Treatment of peripheral arterial disease in diabetes: a consensus of the Italian Societies of Diabetes (SID, AMD), Radiology (SIRM) and Vascular Endovascular Surgery (SICVE).

Diabetic foot (DF) is a chronic and highly disabling complication of diabetes. The prevalence of peripheral arterial disease (PAD) is high in diabetic patients and, associated or not with peripheral neuropathy (PN), can be found in 50% of cases of DF. It is worth pointing out that the number of major amputations in diabetic patients is still very high. Many PAD diabetic patients are not revascularised due to lack of technical expertise or, even worse, negative beliefs because of poor experience. This despite the progress obtained in the techniques of distal revascularisation that nowadays allow to reopen distal arteries of the leg and foot. Italy has one of the lowest prevalence rates of major amputations in Europe, and has a long tradition in the field of limb salvage by means of an aggressive approach in debridement, antibiotic therapy and distal revascularisation. Therefore, we believe it is appropriate to produce a consensus document concerning the treatment of PAD and limb salvage in diabetic patients, based on the Italian experience in this field, to share with the scientific community.

Angioplasty of below-the-elbow arteries in critical hand ischaemia.

BACKGROUND: Critical hand ischaemia (CHI) due to pure below-the-elbow (BTE) artery obstruction is a disabling disease and there is still no consensus concerning the most appropriate revascularisation strategy. The aim of this study was to assess the feasibility, safety and outcomes of percutaneous transluminal angioplasty (PTA) in the treatment of CHI due to pure BTE artery disease. METHODS AND RESULTS: Twenty-eight patients (age 62 ± 11 years; three females) with a total of 34 hands affected by CHI (one pain at rest; 18 non-healing ulcer; 15 gangrene) due to pure BTE artery disease underwent PTA. Most of the patients were males with a long history of diabetes mellitus, end-stage renal disease (ESRD) on haemodialysis and systemic atherosclerosis. The interosseous artery was free of disease in all cases, whereas the radial and ulnar arteries were simultaneously involved in 31/34 hands with long stenosis/occlusions (91%; mean length 155 ± 64 mm). The technical success rate was 82% (28/34), with only three minor complications. In the three cases with a functioning radial arteriovenous fistula, we successfully treated the ulnar artery. PTA was unsuccessful in 18% (6/34) hands due to inability to cross severely calcified lesions. The hand-healing rate was 65% (22/34). The predictors of hand healing were PTA technical success (odds ratio (OR) 0.5, confidence interval (CI) 0.28-0.88; p ≤ 0.0001) and digital run-off (OR 0.37, CI 0.19-0.71; p ≤ 0.003). The mean follow-up period was 13 ± 9 months. Six patients (18%) underwent secondary procedures due to symptomatic restenosis. In all these cases, a successful re-PTA was performed at a mean 6 months after the index procedure, and there were no major procedure-related events. Ten patients (36%) died during follow-up. CONCLUSIONS: Angioplasty of BTE vessels for CHI is a feasible and safe procedure with acceptable rates of technical success and hand healing. Poor digital run-off due to obstructive disease of the digital vessels can reduce the hand-healing rate after a successful PTA. Pure isolated BTE vessel disease seems to characterise patients with ESRD and diabetes mellitus.

Polysaccharide in delayed hypersensitivity. I. Pneumococcal polysaccharide as inducer and elicitor of delayed reactivity in guinea pigs.

A highly purified pneumococcal polysaccharide (Type II SSS) is a very efficient inducer of delayed hypersensitivity in random-bred guinea pigs. The cellular reactivity induced by this polysaccharide administered subcutaneously in complete Freund's adjuvant is of "tuberculin type"; it increases in intensity with time after the sensitizing injection, as judged by skin tests, the macrophage inhibition reaction and transfer of reactivity by peritoneal exudate cells. By contrast, the cellular reactivity induced by this immunogen in the absence of mycobacterial adjuvant has the characteristics of "Jones-Mote" reactivity. It is best seen at about 1 wk after sensitization; the reactions are characteristically little indurated and show histologic differences from tuberculin type responses; and the reactive state begins to disappear by 2-3 wk, with the accession of Arthus reactivity. This type of delayed reactivity may be related to an early phase of antibody synthesis.

Long-term outcomes after angioplasty of isolated, below-the-knee arteries in diabetic patients with critical limb ischaemia.

BACKGROUND: It has been shown that concomitant percutaneous transluminal angioplasty (PTA) of above-the-knee (ATK) and below-the-knee (BTK) arteries is highly beneficial for limb salvage in patients with critical limb ischaemia (CLI), but few published studies have specifically investigated outcomes in diabetic patients with CLI associated with isolated small BTK-vessel disease. This study aimed to evaluate the long-term results of successful PTA for limb salvage in such patients. MATERIALS AND METHODS: From among the 634 patients with CLI in our database, we retrospectively selected a consecutive series of 101 diabetics (16%) with 107 critically ischaemic limbs (33 Rutherford 5 and 74 Rutherford 6) and no critical ATK lesion, who underwent PTA on isolated BTK lesions. RESULTS: The limb salvage rate was 93% after a mean follow-up of 1048+/-525 days (2.9+/-1.4 years). Transcutaneous oxygen tension significantly increased after 1 month (18.1+/-11.2 vs. 39.6+/-15.1; p<0.05). After 1 year, target-vessel re-stenosis had occurred in 42% of the non-amputated limbs, nine patients (9%) had died because of medical conditions unrelated to PTA and three patients had undergone repeat PTA for recurrent CLI. CONCLUSIONS: In our selected patient population with ischaemic diabetic foot and isolated BTK lesions, a successful endovascular procedure led to a high percentage of limb salvage at long-term follow-up.

Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

PURPOSE: To report our initial experience of fully percutaneous deep venous arterialization (pDVA) for the treatment of chronic critical limb ischemia (cCLI) after failed distal angioplasty. MATERIALS AND METHODS: pDVA was performed in five consecutive patients by creating an arteriovenous fistula (AVF) between a below the knee artery and its satellite deep vein. In this early experience, only patients with failed prior interventional attempts at establishing flow with no distal targets for an arterial bypass were selected. Early technical success was defined as successful AVF creation and retrograde venous perfusion of the wound site. Patient demographics, procedural details, morbidity/mortality and wound healing outcomes were assessed prospectively. Patients were followed up in wound care centers, and graft patency was documented on duplex ultrasound. RESULTS: All five consecutive patients (mean age 58 years) underwent successful pDVA without any procedural complications. There were neither 30-day major adverse limb events nor major cardiovascular complications. Three out of the five patients (60%) had clinical improvement as observed by resolution of rest pain and complete wound healing. At the 1-month FU, one patient died and one patient received a major amputation. The median wound healing time was 39 weeks. CONCLUSION: pDVA is a safe and feasible vascularization alternative in patients with end-stage/no-option CLI. The early experience highlights the need for a multidisciplinary approach including a dedicated wound care service.

Correction to: Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

The fifth author's name was incorrectly published as "M. Messas". The correct name is "E. Messas". The original article has been corrected.

Phase II study of recombinant alpha-2 interferon in resistant multiple myeloma.

A multicenter phase II study of INTRON, recombinant alpha-2 interferon (Schering Corp, Kenilworth, NJ), in patients with relapsing or refractory myeloma was initiated. Patients received either intravenous therapy for two weeks followed by subcutaneous therapy or subcutaneous dosing from initiation of treatment. Of 38 evaluable patients, 19 were refractory and 19 had relapsed at entry. Twenty-five of 38 had received prior treatment with multiple drugs. Responses were seen among 2/19 refractory patients and 5/19 relapsing patients. Three of seven responders continue to respond for more than one year while receiving maintenance therapy. Most patients experienced improvement in bone pain, and one patient, with a complete response, had healing of bone lesions. Survival curves show a statistically significant improvement in survival for responders v nonresponders. INTRON was well-tolerated with only four patients discontinuing treatment due to adverse effects. Thirty-two percent of patients had hematologic toxicity requiring dose adjustment; however, there was no evidence of cumulative hematologic toxicity. No patients developed serum neutralizing factors to interferon. Additional trials are warranted to study the activity of INTRON in previously untreated patients.

Synthesis and antiallergic activity of some mono- and disubstituted xanthone-2-carboxylic acids.

A series of xanthone-2-carboxylic acids, substituted mainly with electron-withdrawing groups, has been synthesized and assayed for antiallergic activity, using the passive cutaneous anaphylaxis (PCA) reaction in the rat. The effect of substituent type and substitution pattern on PCA neutralizing capacity is presented.

Efficacy and safety of extended-release isosorbide mononitrate for stable effort angina pectoris.

The efficacy and safety of extended-release isosorbide mononitrate tablets were evaluated in patients with stable effort angina. In a double-blind study, 313 patients with stable effort-induced angina were randomized to receive placebo or extended-release isosorbide mononitrate: 30, 60, 120 or 240 mg once daily in the morning. Serial exercise testing was performed using the standard Bruce treadmill protocol on days 1, 7, 14, 28 and 42 immediately before morning drug administration, and 4 and 12 hours after administration. After initial dosing, all groups that received extended-release isosorbide mononitrate had significant (p < 0.01) increases in mean total exercise time of approximately 30 to 50 seconds in relation to placebo 4 and 12 hours after administration. On day 42, mean changes from baseline in total exercise time of patients who received 120 or 240 mg of extended-release isosorbide mononitrate exceeded placebo by approximately 50 to 60 seconds 4 hours after dosing (p < 0.01), and by 30 to 35 seconds 12 hours after dosing (p < or = 0.05). No significant difference was detected between responses to extended-release isosorbide mononitrate and placebo 24 hours after administration (i.e., immediately before the next dose). Thus, there was neither significant activity nor demonstrable rebound of effort-induced angina (zero-hour effect) at the end of the dosing interval. Transient headache was the most prevalent adverse experience. Extended-release isosorbide mononitrate (120 and 240 mg administered orally once daily) significantly prolonged exercise time to development of moderate effort-induced angina 4 and 12 hours after dosing during long-term therapy, without development of nitrate tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatoma HepG2 cells as a model for in vitro studies on mitochondrial toxicity of antiviral drugs: which correlation with the patient?

Currently, drugs have been synthesised that can significantly delay the course of several viral infections, including those provoked by HBV, HCV or HIV, but that display consistent side effects, including toxicity for organelles such as mitochondria. Several in vitro models and techniques have been developed to analyse the effects of such compounds. HepG2 cells (from human hepatoma) are an excellent model to investigate mitochondrial (mt) toxicity because of their high content of organelles and mtDNA, and actually different investigators are indeed using such cells. Studies in vitro on cell lines are relatively easy, but it is necessary to be careful in the interpretation of data, which are usually obtained on continuously growing, tumour cells, quite different from normal, resting, non-neoplastic cells collected from a patient. Direct analysis of drug-induced mt damage in patients is extremely more complex than that performed using in vitro models because of the difficulty to obtain adequate cells or to have discrete amounts of biological material, the status of the patient at the moment of cell collection, the use of an adequate assay and its correct execution, and finally the possibility to find sex- and age-matched healthy controls as source of reference parameters.

Primary PCI for the treatment of ectatic infarct-related coronary artery.

AIM: There is lack of information on the outcome of patients treated with primary angioplasty for lesions located in an ectatic coronary artery segment in the setting of acute myocardial infarction. The aim of this study was to analyse the 2-year follow-up of this specific patient population. METHODS: By means of a systematic review of the databases and cine-films of 5912 primary angioplasties performed in eight Italian cardiac centers we identified 101 patients with infarct-related coronary artery ectasia. Ectasia was defined as a dilatation exceeding the 1.5-fold of normal adjacent segment and was classified according to its severity. The primary end point was the composite rate of cardiac death, recurrence of acute myocardial infarction and a new revascularisation at 2-year. RESULTS: The procedure was successful in 70.3% of cases, unsuccessful or complicated in 29.7%. The primary endpoint was met in 6.9% of cases during hospitalization (95% CI: 2.0-11.8), in 17.8% (95% CI: 10.3-25.3) at 1 year, and in 38.5% (95% CI: 29.0-48.0) at 2 years. Nine patients had a stent thrombosis: 3 acute and 6 sub-acute. A statistically significant correlation between the dimensions of the stent and stent thrombosis was observed (P=0.005). CONCLUSION: In subjects undergoing primary angioplasty for acute myocardial infarction the rate of patients treated on lesions located in an ectatic coronary artery segment is very small (1.7%). The procedural success was low, whereas the rate of events at follow-up was quit high reflecting the complexity of this disease.

Tips and tricks for a correct "endo approach".

The world is facing an epidemic of diabetes, consequently in the next years critical limb ischemia due to diabetic artery disease will become a major issue for vascular and endovascular operators. Revascularization is a key therapy in these patients because reestablishing an adequate blood supply to the wound is essential for healing avoiding a major amputation. In this paper, we summarize our experience in endovascular treatment of diabetic critical limb ischemia, focusing of the main technical challenges in treating below-the-knee vessels. We describe the following topics: 1) targets of the revascularization therapy: "complete" versus "partial" revascularization and the concept of wound related artery. Every procedure must be tailored on technically realistic strategies and on the general patient status; 2) the antegrade femoral access using both, the X-ray and the ultrasound guided techniques; 3) the chronic total occlusions crossing strategy proposing a step-by-step approach: endoluminal, subintimal, retrograde approaches. Particular attention has been given to the different retrograde approaches: pedal-plantar loop technique, trans-collateral approaches and the different types of retrograde puncture. For each step we provide a complete description of the technical details and of the suitable devices. Eventually we in brief describe: 3) acute result optimization and 4) prevention of restenosis.

Management of ischemic diabetic foot.

Diabetic foot pathology represent the more disabling complication of diabetes. More the 1 million of diabetes patients undergo a lower limb amputation per year; 85% of these amputation are preceded by un ulcer that can be avoided by a prevention program. Critical limb ischemia (CLI), the only independent cause of major amputation in diabetic population, can be correctly treated when an early diagnosis is made. Both endoluminal and surgical revascularization procedures can be applied in diabetes with high rate of success when performed by skilled operator. Infection of diabetic foot, in particular in patients suffering from peripheral artery disease (PVD), may rapidly evolves in severe local or systemic infection putting the patient at high risk of major amputation or death. Together with an early diagnosis of infection and ischemia it is mandatory to apply a correct medical and surgical treatment protocol with the aim to control infection and to improve blood perfusion to the foot. In case of infection surgical procedure should be applied first while revascularization procedure will follow soonest. Antibiotic therapy should be chosen considering different local biological pattern and different type of infection. Reconstructive surgery, the last step in treatment of any diabetic foot lesion, must obtain a functional residual foot or a stump that will allow the patient to go back walking soonest with residual good walking capacity.

Advances in below-the-knee drug-eluting balloons.

The management of critical limb ischemia due to below-the-knee disease remains challenging due to the frequent patient comorbidities, diffuse vascular involvement, and high rates of restenosis and disease progression. The BASIL study has established the substantial equivalence between bypass surgery and percutaneous transluminal angioplasty in this setting, at least at mid-term follow-up, but percutaneous techniques and devices have seen major developments since the publication of this pivotal trial in 2005. A major breakthrough has indeed been the introduction of drug-eluting balloons, which have several theoretical advantages in comparison to standard balloons and metallic stents for infra-popliteal lesions. Two clinical trials have already been reported with favorable results for the In.Pact Amphirion paclitaxel-eluting balloon, when employed for below-the-knee lesions. We hereby discuss the rationale for the use of drug-eluting balloons in this complex setting and the main findings of the study by Schmidt et al. and the DEBATE-BTK trial.