Primary Prevention of Sudden Cardiac Death: Can We Afford the Cost of Cardioverter-Defibrillators? Data from the Search-MI Registry-Italian Sub-study

Background: Large randomized trials show that in appropriately selected patients with left ventricular dysfunction, implantable cardioverter-defibrillators (ICDs) can improve overall survival at 2–5 years. Since direct implementation of the criteria used in the MADIT II and SCD-HeFT will lead to a marked rise in ICD implants, there is a growing fear that increased use of ICDs may cause a dramatic burden to health care systems. The ICD has traditionally been seen as an expensive form of treatment, which is difficult to accept at the first look. This is mainly due to the nonlinear character of the ICD investment, characterized by high initial expenditure, followed by a deferred pay-off in terms of clinical benefits. Cost-effectiveness analysis may help provide a different perspective on the problem of ICD cost, as may estimation of the daily cost of ICD treatment, assuming a time horizon of 5–7 years—a particularly interesting subject for further registry studies.
Methods and Results: Based on real expenditure data from 2002 to 2005, as recorded in the Search-MI Registry-Italian Sub-study of patients implanted on MADIT II indications, we estimated the daily costs associated with the device and leads. Over a 5–7 year time horizon, the average daily cost was estimated to be €4.60–€6.70. Translation of these figures into U.S. market conditions suggests a daily cost of around $7.90–$11.40.
Conclusions: These findings appear useful to help evaluate the affordability of ICD in comparison with other therapeutic options in a context of limited available economic resources.     

Properties of circulating IgA molecules in Henoch-Schonlein purpura nephritis with focus on neutrophil cytoplasmic antigen IgA binding (IgA-ANCA): new insight into a debated issue

Background: The presence and the pathogenetic role of circulating IgA reacting with neutrophil cytoplasmic antigens (IgA-ANCA) in patients with Henoch-Schonlein purpura (HSP) is still debated. This study was aimed to investigate some characteristics of serum IgA and macromolecular IgA in HSP patients, focusing on IgA-ANCA. Methods: Eighty-seven HSP patients with biopsy proved renal involvement (51 adults and 36 children) enrolled in a multicentre study of the Italian Group of Immunopathology were investigated. Results: Significantly high levels of IgA immune complexes were found in both adults (P <0.05) and children (P <0.01), while the binding of IgA to jacalin, was significantly low in children with HSP (P <0.01) only. Two series of ELISA were done for IgA-ANCA, in two different laboratories. Increased binding to PMN crude extracts (P <0.01) without any modification in IgA binding to proteinase 3 was found by either specific ELISA. Conversely, the binding of IgA to myeloperoxidase (MPO) was found to be significantly (P <0.05) increased with positive values in 25% of patients by one assay only. Three of four sera with positive IgA-MPO ANCA exhibited binding in Western-blot studies with the MPO preparation used in ELISA to a 28-kDa species. D-galactose and N-acetyl-glucosamine decreased the binding of serum IgA to MPO more in HSP than in controls (P <0.05). Conclusions: The conflicting reports on IgA-ANCA may reflect some atypical characteristics of the reaction which can be detected only by some ELISAs. We suggest that not an antigen-antibody reaction but a lectinic interaction due to abnormal composition of IgA carbohydrate side chains may account for the IgA-ANCA reaction in patients with HSP nephritis.     

KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.     

Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.     

Screening of HIV-1 isolates by reverse heteroduplex mobility assay and identification of non-B subtypes in Italy

OBJECTIVE: The increasing prevalence of HIV-1 transmission through heterosexual contacts and the growing number of immigrants from non-Western countries, where non-B subtypes and recombinant forms are prevalent, suggest the possible emergence in Italy of a new epidemic wave of HIV-1 non-B subtypes as well as recombinant forms. METHODS: The distribution of HIV-1 subtypes has been evaluated in 63 seropositive individuals residing in Italy, most of whom were infected through a sexual route during the last 5 years. A modified heteroduplex mobility assay (HMA) strategy, reverse HMA (rHMA), has been developed in our laboratory, allowing rapid identification of divergent-from-B-subtype isolates, which have been subsequently characterized by detailed molecular and phylogenetic analyses. RESULTS: Five samples show, on rHMA, an electrophoretic pattern compatible with a non-B subtype classification. Their phylogenetic analysis, performed on both env and gag regions, confirms the rHMA subtyping prediction, given that 3 samples fall into the "A-family" subtype and 2 into the G subtype. The 5 non-B-subtype HIV-1 isolates have been identified among 23 variants (prevalence, 21.74%) isolated during the 2000 to 2001 period in heterosexuals. In parallel, B-subtype isolates show high levels of intrasubtype nucleotide divergence, compatible with a constant HIV-1 molecular diversification. CONCLUSION: The Italian HIV-1 epidemic is still mostly attributable to the B subtype, which shows an increasing nucleotide heterogeneity. Heterosexual transmission and the interracial blending, however, are slowly introducing novel HIV-1 subtypes, and the data indicate that rHMA represents a powerful tool for HIV-1 biomolecular screening in epidemics characterized by a mono-/dual-subtype predominance.     

Epidemiology of adverse drug reactions in intensive care units. A multicentre prospective survey

Summary Clinically relevant events possibly attributable to drug exposure have been monitored prospectively over a period of six months in 27 general intensive care units. Fifty-four events attributed to drugs were reported in 51 patients during their stay in hospital, corresponding to an overall incidence of 1.35%. The behaviour of the physicians following attribution of the events to a prescribed drug is analyzed and discussed in detail with respect to its relationship to the quality and severity of the reaction, and the classes of drugs. Twenty-four of the 4537 monitored admissions during the six months were due to life-threatening emergencies linked to the administration of drugs (14) and radio-contrast media (10) (overall incidence 0.5%). While the clinical burden attributable to adverse drug reactions in Intensive Care Units appears to be relatively small, the analysis shows that there is ample room for a greater reduction in their incidence. Coordinators: Drs M. L. Farina and G. Tognoni, Istituto di Ricerche Farmacologiche Mario Negri, Milan; Dr F. Procaccio, Neurosurgical ICU, Ospedale Ca' Granda, Niguarda, Milan.Investigators: Drs G. Barusco, Rovigo; F. Bassi, Milan; L. Bianchetti, Torino; E. Carchietti, Udine; G. Chilloni, Reggio Emilia; G. Costantini, Savigliano (CN); P. Ferrero, Aosta; E. Geat, Trento; F. Gorgerino, Torino; A. Lusini, Empoli (FI); G. Mantovani, Ferrara; S. Marchi, Bologna; P. Marcovigi, Forli; G. Marraro, Merate (CO); F. Merlo, Vicenza; E. Pagni, Bagno a Ripoli (FI); R. Pellegrino, Cuneo; C. Peruselli, Milan; A. Piovesano, Pordenone; R. Rinaldo, Cremona; R. Ruggerini, Piacenza; S. Sammartino, Torino; A. Sartore, Cittadella (PD); A. Scaglioli, Carpi (MO); G. Scopa, Terni; G. Zeffiro, Treviso; P. Zuccoli, Parma     

The role of surgery in transmitting ≪ post-transfusion hepatitis ≫

The role of surgery as an additional risk in transmitting post-transfusion hepatitis was investigated in a retrospective study on acute hepatitis occurring in 77 transfused patients, 293 transfused and operated patients and 243 hepatitis cases with history of surgery without transfusion.Hepatitis A patients admitted to the same centres in the same period were utilized as controls. In transfused patients the percentage of NANB hepatitis was higher than that of type B (61.0% vs. 36.4%), while in the operated not transfused group the percentage of type B was twice that of type NANB (63.4% vs. 32.5%).In transfused and operated cases intermediate values were observed. The age-adjusted measures of association between exposures and the different hepatitis types showed a lack of effect of transfusion and a dominant role of surgery in transmitting type B hepatitis. In contrast, NANB post-transfusional cases were actually a mixture of post-transfusional and post-surgical cases, since both these exposures were found to be significantly associated with the disease.Our results suggest that studies on the incidence and the etiology of post-transfusion hepatitis should take into account the risk of surgical exposure which might have occurred.Corresponding author.     

Management of long bone metastases: recommendations from the Italian Orthopaedic Society bone metastasis study group

The purpose of this article is to outline the current approach to patients affected by metastasis to the long bones and to present a clinical and surgical algorithm available for clinicians and for future research. A modern approach to patients affected by long bone metastasis in fact requires a multidisciplinary contest where oncologists, radiotherapists, surgeons and physical therapists cooperate with a shared vision, in order to provide the best possible integrated treatments available. The authors of this article constitute the Bone Metastasis Study Group of the Italian Orthopaedic Society (SIOT): a national group of orthopedic tumor surgeons who are dedicated to studying the approach, techniques and outcomes of surgery for metastatic tumours of the musculoskeletal system.     

The brain in congestive heart failure

In the present paper we discuss two issues about relationships between congestive heart failure and the brain. First, major acute cerebrovascular events are very frequent among elderly people, but stroke does not appear to be frequently associated with congestive heart failure. Second, some cardiovascular conditions may determine progressive damage of cerebral tissue, with consequent impairment of cognitive functions. The association of cognitive impairment and cardiovascular diseases may dramatically increase morbility and mortality risks in the elderly. Recent studies seem to show that hypotension and congestive heart failure are risk factors for dementia in elderly people. In view of this data, an Italian multicentric study on congestive heart failure in hospitalized elderly patients (CHF Italian Study I) included a brief screening of cognitive abilities (MMSE). The presence of congestive heart failure induced a significant decrease of MMSE scores: mean MMSE score after statistical adjustment for the other variables was about one point lower in patients with congestive heart failure respect to elderly patients affected by heart disease but without congestive heart failure. A novel multicentric study (CHF Italian Study II) has been performed to identify cognitive functions more specifically impaired during congestive heart failure in the elderly. Preliminary data relative to 385 patients, confirmed that congestive heart failure may induce a generalized impairment of cognitive functions. These data have relevant clinical implications because they demonstrate that a multidisciplinary approach is necessary in these patients, both for prevention and rehabilitation therapy.