[Statine and endothelium dysfunction in diabetes]. / Statine e disfunzione endoteliale nel diabete.

Diabetes is associated with significant morbidity and mortality in the setting of acute coronary syndromes. Exists a progressive relationship between glucose levels and cardiovascular risk. Hyperglycemy in fact produces endothelial dysfunction recognised to be a key accessory to diabetic microangiopathy and macroangiopathy. Furthermore diabetics present high levels of cholesterol which elevate the risk of CHD. The statins, for their effects, may represent the fit therapy. The beneficial effects of statins may extend beyond improving the lipid profile. There are several proposed mechanisms for event reduction by lipid-lowering therapy, which include improved endothelium-dependent vasodilation, stabilization of atherosclerotic lesions, reduction in inflammatory stimuli, and prevention, slowed progression, or regression of atherosclerotic lesions (pleiotropic effects). Cellular experiments suggest that statins have an impact on endothelial function by preventing oxidized LDL-induced reduction of nitric oxide production and increased nitric oxide synthesis. Statins also impact chronic inflammation by reducing mitogen (PDGF) responsiveness, inhibiting smooth muscle cell proliferation, inhibiting monocyte chemotaxis and migration, and by reducing macrophage protease production. The absolute clinical benefit achieved may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.

[Sweet syndrome in a female patient with intestinal multiple lipomas and diverticular disease of the colon]. / Sindrome di Sweet in una paziente con lipomi multipli intestinali e malattia diverticolare del colon.

Sweet's syndrome (SS), or acute febrile neutrophilic dermatosis, is a condition characterized by the sudden onset of fever, leukocytosis, and painful, erythematous, well-demarcated papules and plaques which show dense, neutrophilic infiltrates on histologic examination. Myalgias and arthralgias are common. Although it may occur in the absence of other known disease, SS is often associated with hematologic disease (including leukemia), and immunologic disease (rheumatoid arthritis, inflammatory bowel disease). A case of SS is reported. Furthermore the patient presented multiple intestinal lipomas and diverticular colon disease. The authors, on the ground of recent studies which correlate SS with several digestive system disorders, hypothesize an association between acute febrile neutrophilic dermatosis and patient's intestinal diseases. Treatment with systemic corticosteroids is usually successful.

Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review.

Doxorubicin, a very potent and often used anti-cancer drug, has a wide spectrum of biological activity. Classic studies have demonstrated that doxorubicin and other members of the anthracycline family intercalate with DNA and partially uncoil the double-stranded helix. Doxorubicin has a high affinity for cell nuclei: as much as 60% of the total intracellular amount of doxorubicin is found in the nucleus. Once binding to DNA occurs, several consequences may ensue. The binding of anthracyclines to DNA inhibits DNA polymerase and nucleic acid synthesis. In addition, anthracyclines are known to stabilize the otherwise cleavable complex between DNA and homodimeric topoisomerase II enzyme subunits, resulting in the formation of protein-linked DNA double strand breaks. In tumor cells, these anthracycline-induced perturbations are believed to result in a final common pathway of endonucleolytic DNA fragmentation known as apoptosis. Because proliferation is an important determinant of tumor growth, interference with the genome is regarded as the primary cause of the anti-tumor action of doxorubicin. Intercalation with DNA may not be important in the cardiotoxicity associated with doxorubicin therapy (see next section), because cardiac cell proliferation in humans stops after 2 months of age. This review is focussed on the effects of doxorubicin on mechanical performance in skinned cardiac trabeculae after acute and chronic administration of doxorubicin. We look especially at the mechanical performance and the molecular changes observed and related to mechanical performance.

Doxorubicin impairs crossbridge turnover kinetics in skinned cardiac trabeculae after acute and chronic treatment.

Crossbridge dynamics underlying the acute and chronic inotropic effects of doxorubicin (Dox) were studied by application of releasing length steps (amplitude, 0.5-10%) to skinned cardiac trabeculae. Acute incubation of trabeculae with 20 microM Dox for 30 min resulted in a decrease of the velocity of unloaded shortening (V(0), from 9.3 +/- 1.1 to 7.7 +/- 0.7 microm/s, P <.05) and in an increase of the rate of force redevelopment (tau(r), from 56 +/- 4 to 65 +/- 3 ms, P <.05) in response to step amplitudes ranging from 5 to 10%. In contrast, chronic Dox treatment in rats (2 mg/kg/week for 4 weeks) significantly impaired trabecular crossbridge dynamics after step releases of 0.5%. This was reflected by an increase of all time constants describing tension recovery: tau(1), from 10 +/- 1 to 14 +/- 1 ms; tau(2), from 65 +/- 6 to 82 +/- 6 ms; tau(3), from 92 +/- 7 to 293 +/- 67 ms; P <.05. In addition, V(0) was decreased (from 8.6 +/- 0.6 to 6.8 +/- 0.3 microm/s, P <.05) and tau(r) was increased (from 67 +/- 4 to 89 +/- 3 ms; P <.05) in the slack-test. We found that chronic Dox treatment resulted in a shift from the "high ATPase" alpha-myosin heavy chain (MHC) isoform toward the "low-ATPase" beta-MHC isoform in the ventricles (control: alpha-MHC 79 +/- 2% and beta-MHC 21 +/- 2%; Dox-treated: alpha-MHC 53 +/- 2% and beta-MHC 47 +/- 2%; P <.05). The present results show that acute Dox incubation affects the detachment rate of crossbridges, which leads to a delayed relaxation and an arrest of crossbridges in strongly bound states. In contrast, chronic Dox treatment leads to an impairment of both the attachment and detachment rates in the crossbridge cycle, which may be explained by an altered MHC isoform composition in ventricular myocardium. Interfering with Dox-induced alterations of crossbridge kinetics may provide a new strategy to prevent Dox-associated cardiotoxicity.

Corticosterone treatment differentially affects adrenocorticoid receptors expression and binding in the hippocampus and spinal cord of the rat.

We have studied the immediate and long-term effects of high doses of corticosterone (CORT) on mRNA expression and binding properties of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus and spinal cord of rats. Animals were treated with corticosterone (10 mg/d subcutaneously) for 21 consecutive days, and mineralocorticoid and glucocorticoid receptors were studied either 24 h or 2 wk after the last injection. Major results show that corticosterone treatment reduces mineralocorticoid and glucocorticoid receptor maximum binding capacity (Bmax) in both the hippocampus and spinal cord and that this reduction is partially reversed after cessation of treatment. With respect to mRNA expression, in the hippocampus recovery after cessation of treatment is complete. By contrast, in the spinal cord, mineralocorticoid receptor mRNA expression is irreversibly increased after treatment, but the glucocorticoid receptor mRNA level remains unaffected during and after treatment. Thus, these data suggest the presence of distinct regulatory mechanisms for adrenocorticoid receptors in rat brain and spinal cord, in response to long-term exposure to high levels of circulating corticosterone and after recovery from treatment.

Impairment of the actin-myosin interaction in permeabilized cardiac trabeculae after chronic doxorubicin treatment.

The development of chronic cardiotoxicity in cancer patients treated with doxorubicin (DOX) and other anthracycline antineoplastic agents is a major dose-limiting factor. In a previous study, we demonstrated an acute effect of anthracyclines on the actin-myosin contractile system. Here, we report chronic effects of DOX both on the contractile system and on the function of the sarcoplasmic reticulum (SR). Male Wistar rats were treated with DOX (2 mg/kg, i.v., once a week for 4 weeks), whereas control rats received equal volumes of saline. Right ventricular trabeculae were isolated and skinned by exposure to Triton X-100 or saponin at 1, 2, 4, and 6 weeks after the final DOX administration. The maximal tension of trabeculae was similar between DOX-treated and control animals at 1 week posttreatment. At 2, 4, and 6 weeks posttreatment, the maximal tension of trabeculae of DOX-treated animals was significantly decreased by 27, 32, and 37%, respectively (P < 0.01). The rigor tension in trabeculae of DOX-treated animals was similar at 1 week posttreatment but significantly decreased at 2, 4, and 6 weeks posttreatment (by 25, 25, and 37%, respectively; P < 0.01). The ratio between rigor tension and maximal tension was significantly higher in DOX-treated groups as compared to controls (0.39 +/- 0.01 and 0.36 +/- 0.01; P < 0.05). Calcium sensitivity of DOX-treated preparations was significantly decreased as compared to controls (5.59 +/- 0.02 and 5.65 +/- 0.01; P < 0.05), whereas no effects were found on the cooperativity of the regulatory proteins, as measured by the Hill coefficient. The calcium release function of the SR, measured by caffeine (25 mM) stimulation in saponin-skinned trabeculae, was the same in DOX-treated and control groups at all posttreatment periods. The results of the present study show that long-term DOX treatment causes substantial impairment of the cross-bridge interaction in skinned trabeculae, which is reflected by a progressive attenuation of the contractile performance. The function of the SR, however, remains unaffected by DOX treatment in our preparations. The direct effect of chronic DOX treatment on the actin-myosin system provides an additional mechanism through which anthracyclines exert their cardiotoxic effects and may facilitate the development of cardioprotective strategies.

Anthracyclines enhance tension development in cardiac muscle by direct interaction with the contractile system.

Anthracyclines are highly effective anticancer agents which induce a well described but incompletely understood cardiac toxicity. In this study, a direct action of several anthracyclines on the force generating mechanism of heart muscle preparations is described. To allow discrimination between membrane related effects and a direct action of anthracyclines on the actin-myosin contractile system, both inner and outer membranes of cardiac fibres were permeabilized. All anthracyclines tested in this study [doxorubicin (Dox), epirubicin, daunorubicin and idarubicin] showed positive inotropic actions. Dox and epirubicin, which are considered the most cardiotoxic drugs of the anthracycline family, significantly increased the maximal calcium activated tension by 33% (n = 8, P < 0.01) and by 26% (n = 8, P < 0.01) respectively. Daunorubicin and idarubicin increased the maximal tension by 12% and 9% respectively (P = n.s.). Other chemotherapeutic drugs (Taxol and 5-FU) had no effect on maximal tension. To elucidate the mechanism behind this Dox-induced increase in maximal tension, calcium sensitivity curves were measured and rigor experiments were performed. A small but significant increase in pCa50 value (+0.14 +/- 0.03, P < 0.05) was observed only after incubation with 20 microM Dox. Dox acted during the transition to force generating cross-bridges as reflected by the significant increase in rigor tension (12%, P < 0.05) after preincubation of cardiac fibres with Dox. Cycling of cross-bridges is a prerequisite for Dox to increase tension because no effect on tension was seen after Dox was added to fibres in an established rigor. In summary, anthracyclines increased the maximal tension in cardiac muscle fibres by direct interaction with the actin-myosin cross-bridges. Changes in calcium sensitivity are unlikely to contribute to the observed increase in maximal tension. The rise in tension as is seen in this experimental set-up may contribute to destruction of the contractile machinery of cardiac muscle. In agreement with this hypothesis is the observation that the more cardiotoxic anthracyclines induced the largest increase in maximal tension of the cardiac fibres.

Deficiency of nitric oxide in allergen-induced airway hyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study.

1. Using a guinea-pig model of allergic asthma, we investigated the role of nitric oxide (NO) in allergen-induced airway hyperreactivity after the early asthmatic reaction, by examining the effects of the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on the responsiveness to methacholine and histamine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge. 2. All animals developed airway hyperreactivity to inhaled histamine at 6 h after ovalbumin challenge, with a mean 3.11 +/- 0.45 fold increase in sensitivity to the agonist (P < 0.001). 3. In perfused tracheal preparations from the ovalbumin-challenged guinea-pigs, the maximal responses (Emax) to methacholine and histamine were significantly enhanced compared to controls, both after intraluminal (IL) and extraluminal (EL) administration of the contractile agonists. In addition, a small but significant increase in the pD2 (-log10 EC50) for IL and EL methacholine and for IL histamine was observed. As a consequence, the delta pD2 (EL-IL) for histamine was slightly decreased from 1.67 +/- 0.13 to 1.23 +/- 0.14 (P < 0.05). However, the delta pD2 for methacholine was unchanged (1.85 +/- 0.11 and 1.77 +/- 0.12, respectively; NS). 4. Incubation of control tracheae with 100 microM L-NAME (IL) significantly enhanced the Emax for both IL and EL methacholine and histamine to approximately the same degree as observed after ovalbumin challenge, with no effect on the pD2 and delta pD2 for both agonists. On the contrary, L-NAME had no effect on Emax and pD2 values of tracheal preparations from ovalbumin-challenged guinea-pigs. 5. L-NAME (10 microM-1 mM) had no effect on methacholine-induced contraction of isolated tracheal strip preparations obtained from control animals, indicating that L-NAME has no antimuscarinic effect on tracheal smooth muscle. 6. Histological examination of the intact tracheal preparations indicated epithelial and subepithelial infiltration of eosinophils after ovalbumin challenge. However, no apparent damage of the airway epithelium was observed in these preparations. 7. The results indicate that a deficiency of NO contributes to allergen-induced airway hyperreactivity after the early asthmatic reaction and that this deficiency appears not to be due to epithelial shedding.

Differential regulation of adrenocorticoid receptors in the hippocampus and spinal cord of adrenalectomized rats.

Using multiple polymerase chain reaction assay and cytosolic receptor binding assay we studied type I, mineralocorticoid receptor (MR), and type II, glucocorticoid receptor (GR), adrenocorticoid receptors expression in rat hippocampus and spinal cord, at various times after adrenalectomy: 12 hr, 24 hr, 3 days, and 1 week. Analysis of the data demonstrates that in hippocampus the expression of MR and GR mRNA was not significantly affected by adrenalectomy. On the contrary, Bmax of MR was significantly increased at each time post-surgery, with only slight modifications of Kd. Bmax and Kd for GR showed a significant increase after 3 days and 1 week. In the spinal cord, MR mRNA was increased 12 hr after adrenalectomy, reaching a maximum at 3 days. Bmax of MR was also significantly increased after 3 days, whereas its Kd remained unchanged for the entire duration of the the study. Both GR mRNA and binding parameters were poorly affected by adrenalectomy. The results of the present experiments demonstrate that the absence of adrenocortical hormones influences differentially MR and GR expression in hippocampus and spinal cord, suggesting the existence of various and independent mechanisms of regulation of adrenocorticoid receptor.

Low-field magnetic resonance imaging in the evaluation of mechanical and biological heart valve function.

Magnetic resonance imaging (MRI) has been frequently considered unsafe for patients with ferromagnetic implants: risks to be considered include induction of electric current, heating and dislocation of the prosthesis. Previous in vitro and in vivo studies have indicated the possibility of performing MRI examinations on patients with prosthetic heart valves. The aim of our study was to verify the presence of artifacts at the level of the prosthetic heart valve in vivo using a low-field MR unit (0.2 T) and to define the possibility of a functional analysis of the valve in patients with biomedical or mechanical prostheses. We evaluated 14 patients surgically treated for implantation of nine biological and seven mechanical aortic and mitral valves. A low-field MR unit (0.2 T) was employed using cine-MR technique on long- and short-axis view. The images were acquired on planes parallel and perpendicular to the valvular plane. Semiquantitative analysis with double-blind evaluation for definition of the extent of the artifact was performed. Three classes of artifacts were distinguished from minimal to significant. The examinations showed the presence of minimal artifacts in all biological heart valves and moderate artifacts in mechanical valves giving good qualitative data on blood flow near the valve. Analysis of the flow behind the valve showed signs of normal function in 13 prostheses and pathological findings in the remaining three. In these latter cases, MRI was able to define the presence of a pathologic aortic pressure gradient, mitral insufficiency and malpositioning of the mitral valve causing subvalvular turbulence. Nevertheless, we believe that the application of velocity-encoding cine-MR is more promising than semiquantitative analysis of artifacts.

Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding.

To investigate the role of neuropeptide Y (NPY) in the paraventricular nucleus of the hypothalamus (PVN) in the regulation of autonomic outflow, hormonal (plasma insulin and catecholamines), metabolic (blood glucose and plasma free fatty acids) and cardiovascular (heart rate and main arterial pressure) indices were measured before, during, and after bilateral infusion of NPY (1.0, 0.2, 0.04 micrograms in 1 microliter synthetic CSF) into the PVN of conscious resting rats. Administration of the highest dose (1.0 microgram/microliter) caused bradycardia and reduced circulating norepinephrine levels without effecting circulating fuels, insulin or epinephrine. In a second experiment, feeding-induced changes in hormonal and metabolic indices were assessed after NPY administration (1.0 microgram/microliter) into the PVN. During and after feeding, NPY enhanced the feeding-induced insulin response (P < 0.01) and attenuated the feeding-induced norepinephrine response (P < 0.05). The results of the present study suggest that stimulation of NPY receptors in the PVN decreases sympathetic activity and increases parasympathetic activity in resting conditions, and that these effects are potentiated during feeding.

Renal sarcoidosis coexisting with hypernephroma.

Hypernephroma arising in a kidney infiltrated by sarcoidosis is unusual. To date, there has been no such case reported. The hypernephroma was suspected by the presence of localized parenchymal calcifications and confirmed by selective renal angiography.