Chronic Pathological Processes Research Articles

Staurosporine-induced apoptosis in astrocytes is prevented by A 1 adenosine receptor activation

Astrocyte apoptosis occurs in acute and chronic pathological processes at the central nervous system and the prevention of astrocyte death may represent an efficacious intervention in protecting neurons against degeneration. Our research shows that rat astrocyte exposure to 100 nM staurosporine for 3 h caused apoptotic death accompanied by caspase-3, p38 mitogen-ed protein kinase (MAPK) and glycogen synthase kinase-3β (GSK3β) activation. N 6-chlorocyclopentyladenosine (CCPA, 2.5–75 nM), a selective agonist of A 1 adenosine receptors, added to the cultures 1 h prior to staurosporine, induced a dose-dependent anti-apoptotic effect, which was inhibited by the A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine. CCPA also caused a dose- and time-dependent phosphorylation/activation of Akt, a downstream effector of cell survival promoting phosphatidylinositol 3-kinase (PI3K) pathway, which in turn led to inhibition of staurosporine-induced GSK3β and p38 MAPK activity. Accordingly, the anti-apoptotic effect of CCPA was abolished by culture pre-treatment with LY294002, a selective PI3K inhibitor, pointing out the prevailing role played by PI3K pathway in the protective effect exerted by A 1 receptor activation. Since an abnormal p38 and GSK3β activity is implicated in acute (stroke) and chronic (Alzheimer's disease) neurodegenerative diseases, the results of the present study provide a hint to better understand adenosine relevance in these disorders.

Enriched environment and astrocytes in central nervous system regeneration

Rehabilitation medicine is entering a new era, based on the knowledge that the central nervous system has a substantial capacity for repair and regeneration. This capacity is used in 3 distinct but overlapping situations: (i) routine housekeeping throughout life (i.e. taking care of normal wear-and-tear); (ii) older age, when functional reserves of various kinds are depleted, resulting in cognitive, motor, and other deficits; and (iii) contexts in which a neurological deficit reflects an acute or chronic pathological process, such as neurotrauma, stroke, or neurodegenerative disease. The positive message here is two-fold. First, some aspects of regeneration occur even in the adult and ageing brain and spinal cord, and we are starting to unravel the underlying molecular mechanisms. Secondly, novel therapeutic approaches and targets are emerging that will substantially increase the efficiency and efficacy of rehabilitation and will transform rehabilitation into a discipline focusing both on its traditional domain and on prevention, ultimately across all the age categories. This review attempts to sum up the present knowledge about an enriched environment, currently the single most efficient plasticity- and regeneration-promoting paradigm. It also summarizes research showing that astrocytes - considered only years ago merely to nurse and support neurones - are a novel and highly interesting target for regenerative strategies in the brain and spinal cord.

Otoemisja akustyczna wywołana trzaskiem u dzieci z młodzieńczym idiopatycznym zapaleniem stawów

Juvenile idiopathic arthritis (JCA) is an inflammatory systemic disease of connective tissue which etiology is still unknown. Progressive arthritis is the basic symptom, with pain, oedema, stiffness and movement impediment are typical for. Chronic process of arthritis might be accompanied by rheumatoid nodes, pericarditis, myocarditis, changes in the lungs and kidney, which appear with various frequency and indicates on systemic form of disease. The incudo-malleolar and incudo-stapedial joints are synovial in type. It should be expected that these joints might be affected by rheumatoid changes similar to those observed in joints in other parts of the body. Copeman was the first who described transient conductive hearing loss in patients with exacerbated rheumatoid process--and he called it oto-arthritis. He stressed that it was the consequence of the rheumatoid lesions in joints of ear ossicules. In adult patients with JCA in 60% of cases the perceptive hearing-loss is observed possibly because of the chronic course of the disease and its farmacological treatment. The aim of the study was the assessment of the functional state of the peripheral part of hearing organ on the basis of TEOAE. This study was preceded by examination of hearing with pure tone audiometry, speech audiometry, high frequency audiometry and impedance audiometry. The analysis of results was done in correllation to form of JCA and its activity. The research was carried out on the group of 45 children suffering from JCA; 14 boys and 31 girls between 5-18 years of age. In all children from experimental group the examination was performed in the active phase of disease process. Mean duration of the disease was 33.5 month. In all children TEOAE was obtained no matter on the form of JCA. Children with systematicus form of JCA--more aggressive type than others--have the recordings of TEOAE with small amplitude and narrow range of frequency. Those results show that rheumatoid lesions in conductive mechanism of the middle ear are insufficient for the development of the conductive hearing loss. As a results of chronic pathological process destructions of hearing organ may lead to the cochlear lesions and this way to perceptive hearing loss.

Activation of Platelet Function Through G Protein–Coupled Receptors

Because of their ability to become rapidly activated at places of vascular injury, platelets are important players in primary hemostasis as well as in arterial thrombosis. In addition, they are also involved in chronic pathological processes including the atherosclerotic remodeling of the vascular system. Although primary adhesion of platelets to the vessel wall is largely independent of G protein-mediated signaling, the subsequent recruitment of additional platelets into a growing platelet thrombus requires mediators such as ADP, thromboxane A(2), or thrombin, which act through G protein-coupled receptors. Platelet activation via G protein-coupled receptors involves 3 major G protein-mediated signaling pathways that are initiated by the activation of the G proteins G(q), G(13), and G(i). This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein-mediated signaling pathways.

Morphological and immunological analysis of the oral mucosa in tobacco smoking and odontopreparation

Tobacco smoking causes pronounced structural reorganization of the gingival mucosa and its atrophic changes. Odontopreparation stimulates destructive processes in the gingival mucosa promoting activation of local immunity (stimulation of immunoglobulin synthesis). Significant differences in the local humoral immunity (IgG dysimmunoglobulinemia) and cytokine spectrum in nonsmoking and tobacco-smoking patients were detected. Subcompensated level of immune resistance in tobacco smokers prompts referring them to a group at a high risk of chronic pathological processes of the oral cavity.

Effects of age on relationship of alcohol drinking and obesity to atherosclerotic risks

Atherosclerosis is a chronic pathological process in the arteries, in which a variety of its risk factors, such as hypertension, dyslipidemia, smoking, diabetes mellitus and obesity, are involved. Atherosclerotic progress is also closely linked with aging. We investigated effects of age on the relationships of alcohol drinking and obesity to atherosclerotic risks. Elevating effects of light drinking on blood pressure were significant in middle‐aged and relatively old subjects but not in young subjects. The decreasing effects of light drinking on blood LDL cholesterol were significant in relatively young and middle‐aged subjects, but not in elderly subjects, while increasing effects of light drinking on blood HDL cholesterol were significant in young, middle‐aged, and elderly groups. In patients with type 2 diabetes, light drinking significantly decreased aortic pulse‐wave velocity, which reflects atherosclerotic progress, without significant changes in blood HDL and fibrinogen levels, and this tendency was also found in elderly diabetes patients. Body mass index (BMI) was significantly correlated with arterial pressure and serum tryglyceride, HDL cholesterol, uric acid, and sialic acid levels in elderly patients with type 2 diabetes. Thus, age may be an important factor that affects the relations of some atherosclerotic risk factors to atherosclerotic progress.

Morphogenesis of chronic lung lesions under the influence of proteolytic enzymes

Acute and chronic pathological processes induced in murine lungs by influenza virus or intranasal administration of proteolytic enzymes chymotrypsin and proteinase K were compared. Histologic and electron microscopic analysis showed that a number of characteristics of these two processes were similar. These characteristics included serosanguineous lung edema on days 1–5 postinfection, infiltration of lung tissue with cell elements, metaplasia of bronchial epithelium, and presence of mycoplasma in chronic pneumonia foci. These parameters persisted during 150 days of the experiment without regression. The results suggest the key role of primary cell destruction and proteolytic activity enhancement in the development of chronic influenza-induced pneumonia.

Epidermal growth factor is a motility factor for microglial cells in vitro: evidence for EGF receptor expression.

Epidermal growth factor (EGF) and its receptor are present in the central nervous system and modulate a variety of neural functions. Here we show that microglial cells, the brain-intrinsic macrophages, express the receptor for EGF and migrate in response to EGF. Transcripts encoding the EGF receptor could be detected in purified microglial cultures obtained from newborn mouse cortex. More specifically, cDNA fragments derived from EGF receptor mRNA could be amplified from 21% of electrophysiologically characterized microglial cells by the use of a single-cell reverse transcription-polymerase chain reaction method. Expression of the protein was confirmed on rat microglia by flow cytometry. EGF dose-dependently stimulated chemotactic migration, as revealed with a microchemotaxis assay. The dose-response curve peaked-at 10 ng/ml EGF, reaching a 3-fold increase in migration over the unstimulated control; migration was about half of that induced by complement 5a (10 nM), a previously described microglial chemoattractant. Chequerboard analysis showed that EGF-induced motility was composed of both chemotaxis and chemokinesis. In contrast to its pronounced effect on cell motility, EGF (0.01-10 ng/ml) was not a mitotic signal for microglia, as shown by lack of bromodeoxyuridine incorporation. Acute and chronic pathological processes within the brain stimulate the synthesis and release of immunoregulators and growth factors (including EGF) that play a major role in the brain's response to injury. EGF may serve as a paracrine factor to direct microglial cells to the lesion site. Moreover, since EGF is secreted by activated microglia themselves in vivo, it may act as an autocrine modulator of microglial cell function.

Pressure-Heart Rate Relationship in Intact and After Stepwise Elimination of Three Major Baroreflex Loops in Dogs

Systemic arterial blood pressure (BP)-heart rate (HR) relationship (the pressor test) is often used as an index of baroreflex. We evaluated this index by simultaneously comparing BP-HR, right carotid sinus pressure (CSP)-nerve action potentials (NAP), and NAP-HR relationships in dogs anesthetized with pentobarbital. BP was increased or decreased stepwise by intravenous (IV) infusions of phenylephrine or sodium nitroprusside, respectively. In nine dogs BP-HR and CSP-NAP relationships were measured and NAP-HR relationship was constructed before and after sequential and stepwise sectioning of the left aortic depressor nerve (LADN), the right aortic depressor nerve (RADN), and blockade of the left carotid sinus nerve (BLK) with 1% lidocaine. We found that HR was a negative sigmoidal function of BP in intact dogs. Linear slope of this relationship was significantly reduced after sectioning of LADN and RADN, but returned toward baseline after BLK. NAP was a positive sigmoidal function of CSP in intact dogs. Linear slope of this relationship was significantly depressed after sectioning of LADN and RADN. However, after BLK, the slope surpassed control, suggesting the existence of a central communication between the two carotid sinuses. HR was a negative function of NAP in intact dogs. However, as the other baroreflex feedback loops were eliminated, the slope of the NAP-HR relationship approached zero indicating that a closed integrated parallel feedback system is required for reflex regulation of HR. Our findings suggest that under normal conditions the pressor test is a valid index for baroreceptor function, but its use may not be warranted in chronic pathological states, such as atherosclerosis and hypertension. However, in contrast to the present acute experimental model, chronic pathological processes may not develop in sequence, and baroreceptor function on the affected site may not be completely eliminated from the baroreceptor loop such as performed in this study. (Anesth Analg 1996;83:965-74)

Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection

Carvedilol is a vasodilating beta-blocker currently marketed for the treatment of mild to moderate hypertension and application is being filed to the FDA for treatment of congestive heart failure. Carvedilol reduces peripheral vascular resistance by blocking arterial alpha 1-adrenoceptors, thereby producing vasodilation, while preventing reflex tachycardia by blocking cardiac beta 1- and beta 2-adrenoceptors. In addition to the safety and efficacy of carvedilol as an antihypertensive agent, experimental studies indicate that carvedilol also provides significant cardioprotection in animal models of acute myocardial infarction as well as protection against the vascular remodelling that occurs following injury of the vasculature. Recent pharmacological studies have uncovered several novel properties of carvedilol which may function to protect the heart and vasculature from chronic pathological processes, such as ischaemia, atherosclerosis and the remodelling that occurs in the heart and blood vessels as a consequence of pressure overload, injury or shear stress. Specifically, carvedilol, likely as a result of the carbazol moiety, is a potent anti-oxidant. In physicochemical, biochemical and cellular assays carvedilol and several of its metabolites inhibit lipid peroxidation, scavenge oxygen free radicals, inhibit the formation of reactive oxygen radicals and prevent the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol blocks the oxidation of low-density lipoproteins (LDL), and thereby prevents the formation of oxidized-LDL which is believed to stimulate foam cell formation and augment the development of atherosclerotic plaque. The ability of carvedilol to prevent the formation of oxidized LDL, in addition to the general anti-oxidant properties of the compound, results in the protection of the endothelium from oxygen free radical injury, and thereby prevents the subsequent events triggered by endothelial damage. Recently, carvedilol has also been shown to inhibit vascular smooth muscle cell proliferation and migration. Because carvedilol can inhibit vascular smooth muscle cell proliferation induced by a wide variety of mitogens (e.g. growth factors, angiotensin II, endothelin, thrombin), it is likely that the site of inhibition occurs at some point beyond the specific mitogen receptors, possibly at a distal common pathway that affects the smooth muscle cell cycle. These unique activities of carvedilol have also been confirmed in vivo in a rat model of neointimal formation following vascular injury by balloon angioplasty, where vascular smooth muscle cell migration and proliferation are the key processes involved in the formation of neointima leading to vascular stenosis. In this model, carvedilol suppressed neointimal growth to a remarkable extent ( > 85% inhibition of neointimal formation) at a dose that is similar to the antihypertensive dose used clinically in hypertensive patients. Taken together, these unique multiple actions of carvedilol provide not only for adequate control of elevated blood pressure, but may also provide for protection of the heart and vasculature from secondary damage due to hypertension itself, as well as from other causes, such as ischaemia, pressure overload, shear stress, vascular injury and atherosclerosis.

Histologic evidence of old intrauterine bleeding is more frequent in prematurity

OBJECTIVE: Our purpose was to study the incidence and location of histologic evidence of intrauterine bleeding in preterm and term placentas. STUDY DESIGN: A total of 462 consecutive placentas delivered at <32 weeks' gestation, from which cases of placenta previa, stillbirth, and multiple gestation were excluded, were compared with 108 consecutive term placentas (with similar exclusion criteria) in regard to the presence of hemosiderin in decidua of basal plate or placental membranes. Of the 462 preterm cases, 448 charts made specific reference to the presence or absence of vaginal bleeding. Bloody show alone was not considered bleeding. The blinded scoring of lesions (including acute ascending infection, uteroplacental vascular pathologic processes and related ischemic damage, chronic inflammation, and coagulation related lesions) was analyzed by contingency tables ( p < 0.05 significant). RESULTS: A total of 196 of 462 (43%) preterm placentas had any decidual hemosiderin compared with one of 108 (0.8%) at term ( p < 0.00001). Among the preterm cases, hemosiderin was significantly more common in preeclampsia ( 45 76 , 60%) and in cases clinically diagnosed as nonhypertensive abruptio placentae ( 21 33 , 64%) than in premature membrane rupture ( 72 192 , 37.5%) and preterm labor ( 58 161 , 36%, p < 0.003 ). The incidence of placental lesions in preterm cases with extraplacental membrane hemosiderin was not different than it was in cases without hemosiderin. Placental lesions related to basal-plate decidual hemosiderin in the preterm cases were villous infarct ( p < 0.0001), uteroplacental vessels with absence of phsyiologic change ( p < 0.003) and increased numbers of circulating nucleated erythrocytes ( p < 0.0007), uteroplacental thrombosis ( p < 0.0001), and villous fibrosis ( p < 0.0001) and hypovascularity ( p < 0.0001). Among the preterm cases, 23 of 48 (48%) with first-trimester bleeding, 33 of 66 (50%) with second-trimester bleeding, and 31 of 64 (48%) with multiple episodes of bleeding had decidual hemosiderni ( p < 0.0001). A clnical history of gestational bleeding was significantly less common in cases of preterm preeclampsia with histologic evidence of bleeding (four of 73, 5.5%) than in nonhypertensive abruptio placentae ( 18 31 , 58%), premature rupture of membranes ( 52 183 , 28%), or preterm labor ( 31 161 , 19%, p < 0.0001 ). Hemosiderin was not related to clinical bleeding <72 hours of delivery ( p > 0.20). CONCLUSIONS: Decidual bleeding is common in all clinical types of preterm birth and is most common in preterm preeclampsia and nonhypertensive abruptio placentae. A clnical history of bleeding is not correlated with the presence of decidual hemosiderin. Bleeding in the basal plate is related to histologic evidence of chronic uteroplacental vascular pathologic processes, which in cases of spontaneous prematurity (premature rupture of membranes, preterm labor, nonhypertensive abruption placentae) may be associated with decidual bleeding which occasionally may be clinically manifested as gestational bleeding.

Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection.

Carvedilol is a vasodilating, beta-adrenoceptor antagonist currently marketed for the treatment of mild to moderate hypertension. Carvedilol acts to reduce total peripheral resistance by blocking peripheral vascular alpha 1-adrenoceptors, thereby producing systemic arterial vasodilation, while at the same time inhibiting reflex tachycardia through the blockade of myocardial beta-adrenoceptors. In addition to its established efficacy and safety as an antihypertensive agent, carvedilol has been shown to produce significant cardioprotection in experimental animal models of acute myocardial infarction, with the most dramatic effect being observed in the pig model of myocardial ischaemia and reperfusion, where the reduction in infarct size reached 91%. Recent pharmacological studies have revealed additional novel properties of carvedilol which may account for the marked protection produced by the drug in the ischaemic myocardium and which may also result in protection against other chronic pathological processes, such as atherosclerosis and acute vascular injuries. The latter arise from surgical procedures, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Specifically, carvedilol, as well as some of its hydroxylated metabolites, are potent antioxidants. In physicochemical, biochemical and cellular assays, carvedilol and several of its metabolites prevent lipid peroxidation and the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol and its metabolites prevent the oxidation of LDL to oxidized LDL, the latter being directly cytotoxic and known to activate monocytes/macrophages and to stimulate foam cell formation. In addition, carvedilol was found to inhibit both rat and human vascular smooth muscle cell proliferation and migration.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural analysis of liver biopsy specimens in chronic hepatitis and hepatopathy

Three types of morphogenesis of a chronic general pathological process in the liver are distinguished: active hepatitis, hepatitis attended by a pronounced and early tendency toward sclerosis, and hepatopathy, a morphological phenotype of parenchymal dystrophy in the absence of a stromal inflammatory component, which is defined as a syndrome of regenerative-plastic insufficiency.

Interleukin-1β depresses calcium currents in CA1 hippocampal neurons at pathophysiological concentrations

Interleukin-1 is present in the central nervous system (CNS) during acute and chronic pathological processes. In the present study, we examined the interaction between recombinant human interleukin-1β (rhIL-1β) and the voltage-dependent calcium (Ca 2+) current using the whole-cell patch clamp technique. RhIL-1β depressed the voltage-gated Ca 2+ current in acutely dissociated guinea pig hippocampal CA1 neurons. This depression is rapid and is observed at pathophysiological concentrations (⩾ 1.97 pg/10 μl)- Concomitant application of rhIL-1β and rhIL-1 receptor antagonist had no effect indicating neuroactive specificity of rhIL-1β. The depression of the inward Ca 2+ current by IL-1β may play a role in: 1. 1) the regulation of neuronal excitability; 2. 2) the induction of neurological manifestations during disease; and 3. 3) in the induction and/or progression of neurodegenerative processes.

Intracerebroventricular administration of a specific IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1β

Intracerebroventricular (ICV) microinfusion of recombinant human interleukin-1β (rhIL-1β, 1.0 ng/rat) suppressed the short-term (2 h) food and water intakes in rats. ICV infusion of recombinant human IL-1 receptor antagonist (rhIL-1ra) had no effect on food or water intake. Concomitant ICV infusion of rhIL-1β (1.0 ng/rat) and increasing concentrations of rhIL-1ra (25 to 1000 ng/rat) resulted in a dose-dependent inhibition of the short-term food and water intake suppression induced by rhIL-1β. The highest doses of rhIL-1ra (500 and 1000 ng/rat) completely blocked the food and water intake suppression induced by rhIL-1β. This suggests specificity of IL-1β suppression of short-term feeding and drinking by a direct action in the central nervous system (CNS). This ability of rhIL-1ra may have potential therapeutic implications in acute and chronic pathological processes associated with increased levels of IL-1 and appetite suppression.

Dexamethasone inhibits food intake suppression induced by low doses of interleukin-1 β administered intracerebroventricularly

Intracerebroventricular (ICV) microinfusion of recombinant human interleukin-1β (rhIL-1β, 0.125 to 2.0 ng/rat) dose-dependently suppressed 2 h and nighttime food intake in rats. The following daytime food intake did not change or increased. ICV infusion of bovine serum albumin (BSA), or heat-treated rhIL-1β had no effect on food intake. Pretreatment with dexamethasone (200 μg/rat, intraperitoneal) blocked the food intake suppression induced by low doses of rhIL-1β. This ability of dexamethasone, a synthetic corticosteroid, may have potential therapeutic implications in acute and chronic pathological processes associated with increased levels of IL-1 and appetite suppression.

Immunoregulators in the nervous system

The nervous system, through the production of neuroregulators (neurotransmitters, neuromodulators and neuropeptides) can regulate specific immune system functions, while the immune system, through the production of immunoregulators (immunomodulators and immunopeptides) can regulate specific nervous system functions. This indicates a reciprocal communication between the nervous and immune systems. The presence of immunoregulators in the brain and cerebrospinal fluid is the result of local synthesis--by intrinsic and blood-derived macrophages, activated T-lymphocytes that cross the blood-brain barrier, endothelial cells of the cerebrovasculature, microglia, astrocytes, and neuronal components--and/or uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. Acute and chronic pathological processes (infection, inflammation, immunological reactions, malignancy, necrosis) stimulate the synthesis and release of immunoregulators in various cell systems. These immunoregulators have pivotal roles in the coordination of the host defense mechanisms and repair, and induce a series of immunological, endocrinological, metabolical and neurological responses. This review summarizes studies concerning immunoregulators--such as interleukins, tumor necrosis factor, interferons, transforming growth factors, thymic peptides, tuftsin, platelet activating factor, neuro-immunoregulators--in the nervous system. It also describes the monitoring of immunoregulators by the central nervous system (CNS) as part of the regulatory factors that induce neurological manifestations (e.g., fever, somnolence, appetite suppression, neuroendocrine alterations) frequently accompanying acute and chronic pathological processes.

Interleukin‐1, Anorexia, and Dietary Fatty Acidsa

IL-1 and other cytokines mediate several components of both acute and chronic pathological processes observed in patients with cancer and chronic infection. Cachexia ranks as one of the more prominent aspects of several diseases and the present studies demonstrate that recombinant forms of either IL-1 beta or IL-1 alpha reduce food intake in experimental animals. In meal-fed rats, a single injection of IL-1 induces a 40% reduction [table: see text] in food intake, whereas daily injections slow normal weight gain. The anorexic response to IL-1 is prevented by cyclooxygenase inhibitors, although this is unlikely due to a central nervous system effect. Reduced production of cyclooxygenase products such as PGE2 also occurs in rats fed supplemental N-3 fatty acids, and this was associated with a decreased anorexic response to IL-1. Therefore, one mechanism by which IL-1 induces anorexia appears to require cyclooxygenase metabolites, such as PGE2. N-3 fatty acid supplements also reduce the severity of host responses to inflammation and infection. Part of this is due to decreased cyclooxygenase products; however, part also may be due to reduced synthesis of IL-1. Blood leukocytes from human subjects taking oral N-3 supplements produce 60% less IL-1. The ability of N-3 fatty acids to reduce IL-1 synthesis appears to be via the lipoxygenase pathway. Therefore, N-3 fatty acids may be beneficial to patients with anorexia, since such supplements would decrease both the anorexic response to IL-1 via reduced cyclooxygenase metabolites and the production of IL-1, via altered lipoxygenase metabolites.

The Biology of Interleukin-1 and Its Relevance to Hemodialysis

The host responds to infectious, toxic inflammatory and immunological challenges with a remarkably consistent set of changes which are often grouped together and called the acute phase response. This response includes fever, negative nitrogen balance, increased synthesis of certain hepatic proteins, decreases in plasma iron and zinc levels and increases in circulating neutrophils. The continued presence of the disease results in the persistence of acute phase changes such that these changes can also be markers of a chronic pathological process. The ability of the host to produce several components of the acute phase response is due to the synthesis and release of a mediator peptide derived from activated mononuclear phagocytes and now called interleukin-1 (IL-1). Many of the clinical and laboratory changes noted in chronic hemodialysis are indicative of an acute phase response and are probably mediated by IL-1. This review considers the production and biological properties of IL-1 and the role of this mediator in host responses. In addition, particular attention is paid to the importance of monocyte activation and IL-1 release which may be a consequence of hemodialysis.

The Sequential Analysis of Cancer Development

Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.