The Use of Integra Dermal Regeneration Template Versus Flaps for Reconstruction of Full-Thickness Scalp Defects Involving the Calvaria: A Cost-Benefit Analysis.

BACKGROUND: INTEGRA® Dermal Regeneration Template is a well-known and widely used acellular dermal matrix. Although it helps to solve many challenging problems in reconstructive surgery, the product cost may make it an expensive alternative compared to other reconstruction procedures. This retrospective study aims at comparing INTEGRA-based treatment to flap surgery in terms of cost and benefit. PATIENTS AND METHODS: We considered only patients treated for scalp defects with bone exposure in order to obtain two groups as homogeneous as possible. We identified two groups of patients: 17 patients treated with INTEGRA and 18 patients treated with flaps. All patients were admitted in our institution between 2004 and 2010, and presented a defect of the scalp following trauma or surgery for cancer, causing a loss of the soft tissues of the scalp with bone exposure without pericranium. To calculate the cost in constant euros of each treatment, three parameters were evaluated for each patient: cost of the surgical procedure (number of doctors and nurses involved, surgery duration, anesthesia, material used for surgery), hospitalization cost (hospitalization duration, dressings, drugs, topical agents), and outpatient cost (number of dressing changes, personnel cost, dressings type, anti-infective agents). The statistical test used in this study was the Wilcoxon Mann-Whitney (α = 0.05). RESULTS: No significant difference was characterized between the two groups for gender, age, presence of diabetes, mean defect size, and number of surgical procedures. All patients healed with good quality and durable closure. The median total cost per patient was €11,121 (interquartile range (IQR) 8327-15,571) for the INTEGRA group and €7259 (IQR 1852-24,443) for the flap group (p = 0.34). A subgroup of patients (six patients in the INTEGRA group and five patients in the flap group) showing defects larger than 100 cm2 were considered in a second analysis. Median total cost was €11,825 (IQR 10,695-15,751) for the INTEGRA group and €23,244 (IQR 17,348-26,942) for the flap group. CONCLUSION: Both treatments led to a good healing of the lesions with formation of soft and resistant tissue. No significant difference was characterized between the two groups for days of hospitalization and costs. In cases of patients with defects larger than 100 cm2 for whom major surgery is needed, the treatment with INTEGRA seemed to be less expensive than the treatment with free flaps or pedicle flaps. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A5 online Instructions to Authors. www.springer.com/00266 .

Neuropsychological assessment at school-age and prenatal low-level exposure to mercury through fish consumption in an Italian birth cohort living near a contaminated site.

The relative effects of prenatal and postnatal low-level mercury exposure and fish intake on child neurodevelopment are still controversial. Limited evidence is available from Mediterranean populations. In this prospective study, we measured the Verbal and Performance IQ in Italian children at school-age who were resident in an area declared as a National contaminated site because of mercury pollution, taking into account the possible beneficial effect of fish consumption and potential confounders. A mother-child cohort made up of 242 children was established at birth in Northeastern Italy in 2001. Their mothers were interviewed approximately 2 months after delivery to determine type, quantity, and origin of fish consumed during pregnancy and about a number of mother, child and family characteristics. Total mercury (THg) and methyl mercury (MeHg) were assessed in maternal hair and breast milk and in the child's hair. When children reached 7-9 years of age, 154 (63.6%) parents gave consent to participate in a follow-up evaluation. On that occasion, a child's hair sample was collected to determine the current concentration of THg, mothers were asked to complete a self-administered questionnaire, and children underwent neuropsychological testing. Verbal IQ, performance IQ and full scale IQ were measured by the Wechsler Intelligence Scale for Children (WISC III) administered by psychologists at school or local health centers. Demographic, socioeconomic and lifestyle information, medical information of the child's family and the child's dietary habits were collected using a questionnaire filled in by mothers. Multivariable linear regression models were used to evaluate the association between prenatal THg exposure through fish consumption of mothers in pregnancy and children's IQ after adjustment for possible confounders such as fish consumption of mothers in pregnancy, child's fish consumption at follow-up, child's birthweight, maternal cigarette smoking during pregnancy, house size and property place of residence during pregnancy and gender. THg in the child's hair at 7 years of age was fairly correlated with THg in maternal hair at delivery (rs=0.35; p<0.0001) and was strongly correlated with child's seafood consumption (rs=0.50, p<0.0001). No differences in maternal THg levels were found when comparing children with low or extremely low or high or extremely high scores vs others, considering separately full scale, verbal, and performance IQs. Children born from mothers with hair THg levels greater than or equal to 2000ng/g had full scale, verbal and performance IQs which were 4-5 points lower than children born from women with lower THg levels, but these differences were not statistically significant. Fresh fish intake of mothers in pregnancy was slightly positively associated with full scale and performance but not so with verbal IQs. Canned fish showed to be negatively associated with all the outcome variables. Unexpectedly, children born to mothers from one town showed IQ scores significantly lower than the other children; however, none of the many variables considered in these analyses could explain this result. The relatively low Hg levels found in the biological samples did not provide evidence of high and extensive Hg exposure in this population. Although THg levels in maternal and child's biological samples are correlated with fish consumption, the effects of THg and fish on neurological outcomes go in opposite directions. These results do not allow to develop recommendations regarding fish consumption in pregnancy but suggest that keeping THg hair levels<2000ng/g might be desirable.

Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab.

AIMS AND METHODS: This study assessed incidence, predictive factors, and outcome of Epstein-Barr virus (EBV) DNAemia in 100 recipients of allogeneic hematopoietic stem cell transplant. A total of 68 patients received anti-thymocyte globulin before unrelated grafts. RESULTS: Cumulative incidence of high-load EBV DNAemia defined by levels >10,000 copies/mL was 14% at 12 months. In multivariate analysis, a CD4+ T-lymphocyte count >50 µL at day +30 was the only factor significantly associated with a reduced risk of high-load EBV DNAemia. Thirteen of 16 patients with high viral loads were preemptively treated with rituximab and achieved EBV DNA negativity. Three patients had already developed post-transplant lymphoproliferative disorder (PTLD) at the time of detection of high EBV DNA loads, and they obtained complete response after rituximab infusions and chemotherapy. Patients with high EBV DNA load had a significantly higher transplant-related mortality (TRM) compared with patients with negative or low viral load (54% vs. 16%, P = 0.009) and a trend to lower overall survival (55% vs. 29%, P = 0.060). CONCLUSION: We conclude that CD4+ cell count at day +30 is a predictive factor for EBV DNAemia and may help identify patients requiring closer monitoring. Although only 3% of patients progressed to PTLD and were all successfully managed, EBV reactivation was associated with higher TRM, mainly because of infections.

Macronutrients, fatty acids and cholesterol intake and endometrial cancer.

BACKGROUND: There is some evidence that dietary habits may influence the risk of endometrial cancer independently of body mass, although the role of diet on endometrial carcinogenesis is unclear. PATIENTS AND METHODS: We carried out a multicenter case-control study from 1992 to 2006 in Italy on 454 women with incident, histologically confirmed endometrial cancer (age range 18-79 years) and 908 controls (age range 19-79 years) admitted to hospitals for acute, non-neoplastic diseases. A validated food-frequency questionnaire was used to estimate macronutrients, fatty acids and cholesterol intake. Logistic regression models, conditioned on age and study centre, and adjusted for major known risk factor of endometrial cancer and residual of energy intake were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Significant direct associations were observed with intake of energy (OR = 1.7 for the highest versus the lowest quintile, 95% CI = 1.1-2.5), and cholesterol (OR = 2.1, 95% CI = 1.4-3.2), while a direct borderline association emerged with saturated fatty acids (OR = 1.3, 95% CI = 0.9-2.0). There was no association with proteins, sugars, starch, total fat and other selected fatty acids. CONCLUSION: Energy and cholesterol intake were associated with endometrial cancer.

Pluraflavins, potent antitumor antibiotics from Saccharothrix sp. DSM 12931.

The new pluramycin-type antibiotics pluraflavin A, C43H54N2O14, pluraflavin B, C43H56N2O15, and pluraflavin E, C36H41NO14 were isolated from cultures of the Saccharothrix species DSM 12931. The structures of the novel compounds were elucidated with the aid of 2D NMR and mass spectrometric investigations. The characteristic structural element of pluraflavins A and B is an additional 4-epi-vancosamine unit at position 13 of the anthraquinone-gamma-pyrone ring system. Pluraflavin E has a carboxyl group in this position. Pluraflavin A has a reactive dimethyl epoxide side chain at position 2 of the anthraquinone-gamma-pyrone aglycon, which may explain the high activity of the antibiotic. The outstanding biological characteristic of pluraflavin A is its powerful, organ-dependent cytostatic action: the IC50 in the colon carcinoma proliferation assay is in the subnanomolar range.

The design and synthesis of purine inhibitors of CDK2. III.

Cyclin-dependent kinases (CDKs) belong to a class of enzymes that control the ability of a cell to enter into and proceed through the cell division cycle. Using purine as a scaffold, we have synthesized a number of nanomolar inhibitors of CDK-2/cyclin E. In this report, the synthesis of a series of piperidine-substituted purine analogs will be presented, as well as some of their in vitro and in vivo biological effects.

Residential radon and risk of lung cancer in an Italian alpine area.

To evaluate whether residential radon exposure explains the excess mortality for lung cancer in an Italian alpine valley with high natural radioactivity, the authors conducted a population-based case-control study on 138 deceased cases and 291 sex- and year-of-birth-matched controls. Year-long alpha-track measurements of radon were performed in the most recent residence, and information about occupational history and lifetime smoking habits was obtained. The authors adjusted for smoking, and radon was associated with lung cancer risk among men: compared with a radon level of < 40 becquerels (Bq) per cubic meter (m3), the odds ratios for 40-76 Bq/m3, 77-139 Bq/m3, 140-199 Bq/m3, and 200+ Bq/m3 were 2.1, 2.0, 2.7, and 1.4, respectively. The association between radon and lung cancer, as determined with a multiplicative model, was found only among male smokers.

Diet and risk of oral and pharyngeal cancer. An Italian case-control study.

The relation between diet and risk of oral and pharyngeal cancer was analysed in a case-control study conducted in North-East Italy between 1996 and 1999. Cases were 132 patients (including 33 women), with incident, histologically confirmed cancer of the oral cavity or pharynx, and controls were 148 subjects (including 45 women) admitted to hospitals for acute conditions unrelated to smoking or alcohol drinking. After allowance for tobacco, alcohol and several other potential confounding factors, significant inverse association with the risk of oral and pharyngeal cancer was found for consumption of total green vegetables (OR 0.37) and total fruit (OR 0.34) with significant trends in risk Compared with alcohol drinkers of < 20 drinks/week and eating > 13 portions/week of total green vegetables, the OR for drinkers of > or = 20 drinks/week and eating < 7 portions/week of green vegetables was 15.44. Our study provides further support to the beneficial effect of high intake of vegetables and fruit, particularly in heavy smokers and alcohol drinkers.

Protocol implementation in hospital infection control practice: an Italian experience of preoperative antibiotic prophylaxis.

This study evaluates the effectiveness of a protocol implemented to induce behavioural modifications in healthcare workers (HCWs). A preoperative antibiotic prophylaxis protocol for surgical procedures in clean and clean-contaminated wounds was used. The study was conducted in a 300-bed Italian university hospital between 1998 and 1999. The protocol's impact was analysed by retrospective examination of the clinical records for selected common surgical procedures. The study also investigated the reasons for the low compliance with the protocol through a focus group methodology. We examined 723 surgical procedures and the overall compliance was 30.8% (56/182) before the implementation of the protocol and 45.2% (76/168) after 1 year (P< or = 0.01). During the same period compliance with the use of antibiotics increased when antibiotics were recommended by the protocol (5/115 vs. 19/109, P< or = 0.01) and use decreased when they were not (51/67 vs. 57/59, P< or = 0.01). As reported in the focus groups, reasons for low compliance included hospital policy weaknesses in protocol definition and implementation and the cultural behaviour of HCWs. Our results reinforce previous findings that monitoring the effectiveness of protocol implementation in the medical care setting is essential. Critical points that might increase the effectiveness of protocol implementation have also been identified.

Combined analysis of MIB-1 and thyroid transcription factor-1 predicts survival in non-small cell lung carcinomas.

The prognostic value of combined immunohistochemical analysis for the thyroid transcription factor-1 (TTF-1) and the proliferation marker MIB-1 was assessed in a consecutive series of non-small cell lung carcinomas (NSCLC). Tumor immunoreactivity for TTF-1 and MIB-1 was classified in three groups (-,+,++) and in two groups (-,+), respectively. Comparison across groups for TTF-1 reactivity showed significantly different survival curves (P=0.04). In particular, the best prognosis was associated with a TTF-1 negative pattern, whereas the TTF-1 '++' cases showed the worst prognosis. A trend towards better prognosis was observed for MIB-1 negative cases (P=0.09). Multivariate analysis confirmed independent prognostic significance of TTF-1 (P=0.002), MIB-1 (P=0.01) and pStage (P=0.04). Accordingly, analysing TTF-1 and MIB-1 together, a better prediction of survival was obtained (P=0.02), with the poorest prognosis for the 'TTF-1++/MIB-1+' cases.

Prognostic significance of Ape1/ref-1 subcellular localization in non-small cell lung carcinomas.

PURPOSE: To evaluate the prognostic value of the DNA repair/redox-protein Ape1/ref-1 in a retrospective series of consecutive non-small cell lung carcinomas (NSCLC). PATIENTS AND METHODS: Sections from 91 radically resected NSCLC were analyzed for immunohistochemical expression of Ape1/ref-1. For each case 1,000 tumor cells were evaluated to detect nuclear and cytoplasmic reactivity scored as a percentage of positive cells. With respect to sub-cellular localization and percentage of immunoreactive cells, each tumor was classified as "cytoplasmic" or "non cytoplasmic". The survival rate according to Ape1/ref-1 sub-cellular localization was calculated. RESULTS: The main pattern of Ape1/ref-1 expression was nuclear. No significant difference was observed in Ape1/ref-1 pattern according to histotype (squamous vs adenocarcinoma). Among adenocarcinomas, a cytoplasmic expression of Ape1/ref-1 was significantly associated with poor survival rate in univariate (p=0.01) and multivariate (p=0.07) analyses. In addition, a cytoplasmic expression of the DNA repair protein was also predictive of worse prognosis (log-rank test, p=0.02) in cases with lymph node involvement, regardless of histotype. CONCLUSION: The results suggest a potential role of Ape1/ref-1 sub-cellular localization as a prognostic indicator in patients with NSCLC. In particular, cytoplasmic localization of the protein seems to confer a poor outcome in subgroups of patients with nodal involvement or adenocarcinoma histotype.

Scleroderma and occupational exposure to hand-transmitted vibration.

OBJECTIVES: To determine whether occupational exposure to hand-transmitted vibration is a risk factor for scleroderma (systemic sclerosis, SSc), two case-control studies were conducted in the provinces of Trento and Verona, northeastern Italy. METHODS: In the Trento study, 21 patients with a diagnosis of either systemic or localised scleroderma were recruited from those admitted to all hospitals of the province from 1 January 1976 to 31 December 1991. For each case, two age- and gender-matched controls were selected. In the Verona study, cases included 55 patients diagnosed with SSc and clinically followed at the rheumatology clinic of the local university hospital between 1 January 1997 and 30 June 1999. The controls included 171 subjects frequency-matched by gender and age group. In both studies, all subjects were interviewed by structured questionnaire containing items on personal characteristics, smoking and drinking habits, use of medicines, occupational history and complete medical history. Women were also investigated about silicone implants and cosmetic surgery. Jobs and job tasks involving the use of vibratory tools, with or without concomitant exposure to silica dust in mining and non-mining occupations, were carefully investigated. A minimum criterion of 6 months was required for exposure duration. RESULTS: In the Trento study, men with scleroderma were more likely than controls to have had exposure to hand-transmitted vibration (odds ratio (OR) 1.5, 95% confidence interval (95% CI) 0.1-74.1) or silica dust (OR 5.2, 95% Cl 0.5-74.1), but the association was not significant. The scleroderma patients were miners or stone workers who had operated jackhammers and rock drills. In the Verona study, a greater, although not statistically significant, odds of SSc was observed in men exposed to hand-transmitted vibration (OR 2.4, 95% CI 0.4-14.0) and in women exposed to silica (OR 2.4, 95% Cl 0.4-15.5). The SSc patients with vibration exposure were machinery operators or metal workers who had used grinders and impact wrenches. CONCLUSIONS: Our case-control studies did not show a significant association between scleroderma and hand-transmitted vibration, with or without concomitant exposure to silica dust. Owing to the rarity of the disease and the small number of cases in the present studies, a genetic susceptibility to connective tissue disorders in SSc patients with occupational exposure to hand-transmitted vibration and/or silica cannot be ruled out.

Oral hygiene, dentition, sexual habits and risk of oral cancer.

In an Italian case-control study of oral cancer, number of missing teeth and other aspects of dental care were similar, but the general condition of the mouth, as indicated by gum bleeding, tartar deposits and mucosal irritation, was worse among oral cancer cases than controls. No differences were detected in sexual practices (including oral sex) and (previous) sexually transmitted infections.

Migration, socio-economic status and the risk of colorectal cancer in Italy.

To assess how the risk of cancer of the colon and rectum relates to place of birth and socio-economic status, we analysed data from an Italian case-control study. Data included 1225 cases with a recent diagnosis of cancer of the colon (ages 19-74 years), 728 cases of cancer of the rectum (ages 23-74 years) and 4154 controls (ages 19-74 years), frequency-matched with cases by age and catchment area and admitted to hospitals for a wide spectrum of acute non-neoplastic conditions. Compared with residents born in the north of Italy, migrants from the centre and south had an odds ratio (OR) of 0.7 (95% CI 0.5-0.9) for colon cancer and OR of 0.9 (95% CI 0.7-1.2) for cancer of the rectum. The inverse association of migration with colon cancer was stronger among women (OR 0.5, 95% CI 0.4-0.8) than among men (OR 0.8, 95% CI 0.6-1.1), and was independent of education and occupation. Among migrants, the direct association between education and colon cancer risk was less clear than among non-migrants. In conclusion, place of origin played an independent role in colon cancer aetiology. Results on rectal cancer were less clear, although in the same direction. Among migrants, those less susceptible to behavioural changes (e.g. women) retained most of the benefit associated with their place of origin.

Immunoreactivity to putative B-cell epitopes of hepatitis G virus polyprotein in viremic and nonviremic subjects.

The hepatitis G virus (HGV) polyprotein was scanned by computer-aided prediction of antigenicity to search for B-cell epitopes. Four polypeptide sequences, V37D (amino acids [aa] 1685 to 1721), V36S (aa 2102 to 2137), P37R (aa 2156 to 2192), and C40P (aa 2280 to 2319), were identified and synthesized for use in immunoassays. Antibodies to these peptides were searched for in a panel of 239 serum samples, which were also tested for anti-E2 antibodies and HGV RNA. Furthermore, the course of HGV markers was studied prospectively in four patients who had been transfused with HGV RNA-positive blood. There was a negative association between immunoreactivity to V37D and P37R and presence of HGV RNA (2 of 53 and 1 of 53, respectively; P < 0.05); none of the subjects with dual antibody positivity was HGV RNA positive. Anti-V37D and anti-P37R antibodies compared favorably with anti-E2 antibodies as markers of recovery from HGV infection. These results might be useful for the development of new, more sensitive diagnostic assays.

New epoetin molecules and novel therapeutic approaches.

Erythropoietin (EPO) is a 34 kDa protein that is the primary regulator of red blood cell production. EPO facilitates its effect by binding to the cell surface EPO receptor which initiates the JAK-STAT signal transduction cascade. The search for small mimetic molecules of EPO has led to the discovery of a family of peptides that demonstrate EPO mimetic activity. A member of this peptide family, EMP1 (EPO mimetic peptide 1), was used to solve the crystal structure of the soluble EPO receptor in complex with this peptide. The structure revealed a 2:2 stoichiometry of receptor to peptide, with each peptide contacting both receptor molecules in a symmetrical fashion. The potency of the EMPs could be improved through the covalent dimerization of two peptide molecules. Further investigations of EMP EPO receptor complex structures revealed the formation of a non-productive receptor dimer using an inactive peptide. An alternative approach towards the identification of an EPO-like mimetic is to target an intracellular signalling molecule such as haematopoietic cell phosphatase (HCP), also known as SHP1. Inhibiting HCP causes responsive cells to be hypersensitive to EPO. The cloned HCP protein has been utilized in screening assays to identify small molecule inhibitors of HCP.

Risk factors for breast cancer in nulliparous women.

The relation between hormonal and lifestyle factors and breast cancer risk in nulliparae was investigated using data from two case-control studies conducted in Italy between 1983 and 1994. The study included 1041 nulliparae with histologically confirmed incident breast cancer and 1002 nulliparous controls admitted to hospital for a wide range of acute, non-neoplastic, nonhormone-related diseases. In premenopausal nulliparae, there was an inverse relation with age at menarche [odds ratios (OR) 0.45; 95% confidence intervals (CI) 0.24-0.86 for > or = 15 years vs < 12], while no association emerged in postmenopausal. Breast cancer risk increased with age at menopause, the OR being 1.91 (95% CI 1.26-2.90) for nulliparae reporting age at menopause > or = 53 years compared with < 45. Abortion was not related to breast cancer risk, the OR being 0.92 for any spontaneous, 0.97 for any induced and 0.77 for > or = 2 total abortions compared to none. The OR was 1.75 (95% CI 1.03-2.97) for women reporting their first abortion at age > or = 30 years compared with < 30. Oral contraceptives and hormone replacement therapy in menopause were moderately related to risk. The OR was 2.71 (95% CI 1.85-3.95) in nulliparae with a family history of breast cancer and 1.60 (95% CI 1.20-2.14) in those with a history of benign breast disease. Compared with nulliparae reporting a low physical activity, the OR was 0.79 (95% CI 0.54-1.16) for those reporting intermediate/high activity. Breast cancer risk increased with total energy intake, the OR being 1.65 (95% CI 0.99-2.75) in the highest tertile; beta-carotene was inversely related to risk (OR 0.60, 95% CI 0.38-0.95) for the highest tertile. Thus, most risk factors for breast cancer in nulliparae were similar to those in women generally.

A study on the role of the family and other risk factors in HCV transmission.

BACKGROUND/AIMS: To understand the intrafamilial transmission and the existing risk factors related to HCV infection in subjects confirmed anti-HCV positive, their sexual partners and household contacts in Friuli, North-East Italy. METHODS: We enrolled all the subjects that were consecutively identified as HCV positive during routine laboratory testing in six health districts and their household contacts. From each subject we obtained a blood sample, demographic data and a medical history including the existence of risk factors for HCV. Antibodies to HCV were detected employing a commercially available second-generation enzyme immunoassay (EIA); positive serum specimens were retested using a second-generation recombinant immunoblot assay (RIBA-2). RESULTS: We recruited 743 subjects, 229 first subjects identified as HCV positive and 514 household contacts. There were no statistically significant differences in positivity among household contacts. Analysing intracouple transmission we found no significant differences by gender in couples both with and without parenteral risk factors. We found, both with univariate and multivariate analysis, as statistically significant risk factors in all the subjects: age older than 60, blood transfusions (particularly those performed before 1984), surgical procedures such as abortion and/or uterine curettage, history of HBV infection, intravenous drug use, and tattooing. CONCLUSIONS: Our results stress the low relevance of sexual transmission in the intrafamilial context, the importance of abortion and/or uterine curettage, the important role of blood transfusions in the past, a higher prevalence of HCV infection within a household of a HCV positive member compared to all other existing data in the area.