[Morphological aspects of atherosclerosis lesion: past and present]. / Aspetti morfologici della lesione ateromasica tra passato e presente.

Atherosclerosis is an inflammatory process disease that involves the artery wall and that is characterized by the progressive accumulation of lipids. The term arteriosclerosis has been created by Lobstein in 1833. Subsequently, during the 19th century, the contribution of Rokitansky and Virchow was important to elucidate the pathogenesis of arteriosclerosis and the morphologic aspects of the plaque. In the beginning of the 20th century, Aschoff was a leading proponent who regarded the morphologically different intimal lipid deposits of children and adults as early and late stages of one disease and he called them atherosis and atherosclerosis, respectively. The first classification of atherosclerosis was made by the World Health Organization (WHO) in 1958 and it consisted of the following sequence: fatty streak, atheroma, fibrous plaque and complicated lesions. In 1990s, thanks to much more sensitive techniques, the American Heart Association (AHA) proposed a new morphological classification based on eight lesion types designated by Roman numerals which indicate the usual sequence of lesion progression. Finally, Virmani et al. (2000) described a classification with the add of a specific plaque type, not recognized by the AHA classification, called "thin fibrous cap atheroma" which is more likely to rupture. The atherosclerotic process is characterized by typical ultrastructural changes that mainly involve the endothelial and smooth muscle cells. The morphological alterations of the endothelium are associated with dysfunctions leading to a proinflammatory and prothrombotic phenotype. This process seems to be due to turbulent blood flow and low fluid shear stress that normally occurs in particular regions of the vascular tree. Inflammation has a key role in the pathogenesis of atherosclerosis and it is supported by numerous factors such as modified LDL, hypertension, diabetes mellitus, free radicals and, in particular, by infectious agents such as Chlamydia pneumoniae.

Influence of ascorbic acid on platelet aggregation in vitro and in vivo.

With the objective of investigating more thoroughly the relationship between ascorbic acid and platelet aggregation (PA) in particular, in vitro and in vivo studies were made whether interferences exist, Scaling amounts of ascorbic acid were added to platelet-rich plasma (PRP) samples to determine the level at which the inhibition of the PA was induce by ADP and arachidonic acid (AA), and endoplatelet malondialdehyde (MDA) concentrations decreased. Changes in PA and MDA were not observed in the PRP control samples Also, in 10 healthy volunteers, an i.v. infusion of ascorbic acid (2 g) produced PA inhibition and a reduction of MDA concentrations.

Influence of vitamin E on plasma malondialdehyde-like material in man.

The behaviour of plasma malondialdehyde-like material (MDA-LM) was evaluated in 13 healthy subjects by a single-blind study that consisted of placebo (30 days), vitamin E treatment (300 mg/day) (30 days) and placebo (30 days). The study demonstrated that MDA-LM did not change during placebo treatment while it significantly decreased after vitamin E administration.

Natriuretic hormones in young hypertensives and in young normotensives with or without a family history of hypertension.

The behavior of plasma atrial natriuretic factor (ANF) and digoxin-like substance (DLS), and the daily urinary excretion of kallikrein (uKK) were evaluated in young hypertensives and in young normotensives with or without a family history of essential hypertension. Each group was also evaluated, separating those with low plasma renin activity from the total sample. The sample group was made up of 75 young males; 31 hypertensives (mean age 22.7 +/- 2.5 years), 28 normotensives with hypertensive heredity (normotensives F+) (mean age 22.2 +/- 1.9 years) and 16 normotensives (mean age 22.0 +/- 2.1 years). An inverse correlation between ANF and PRA was shown in all groups. In hypertensives, ANF was inversely correlated with uKK (r = -0.664, P less than .0001). Plasma ANF (P less than .012) and DLS (P less than .0001) were higher in hypertensives than in normotensives, while uKK excretion was lower (P less than .0001). Plasma levels of DLS were higher in F+ normotensives than in normotensives (P less than .003). Low renin hypertensives showed the lowest uKK excretion (P less than .0001 v normal-high renin hypertensives). Furthermore, low renin hypertensives showed the highest plasma levels of ANF (P less than .0001 v normal high renin hypertensives) and DLS (P less than .012 v normal-high renin hypertensives). Plasma ANF (P less than .0001) was higher, while uKK was lower (P less than .045) in low renin F+ normotensives than in normal-high renin ones. In conclusion, our data indicate that plasma ANF and DLS are elevated since the early phase of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma atrial natriuretic peptide in young normotensive subjects with a family history of hypertension and in young hypertensive patients.

Plasma atrial natriuretic peptide (ANP) behavior was evaluated in 26 untreated essential hypertensives, 21 normotensives, and 20 normotensives with hypertensive heredity under normal sodium intake (120 mEq of Na+/day). All subjects were men, mean age 22.1 +/- 1.9 years. Plasma ANP was evaluated by radioimmunoassay on samples collected in supine position upon waking and again after 1 h of orthostatism. Resulting data showed that ANP in hypertensives (supine = 44.5 +/- 19.4 pg/mL, orthostatism = 24.1 +/- 11.6 pg/mL) was at higher levels than in controls (supine = 38.3 +/- 19.4 pg/mL, orthostatism = 19.9 +/- 10.6 pg/mL) or in normotensives with hypertensive heredity (supine = 42.1 +/- 16.8 pg/mL, orthostatism = 23.2 +/- 10.8 pg/mL). Mean ANP level was higher in the latter group than in the control group (supine = +9%; orthostatism = +14.2%). In conclusion, plasma ANP is raised in young essential hypertensives, resulting in slightly elevated levels in normotensives with hypertensive heredity.

Prekallikrein and factor VII as prognostic indexes of liver failure.

Normotest, serum albumin, prekallikrein (Prekk), and Factor VII plasma activity were investigated in 64 patients with chronic liver disease--13 with type I chronic active hepatitis (CAH), 10 with type II CAH, 16 with compensated liver cirrhosis (LC), and 25 with decompensated LC--and in 20 matched-for-age healthy individuals. All of these blood parameters were reduced significantly as a result of liver damage. Patients with type II CAH and compensated LC had similar blood coagulation values. Eight decompensated LC patients, who died 30 to 45 days after the last blood coagulation parameter measurements, showed significantly low Prekk and Factor VII values compared with eight matched for sex and age survivors of decompensated LC. Prekk and Factor VII values of nonsurvivors did not overlap those of the survivors. This striking difference was not detected if Prekk and Factor VII were studied 2 to 4 months before death. These data suggest that Prekk and Factor VII are very sensitive to liver damage and could be useful prognostic indexes of liver insufficiency.

Interrelation between factor VII, prekallikrein, and hyperfibrinolysis in advanced cirrhosis.

Factor VII and prekallikrein activities were studied in 37 patients with liver cirrhosis who were in a decompensated state. Sixteen of them died 30-70 days after admission; 21 survived and were discharged after 30-80 days. Seven who died and six survivors had signs of hyperfibrinolysis: factor VII activity differentiated the two groups independently of the presence of hyperfibrinolysis. The presence of hyperfibrinolysis significantly reduced prekallikrein activity, which did not differentiate clearly survivors from non-survivors. Long term follow up of survivors showed a good correlation between factor VII and prekallikrein activities with long term survival. Hyperfibrinolysis seemed to influence the clinical course of patients: 87% of patients with hyperfibrinolysis who died had fatal haemorrhagic episodes. Low factor VII activity may be a precursor of terminal liver insufficiency.

Apolipoproteins A-I, A-II and B in chronic active hepatitis and in liver cirrhotic patients.

Apolipoproteins A-I, A-II and B were evaluated in 18 chronic active hepatitis and 27 liver cirrhotic patients. The latter were also divided into compensated and decompensated subgroups. Significantly low values of apolipoproteins A-II and B were seen in chronic active hepatitis and liver cirrhotic patients, while apolipoprotein A-I was decreased in liver cirrhotic patients only. Chronic active hepatitis had higher apolipoprotein values than liver cirrhosis and in the latter one decompensated subgroup showed lower apolipoprotein levels than the compensated one. Apolipoproteins A-I, A-II and B correlated also well with prothrombin activity (Normotest) in liver cirrhotic patients, especially the apolipoprotein A-II values. This study suggests that serum values of apolipoproteins are affected by the type of liver damage and that their decrease could be partly due to impaired liver synthesis.

Effects of mud-pack treatment on plasma cytokine and soluble adhesion molecule levels in healthy volunteers.

BACKGROUND: The suggested hypothesis of a direct anti-inflammatory property of mud-pack treatment has led us to speculate that its action on the cytokine network might counteract the heat-stress-related effects on platelet and endothelial cell function often reported following hot-spring baths. Therefore, the present study was designed to investigate the effects of a cycle of 12 daily mud-pack treatments on bio-humoral markers of inflammation, as well as on markers of in vivo platelet and/or endothelial cell activation, in plasma samples obtained from healthy volunteers. METHODS: Blood samples were obtained before (T(0)), at the end of the first treatment (T(1)) and after a cycle of 12 daily mud-pack treatments (T(2)). Plasma cytokines (TNF-alpha IL-1beta, and IL-6) and adhesion molecules (sP-selectin, sE-selectin and sVCAM) levels, as well as hematocrit and complete and differential blood cell counts were determined at every time point. RESULTS: Plasma sP-selectin levels were not modified during treatment, as were not sE-selectin or sVCAM. Similarly, IL-1beta and TNF-alpha levels were unchanged through a 12 daily mud-pack treatment. Conversely, plasma IL-6 levels were significantly lowered at the end of a 20-min 47 degrees C mud-pack treatment (p<0.01). CONCLUSIONS: The lack of effects on in vivo platelet and/or endothelial cell activation suggests that hot mud-pack treatment might be used as a relatively safe procedure in patients with atherothrombotic disorders.

Peripheral neuropathy without cryoglobulinemia in patients with hepatitis C virus infection.

BACKGROUND: An association between essential mixed cryoglobulinemia and hepatitis C virus infection has been documented by many reports. Some clinical manifestations such as purpura, arthralgia, vascular lesions and peripheral neuropathies are also connected with the presence of detectable cryoglobulins. The association between HCV infection, the presence of mixed cryoglobulinemia and peripheral neuropathy is well documented. The aim of this study was to define the possible presence of peripheral neuropathy in HCV patients without detectable cryoglobulins and the possible association with the different genotypes. METHODS: Twenty patients (11 females, 9 males) with chronic HCV hepatitis and without detectable cryoglobulins were submitted to neurological and electrophysiological studies to detect a possible peripheral neurological involvement. In all patients the HCV infection was assumed by the presence of antibodies to HCV with ELISA assay and then confirmed with recombinant immunoblot assay. HCV genotyping was obtained by INNO LIPA in 15 out of 20 patients. In 4 patients a sural nerve biopsy was possible. RESULTS: Genotype 1b was present in 80% of patients, while 1a in 13.3% and 4 in 6.6%. Thirteen patients had positive neurological anamnesis (65%), while neurological examination was positive in 40% of the cases. Electromyographic study was positive in 50% of subjects. The sural nerve biopsies agreed with axonal degeneration in amyelinated fibres. CONCLUSIONS: Our results suggest a possible peripheral neurological system involvement in patients with HCV infection without cryoglobulins.

Prevalence and clinical features of skin diseases in chronic HCV infection. A prospective study in 96 patients.

BACKGROUND: Between extra-hepatic manifestations of hepatitis C virus (HCV) infection particular interest is focused on some dermatological diseases such as: leukocytoclastic vasculitis, oral lichen planus, pruritus-urticaria, psoriasis, etc. The aim of this study was to determine the prevalence of some dermatoses in our population of patients with HCV infection and describe the more characteristics clinical pictures. METHODS: Ninety-six patients (36 men and 60 women) aged from 35 to 74 years with HCV documented by 3rd generation ELISA and RIBA tests were prospectively examined for 3 years to determine the prevalence of some skin disorders, reported as associated with HCV infection. All patients were also studied for presence and quantification of HCV-RNA by polymerase chain reaction and genotyping when possible. Eighty-one underwent a liver biopsy. Routine laboratory tests and some immunological investigations (ANA, AMA, SMA, LKM, ANCA, ICC, crioglobulins) were performed using standard procedures and indirect immunofluorescence, nephelometric, RIA methods. RESULTS: Twelve of 96 patients (12.5%) presented skin disorders in progress of chronic virus C hepatitis: 5 cases of leukocytoclastic vasculitis (LCV) by mixed cryoglobulinemia, 1 case of pruritus, 2 cases of oral lichen planus (OLP), 2 cases of alopecia areata, 1 case of urticaria, 1 case of psoriasis. CONCLUSIONS: Our findings show a calculated prevalence of clinical dermatoses in HCV infected patients around 12.5%. These findings confirm however the importance of liver examination in presence of skin diseases not related to other pathogenetic mechanisms.

Increased soluble P-selectin levels in hepatitis C virus-related chronic hepatitis: correlation with viral load.

BACKGROUND: Platelet functional abnormalities are commonly found in patients with chronic liver disease; however, their nature and clinical significance are still a matter of discussion. METHODS: Soluble P-selectin (sP-selectin, a marker of in vivo platelet activation) levels, lipid pattern, and clotting activity were investigated in 39 patients with histologically confirmed chronic C hepatitis. RESULTS: Serum factor VIIc (P < 0.01), total cholesterol (P < 0.005), high density lipoprotein (P < 0.001), and low density lipoprotein (P<0.05) levels were lower in patients compared with healthy subjects, whereas triglyceride and fibrinogen levels were similar in both groups. Platelet counts were lower in chronic hepatitis patients compared with controls (P < 0.0001), and approximately 20% of patients had thrombocytopenia (platelet counts < 110 x 10(3)/microL). Platelet-associated immunoglobulin G (PAIgG) was present in 30.8% of patients. Plasma sP-selectin levels were higher in hepatitis C patients compared with controls (P < 0.0001), and significant differences were observed with respect to the Scheuer score (P < 0.01). The analysis of the distribution of plasma sP-selectin showed the presence of higher levels in patients with low platelet counts compared with patients with normal platelet counts and controls (P < 0.0001); moreover, sP-selectin levels did not correlate with the presence of PAIgG. On the other hand, sP-selectin levels directly correlated with serum hepatitis C virus (HCV)-RNA (P < 0.05) and inversely correlated with platelet count, blood lipids, and factor VIIc. CONCLUSIONS: The results obtained in this study support the hypothesis that HCV infection might be directly responsible for a condition of in vivo platelet activation in patients with chronic C hepatitis.

Immunoadsorption apheresis (Selesorb) in the treatment of chronic hepatitis C virus-related type 2 mixed cryoglobulinemia.

In this short-term open label clinical pilot study, conducted at one center, the immune complex dextran sulphate adsorber (Selesorb) was used to treat four female patients aged 59-69 with HCV-related cryoglobulinaemia, vasculitis and/or neuropathy. The primary trial objective was to assess the clinical efficacy of the immunoadsorber. The secondary objective of the trial was to determine the safety of the adsorber and to investigate the adsorption capacity, measured as the adsorption of cryoglobulin-related immune complexes and the resulting influence on plasma components of the immune system. The patients have been submitted to treatment with the immunoadsorber, at approximately 1-3 days intervals, completing six sessions. The follow-up was one month. In the patients treated with Selesorb, we observed a statistically significant decrease in plasma of all classes of immunoglobulins (IgA: 5-28%; IgG: 14-44%; IgM: 8-38%). In two patients with peripheral neuropathy secondary to cryoglobulinemia, the symptomatology was improved. In a third patient the neurological involvement was substantially unchanged, and the same unsuccessful outcome was observed for Sjögren syndrome is concerned. Nevertheless, the two patients with lower extremity vasculitis showed an appreciable improvement. We failed to observe significant side effects directly related to the use of this immunoadsorbent.

Adrenomedullin assay and its clinical significance.

Adrenomedullin (Am) is a recently discovered peptide, first purified from pheochromocytoma specimens, with a chemical structure similar to that of CGRP and amylin. Adrenomedullin is present in numerous human body tissues and its powerful vasodilatatory activity is thought to play an essential role in cardiovascular and renal homeostasis.

CGRP and ET-1 plasma levels in normal subjects.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide displaying about 50% homology with amylin which is secreted from the pancreatic islets of Langerhans. The main form, the beta-CGRP, is produced by the enteric nervous system and perivascular nerves of the vasa-vasorum. It represents one of the most powerful vasodilator yet discovered but its role is not yet completely clarified. High levels of this peptide have been shown in patients affected with thyroid medullary carcinoma, phaemocromocytoma and lung carcinoma. Recently circulating levels of CGRP have been found in normal subjects. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, isolated from porcine endothelial cells, is an important regulator of the vascular tone acting in physiological antagonism with atrial natriuretic hormone (ANH). With this study we intended to investigate the presence of any correlation between CGRP and ET-1 in normal subjects. PATIENTS: For the study we considered 20 normal subjects (11 males and 9 females) aged 23 to 50. MEASURES: Plasma levels of CGRP and ET-1 were measured by radioimmunological Kit. RESULTS: A positive and significant correlation between calcitonin gene-related peptide and endothelin-1 was found. CONCLUSIONS: Our results confirms that CGRP and ET-1 have opposing actions on vessels and that they can act together in haemodinamic regulation.

Circulating HBsAg/IgM complexes in acute and chronic hepatitis B.

Complexes between HBsAg and IgM have recently been described in the sera of HBsAg carriers. A solid phase RIA for HBsAg/IgM complexes has been described. Fifteen patients with acute viral hepatitis type B, and 52 HBsAg chronic carriers were studied. Testing of serial sera in acute hepatitis patients revealed that HBsAg/IgM complexes disappeared (preceding HBsAg negativization and usually at the same time as seroconversion from "e" to "anti-e") with 4 weeks in all but one patient who became a chronic HBsAg carrier. In addition, HBsAg/IgM complexes were found in 48% of HBsAg chronic carriers, in 69% of CPH patients, but in only 20% of healthy carriers (p less than 0.005). Although complexes were detectable in 93% HBeAg positive chronic carriers, they were also frequently found in anti-HBe positive patients, but never in e/anti-e negative patients (p less than 0.001). HBsAg/IgM complexes seem to be of important prognostic and diagnostic value in acute and chronic hepatitis B.

HBeAg/anti-HBe system and development of primary hepatocellular carcinoma in patients with HBsAg-positive liver cirrhosis.

The significance of the HBeAg/anti-HBe system and other HBV markers in the evolution of HBsAg-positive liver cirrhosis to primary hepato-cellular carcinoma (PHC) was studied by following up 70 cirrhotic patients from February 1978 to February 1981. Eight out of 19 (42.1%) patients with HBsAg positive liver cirrhosis developed PHC. On the other hand, only 7.8% of the patients with HBsAg-negative liver cirrhosis developed PHC. In the HBsAg-positive group only the patients who had already seroconverted to anti-HBe (7 out of 11) or were negative for both HBeAg and anti-HBe (1 out of 3) at the time of first observation and showed a histological picture of inactive cirrhosis, developed PHC during the follow-up period. No HBeAg-positive cirrhosis showed such an evolution. The absence of HBeAg in the sera of patients who developed PHC suggests that active HBV replication becomes increasingly defective during the course of malignant transformation.

Hashimoto's disease during interferon-alpha therapy in a patient with pre-treatment negative anti-thyroid autoantibodies and with the specific genetic susceptibility to the thyroid disease.

OBJECTIVES: The authors described a case of Hashimoto's disease during interferon-alpha (IFN-alpha) treatment for chronic viral C hepatitis in a patient with the specific genetic susceptibility associated with the thyroid disease. RESULTS: A 60-year-old woman with chronic active viral C hepatitis (HCV genotype = 3a) started IFN-alpha therapy in November '96. Before treatment thyroid function tests were normal and anti-thyroid (anti-thyroglobulin and anti-thyroid peroxidase) Abs were negative. During IFN therapy, serum aminotransferases fell within the normal range and viremia (serum HCV-RNA) became negative after one year. After 20 months, the patient presented clinical features of primary hypothyroidism. Anti-thyroid Abs were found positive. Hormonal, ultrasonographic, radioiodine scanning and fine needle aspiration findings were consistent with the diagnosis of Hashimoto's thyroiditis. The tissutal typing of the patient showed the presence of Human Leukocyte Antigen (HLA) DRB1*11 gene (corresponding to DR5 antigen). IFN-alpha therapy was suspended and a treatment with l-T4 started. Chronic viral infection relapsed after the suspension of the IFN-alpha therapy. CONCLUSIONS: This case report showed that the clinical appearance of Hashimoto's disease after IFN-alpha therapy for chronic C hepatitis in our patient was associated with a specific genetic predisposition (DR5) for this pathology. Further studies are necessary to evaluate whether the study of HLA antigens may be a very useful tool to detect the patients with a predisposition to develop autoimmune thyroiditis, in order to make a early diagnosis of thyroid disorders during the IFN-alpha treatment.

Evaluation of myocardial involvement in systemic lupus erythematosus by signal-averaged electrocardiography and echocardiography.

OBJECTIVE: The myocardial involvement in systemic lupus erythematosus (SLE) patients, frequently found at autopsy or at endomyocardial biopsy, is less easily detected clinically. The myocardial lesions are characterized by an increase in interstitial connective tissue and myocardial scarring. Signal-averaged electrocardiography (ECG-SA) is currently used for recording ventricular late potentials which are the expression of slowed and disorganized conduction through zones of myocardial scarring. M-mode, two-dimensional and Doppler echocardiography (ECHO) represent relatively simple methods for evaluating the left ventricular function. This study was aimed to evaluate by ECG-SA and ECHO the myocardial involvement of SLE patients without clinical and electrocardiographic evidence of cardiac disease. METHODS AND RESULTS: Twenty outpatients with SLE were studied and compared with 18 normal controls. Late potentials were recorded in 20% of SLE patients and in 5.5% of controls. A significant increase of abnormal left ventricular diastolic filling was found in the SLE patients, characterized by reduced E/A (p = 0.018), a lower deceleration rate of early diastolic flow velocity (p = 0.048) and a prolonged isovolumic relaxation time (p = 0.001). SLE patients had diastolic dysfunction of various degrees although the depolarization abnormalities detected by ECG-SA were found only in a few subjects. CONCLUSIONS: The depolarization abnormalities, revealed by ECG-SA, probably reflect a longer extent of myocardial fibrosis in SLE patients with ECHO evidence of abnormal left ventricular filling. The simultaneous occurrence of ECHO and ECG-SA alterations could be a marker of subclinical myocardial involvement.

Natural history of cardiac involvement in myotonic dystrophy (Steinert's disease): a 13-year follow-up study.

Myotonic dystrophy (MD) is associated with a wide spectrum of cardiac abnormalities, but only a few longitudinal studies have investigated the natural course of heart disease in MD. To assess whether neuromuscular involvement significantly predicts cardiac disorders in MD, 83 patients with various grades of disease severity were enrolled in a 13-year follow-up study (mean, 60.6 +/- 37.8 months) that included periodic physical and instrumental cardiac examinations (standard and Holter electrocardiography, echocardiography). During follow-up, muscular disease worsened clinically in 9 patients (11%) whose baseline severity grade changed accordingly; only 3 of them demonstrated parallel worsening of cardiac disturbance, however, compared with a large number of patients who showed additional cardiac abnormalities. These included further worsening of pre-existing pathologic features (19/83) and the appearance de novo of serious arrhythmias and/or conduction defects (23/83). Pacemaker implantation was necessary in 11 of 83 patients (13.2%) who had symptomatic bradyarrhythmias, bifascicular block, and P-R prolongation with a His-to-ventricle interval exceeding 55 ms, as documented by electrophysiologic study. Eight (9.6%) patients died: 2 from noncardiac and 1 from unknown causes, 1 from heart failure, and 4 from sudden death closely related to documented ventricular tachycardia. The incidence and seriousness of arrhythmic and conduction disturbances correlated with the severity of the muscular involvement. Nevertheless, cardiac and muscular disease did not show a linear progression. Cardiac involvement generally worsened more rapidly than did skeletal muscle disease.