclampsia requires substantiation in further studies.

Blood Vessels↗

Distal-type cervical spondylotic amyotrophy: assessment of pathophysiology from radiological findings on magnetic resonance imaging and epidurally recorded spinal cord responses.

STUDY DESIGN: Six cases with distal-type cervical spondylotic amyotrophy are reported. OBJECTIVE: To investigate the pathophysiology of distal-type cervical spondylotic amyotrophy from magnetic resonance imaging and intraoperative evoked spinal cord responses. SUMMARY OF BACKGROUND DATA: Cervical spondylotic amyotrophy had a characteristic clinical symptom of severe muscular atrophy with no or insignificant sensory deficit. Selective ventral root lesions or intrinsic spinal cord lesions have been proposed as the pathophysiology of cervical spondylotic amyotrophy, but they have not been well understood. METHOD: Six patients with distal-type cervical spondylotic amyotrophy were described, and their magnetic resonance imaging and evoked spinal cord potentials after median nerve, motor cortex, and spinal cord stimulation were investigated. RESULTS: Sagittal T2-weighted magnetic resonance imaging showed high signal intensity change within the spinal cord at C4-C5, C5-C6, and C6-C7. All patients underwent laminoplasty. The attenuation of postsynaptic potentials with preserved presynaptic potentials at C4-C5, C5-C6, and C6-C7 was characteristic in the evoked spinal cord potentials after median nerve stimulation. The amplitude of the evoked spinal cord potentials after median nerve stimulation was preserved at C2-C3. This means that lateral posterior column in the spinal cord had less or no involvement in distal-type cervical spondylotic amyotrophy. Concomitant hyperactivity of the patellar tendon reflex was correlated with the abnormality in the evoked spinal cord potentials after transcranial electric stimulation. CONCLUSIONS: The results suggest a longitudinal gray matter lesion as one pathophysiologic feature, and that less damage to the lateral posterior column is the reason for the preservation of sensory function in the patients with distal-type cervical spondylotic amyotrophy described in this study.

Aged↗

Pathophysiologic plasma levels of leukotriene C4 in relation to the hemodynamic dysfunction and mediator release of graded bacteremia.

This study was undertaken to identify those events of bacteremic shock that pathophysiologic levels of leukotriene C4 (LTC4) alone were sufficient to cause. Sixteen adult swine were studied for 4 h in three groups: ANES (n = 6) received anesthesia only; Septic (n = 6) received Aeromonas hydrophila, 10(9)/mL, intravenously, increased incrementally from .2 to 4.0 mL/kg/h; LTC4 (n = 4) received LTC4 infused intravenously, at rates that approximated LTC4 levels of Septic animals. Measurements included mean arterial pressure and arterial PO2, mmHg, pulmonary and systemic (SVRI) vascular resistance indexes, cardiac index (CI), oxygen extraction ratio, hematocrit; thromboxane B2 (TxB2), prostaglandin 6 keto F1 alpha (6 keto), leukotrienes B4 and C4D4E4, and tumor necrosis factor were measured in pg/mL by ELISA. Statistical analysis was performed by ANOVA and general linear model). Mean arterial pressure increased from 100 +/- 5 to 141 +/- 9 in the LTC4 group, but decreased in the Septic group from 90 +/- 7 at baseline to 62 +/- 6 at 3 h. In the LTC4 group, SVRI did not differ from ANES, and pulmonary vascular resistance, PO2, and CI did not change from baseline. In the LTC4 group, TxB2 and 6 keto levels decreased from 149 +/- 26 to 87 +/- 18 and 58 +/- 10 to 44 +/- 12, respectively; in the Septic group, TxB2 increased 140-fold and 6 keto increased 60-fold. Pathophysiologic LTC4 is not sufficient alone to cause the derangements in CI and SVRI, and tissue metabolism induced by graded bacteremia. Significantly increased systemic blood pressure suggests that endogenous pathophysiologic LTC4 may be involved. LTC4 does not increase plasma eicosanoids and tumor necrosis factor, but may down-regulate prostaglandin and leukotriene release.

Animals↗

Thrombotic thrombocytopenic purpura. I. Pathophysiology and clinical manifestations.

Thrombotic thrombocytopenic purpura is an uncommon, life-threatening disorder that affects older children and adolescents as well as adults. A variety of theories have been proposed to explain its clinical and pathologic manifestations, but the pathophysiology remains poorly understood. It is not even clear whether this disease primarily affects the endothelial cell, the platelet, or both. Most patients have no discernable predisposition to this disease. Our failure to define the pathophysiology of thrombotic thrombocytopenic purpura adequately has hampered our ability to design rational and consistently successful therapy. The present knowledge of this pathophysiology is discussed in detail. The high mortality of this disease necessitates rapid diagnosis so that therapy can be instituted as quickly as possible. The clinical manifestations and diagnostic criteria of thrombotic thrombocytopenic purpura are therefore reviewed.

Anemia, Hemolytic↗

Pathophysiology of heart failure update: the role of neurohumoral activation in the progression of heart failure.

Understanding the pathophysiologic mechanisms responsible for producing heart failure is necessary before effective treatments can be developed that increase survival and improve quality of life. Recent advances in the treatment of heart failure can be traced directly to improved appreciation of the role of neurohumoral activation in the pathophysiology of heart failure. Initially adaptive, neurohumoral activation ultimately results in a series of overadjustments that actively participate in the progression of heart failure. In this article, the role of neurohumoral activation, ventricular remodeling, and various peripheral vascular abnormalities in the pathophysiology of heart failure are explored.

Disease Progression↗

The relevance of malaria pathophysiology to strategies of clinical management.

PURPOSE OF REVIEW: Malaria claims 1-2 million lives a year, mostly children in sub-Saharan Africa. The majority of hospital deaths occur within 24 h of admission despite adequate treatment with antimalarial chemotherapy. Understanding the pathophysiological disturbances of malaria should allow the development of supportive therapy to "buy time" for antimalarial chemotherapy to clear the infection. It is sobering, however, that despite many trials over the last quarter of a century all large trials of adjunctive therapy so far have resulted in either increased morbidity or mortality, or both. RECENT FINDINGS: Severe malaria may be divided broadly into neurological and metabolic complications. We review recent findings about the pathophysiology of these complications and the implications for future adjunctive therapy of malaria, including the proposed importance of fluid volume depletion and sequestration of parasitized red cells in severe malaria. We also consider other anaemia, hyperparasitaemia and renal failure, which also require urgent treatment in severe malaria. SUMMARY: We review the important pathophysiological features of severe malaria and promising adjunctive therapies such as dichloroacetate that warrant further larger trials to determine whether they improve the so-far intractable death rate of severe malaria.

Acidosis, Lactic↗

Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology.

PURPOSE OF REVIEW: Chronic fatigue syndrome is a controversial condition especially concerning its clinical definition and aetiopathogenesis. Most recent research progress has been made in phenomenology and pathophysiology and we focused our review on these two areas. RECENT FINDINGS: The phenomenology research supports the notion of a discrete fatigue syndrome which can be distinguished from depression and anxiety. The current case definition, however, may need an improvement based on empirical data. Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered. Immune system involvement in the pathogenesis seems certain but the findings on the specific mechanisms are still inconsistent. Genetic studies provide some evidence of the syndrome being a partly genetic condition, but environmental effects seem to be still predominant and identification of specific genes is still at a very early stage. SUMMARY: The recent findings suggest that further research is needed in improving the current case definition; investigating overlaps and boundaries among various functional somatic syndromes; answering the question of whether the pathophysiologic findings are a cause or consequence; and elucidating the involvement of the central nervous system, immune system and genetic factors.

Brain↗

A clinical algorithm to differentiate heart failure with a normal ejection fraction by pathophysiologic mechanism.

The incidence and prevalence of heart failure are increasing as the population ages. Epidemiologic studies demonstrate that more than half of heart failure patients have a normal ejection fraction. The pathophysiology of this disorder is not completely understood. It is primarily attributed to left ventricular diastolic dysfunction (a leftward- and upward-shifted end-diastolic pressure-volume relation), where left ventricular diastolic chamber size is normal or reduced despite greater-than-normal filling pressures, resulting in reduced stroke volume and cardiac output. Using classic measures derived from pressure-volume analysis, we delineate other possible combinations of the end-systolic and end-diastolic pressure-volume relation, and hence possible pathophysiologic mechanisms that could underlie the syndrome of heart failure with normal ejection fraction. We propose an algorithm for identifying the primary pathophysiologic mechanism of heart failure in the setting of a normal ejection fraction using three simple factors: blood pressure, electrocardiographic/echocardiographic evidence of left ventricular hypertrophy, and left ventricular size. The application of this algorithm may aid in guiding management and targeting much-needed therapies for this population.

Aged↗

Pathophysiological characteristics of patients with non-erosive reflux disease differ from those of patients with functional heartburn.

BACKGROUND: Patients with endoscopy-negative heartburn can be subdivided into non-erosive reflux disease and functional heartburn on the basis of abnormal and normal, respectively, oesophageal acid exposure. Different pathophysiological characteristics could explain the reportedly low efficacy of proton pump inhibitors in functional heartburn. AIM: To assess if non-erosive reflux disease and functional heartburn are pathophysiologically distinguishable. METHODS: Oesophageal manometry and pH-monitoring were performed in 145 patients with endoscopy-negative heartburn, in 72 patients with erosive reflux disease, in 58 patients with complicated reflux disease, and in 60 controls. RESULTS: Patients with non-erosive reflux disease (84 cases) and functional heartburn (61 cases) differed with regard to the prevalence of hiatal hernia (49% vs. 31%, P = 0.008), the mean lower oesophageal sphincter tone (18.5 vs. 28.4 mmHg, P < 0.05), and the number of upright diurnal acid refluxes lasting more than 5 min (3.6 vs. 0.37, P < 0.05). The results were very close in thenon-erosive reflux disease, erosive reflux disease and complicated reflux disease groups, whilst patients with functional heartburn were indistinguishable from controls. CONCLUSIONS: Pathophysiological characteristics typical of gastro-oesophageal reflux disease are found in patients with non-erosive reflux disease but not in patients with functional heartburn. This could explain the reportedly low efficacy of proton pump inhibitors in functional heartburn and suggests considering different management strategies.

Adult↗

Alpha-adrenoceptors are a common denominator in the pathophysiology of erectile function and BPH/LUTS--implications for clinical practice.

A literature search of PubMed documented publications and abstracts from proceedings of scientific meetings was made to review the available data on benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED) with a special focus on the role of alpha-adrenoceptors as critical mediators of pathophysiology. The reader is introduced to clinical results on the therapeutic potential of alpha-blockers alone and in combination with phosphodiesterase type 5 (PDE-5) inhibitors in the treatment of ED associated with LUTS/BPH. Epidemiological studies clearly show that an association exists between ED and LUTS/BPH. The severity of LUTS is correlated with the risk for ED. A significant number of LUTS/BPH patients are nonresponsive to the common ED treatment with PDE-5 inhibitors. As smooth muscle contractility is regulated by adrenoceptors in the corpus cavernosum, prostate and detrusor, the alpha-adrenoceptor system may be considered a common pathophysiological mediator in the development of ED and LUTS/BPH. Blockade of alpha-adrenoceptors for the treatment of BPH/LUTS may have the potential of improving sexual function. Conversely, PDE-5 inhibitors may exhibit positive effects in LUTS patients. Pilot studies on combination regimens of alpha-adrenoceptor antagonists and PDE-5 inhibitors have yielded encouraging results in LUTS patients with persistent ED. On the basis of pharmacological and clinical evidence, it is established that the alpha-adrenoceptor system plays an important role in the pathophysiology of ED and LUTS secondary to BPH. Larger trials on the combination of alpha-adrenoceptor antagonists with PDE-5 inhibitors are necessary to develop an integrated treatment approach for BPH/LUTS patients with comorbid ED.

Adrenergic alpha-Antagonists↗

Pathophysiology and subjective symptoms in women with impaired bladder emptying.

AIM: To assess the pathophysiology and subjective symptoms in female patients with impaired bladder emptying. METHODS: Eighty-three consecutive female patients attending a urology clinic with postvoid residual urine of more than 100 mL were recruited. Free uroflowmetry, measurement of postvoid residual urine and pressure-flow study were performed in all patients. The detailed assessment of subjective symptoms and their bothersomeness to the patients were assessed using a self-administered questionnaire comprising 12 items: five associated with voiding symptoms, five with storage symptoms, and two with discomfort and pain on voiding. The questionnaire was applied to 83 patients with impaired bladder emptying, 41 patients with urinary incontinence, and 21 normal controls. RESULTS: Although 77% of the patients with impaired bladder emptying consulted a urology clinic because of voiding symptoms, the remaining 23% complained of storage symptoms or symptoms other than lower urinary tract symptoms (LUTS). The pressure-flow study revealed the pathophysiology of impaired bladder emptying as impaired detrusor contraction in 68 patients (81.9%), and bladder outlet obstruction in 12 patients (14.8%). The assessment of subjective symptoms using the questionnaire revealed that the patients with urinary incontinence showed a high frequency only in storage symptoms; however, those with impaired bladder emptying revealed a high frequency not only in voiding but also in storage symptoms. CONCLUSIONS: Female patients with impaired bladder emptying present with a wide range of lower urinary tract symptoms associated with both voiding and storage symptoms. To determine an appropriate treatment modality, the correct diagnosis of the underlying pathophysiology of impaired bladder emptying by pressure-flow study is of primary importance.

Adult↗

Anatomy and pathophysiology of varicose veins.

The venous anatomy of the leg is described with special reference to the superficial venous system. The histologic and histochemical differences between varicose and normal veins are presented. The pathophysiology of varicose veins is related to congential or acquired abnormalities of the deep venous system, venous valves, and/or fascial or vein wall weakness. Increased deep venous pressure may be both proximal and distal in etiology, arising from arteriovenous anastomoses, incompetent communicating veins, or venous obstruction. Primary valvular incompetence arises from venous obstruction (thrombosis), thrombophlebitis, or valvular agenesis. Secondary valvular incompetence occurs from deep venous obstruction or increased venous distensibility (usually secondary to circulating estrogens). Finally, fascial weakness of the vein wall or supporting fascia provided a genetic basis for the pathophysiology of varicose veins. Understanding the anatomy and pathophysiology of varicose veins should lead to a more rational and efficacious treatment.

Elastic Tissue↗