Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.     

p53 and skin carcinomas with skull base invasion: a case-control study.

BACKGROUND: Some skin carcinomas may be very aggressive. Increased expression of the protein p53 has been associated with tumor aggressiveness. In this study, p53 expression was evaluated in basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) with skull base invasion, and was compared to tumors with good outcome. STUDY DESIGN AND SETTING: Expression of p53 was immunohistochemically analyzed and it was reported as present or absent in 24 BCC and 11 SCC with skull base invasion. Control group (good outcome) included 23 BCC and 10 SCC. RESULTS: Expression of p53 was noted in 70.83% of BCC with skull base invasion, compared to 43.48% in the control group (P = 0.058). Regarding SCC, p53 positivity was noted in only 9.09% of SCC with skull base invasion, compared to 40.00% in the control group (P = 0.149). CONCLUSIONS: In this study, p53 expression was more common among BCC with skull base invasion, compared to controls with good outcome, and the difference was considered marginally significant. This proportion was reversed in SCC, but the difference was not statistically significant. EBM rating: B-3b.     

Chronic peritoneal dialysis in paediatrics: Experience of a national registry

The results of the first 3 year' collaboration of the Italian Registry of Paediatric Chronic Peritoneal Dialysis (CPD) (1986–1988) are presented. This Registry acquired data on the majority of the paediatric patients treated with CPD in Italy, thus providing a national picture in a field where few nationwide surveys are available. Patients of less than 15 years of age at the start of dialysis were enrolled and clinical data collected until the age of 19 years. The number of nephrological paediatric centres participating in the Registry increased from 7 in 1986 to 11 in 1988. The total number of patients on CPD was 70 and the percentage of dialysed children treated with CPD ranged from 40.2% to 43.6%. Data on 89 peritoneal catheters were collected: during 1417 dialysis-months 70 catheter-related complications were observed (1:20.8 dialysis-months); actuarial catheter survival was 92.7% at 6 months, 84.8% at 1 year and 68.8% at 2 years. The incidence of peritonitis changed from 1 episode every 10.9 patient-months in 1986 to 1 every 19.8 in 1988. Abdominal hernias were the other main clinical complication observed. The survival of patients was 92.5% at 3 years, while the technique survival at the same time was 84%.     

Inhibition by N-acetylcysteine of carcinogen-DNA adducts in the tracheal epithelium of rats exposed to cigarette smoke

The ability of the aminothiol N-acetylcysteine (NAC) to preventthe formation of carcinogen-DNA adducts in tracheal epithelialcells was investigated in Sprague-Dawley rats exposed whole-bodyto mainstream cigarette smoke for either 40 or 100 consecutivedays. ³²P-Postlabelling analyses showed the occurrence of DNAadducts (12.49 adducts/10⁸ nucleotides) after 40 days of exposure,with a trend to formation of characteristic diagonal radioactivezones. Total adduct levels were not further enhanced after 100days of exposure to smoke, although significant changes occurredin the amounts of individual adducts. NAC, given by gavage inthe 40 day study and in drinking water in the 100 day study,significantly inhibited the formation of smoke-related carcinogen-DNAadducts in the tracheal epithelium, to such an extent that adductlevels were not significantly higher than those detected insham-exposed control rats. Together with a variety of othermolecular, clastogenicity, metabolic, cytological and histopathologicalend-points investigated in rodents and with the preliminaryevidence arising from a study in humans, these results documentthe considerable efficacy of oral NAC in inhibiting smoke-relatedcarcinogen-DNA adducts.     

Significance of malperfusion syndromes prior to contemporary surgical repair for acute type A dissection: outcomes and need for additional revascularizations.

OBJECTIVE: The aim of this study was to assess the significance of malperfusion syndromes in patients with acute type A aortic dissection following a contemporary surgical management algorithm and the effects on morbidity, hospital mortality, and long-term survival. We believe that obliteration of the primary tear site with restoration of flow in the true aortic lumen results in decreased need for revascularization of malperfused organ systems. METHODS: Our operative approach aims at replacing the entire ascending aorta, resuspension of the aortic valve with repair or replacement of the sinus segment, and routine open replacement of the arch under hypothermic circulatory arrest with retrograde cerebral perfusion with obliteration of false lumen at the distal arch/proximal descending thoracic aorta, thus reestablishing normal flow in the descending thoracic true lumen. From January 1993 to December 2004, 221 consecutive patients underwent repair of acute type A aortic dissection at our institution. Data were collected retrospectively and prospectively. Various types of malperfusion syndromes were present in 26.7% of patients. The organ systems with malperfusion were as follows: cardiac, 7.2%; cerebral, 7.2%; ileofemoral, 12.7%; renal, 4.1%; mesenteric, 1.4%; innominate, 5.4%; and spine, 2.2%. RESULTS: Coronary malperfusion required coronary revascularization in 62.5% of cases. Distal revascularization was needed in 42.9% of patients with ileofemoral malperfusion. Patients with malperfusion were more likely to suffer perioperative myocardial infarction (p<0.001), postoperative coma (p=0.012), delirium (p=0.011), sepsis (p=0.006), acute renal failure (p=0.017), dialysis (p=0.018), and acute limb ischemia (p<0.001). The in-hospital mortality was 30.5% in patients presenting with any malperfusion syndrome while only 6.2% in patients without malperfusion syndrome (p<0.001). Both cardiac (p=0.020) and cerebral malperfusions (p<0.001) were risk factors for in-hospital mortality. The actuarial long-term survival in patients with malperfusion syndrome was estimated by Kaplan-Meier methods to be 67.8%+/-6.1% at 1 year, 54.0%+/-7.0% at 5 years, and 43.1%+/-8.0% at 10 years and for patient without malperfusion 82.7%+/-3.0% at 1 year, 66.3%+/-3.9% at 5 years, and 46.1%+/-6.7% at 10 years (log rank 2.55, p=0.110). Cerebral malperfusion was a significant risk factor for decreased long-term survival (p=0.0002). CONCLUSIONS: The occurrence of malperfusion in patients with acute type A dissection is associated with significant increased risk of in-hospital mortality and complications. Additional revascularization is generally needed in patients with coronary malperfusion and ileofemoral malperfusion. Patients presenting with cardiac and cerebral malperfusions have a high hospital mortality and preoperative cerebral malperfusion is associated with dismal long-term survival.     

Analysis of the inflammatory response in endovascular treatment of aortic aneurysms.

OBJECTIVE: The objective of this study is to evaluate the inflammatory response caused by endovascular stents in the treatment of aortic aneurysms. METHODS: Twenty-five patients underwent endovascular stent treatment from March through December 2005. The evolution of mediators (sedimentation velocity, C reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-alpha, intercellular adhesion molecule-1, l-selectin), inflammatory cells (leukocytes, lymphocytes, platelets), serum creatinine and body temperature within preoperative period and in the following postoperative periods--1, 6, 24 and 48 h, 7 days, 1-3 months, was analyzed. In order to achieve statistic significance, Friedman test and Wilcoxon test were used, with index of significance of 5% (p<0.05). RESULTS: Peak values of sedimentation velocity, C reactive protein and interleukin-6 were observed at 7 days (p<0.0001), 48 h (p<0.0001) and 24h (p<0.0001), respectively. Tumor necrosis factor-alpha and interleukin-8 did not show statistically significant variability during the entire follow-up. In terms of intercellular adhesion molecule-1 and l-selectin, their expressive values were found in late phase of follow-up, although without statistical significance. Elevation of leukocytes count occurred in premature phase of follow-up (p<0.0001), while lymphocyte and platelet count occurred in a late phase of follow-up (p<0.0001). Serum levels of creatinine did not show significant variability during follow-up. The period between 24 and 48 h corresponded to major frequency for fever (p<0.0001). CONCLUSION: Individual mediators analysis and inflammatory cells demonstrated variability of their values during postoperative follow-up. This could help in the analysis of the inflammatory response evolution caused by endovascular stent treatment for aortic aneurysms in premature and late phases after implantation of the vascular prosthesis.     

Interhemispheric and ipsilateral connections in Parkinson's disease: relation to mirror movements.

Mirror movements (MM) occur in early, asymmetric Parkinson's disease (PD). To examine the pathophysiology of MM in PD, we studied 13 PD patients with MM (PD-MM), 7 PD patients without MM (PD-NM), and 14 normal subjects. Cross-correlogram did not detect common synaptic input to motoneuron pools innervating homologous hand muscles in PD-MM patients. Transcranial magnetic stimulation studies showed no significant difference in ipsilateral motor-evoked potentials between PD-MM patients and normal subjects. The MM side of PD-MM patients showed a slower increase in ipsilateral silent period area with higher level of muscle contraction than the non-MM side and normal subjects. There was less interhemispheric inhibition (IHI) at long interstimulus intervals of 20 to 50 ms in PD-MM than PD-NM. IHI reduced short interval intracortical inhibition in normal subjects and PD-NM, but not in PD-MM. IHI significantly increased intracortical facilitation in PD-MM and PD-NM patients, but not in normal subjects. Our results suggest that MM in PD is due to activation of the contralateral motor cortex. PD-MM patients had reduced transcallosal inhibitory effects on cortical output neurons and on intracortical inhibitory circuits compared to PD-NM patients and controls. These deficits in transcallosal inhibition may contribute to MM in PD patients.