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.     

Inhibin B in male reproduction: pathophysiology and clinical relevance.

The recent availability of specific inhibin assays has demonstrated that inhibin B is the relevant circulating inhibin form in the human male. Inhibin B is a dimer of an alpha and a betaB subunit. It is produced exclusively by the testis, predominantly by the Sertoli cells in the prepubertal testis, while the site of production in the adult is still controversial. Inhibin B controls FSH secretion via a negative feedback mechanism. In the adult, inhibin B production depends both on FSH and on spermatogenic status, but it is not known in which way germ cells contribute to inhibin B production. The regulation of inhibin B production changes during life. There is an inhibin B peak in serum shortly after birth only partly correlated with an increase in serum FSH, probably reflecting the proliferating activity of the Sertoli cells during this phase of life. Afterwards, inhibin B levels decrease and remain low until puberty, when they rise again, first as a consequence of FSH stimulation and then as a result of the combined regulation by FSH and the ongoing spermatogenesis. In the adult, serum inhibin B shows a clear diurnal variation closely related to that of testosterone. The administration of FSH increases the secretion of inhibin B in normal men, but is much more pronounced in males with secondary hypogonadism. The treatment of infertile men with FSH, however, does not result in an unequivocal inhibin B increase. There is a clear inverse relationship between serum inhibin B and FSH in the adult. Serum inhibin B levels are strongly positively correlated with testicular volume and sperm counts. In infertile patients, inhibin B decreases and FSH increases. In general, there is very good correlation with the degree of spermatogenetic damage, with the arrest at the earlier stages having the lowest inhibin B levels. However, for unknown reasons, there are cases of Sertoli-cell-only syndrome with normal inhibin B levels. Inhibin B and FSH together are a more sensitive and specific marker for spermatogenesis than either one alone. However, the inhibin B concentrations are not a reliable predictor of the presence of sperm in biopsy samples for testicular sperm extraction. Suppression of spermatogenesis with testosterone and gestagens leads to a partial reduction of inhibin B in serum but it is never completely suppressed. In contrast, testicular irradiation in monkeys or humans leads to a rapid and dramatic decrease of inhibin B, which becomes undetectable when germ cells are completely absent. In summary, although inhibin B is a valuable index of spermatogenesis, the measurement of serum inhibin B levels is still of limited clinical relevance for individual patients.     

Resistance to antiplatelet treatment: The clinical relevance of platelet function assays

In cardiology, functional platelet activity is not routinely monitored. Platelet function assays should be able to identify patients with high residual platelet reactivity (HPR). High on-treatment platelet reactivity is apparent risk factor for atherothrombosis, however not the only one. Since there are many contributing factors (platelet activation, endothelial dysfunction, and plaque rupture) influencing atherothrombosis. Antiplatelet treatment is targeted to diminish platelet activation. The unique pharmacodynamics, pharmacokinetics of each agent and the pharmacogenetic profile of the recipient need to be taken into consideration. The aim of this review article is to summarize current knowledge of platelet function monitoring and its usefulness in clinical cardiology.     

Quality of ulcer healing in gastrointestinal tract: Its pathophysiology and clinical relevance

In this paper, we review the concept of quality of ulcer healing (QOUH) in the gastrointestinal tract and its role in the ulcer recurrence. In the past, peptic ulcer disease (PUD) has been a chronic disease with a cycle of repeated healing/remission and recurrence. The main etiological factor of PUD is Helicobacter pylori (H. pylori), which is also the cause of ulcer recurrence. However, H. pylori-negative ulcers are present in 12%-20% of patients; they also recur and are on occasion intractable. QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated. Within the scars of healed ulcers, regenerated tissue is immature and with distorted architecture, suggesting poor QOUH. The abnormalities in mucosal regeneration can be the basis for ulcer recurrence. Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence. Our studies in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macrophages, which in turn produce increased amounts of cytokines and chemokines, which attract neutrophils to the regenerated area. Neutrophils release proteolytic enzymes that destroy the tissue, resulting in ulcer recurrence. Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a deficiency and/or an imbalance of endogenous growth factors. Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar. In addition to PUD, the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn’s disease and ulcerative colitis.     

The clinical relevance of lipohypertrophy

International Journal of Diabetes in Developing Countries -     

Platelet-leukocyte interactions in coronary heart disease: pathophysiology, clinical relevance, pharmacological modulation

The interactions between leukocytes and endothelial cells have been studied extensively under conditions of ischemia and reperfusion. In contrast, attraction of leukocytes by platelets at the site of damage is poorly understood. This recruitment facilitates inflammation and atherogenesis. Studies performed ex vivo in coronary artery disease show that neutrophil-platelet adhesion increases in unstable angina, coronary angioplasty and coronary artery bypass surgery, in comparison with stable angina. Experimental works have shown the major role of platelet P-selectin in platelet-leukocyte interactions, and of fibrinogen, which is the ligand of both platelets and leukocytes (B2 integrins). Studied performed in anti-GPIIb/IIIa-treated patients demonstrate a modulation, as inhibition, of platelet-leukocyte interactions. This new drug inhibits platelet function and coagulation, and moreover inflammation.     

Oxidative stress and hyperuricaemia: pathophysiology,clinical relevance,and therapeutic implications in chronic heart failure

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant‐producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up‐regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up‐to‐date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.     

冠心病患者血小板α—颗粒膜蛋白测定的临床意义

目的：探讨血小板α-颗粒膜蛋白（GMP－140）测定在冠心病患中的临床意义。方法：选择131例冠心病患、30例正常对照,采用酶联免疫吸附双抗体夹心法（ELISA）,测定GMP－140含量。结果：冠心病患GMP含量显多于正常对照组（P＜0．001）;合并AMI组GMP含量显高于无合并症和合并高血压、稳定型心绞痛组（P＜0．01）;不稳定心绞痛组GMP含量仅次于AMI组,但二无显差异。结论：冠心病病情愈重,GMP含量增多愈显,因此它可以作为冠心病的诊断和观察病情的指标之一。     

The clinical relevance of extreme dipping

Hypertensive patients who demonstrate an exaggerated circadian blood pressure rhythm are known as 'extreme dippers'. 'Non-dippers' are those patients whose blood pressure remains elevated throughout the night. There are many cross-sectional studies in which greater hypertensive target organ damage has been seen in non-dippers. However, almost as many studies have demonstrated a positive association between organ damage and the magnitude of the circadian change in blood pressure. This apparent paradox may be explained by both nighttime pressure and the daytime rise in blood pressure being independently and positively associated with severity of hypertensive target organ damage. More recently, a number of prospective cohort studies have suggested that 'extreme dippers' are at a greater risk of cardiovascular events than those with more moderate circadian rhythms. These small studies have been criticised as being likely to include significant random and systematic errors. Large prospective studies will need to address issues such as optimal quantification of circadian rhythms, poor reproducibility and the likely confounding of results due to diverse antihypertensive therapies, if the association between dipping and adverse cardiovascular outcome is to be further clarified.     

Regulation of platelet heterogeneity: effects of thrombocytopenia on platelet volume and density

We have examined the effects of variable degrees of acute thrombocytopenia on platelet levels, mean platelet volume (MPV), and buoyant density after induction of thrombocytopenia by platelet antiserum (PAS) in mice with or without spleens. Mice were studied serially 10-16, 36, 48, 60-64, 84, 108, 144, 180, 228, 276, 348-360, 372, and 516 h after PAS treatment. MPV and platelet count (PC) x 10(6)/microliters for normal intact mice (n = 136) were 4.7 +/- 0.3 fl (SD) and 1.69 +/- 0.52 (SD), respectively. Twelve hours after PAS-induced severe thrombocytopenia (PC less than 0.05 x 10(6)/microliters), MPV increased significantly (p less than 0.01) to 6.4 fl, was maximal at 36 h (8.2 fl), remained elevated until 144 h following PAS treatment, and then returned to normal. Platelet density decreased significantly (p less than 0.05) 64 h after PAS treatment and returned to normal at 144 h. Hematocrits of repeatedly bled intact control mice decreased from 45% to 30%, accompanied by thrombocytosis (maximal PC 2.24 x 10(6)/microliters) without significant changes in either MPV or platelet density. Moderate thrombocytopenia (PC 0.1-0.2 x 10(6)/microliters) in intact mice produced significantly (p less than 0.05) increased MPV, at 5.7 fl 12 h after PAS treatment, with a peak MPV of 7.6 fl (p less than 0.001) at 36 h; MPV returned to normal at 84 h. Platelet density decreased (p less than 0.001) 12 h after PAS treatment and returned to baseline at 228 h. Control splenectomized mice (n = 185) had an MPV of 5.0 fl +/- 0.7 fl and a PC of 2.14 +/- 0.6 x 10(6)/microliters. Comparably severe and moderate thrombocytopenia in splenectomized mice produced alterations in platelet count, MPV, and density similar to those in intact mice, although maximal MPV and the degree of rebound thrombocytosis after severe thrombocytopenia were more marked in splenectomized mice. In response to reduction of the platelet mass in both intact and splenectomized mice, MPV increased in proportion to the severity of thrombocytopenia, occurred as early as 4 h after induction, and persisted during early rebound thrombocytosis. Previous observations that megakaryocyte ploidy did not shift until 48 h after onset of thrombocytopenia confirm that both initial and maximal changes in MPV in response to this stimulus are regulated by processes other than alterations of megakaryocyte DNA levels.(ABSTRACT TRUNCATED AT 400 WORDS)     

The complex pathophysiology of cardiac cachexia: A review of current pathophysiology and implications for clinical practice

Cardiac cachexia is a muscle wasting process that often develops in those with chronic heart failure resulting in weight loss, low levels of physical activity, reduced quality of life, and is associated with a poor prognosis. The pathology of cardiac cachexia is complex with new evidence emerging that implicates several body systems. This review describes the pathophysiology associated with cardiac cachexia and addresses: 1) hormonal changes- neurohormonal abnormalities and metabolic hormone imbalance; 2) mechanisms of muscle wasting in cardiac cachexia, and the integral mechanisms between changed hormones due to cardiac cachexia and muscle wasting processes, and 3) associated abnormalities of gastrointestinal system that contribute to cardiac cachexia. These pleiotropic mechanisms demonstrate the intricate interplay between the affected systems and account for why cardiac cachexia is difficult to manage clinically. This review summarises current pathophysiology of cardiac cachexia and highlights symptoms of cardiac cachexia, implications for clinical practice and research gaps.     

The pharmacology and clinical relevance of proton pump inhibitors

Gastroesophageal reflux disease is a complex, multifaceted disorder affecting a large proportion of the US population. Its management is based on the principle of optimal antisecretory therapy, mainly with proton pump inhibitors (PPIs). The optimal treatment outcome is complete symptom relief, which can be achieved with optimal use of PPIs. PPI treatment requires an understanding of the pharmacology of these agents as well as their clinical efficacy, strengths, and weaknesses. This paper reviews the pharmacology of PPIs, the principles of optimal dosing, nocturnal gastric acid breakthrough and its clinical importance, and a treatment approach to gastroesophageal reflux disease using these agents.     

Microbubbles: pathophysiology and clinical implications

Gas embolism is a known complication of various invasive procedures, and its management is well established. The consequence of gas microemboli, microbubbles, is underrecognized and usually overlooked in daily practice. We present the current data regarding the pathophysiology of microemboli and their clinical consequences. Microbubbles originate mainly in extracorporeal lines and devices, such as cardiopulmonary bypass and dialysis machines, but may be endogenous in cases of decompression sickness or mechanical heart valves. Circulating in the blood stream, microbubbles lodge in the capillary bed of various organs, mainly the lungs. The microbubble obstructs blood flow in the capillary, thus causing tissue ischemia, followed by inflammatory response and complement activation. Aggregation of platelets and clot formation occurs as well, leading to further obstruction of microcirculation and tissue damage. In this review, we present evidence of the biological and clinical detrimental effects of microbubbles as demonstrated by studies in animal models and humans, and discuss management of the microbubble problem with regard to detection, prevention, and treatment.     

Blood platelet heterogeneity: a functional hierarchy in the platelet population

Summary. The platelet population in man and rat can be divided into two classes of about equal size based on the presence/absence of a p-nitrophenylphosphatase, which probably is a phosphotyrosine phosphatase (PTPase). Phosphorylation of tyrosines on several platelet proteins is implicated in platelet activation, and I carried out in vitro and in vivo experiments on rats to determine whether PTPase positive and negative platelets differed in their reaction time. I used adhesion to collagen in vitro and in vivo (longitudinal slits in aorta and vena portae) and platelet aggregates in clots formed in vivo. I present evidence that PTPase negative platelets react the fastest, most conspicuously seen in the arterial bleeding under high flow conditions, where the first platelets to respond and adhere are predominantly PTPase negative.     

Physiologic relevance of heterogeneity in the pancreatic beta-cell population

Diabetologia - In vitro studies on purified rat beta cells have indicated a functional diversity among insulincontaining cells. Intercellular differences were found in the rates of glucose-induced...