Delayed hypersensitivity to new oral anticoagulants. Demonstration of cross reactivity for the drug category and definition of non-irritant concentrations for patch tests.

Summary: The current therapy with direct trombin inhibitors (DTI) is indicated for the prevention of stroke in non-valvular atrial fibrillation. Side effects are reported, particularly skin hypersensitivity, for this whole category of drugs as well as for other modern antiplatelet and anticoagulant drugs. For their clinical features, these reactions appear as delayed T-cell mediated drug hypersensitivity, but at present there are no diagnostic methods of investigation. We reported a case of delayed skin reaction to edoxaban and we found the non-irritant concentration for patch test in the whole category of drugs. The patch test resulted positive for edoxaban. A successive challenge with alternative DTIs and/or a switch to warfarin is proposed as alternative therapy.

Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.

BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

Epistaxis in children under the age of two: possible marker of abuse/neglect? A retrospective study in North-Eastern Piedmont hospitals.

AIM: Epistaxis is an extremely common event at all ages; however, under two years of age epistaxis is a very rare event and recent studies carried out in Great Britain concern this event as related to possible non-accidental trauma. To date, no other studies carried out in Italy are available on this topic. METHODS: A file review of all cases of epistaxis occurred in children under the age of 2 who were admitted into the ED in our area over a period of two years was carried out. RESULTS: We have collected data concerning 10 cases of epistaxis occurred in children under 2 years of age with an incidence of 10.4 cases per 10000 accessions to the ED of children under the age of 2. Four of the cases had attendances for head injury or facial trauma. CONCLUSION: The results obtained are higher than the results of the British studies adopting the same methodology, but comparable to their surveillance data on the general population. Through the analysis of the collected data, two correlated assumptions have been made: a possible relationship between epistaxis and neglect, and a relation between epistaxis and domestic accidents.

[To reduce the pain of heel prick in the newborn: comparison of six types of lancets]. / Ridurre il dolore da prelievo capillare nel neonato: confronto tra 6 dispositivi pungidito.

Heel prick is an usual method performed to get a blood sample for newborn screening. Its wide use justifies the effort in reducing the pain as much as possible and some simple steps, including the use of spring heelsticks, are recommended by national and international guide-lines. But not all the heelsticks cause the same pain and allow to get enough blood for the screening. The aim of this work was to test six automatic heelstick devices with regard to the pain in heel prick measured with NIPS scale and, at the same time, to value their effectiveness in getting a blood sample suitable for filter paper for newborn screening. The following devices were assessed: Amnes Minilet Lancets, Wuxi Xinda Ltd, Exxe Safe Blade, Lifescan Stik Johnson & Johnson, One Touch Ultra Soft, Accu-Chek Safe T Pro Plus. The device Exxe Safe Blade statistically differs from all others: it is the least painful and it doesn't need any prick repetition.

[Congenital Milroy Oedema: a case report of a family]. / Edema congenito di Milroy. descrizione di una famiglia.

The authors describe the case of a newborn and their family with Nonne-Milroy disease (hereditary lymphedema type I), a genetic disease that is usually characterized by lymphedema, that most often affects the lower extremities or less frequently the back of the hands. We discuss etiology, inheritance pattern, differential diagnosis and follow-up.

Vitamin D at term of pregnancy and during lactation in white and black women living in Northern Italy.

AIM: Evaluate the vitamin D serum status in a population of white and black mothers who live in the same geographic area of northern Italy (45 degrees 8' N of latitude) and its correlation with vitamin D serum concentrations of the respective newborns at birth, at 2 and 12 months. METHODS: Twelve white woman-infant pairs and 12 black woman-infant pairs were recruited from January through March 2006. The study population had no pre-existing disease and delivered at term of pregnancy (37-41 weeks of gestational age). Only black infants were given vitamin D supplementation from birth to 1 year of age. RESULTS: Eleven black and 12 white women had low vitamin D serum levels at term of pregnancy. Similarly, black and white newborns were both vitamin D deficient at birth. After 12 months white women re-gained physiological vitamin D serum levels, whereas black women maintained a status of vitamin D deficiency. Black newborns who were given supplementation showed lower vitamin D serum concentrations as compared with white newborns at 1 year of age. CONCLUSION: These data showed that all the women living in the same region of northern Italy without any supplementation are equally vitamin D deficient at term of pregnancy regardless of their skin pigmentation. Consequently, every woman should be supplied with additional vitamin D during pregnancy and lactation, though such supplementation seems to exert the most beneficial effects in black women.

Liver HCV-antigens and steatosis in chronic hepatitis C: role of different genotypes.

BACKGROUND: HCV infection is frequently associated with liver steatosis. AIMS AND METHODS: We studied 126 frozen liver HCV positive specimens (genotype-3=27) without any features of metabolic syndrome, searching for a correlation between the number of HCV infected hepatocytes and the presence, amount and distribution of steatosis in relation to different genotypes. RESULTS: Mean steatosis score was higher in genotype-3 with respect to non-3 (1.11 vs 0.66, p=0.022). HCV-antigens were detected by an immunoperoxidase technique in 91/126 (72.2%) cases. A significant correlation between the number of HCV-antigen positive cells and the degree of liver steatosis was observed in genotype-3 (p=0.01) but not in non-3 patients, matched for sex and age. Steatotic cells usually outnumbered HCV-infected cells. Steatosis was observed both in HCV-antigen positive and negative hepatocytes, and HCV-antigens were detected in both hepatocytes with and without steatosis: while no lobular codistribution was found in genotype non-3, in genotype-3 steatosis and HCV-antigens were usually found in the same areas. CONCLUSION: Our data support the role of HCV-antigen liver expression in the pathogenesis of steatosis in genotype-3, however, since the presence of HCV-antigens is not directly related to steatosis within single hepatocytes, an indirect mechanism might be operative too.

Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. AIM: To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. METHODS: Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 micro/kg/week plus RBV 8-10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). RESULTS: Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02-106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. CONCLUSIONS: Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with > or =2 log10 drop in HCV-RNA at week 24.

Recent acquired STD and the use of HAART in the Italian Cohort of Naive for Antiretrovirals (I.Co.N.A): analysis of the incidence of newly acquired hepatitis B infection and syphilis.

OBJECTIVE: To estimate the incidence of newly acquired syphilis (n-syphilis) and hepatitis B infection (n-hepatitis B) in I.Co.N.A. and to evaluate the impact of HAART, calendar date and risk group. METHODS: Cohort study: Incidence was calculated by person-years analyses. Poisson regression was used for the multivariate model. RESULTS: The rate of n-syphilis was 23.4/1,000 PYFU and it increased over time; HIV transmission risk was the most important predictor: men who have sex with men (MSM) had a considerable higher risk (RR 5.92, 95% CI 2.95-12.13 vs IDU/exIDU, p<0.0001). The rate of n-hepatitis B was 12.2/1,000 PYFU; it declined in recent years and halved per 10 years age. Patients with HIV-RNA<500 copies/ml had a 60% reduced risk of n-hepatitis B if they were treated with HAART compared with not treated individuals. CONCLUSIONS: In our population, the use of HAART was not associated with a higher risk of newly acquired sexually transmitted diseases (STD). Suppressive HAART was associated with a lower risk of HbsAg seroconversion. Incidence of n-hepatitis B has recently been declining possibly due to herd immunity provided by vaccination policies. The risk of acquiring n-syphilis has increased over time and it is higher in the population of MSM compared with other categories of HIV exposure.

Liver transplantation with the Meld system: a prospective study from a single European center.

The efficacy of the Meld system to allocate livers has never been investigated in European centers. The outcome of 339 patients with chronic liver disease listed according to their Meld score between 2003 and 2005 (Meld era) was compared to 224 patients listed during the previous 2 years according to their Child score (Child era). During the Meld era, hepatocellular carcinomas (HCCs) had a 'modified' Meld based on their real Meld, waiting time and tumor stage. The dropouts were deaths, tumor progressions and too sick patients. The rate of removals from the list due to deaths and tumor progressions was significantly lower in the Meld than in the Child era: 10% and 1.2% versus 16.1% and 4.9%, p < 0.05. The 1-year patient survival on the list was significantly higher in the Meld era (84% vs. 72%, p < 0.05). The prevalence of transplantation for HCC increased from 20.5% in the Child to 48.9% in the Meld era (p < 0.001), but between HCCs and non-HCCs of this latter era the dropouts were comparable (9.4% vs. 14.9%, p = n.s.) as was the 1-year patient survival on the list (83% vs. 84%, p = n.s.). The Meld allocation system improved the outcome of patients with or without HCC on the list.

Anti-cyclic citrullinated peptide antibodies in type 1 autoimmune hepatitis.

BACKGROUND: Besides the autoantibodies included in the diagnostic criteria of type 1 autoimmune hepatitis, many other autoantibodies have been described in this condition. Recently, antibodies against cyclic citrullinated peptide have been validated as specific diagnostic and prognostic markers of rheumatoid arthritis. AIM: To assess whether these antibodies are part of the autoantibody repertoire of type 1 autoimmune hepatitis and correlate with rheumatological manifestations. METHODS: Antibodies against cyclic citrullinated peptide were tested by a commercially available enzyme-linked immunosorbent assay. RESULTS: The antibodies were found in 12 of 133 (9%) type 1 autoimmune hepatitis, two of 49 (4%) with primary biliary cirrhosis, one of 80 (1%) with hepatitis C virus-related chronic liver disease and 53 of 89 (60%) with rheumatoid arthritis serum samples. High titres were found only in rheumatoid arthritis and type 1 autoimmune hepatitis. No clinical (in particular rheumatological manifestations), biochemical or immunoserological differences were detectable between antibodies against cyclic citrullinated peptide positive and negative type 1 autoimmune hepatitis sera, with the exception of rheumatoid factor, always negative in the positive ones. CONCLUSIONS: Antibodies against cyclic citrullinated peptide can be detected in a subgroup of patients with type 1 autoimmune hepatitis. They might be part of the wide range of autoantibody production characteristic of this condition and/or, less probably, be predictive of future rheumatoid arthritis development.

HCV liver infection and liver steatosis: evidence for indirect mechanisms in genotype 3?

BACKGROUND: Hepatitis C virus (HCV) infection is associated with the appearance of liver steatosis. AIM: To search for a correlation between the number of HCV infected hepatocytes and the presence, amount and distribution of steatosis. METHODS: A total of 124 frozen liver biopsies from HCV patients (genotype 3 = 21) were studied. HCV-antigens were detected on frozen liver sections using a four steps immunoperoxidase technique. Steatosis was graded by haematoxilin-eosin counterstaining on a serial section. RESULTS: Steatosis was detected in 82 of 124 (66.1%) patients without differences between different genotypes. Uric acid, body mass index, gammaGT levels significantly correlated with steatosis in non-3 (P < 0.01, P < 0.05, P < 0.01, respectively) but not in genotype 3 patients. HCV-antigens were detected in 95 of 124 (76.6%) cases. A positive correlation between steatosis and the number of infected hepatocytes was observed only in genotype 3 patients (P = 0.06). In most cases the number of cells with steatosis greatly outnumbered that of HCV infected cells. CONCLUSION: We confirm a possible role of the virus in the genesis of steatosis in HCV genotype 3 infected patients; however, as steatosis do not appear to be directly related to the presence of HCV-antigens within single hepatocytes, an indirect, possibly cytokine mediated, mechanism might be operative.

Efficacy of MELD score in predicting survival after liver retransplantation.

OBJECTIVE: We retrospectively investigated the efficacy of the MELD score to predict the outcome of liver retransplantation and serve as selection criteria. MATERIALS AND METHODS: From 1987 to 2003, the 765 liver transplantations included 87 patients (11.4%) who received a second graft. In addition to graft and patient survivals, ROC curves were used to establish the best MELD score to select cases with poor outcomes. RESULTS: Indications for retransplantation were: 38 (43.7%) surgical complications; 12 (13.8%) chronic rejections; 15 (17.2%) disease recurrences; and 22 (15.3%) primary graft nonfunction. Overall patient survivals at 1, 3, and 5 years were 62.4%, 50.7%, and 49.1%, respectively. A MELD score of 25, calculated by ROC curves, significantly predicted graft and patient survival (44.2% vs 22.5%, P < .05 and 58.6% vs 27.8%, P < .005). During the first 30 postoperative days, patients with a MELD higher than 25 lost the second graft in 48% of cases compared to 16% in the other group (P < .005). Patients retransplanted for primary graft nonfunction showed significant lower 5-year survival rates than those for other indications (28.6% vs 54.5%, P < .05) and higher mean MELD score (30.7 vs 21.9, P < .05). CONCLUSION: A MELD score of 25 is a valid cut-off to predict the outcome of retransplantations, it may be useful to select patients among those who require a second graft. Cases with primary graft nonfunction displayed lower survival, because of their compromised clinical status as evidenced by their high MELD scores.

Botulinum toxin type A (Dysport) for the treatment of Zenker's diverticulum.

The standard treatment for Zenker's diverticulum (ZD) is surgical, but transendoscopic section of the diverticular spur has also been performed with good results. We treated two patients with the injection of 300-350 IU of botulinum toxin type A (Dysport) into the diverticular spur. Both patients were dysphagic because of a large ZD. A few hours after the treatment, the patients were able to return to a normal, nonrestricted diet. They remain symptom-free 12 and 3 months later, respectively. No complications have been observed. As a result of its ease of application and efficacy, this treatment can be recommended for patients who are unable to undergo the surgical operations; it can be considered a valid alternative to the other endoscopic procedures.

Bile duct cell apoptosis is a rare event in primary biliary cirrhosis.

BACKGROUND: The frequency of apoptosis in bile duct cells of primary biliary cirrhosis is still unclear spanning from rare to 50% in the various reports. AIM: To study bile duct cell apoptosis in stage I primary biliary cirrhosis lesions. PATIENTS: Nine stage I-II biopsies with a total number of 26 bile ducts of different sizes, selected from a larger series on the basis of the expression on serial frozen sections of HLA-DR and Fas antigens. METHODS: Apoptosis was evaluated by a DNA fragmentation assay on frozen sections, according to the manufacturer's protocol and by expression of apoptosis related cytokeratin neoepitopes. Bile duct cell proliferation was assessed by MIB1 (Ki-67) expression. RESULTS: Apoptosis was frequently found in inflammatory cells of portal tracts and sinusoids. Apoptosis of hepatocytes was also systematically observed. Only 4 positive bile duct cells were found in 3 bile ducts from 3 biopsies. Quantitative evaluation was not attempted. Cholangiocyte proliferation was observed in the same ducts and occasionally in other biopsies. CONCLUSIONS: These data suggest that cholangiocyte death by apoptosis at the level of typical primary biliary cirrhosis lesions is a rare event, at least in early stages of the disease. The observed rate of proliferation was consistent with the rate of apoptosis.

Immunohistochemical detection of hcv in cirrhosis, dysplastic nodules, and hepatocellular carcinomas with parallel-tissue quantitative RT-PCR.

Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.