Melanocortins as innovative drugs for ischemic diseases and neurodegenerative disorders: established data and perspectives.

Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases.

Assessment of the health status in the Massa Lombarda cohort: a preliminary description of the program evaluating cardio-cerebro-vascular disease risk factors and quality of life in an elderly population.

The Massa Lombarda program (MLP) is the first step of a European multi-center program, promoted and coordinated from Bologna University's Academic Spin off Health Research and Development, which attempts to manage advanced sanitary research in general population. The instant individual definition (IID) study is the first phase of the program concerning the study of risk factors (RF) and early diagnosis of coronary heart disease (CHD), through a new diagnostic technology called myocardial perfusion scoring system (MPS). The study consists of a longitudinal observational epidemiological investigation of adult population (above 25 years of age) resident in Massa Lombarda (Ravenna), with the survey of social and biological parameters. The elderly part of the population (1000 subjects above 75 years) was submitted to a more complex analysis, as part of the study on health status in European aging populations, aimed at revealing the determinants influencing the healthy aging, and at identifying their impact on mortality,cardiovascular and respiratory morbidity, disability and decline of quality of life. Laboratory analyses were aimed at identifying the following factors: (i) Genetic markers related to pro and anti-inflammatory cytokine- codifying genes. (ii) Oxidative stress-involved molecules,and inflammation-involved genes, and more in general genes involved in the brittleness(iii) (ApoE). Appraising the degree of interaction with non-genetic factors, like measurable immunological markers in the peripheral blood, markers of reactions to oxidative stress,evaluation of metabolic parameters. Moreover, old population is expected to answer the questionnaires for evaluation of the dietary habits, physical activity, self-sufficiency,cognitive ability, motor coordination, perceived stress and social relationships.

Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1-24).

Haemorrhagic shock, usually as a consequence of major trauma, is the most frequent cause of death among people younger than 40 years. Reports indicate that melanocortin peptides are effective in reversing haemorrhagic shock. We found that in patients with aortic-dissection-induced haemorrhagic shock, the addition of an early intravenous bolus injection of the melanocortin andrenocorticotrophic hormone (ACTH)-(1-24) to standard treatment significantly improved cardiovascular function and increased survival rate. Because administration of ACTH-(1-24) is simple, and because melanocortin peptides have no acute toxicity, their use in the early critical care of patients in shock should be more extensively assessed.

Is the tricuspid position suitable for testing replacement bioprosthetic valves in the sheep model?

BACKGROUND AND AIM OF THE STUDY: Glutaraldehyde may promote calcification in xenograft tissue by the action of toxic aldehyde group residues involved in the cross-link process. Post-fixation treatment with homocysteic acid (HA) neutralizes this toxicity by bonding aldehyde groups, and enhances biocompatibility on the basis of strongly electronegative sulfonic groups. Previous studies in a rat subcutaneous model showed significant long-term mitigation of mineralization of glutaraldehyde-fixed pericardium treated with HA. This study aimed to assess the anticalcific efficacy of HA in a valvular implant in growing sheep, and establish if the tricuspid position is suitable for testing replacement bioprosthetic valves. METHODS: Eleven stented 25 mm Pericarbon bioprostheses (seven HA-treated, four standard) were implanted in the tricuspid position of growing sheep. Infective endocarditis occurred in four prostheses. Among the remaining seven, three (two HA-treated, one standard) were explanted at 91 days (mid-term), and four (two HA-treated, two standard) at 140-141 days (long-term). All explants were studied by gross, X-ray, light, transmission and scanning electron microscopy, as well as by atomic absorption spectroscopy. RESULTS: No histological and ultrastructural difference in tissue preservation were observed between HA-treated and standard Pericarbon bioprostheses, either in the mid or long term. The mean calcium content of mid-term HA-treated explants was 9.55 mg/g compared with 16.26 mg/g in mid-term standard explants. Only one late standard explant failed as a result of severe stenosis caused by massive dystrophic calcification. Among four late explants, two showed significant increase in mineralization (HA-treated, 87.45 mg/g; standard, 181.20 mg/g), while two showed calcium contents similar to those in mid-term explants (HA-treated, 11.96 mg/g; standard, 17.32 mg/g). CONCLUSION: Post-fixation treatment with HA preserves structural properties after tricuspid implantation in growing sheep. The tricuspid implant in the sheep model failed to reproduce remarkable accelerated progressive calcification in all xenografts so as to demonstrate a significant difference between HA and standard explants. The tricuspid position for testing replacement bioprosthetic valves should be abandoned, and investigations repeated with the prosthesis in the mitral position.

Protective effect of low frequency low energy pulsing electromagnetic fields on acute experimental myocardial infarcts in rats.

This series of experiments assesses the effect of exposure to low-frequency pulsing electromagnetic fields (PEMFs) in 340 rats with acute experimental myocardial infarcts. The left anterior descending artery was ligated with suture thread, and the rats underwent total body exposure to PEMFs until they were killed. Twenty-four hours after surgery, the necrotic area was evaluated by staining with triphenyltetrazolium chloride. A significant reduction of the necrotic area was observed in the animals exposed to PEMFs compared with the nonexposed controls. Exposure for up to 6 days does not appear to affect the area of necrosis, although in exposed animals an increase of vascular invasion of the necrotic area is observed: 24.3 % as against 11.3 % in controls. No effect on the necrotic area size from exposure was found when the left anterior descending artery was occluded for 60 min, followed by reperfusion. The results reported show that exposure to PEMFs is able to limit the area of necrosis after an acute ischemic injury caused by permanent ligation of the left anterior descending artery. These data are in agreement with the protective effect of PEMFs observed on acute ischemia in skin free flaps in rats and in cerebral infarcts in rabbits.

Femoral Arterial Hemostasis using the Angio-Sealª System after Coronary and Vascular Percutaneous Angioplasty and Stenting.

The procedures of left cardiac catheterization and revascularization by angioplasty are associated with a substantial risk of hemorrhagic complications. This risk increases clearly in patients with an intravascular stent who require early high doses of anticoagulant therapy. The first purpose of our study was to evaluate the effectiveness of a mechanical system of femoral hemostasis (Angio-Sealª, Sherwood Davis & Geck, St. Louis, Missouri) deployed in a group of 411 consecutive patients (302 males, 109 females, mean age 59 +/- 15) who successfully underwent percutaneous angioplasty (PA) and application of an intravascular stent (378 coronary, 33 vascular). The arterial closure system consists of a small absorbable anchor and a collagen pad connected to a suture thread which, at the end of the procedure, is positioned by percutaneous introduction at the site of the femoral puncture. All the patients studied received long-term platelet anti-aggregant therapy (ticlopidine 500 mg/day and ASA 150 mg/day) for 3Ð4 days before and for one month after the procedure, and an anticoagulant regimen of heparin sodium administered via intravenous bolus (10,000 IU) during the procedure, followed by subcutaneous heparin calcium (12,500 IU/day) for 21 days. Thirteen patients were treated intravenously with 10 mg abciximab and seven received pre-procedure coumadin. The ACT when the hemostasis system was positioned was 355 +/- 43 seconds. Successful hemostasis was reached in more than 95% of the patients (394/411 pts., 95.86%). In 17 (4.14%) of the 411 patients studied, the system failed; nine (2.19%) of these were attributed by the operator to a failure of the positioning device procedure, and the remaining 8 (1.95%) were attributed to a malfunction of the system. Overall complications were observed in 23/411 (5.6%) of the patients (pts) studied; eighteen were minor non-surgical hemorrhagic complications (bleeding and/or hematoma) which occurred primarily in the first 4 hours. In 4 cases (1%) vascular surgery was necessary for femoral pseudoaneurysm repair (2 pts) and femoral hematoma (2 pts). One patient (0.24%) complained of severe claudication related to a severe stenosis in the femoral artery caused by a malpositioning of the anchor. This patient was successfully treated with balloon angioplasty and stenting of the femoral artery. The average time to early mobilization was 9 hours, and all the patients without complications were completely mobile within 12 hours after the procedure; 380/411 (92.46%) of the patients were discharged 18Ð24 hours after percutaneous angioplasty. The second purpose of our study was to compare data from 411 consecutive patients treated with the Angio-Sealª device after coronary and vascular angioplasty and stenting (Angio-Seal group), to a group of 387 consecutive patients where the femoral arterial hemostasis was obtained using manual compression after coronary angioplasty and stenting (manual compression group). We found significant differences (p < 0.01) in the most important elements concerning general patient management after the interventional procedure, with excellent improvements using the Angio-Seal device, including: successful hemostasis (95.86% vs. 88.37%); reduction of non-surgical hematomas (1.22% vs. 4.65%); reduction of surgical hematomas (0.49% vs. 2.84%); mobilization time (9 +/- 3 hours vs. 19 +/- 8 hours); and discharge within 18Ð24 hours (92.46% vs. 0.00%).

Hemodynamic evaluation of the Carbomedics R, St Jude Medical HP and Sorin-Bicarbon valve in patients with small aortic annulus.

UNLABELLED: A Doppler echocardiographic study was performed to evaluate the hemodynamic performance of three 19 mm size currently used bileaflet valve prosthesis (St Jude Medical Hydrodinamic Plus, Sorin-Bicarbon and Carbomedic Reduced) implanted in aortic position. METHODS: Patients, 30, with the same profile receiving 19 mm size valve (ten for each valve type) were selected when body surface area (BSA) was > 1.7 m2. Doppler echocardiography was carried out at rest and after exercise, 60 days after surgery. Peak (Pg) and mean (Mg) gradients across the valve were recorded: the effective orifice area (EOA), and performance index (PI) were calculated. RESULTS: No significant differences were observed between St Jude Medical and Sorin Bicarbon as far as peak and mean gradient, effective orifice area and performance index at rest and after exercise. A significant difference (P < 0.05) was demonstrated in the above mentioned parameters when Carbomedics-R valve were tested. This type of valve showed a lower EOA and PI with higher Pg and Mg gradient both at rest and after exercise. CONCLUSION: The St Jude Hydrodymanic plus (Hp) and Sorin Bicarbon valves had similar performance and a better hemodynamic trend when compared to the Carbomedics-R valve in patients with large body surface areas. The Carbomedics-R valve shows a ineffective use of the total area of the prosthesis both at rest and after exercise.

Surgical treatment of asymptomatic and mildly symptomatic mitral regurgitation.

OBJECTIVE: The purpose of this study was to review the risk-benefit ratio of mitral valve repair in patients with severe mitral regurgitation and no or mild symptoms. METHODS: From January 1989 to December 1994, 584 patients were operated on for mitral regurgitation. Of these, 175 patients were in New York Heart Association class I or II with grade 3 to 4 isolated chronic mitral regurgitation. They comprise our study population. Mean age was 51.3 +/- 14.3 years. Principal causes of mitral regurgitation were degenerative in 128 (73%) and rheumatic in 26 patients (15%). Leaflet prolapse was the mechanism responsible for regurgitation in 152 patients (86%). Mitral valve repair was performed in 174 patients, and one patient required initial valve replacement. Mean follow-up was 34.3 +/- 18.8 months. RESULTS: Three patients died, for an overall mortality of 1.7%. Five patients were reoperated on, for an actuarial freedom from reoperation of 97.0% +/- 0.8% at 5 years. Actuarial freedom from thromboembolism and endocarditis was 96.3% +/- 1.7% and 99.4% +/- 0.6%, respectively, for an event-free survival of 91.0% +/- 2.0% at 5 years. Left atrial diameter decreased from 54.3 +/- 11.6 mm to 43.6 +/- 10.5 mm (p < 0.001). Left ventricular end-systolic and end-diastolic diameters decreased from 40.0 +/- 6.8 mm and 64.8 +/- 7.0 mm to 34.6 +/- 6.7 mm (p < 0.001) and 52.7 +/- 7.4 mm (p < 0.001), respectively. Mean residual mitral regurgitation was 0.44 +/- 0.6. CONCLUSION: Mitral valve repair for chronic mitral regurgitation in patients having mild or no symptoms was performed with low mortality and morbidity, good valve function, and preserved late left ventricular performance. Early repair may be advocated on the basis of severity of regurgitation and valve repairability, regardless of symptoms.

Influence of different harvesting techniques on the arterial wall of the internal mammary artery graft: microscopic analysis.

An histological comparison was made between left internal mammary arteries (LIMAs) harvested and prepared with different techniques prior to coronary artery bypass grafting. The mobilization of LIMA was made as follows: conventional technique (group I), extra pleural takedown with lysis of the endothoracic fascia (group II), and LIMA skeletonization (group III). Each group was divided into two other sub-groups according to the LIMA graft preparation: papaverine-saline solution sprayed on the pedicle (sub-group A) and intraluminal hydrostatic dilatation (sub-group B). Free blood flow from the LIMAs was measured immediately before cardiopulmonary bypass and ultrasonic duplex scanning (UDS) was performed to analyze the flow patterns and velocities during the early postoperative course. The results showed that the technique by which the LIMA is harvested bears no significant relationship to microscopical graft damage, while intimal lesions were observed in all sub-groups that adopted intraluminal hydrostatic dilatation (sub-group B). No difference in intraoperative LIMA flows were noted between groups and sub-groups of patients except in the case of group I-sub-group B, in which the flow was markedly reduced. Intramural haematoma or subadventitial blood effusion was observed with low incidence and magnitude in all groups and subgroups of patients, without any reduction of blood flow, and all LIMAs were patent at UDS measurements. In conclusion, the results showed that the method by which the IMA is harvested bears little and insignificant relationship to arterial wall damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrapleural takedown of the internal mammary artery as a pedicle.

Four hundred thirty-three patients underwent coronary bypass grafting using both internal mammary artery (IMA) and saphenous vein graft. In 233 patients the IMA was exposed with a conventional technique (group 1), whereas in the remaining patients the IMA was harvested leaving the pleura intact and performing an associated lysis of the endothoracic fascia (group 2). Postoperative course and complications of these groups were studied and compared in a period of time ranging from 8 to 28 months. Postoperatively, the blood transfused was significantly less in group 2 patients than in group 1; group 2 also had a reduction of surgical reexploration. Pleural effusion and hemidiaphragm impairment were infrequent or absent in group 2 patients, whereas pericarditis, severe postoperative chest pain, and respiratory insufficiency were noted only in group 1 patients. Our data suggest that extrapleural access without pleurotomy may be preferred owing to its low rate of chest wall complications.

Haemorrhagic shock in cardiac surgery. Pharmacological treatment with ACTH (1-24).

Spontaneous rupture of one or more cardiac chambers following open heart surgery is not common. A case is reported of a 45 year-old woman who sustained a spontaneous rupture of the right atrium in the intensive care unit after mitral valve replacement. Exsanguination of the patient was very rapid. On the basis of clinical and experimental convincing studies in this case a high dose of ACTH was used to prevent the damaging effect of haemorrhagic shock. During the reopening manoeuvre and initial conventional management, 10 mg ACTH (1-24) was injected into a peripheral vein. Although the blood lost was 93% of her circulating blood volume and a lot of fluid transfused via the central venous catheter was lost into the pericardium and hemithorax, the patient's condition improved rapidly after the occlusion of the atrial tear with initial small volume of transfusion. Based on the review of recent investigations the use of ACTH is emphasized.

Calcification of chemically treated bovine pericardium.

One of the most important problems arising in cardiac bioprostheses made with bovine pericardium and, more generally, with biologically-derived tissues is tissue calcification. The present study assessed four chemical treatments on patches of bovine pericardium, intended to avoid or minimize calcification. Pericardium specimens were treated with: A) 0.5% glutaraldehyde; B) 0.5% glutaraldehyde + 4% formaldehyde; C) same as A, but with a further neutralization treatment; D) acylation of fresh bovine pericardium. Circular samples of 1 cm diameter were subcutaneously implanted in the abdominal region of three groups of six rats. The explants were retrieved after 2, 4 and 8 weeks. The calcium content and the histological results showed better behaviour for C and D samples than with the commonly used fixation methods (A and B). The lowest calcification was observed with treatment D, even though its morphological structures were somewhat modified with homogenation of collagen bundles. Among the glutaraldehyde-based treatments, treatment C appears to be the most promising because the pericardium shows slower calcium accumulation with a diffusive pattern.

Tricuspid valve incompetence caused by nonpenetrating thoracic trauma.

Tricuspid valve incompetence from ruptured papillary muscle or chordae as a result of nonpenetrating trauma is uncommon. Blunt trauma causing partial detachment of a leaflet from the annulus is very rare. We report the case of a young adult involved in a car accident who had these findings. Operative repair with resuture of the leaflet to the annulus and annuloplasty using a Carpentier ring resulted in complete recovery.

Early alteration of bioprosthetic cardiac valves in sheep: influence of the immunological status.

Ten Pericarbon valve bioprostheses were examined after being implanted in tricuspid position in two different groups of animals: group I sheep with increased immunoglobulins, plasma levels, and eosinophilis count of more than 10%, due to parasitic infection, and group II sheep without any parasitic infection, i.e. with normal blood data. The explanted valve follow up was between 60-95 hours in both groups. Microscopic observation of group I valves revealed a massive blood cell (lymphocytes, eosinophilis and large mononuclear cells) infiltration especially around the natural pericardial blood vessels in the region of flexion and attachment. The epipericardial surface was covered by fibrin sheath, and immunofluorescence studies showed a strongly positive reaction for immunoglobulins (IgG and IgE) on leaflet surfaces and lamellar stratification into the fibrosa. Microcalcifications were detected around pericardial blood vessels in the same zones where infiltrated blood cells were found. In group II valves cell infiltration was absent with no signs of calcification and immunofluorescence was negative. Our data suggest that immunoglobulins adherence followed by blood cell infiltration may be one of the early causes of tissue leaflet degeneration and there is a parallel trend between plasma immunoglobulin levels and the early tissue alteration. Our data show that the experimental model for testing bioprostheses in sheep is influenced by the pre-immunological status and it is important to control it before surgery.