Paola Fernandez

Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot

Diabetic foot syndrome (DFS) is the most frequent cause of hospitalization of diabetic patients and one of the most economically demanding complications of diabetes. People with diabetes have been shown to have higher mortality than people without diabetes. On this basis, the aim of our study was to evaluate the possible role of diabetic foot as a cardiovascular risk marker in patients with type 2 diabetes mellitus. We enrolled 102 consecutive patients with type 2 diabetes mellitus with diabetic foot and 123 patients with type 2 diabetes mellitus without limb lesions to compare the prevalence of main cardiovascular risk factors, subclinical cardiovascular disease, previous cardiovascular morbidity, and incidence of new vascular events on a 5-year follow-up. Diabetic patients with diabetic foot were more likely to have a higher prevalence of cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and microalbuminuria or proteinuria, a higher prevalence of a previous cardiovascular morbidity (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy), and a higher prevalence of subclinical cardiovascular disease. Furthermore, diabetic patients with foot ulceration showed, on a 5-year follow-up, a higher incidence of new-onset vascular events (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy). At multivariate analysis, duration of diabetes, age, hemoglobin A1c, and DFS maintained a significant association with cardiovascular morbidity; but DFS presence showed the highest hazard ratio.

Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis.

INTRODUCTION Accumulating evidence suggests that inflammation plays an important role in the development of acute cerebrovascular disease. The aim of this study is to evaluate the predictive value of a series of candidate serum immuno-inflammatory and thrombotic/fibrinolitic molecules towards diagnosis of acute ischemic stroke. MATERIALS AND METHODS We enrolled 120 consecutive patients with a diagnosis of acute ischemic stroke and 123 consecutive hospitalized control patients without a diagnosis of acute ischemic stroke. We evaluated plasma levels of IL-1beta, TNF-beta, IL-6 and IL-10, E-selectin, P-selectin, sICAM-1 and sVCAM-1 as markers of immuno-inflammatory activation, vWF plasma levels as a marker of endothelial dysfunction, TPA antigen and PAI-1 plasma levels as a marker of a prothrombotic state. RESULTS TNF-alpha, PAI-1 and TPA on bivariate logistic regression were highly correlated to stroke diagnosis. Among the other variables maintained in the final model ILbeta, Selectin E, were significantly associated with acute ischemic stroke diagnosis, whereas IL-6, VICAM-1, ICAM-1 and neutrophil percentage showed only a slight or no association with stroke diagnosis. Furthermore, only the continuous values of TNF-alpha, PAI-1 and TPA showed a significant predictive value and likelihood ratio, with an area under the ROC curve of 98.6%, 97.1% and 99.9%, respectively. DISCUSSION Our findings could suggest the high diagnostic power of these immuno-inflammatory and thrombotic/fibrinolytic variables in patients with acute ischemic stroke. Although our results are encouraging, additional studies are needed to establish the validity of this approach.

Immunoinflammatory activation during the acute phase of lacunar and non-lacunar ischemic stroke: association with time of onset and diabetic state.

Several studies have stressed the involvement of inflammation in the pathophysiology of acute brain ischemia, but the role of immunoinflammatory activation in diabetic stroke patients has not yet been fully evaluated. The aim of our study was to evaluate immunoinflammatory activation of acute phase of stroke in relation to time of symptoms onset, diabetic state and diagnostic subtype. We enrolled 60 patients (32 diabetics; 28 non- diabetics) with acute ischemic stroke and 123 subjects without acute ischemic stroke, and measured levels of IL-1β, TNF-α, IL-6, IL-10, E-selectin, P-selectin, sICAM-1, sVCAM-1, VWF, 24–72 h and 7–10 days after stroke onset; TPA, PAI-1 plasma levels at 24–72h. Our stroke patients exhibited significantly higher plasma levels of cytokines, selectins, adhesion molecules and PAI-1, and diabetic stroke patients exhibited higher plasma levels of PAI-1 in comparison with non-diabetic ones. Lacunar strokes in comparison with those non-lacunar exhibited significantly lower levels of TNF-α and IL1-β, P-selectin and ICAM-1. Moreover, diabetic patients with lacunar strokes exhibited a minor grade of immunoinflammatory activation of the acute phase at 24–72h and 7–10 days after stroke onset. The minor grade of immunoinflammatory activation of patients with lacunar strokes, particularly diabetic ones, could be related to the minor extension of the infarct size, owing to the typical microvascular disease of diabetic subjects which could also explain the reported better outcome of this subtype of ischemic stroke.

Aceruloplasminemia: a case report.

Hereditary aceruloplasminemia is a rare autosomal recessive disease, firstly identified by Miyajima et al. in Japan in 1987 [1]. The disease is caused by the absence of an a2glycoprotein, the ceruloplasmin (Cp), a copper-containing ferroxidase, mainly synthesized in hepatocytes and widely expressed, including the central nervous system, which catalyses the oxidation of ferrous to ferric iron, a change required for release of iron to plasma transferrin [2]. It is hypothesized that in reticuloendothelial (RE) cells and hepatocytes Cp cooperates to export iron with the iron exporter protein ferroportin 1 (FPN1) [3]. As a consequence, Cp deficiency results in iron deposition in the liver, pancreas, basal ganglia, and other organs [2]. The Cp gene maps to chromosome 3q21–24 [4], consists of 19 exons [5] and encodes a protein of 1,046 amino acids [6]. Recently 20th exon has been recognized as the result of a brain-specific alternative splicing. This adds to the protein an aminoacid sequence that makes Cp a glycosylphosphatidylinositol (GPI)-anchored protein in the brain [7]. Under normal circumstances, infact, circulating Cp does not cross the blood–brain barrier. Through the oxidation mediated by GPI-linked Cp expressed in the astrocytes, iron could be taken from the circulation, incorporated into transferring derived from oligodendrocytes and then transferred to the neuronal cells [2]. Ceruloplasmin deficiency is a characteristic feature in copper metabolic disorders, including Wilson’s disease and Menkes’ disease. In Wilson’s disease, an inability to transfer copper into the Cp precursor protein, apoceruloplasmin, and a decrease in biliary copper excretion results in serum ceruloplasmin deficiency and excess copper accumulation. In Menkes’ disease, copper absorption from the intestine is decreased, leading to copper and Cp deficiencies in the body. In contrast, aceruloplasminemia, is an iron metabolic disorder in which ceruloplasmin deficiency is caused by a lack of apoceruloplasmin biosynthesis and copper metabolism is not disturbed. In Wilson’s disease and Menkes’ disease, several gene mutations in the coppertransporting ATPases (ATP-7B and ATP-7A) have been found within the last 10 years. Aceruloplasminemia is characterized by mutations in the ceruloplasmin gene itself [8]. Aceruloplasminemia, after the first description, has been reported mainly in Japanese patients [1, 2, 9–18] and rarely in whites [10, 19]. More than 30 aceruloplasminemiacausing mutations have been identified. Some of the mutations have been found in several families throughout the world, while other have been detected in a single patient. The majority of mutations in the CP gene are the truncated mutations leading to the formation of a premature stop codon. These mutations would be predicted to result in formation of a protein lacking the copper-binding sites resumed to be critical for enzymatic function. First clinical manifestation is usually diabetes mellitus secondary to pancreatic involvement [2]. A progressive neurological disease begins a few years later, typically with focal dystonia, followed by dysarthria, extrapyramidal D. Di Raimondo A. Pinto A. Tuttolomondo P. Fernandez G. Licata Dipartimento Biomedico di Medicina Interna e Specialistica, AOU Policlinico ‘‘P. Giaccone’’, Universita degli Studi di Palermo, Palermo, Italy

Plasma derived protein C in severe sepsis: report of two cases

Severe sepsis is defined as sepsis-associated organ dysfunction, (arterial hypoxemia, acute oliguria, coagulation abnormalities, thrombocytopenia, hyperbilirubinemia), hypoperfusion (hyperlactatemia) and arterial hypotension (mean arterial pressure \70 mmHg, or a systolic blood pressure decrease[40 mmHg) [3, 4]. Septic shock [3, 4] is defined as acute circulatory failure induced by sepsis with hypotension despite adequate fluid resuscitation. A dysfunction of the protein C (PC) pathway is always present in severe sepsis and contributes to the development of coagulopathy and necrosis [12, 13]. This decrease is caused by consumption of protein C during systemic activation of blood coagulation and by reduced hepatic synthesis owing to septic liver dysfunction, but also by degradation of protein C by proteolytic enzymes, such as elastase, released by white blood cells [7]. Numerous studies have demonstrated that decreased circulating levels of protein C in septic patients are associated with increased morbidity and mortality [5, 8, 9, 14, 15]. Most prior clinical trials evaluated pharmacologic agents designed to attenuate the early inflammatory events in sepsis, including glucocorticoids and drugs to neutralize endotoxin, tumor necrosis factor a, or interleukin-1b [18], but none of these treatments were effective, perhaps due to the importance of coagulation disorders in sepsis. A preparation of recombinant human protein C (rhAPC) activated via the thrombin-thrombomodulin complex was found to significantly reduce mortality in a double-blind study carried out on patients with severe sepsis (Prowess Trial) [2]. Plasma-derived PC is produced by specific extractionseparation processes and routinely used to correct the PC activity in patients with hereditary deficiencies. A dozen open studies and only one randomized controlled trial have been published reporting the effects of plasmaderived PC supplementation in patients with meningococcal or bacterial purpura fulminans [11, 19, 21]. We report two cases of severe sepsis treated with plasma derived PC.

Successful salvage therapy of intravenous cyclophosphamide for refractory polymyositis in an elderly patient: case report.

Dermatomyositis and polymyositis may affect children and adults and are now widely recognized as major causes of disability which, thanks to the introduction of immunosuppressive drugs, is often treatable, at least to some extent. Few data exist regarding polymyositis in elderly patients. We describe a case of refractory life-threatening polymyositis in an elderly patient, successfully treated with intravenous cyclophosphamide.

39 POLYMORPHISM OF PROINFLAMMATORY AND ANTI-INFLAMMATORY GENES IN PATIENTS WITH ACUTE ISCHEMIC STROKE

Backgrounds: the improvement in heart surgery and anaesthesiology techniques in last decades have improved morbility and mortality ratio also in high surgical risk patients. Enteral ischemia after heart surgery is a rare complication (0.2 2%), but carries significant mortality (70 100%): its incidence has not been changed in these years and cases reported in literature are even increased. Pathogenesis has not been clearly understood, being complex and multifactorial: the principal cause seems to be the reduction in cardiac outflow during operation. Splancnic atherosclerosis could be also implicated in worsening or favouring enteral ischemia. Actually no relevant articles have been yet published concerning splancnic vessels screening before heart surgery. Atherosclerosis extension is only assessed with carotid duplex ultrasound and anamnestic data about previous cardiovascular events. Scope: aims of the study were to evaluate duplex scanning utility and accuracy to identify atherosclerotic lesions in splancnic vessels and to relate them with other arterial districts involvement. Methods: we studied 91 patients previously subjected to coronary angiography before heart surgery (coronary by-pass, valvular prothesis or both) at “Centro Gallucci” of “Azienda Ospedaliera di Padova”. They were all investigated with echocolordoppler of carotid arteries, aorta and its principal branches, and lower limbs arteries: if some haemodinamic stenosis were found a second level (Angio-CT or Angio-NMR) exam was performed to confirm the previous one. Chi-square test was employed in statistical analysis comparing atherosclerotic lesions distribution. Results: prevalence of carotid lesions and peripheral arterial disease was major among patients with at least one coronary artery critical stenosis; this data was not related with the number of vessels involved. Superior mesenteric artery (SMA) plaques were four times more frequent in patients with critical coronaropaty: no patients without critical lesions in coronary arteries had a >70% SMA stenosis. Carotid plaques (>1.5mm thickness), in particular those >50%, were more frequently associated with critical lesions at coronary angiography, even more than intima-medial thickening (95% vs 45%). Among patients with any degree peripheral arterial disease (PAD), 72% had coronary critical stenosis versus 30% in patients without PAD; if haemodinamic stenosis were found in lower limb arteries the prevalence of coronary critical plaques were 95%. Patients with any carotid plaque had a 44% prevalence of SMA stenosis (whatever degree), while in patients without carotid lesions it was 12.5%. No one with unaffected lower limb arterial wall had atherosclerotic SMA involvement, while if PAD was present, there was a 40% prevalence of SMA plaques (any degree). From this study also stand out that in patients with carotid stenosis >50%, and mainly among those with PAD, splancnic vessels were involved more frequently then in people without them. Both carotid plaques and PAD had a 100% sensitivity to predict a critical stenosis at SMA, even if specificity was below 50%. Conclusions: abdominal vessels duplex scanning is indicated before heart surgery only when atherosclerotic plaques are found in carotid and lower limbs arteries. Finding that kind ok lesions in pre-surgery evaluation should suggest the operator to put to use all devices useful for preventing vascular complications in the splancnic district. Echocolordoppler, if performed by an export operator, could be useful to detect the presence of atherosclerotic plaques or abdominal aortic aneurisms in abdominal vessels.

Recurrent venous thromboembolism complicated by heparin-induced thrombocytopenia as a first manifestation of an occult cancer: a case report.

Heparin-Induced Trombocytopenia (HIT) is a serious and potentially fatal complication of patients on heparins. Its management is difficult and it can be more complicated in patients with cancer because of the hemorrhagic risk carried out by direct inhibitor of thrombin, the currently approved drug for HIT. At present, it is not clear whether cancer patients also have an increased risk of HIT. We describe the case of a patient with occult cancer at the moment of the index venous thrombosis, who developed Deep Vein Thrombosis (DVT) and concomitant HIT with thrombotic complications (recurrent contralateral venous thrombosis). The management of HIT was efficaciously based on the combined use of alternative antithrombotic regimens (Dermatan-Sulphate and Defibrotide), without an increased risk of bleeding. This case highlights the potential relationship between DVT, as first episode of an occult cancer, and the risk of developing HIT. The use of alternative antithrombotic therapy seems to be efficacious even in this high-risk cancer patient.