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The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date.From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors.The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P0.05]. Conversely, age60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together.Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

BACKGROUND: The aim of this study was compare short- and long-term outcomes between robotic (RG) and standard open gastrectomy (OG). METHODS: This is a single-center propensity score-matched study including patients who underwent RG or OG for gastric cancer between 2008 and 2018. RESULTS: In total, 191 patients could be included for analysis. Of 60 RG patients, 49 could be matched. After matching, significant differences in baseline characteristics were no longer present. Operative time was significantly longer (451 min, IQR: 392-513) in the RG group than in the OG (262 min, IQR: 225-330) (P < .0001). No significant differences in postoperative complications between RG (n = 15, 30.6%) and OG (n = 15, 30.6%) were seen (P = 1.000). Overall survival was comparable between the groups. CONCLUSIONS: RG is feasible and safe. With regard to long-term oncologic outcomes, survivals in the RG group were similar to those in OG group.

BACKGROUND: Previous studies have suggested that sigmoidectomy with primary anastomosis is superior to Hartmann's procedure. The likelihood of stoma reversal after primary anastomosis has been reported to be higher and reversal seems to be associated with lower morbidity and mortality. Although promising, results from these previous studies remain uncertain because of potential selection bias. Therefore, this study aimed to assess outcomes after Hartmann's procedure versus sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy, for perforated diverticulitis with purulent or faecal peritonitis (Hinchey III or IV disease) in a randomised trial. METHODS: A multicentre, randomised, open-label, superiority trial was done in eight academic hospitals and 34 teaching hospitals in Belgium, Italy, and the Netherlands. Patients aged between 18 and 85 years who presented with clinical signs of general peritonitis and suspected perforated diverticulitis were eligible for inclusion if plain abdominal radiography or CT scan showed diffuse free air or fluid. Patients with Hinchey I or II diverticulitis were not eligible for inclusion. Patients were allocated (1:1) to Hartmann's procedure or sigmoidectomy with primary anastomosis, with or without defunctioning ileostomy. Patients were enrolled by the surgeon or surgical resident involved, and secure online randomisation software was used in the operating room or by the trial coordinator on the phone. Random and concealed block sizes of two, four, or six were used, and randomisation was stratified by age (

Identification of parameters predicting assisted reproductive technologies (ARTs) success is a major goal of research in reproduction. Quality of gametes is essential to achieve good quality embryos and increase the success of ARTs. We evaluated two sperm parameters, chromatin maturity and expression of the sperm specific calcium channel CATSPER, in relation to ART outcomes in 206 couples undergoing ARTs. Chromatin maturity was evaluated by Chromomycin A3 (CMA3) for protamination and Aniline Blue (AB) for histone persistence and CATSPER expression by a flow cytometric method. CMA3 positivity and CATSPER expression significantly predicted the attainment of good quality embryos with an OR of 6.6 and 14.3 respectively, whereas AB staining was correlated with fertilization rate. In the subgroup of couples with women ≤35 years, CATSPER also predicted achievement of clinical pregnancy (OR = 4.4). Including CMA3, CATSPER and other parameters affecting ART outcomes (female age, female factor and number of MII oocytes), a model that resulted able to predict good embryo quality with high accuracy was developed. CMA3 staining and CATSPER expression may be considered two applicable tools to predict ART success and useful for couple counseling. This is the first study demonstrating a role of CATSPER expression in embryo development after ARTs programs.

Summary To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12–92 years before transplants and in 11 biopsies after transplants with high donor–recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT–qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age-dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT–qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor–recipient extreme age-mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently ‘rejuvenated’ according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor–recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors.

BACKGROUND: The Hirsch index (h-index) is recognized as an effective way to summarize an individual's scientific research output. However, a benchmark for evaluating surgeon scientists in the field of hepatic surgery is still not available. METHODS: A total of 3,251 authors who published between 1949 and 2011 were identified using the Scopus identification number. The h-index, the total number of cited document, the total number of citations, and the scientific age were calculated for each author using both Scopus and Google Scholar. RESULTS:The median h-index was 6 and the median scientific age, assessed with Google Scholar, was 19 years. The numbers of cited documents, numbers of citations, and h-indexes obtained from Scopus and Google Scholar showed good correlation with one another; however, the results from the 2 databases were modified in different ways by scientific age. By plotting scientific age against h-index percentiles an h-index growth chart for both Scopus database and Google Scholar was provided. CONCLUSIONS: This analysis provides a first benchmark to assess surgeon scientists' productivity in the field of liver surgery.

Background The strategy of salvage transplantation for patients with hepatocellular carcinoma is based on the premise that tumour recurrence will be still transplantable at the time of recurrence. However, patients can not only present non-transplantable recurrence but can also be over the age limit accepted for transplantation. Aims To measure the risk of being too old for salvage transplantation of patients resected for hepatocellular carcinoma within Milan criteria. Methods A Markov simulation model was developed on the basis of published literature. Results The risk of being too old for salvage transplantation depends on the time-span between age at hepatic resection and age limit, and the expected median waiting-time. Patients resected at an age 2 or 3 years below the age limit carry a risk of being too old that overcomes the probability of receiving transplantation. Salvage strategy can cause harm that depends on the tumour characteristics and degree of portal hypertension, becoming maximal for patients with multiple tumours, clinical signs of portal hypertension and increased bilirubin levels. Conclusions The best strategy to adopt should be balanced between the risk of being too old and the expected transplant benefit, but salvage strategy could be pursued if it did not turn into significant harm in comparison to primary transplantation.

Summary Interferon beta (IFN-β) is among the first-line treatment options for patients with multiple sclerosis (MS). A potential caveat of therapy, however, is the development of neutralizing antibodies (NAb) and/or neutralizing activity (NA) non-antibody mediated, although debate is still ongoing as to whether NAb significantly hampers the efficacy of the drug or rather represents an immunologically irrelevant epiphenomenon. In the present study, we describe the effect of NAb on IFN-β-1b through clinical and magnetic resonance imaging (MRI) outcome measures of five relapsing–remitting multiple sclerosis (RRMS) patients who were treated with 250 μg of subcutaneously administered IFN-β-1b every other day and developed NAb at varying titres and times during the course of therapy. Despite the small number of NAb+ patients, heterogeneity in MRI/clinical response to IFN-β-1b was identified. Response to IFN-β-1b therapy was observed in the absence or presence of NAb. Also observed was failure to IFN-β-1b coincident with high and sustained NAb titres, but also before NAb development or in the presence of low NAb titres. Multiple MRI and NAb measurements performed within the same individual allow for a better description of the complex heterogeneous response to IFN-β-1b with respect to NAb occurrence.

STUDY QUESTION Is CatSper1 expression in human spermatozoa related to semen parameter values and sperm functions? SUMMARY ANSWER CatSper1 expression is positively related to progressive and hyperactivated (HA) motility, [Ca(2+)]i responsiveness to progesterone but not the acrosome reaction (AR). WHAT IS KNOWN ALREADY The role of cationic channel of sperm (CatSper) in sperm functions is clear in animal models but less defined in human sperm cells. Current knowledge is mostly based on low specificity CatSper inhibitors showing agonistic and toxic effects on human spermatozoa and is thus of little help in clarifying the role of the CatSper channel in human sperm functions. STUDY DESIGN, SIZE, DURATION CatSper1 protein expression was evaluated in 115 men undergoing semen analysis for couple infertility. CatSper1 expression was related to routine semen parameters, motility kinematic parameters and basal and progesterone-stimulated [Ca(2+)]i and the AR. PARTICIPANTS/MATERIALS, SETTING, METHODS CatSper1 expression was evaluated (n = 85 normozoospermic, n = 30 asthenozoospermic patients) by immunofluorescence coupled to flow cytometry leading to quantitative measurement of the percentage of ejaculated sperm cells expressing the protein. Semen analysis was evaluated according to World Health Organization guidelines. Kinematic parameters were evaluated by a computer-aided sperm analysis system. [Ca(2+)]i was measured by a spectrofluorimetric method in fura-2-loaded spermatozoa. The AR was evaluated in live sperm cells by fluorescent-labeled lectin. MAIN RESULTS AND THE ROLE OF CHANCE CatSper1 protein expression in spermatozoa was reduced in asthenozoospermic men (mean ± SD: 53.0 ± 15.5%, n = 30 versus 67.9 ± 17.1% in normozoospermic, n = 85, P < 0.01) and was significantly correlated with progressive (r = 0.36, P < 0.001), total (r = 0.35, P < 0.001) and HA (r = 0.41, P < 0.005) motility. In addition to a higher percentage of spermatozoa not expressing CatSper1, asthenozoospermic men showed a large number of spermatozoa with immunofluorescent signal localized outside the principal piece compared with those in normozoospermia. A significant positive correlation was found between CatSper1 protein expression and the increase of [Ca(2+)]i in response to progesterone (r = 0.36, P < 0.05, n = 40) but not with basal [Ca(2+)]i. No correlation was found with the AR, either basal or in response to progesterone. LIMITATIONS, REASONS FOR CAUTION The study is partly descriptive. Furthermore, we cannot rule out the possibility that some round cells remain after a single round of 40% density gradient centrifugation or that this step may have removed some defective or slow swimming sperm, and therefore this preparation may not be representative of the entire sperm sample. Although our data suggest that CatSper1 may be a useful marker for infertility, and a possible contraceptive target, any clinical application is limited without further research. WIDER IMPLICATIONS OF THE FINDINGS Our results demonstrate an association of CatSper1 expression with human sperm progressive and HA motility and provide preliminary evidence that lack of expression or mislocalization of CatSper1 in spermatozoa may be involved in the pathogenesis of asthenozoospermia. However, mechanistic studies are needed to confirm that the correlations between CatSper1 expression and sperm functions are causative. STUDY FUNDING/COMPETING INTERESTS Supported by grants from Ministry of University and Scientific Research (PRIN project to E.B. and FIRB project to S.M.) and by Regione Toscana (to G.F.). L.T. was recipient of a grant from Accademia dei Lincei (Rome, Italy). The authors have no conflicts of interest to declare.

Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of β5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation. Owing to organ shortage, livers from old donors are increasingly used for transplantation. The function and duration of such transplanted livers are apparently comparable to those from young donors, suggesting that, despite some morphological and structural age-related changes, no major functional changes do occur in liver with age. We tested this hypothesis by performing a comprehensive study on proteasomes, major cell organelles responsible for proteostasis, in liver biopsies from heart-beating donors. Oxidized and poly-ubiquitin conjugated proteins did not accumulate with age and the three major proteasome proteolytic activities were similar in livers from young and old donors. Analysis of proteasomes composition showed an age-related increased of β5i/α4 ratio, suggesting a shift toward proteasomes containing inducible subunits and a decreased content of PA28α subunit, mainly in the cytosol of hepatocytes. Thus our data suggest that, proteasomes activity is well preserved in livers from aged donors, concomitantly with subtle changes in proteasome subunit composition which might reflect the occurrence of a functional remodelling to maintain an efficient proteostasis. Gender differences are emerging and they deserve further investigations owing to the different aging trajectories between men and women. Finally, our data support the safe use of livers from old donors for transplantation.

Background The reliability of endoscopic findings after adult intestinal transplantation on short-term follow-up has been shown. The aim of this study was to evaluate in a long-term follow-up the diagnostic value of endoscopies compared with the biopsy value. Methods We evaluated 52 endoscopies over a period of 2 years (2 in each patient in 2010 and 1 in each patient in 2011, plus 1 endoscopy for suspected post-transplant lymphoproliferative disease [PTLD]) on 17 recipients transplanted between the years 2000 and 2006 (more than 5 years of follow-up). Results All the 52 endoscopic findings were comparable to biopsy definitive results: only 1 case of mild enteritis and 1 case of Epstein-Barr virus (EBV) chronic infection at biopsy were not diagnosed by endoscopy. One case of rectal PTLD and 1 of EBV-related enteritis were diagnosed by use of both procedures. Specificity was 98%: we did not calculate sensitivity because no episodes of rejection were diagnosed because recipients were stable in long-term follow-up. Conclusions Endoscopy is a reliable procedure even on a long-term follow-up after intestinal transplantation, allowing a support to biopsy for diagnosis on adult recipients, especially for EBV infections and PTLD surveillance.

In order to compare the standard swim-up semen preparation with and without test yolk buffer (TYB) incubation in intrauterine insemination (IUI), we conducted a prospective multicentre randomized trial. A total of 121 infertile couples with male factor (n = 52) or unexplained infertility (n = 69) was randomly assigned to two groups following ovulation induction. Semen was prepared by standard swim-up in group A (n = 64) and by swim-up followed by TYB incubation in group B (n = 57). A maximum of two IUI cycles was performed. A total of 104 cycles was performed in the swim-up group and 90 in the TYB group. Overall, 15 pregnancies were achieved in group A and 23 in group B, with an overall pregnancy rate of 24.8 and 50.0% per patient respectively (chi2(1), P < 0.05). In the male factor group, pregnancy was achieved in six out of 24 couples (25%) following standard swim-up and in six out of 28 (21.4%) following swim-up and TYB incubation (chi2(1), not significant). In the unexplained infertility group, pregnancy was recorded in nine out of 40 couples (22.5%) following standard swim-up and in 17 out of 29 couples (58.6%) following swim-up and TYB incubation (chi2(1), P < 0.05).

The incidence of early rejection after intestinal transplantation correlates with heightened risk of graft loss and mortality. Many different induction or pre-conditioning protocols have been reported in the last 10 yr to improve outcomes; however, sepsis remains prevalent and diminishes long-term results. We recently began a "2-dose" alemtuzumab trial protocol - 15 mg at day 0 and 15 mg repeated on day 7 - with the hope of reducing our infection rate. We compared three different protocols used at our institution (daclizumab, conventional "4-dose" alemtuzumab, and "2-dose" alemtuzumab). There was a significantly lower rate of early rejection with the "2-dose" alemtuzumab protocol in our study group of mainly (88%) intestinal grafts without accompanying liver engraftment with its protective immunologic effect. Sepsis remained low. Longer follow-up will be required to evaluate the effects of this new protocol on longer-term outcomes.

Background Chronic intestinal pseudo-obstruction (CIPO) has been treated in adults by total parenteral nutrition (TPN) or, if complications arise, by multivisceral transplantation because the stomach is often involved. Eleven adults with CIPO were transplanted by intestinal graft in our center from 2000 to 2011. Methods Nine patients underwent isolated intestinal transplant and 2 patients had multivisceral transplant. Immunosuppression was represented by FK and steroids plus induction with alemtuzumab, daclizumab, or thymoglobulin. Average age at transplant was 33.5 years. We reported 1 graftectomy, followed by retransplantation. Results Seven patients are currently alive with working small bowel; cause of death was infection in the 4 remaining cases. In 9 isolated intestinal transplants, we performed different digestive reconstructions to allow gastric emptying. In 2 cases we were forced, after transplant, to perform ileostomy to improve intestinal motility. Graft and patient survival after 5 years are 60% and 70%, respectively, while after 10 years, 45% and 56%, respectively. Conclusions Adults with CIPO and irreversible TPN complications benefit from isolated intestinal transplant with different surgical techniques to empty the native stomach: this strategy achieves good gastric emptying, with effective establishment of oral feeding and graft and patient survivals comparable to isolated intestinal transplant for short bowel syndrome.

Steroid-resistant acute cellular rejection (ACR) and chronic rejection (CR) are still major concerns after intestinal transplantation. We report our experience from a single center on 48 adults recipients using 49 grafts from 2001 to 2011, immunosuppressing them initially with daclizumab initially and later Alemtuzumab. Overall patient survival was 41.9% at 10 years while graft survival was 38.5%. The steroid-resistant ACR population of 14 recipients (28.5%) experienced 50% mortality mainly due to sepsis, while the five (8%) CR recipients, included two survivors. All but 1 graft was placed without a liver. CR was often preceded by ACR episodes. Mortality related to steroid-resistant ACR and CR still affects the intestinal transplant population despite induction/preconditioning, especially in the absence of a protective liver effect of the liver. New immunosuppressive strategies are needed.

Background Combined liver-kidney transplantation (LKT) is considered to be a safe procedure, but the appropriate immunosuppressive regimen is unclear. Patients and methods Between January 1997 and October 2011, 55 patients were listed for LKT: 45 (82%) were effectively transplanted, 5 (9.2%) died whereon here the waiting list, 3 (5.5%) temporarily out of waiting list, 1 (1.8%) was on waiting list and 1 (1.8%) refused LKT. Five LKTs treated with cyclosporine (CyA) were excluded from the analysis. Mean recipient age was 50.32 ± 10.32 years (14–65), MELD score at time of LKT was 19.22 ± 4.69 (8–29), mean waiting list time was 8.14 ± 9.50 months (0.1–35.76), and follow-up, 4.09 ± 3.02 years (0.01–10.41). Main indications for LKT were policystic disease (n = 15; 37%), hepatitis virus C (HCV)-related cirrhosis (n = 9; 22%) metabolic disease (n = 5; 13%), hepatitis virus B (HBV) cirrhosis (n = 4; 10%), alcoholic cirrhosis (n = 4; 10%), and cholestatic disease (n = 3; 8%). Immunosuppressive regimen was based on tacrolimus and steroids in 40 cases with induction therapy with alemtuzumab (Campath; 0.3 mg/kg) in 13 of 40 instances cases administered on day 0 and day 7. Results Postoperative mortality was 2.5%. Acute cellular rejection episodes were biopsy-proven in 2 (5%) cases, post-LKT infections developed in 17 cases (42.5%), and de novo cancer developed in 3 (7.5%) cases. Similar 5-year overall survivals were obtained irrespective of the LKT indication: 100% in cholestatic and alcoholic cirrhosis patients, 86% in policystic disease, 75% in metabolic disease and HBV patients, and 66% in HCV cirrhosis. Overall survivals for the alemtuzumab vs without-induction therapy groups at 1, 3, and 5-years were 100%, 85.7%, and 85.7% vs 76%, 76%, and 70%, respectively ( P = .04). Conclusion An immunosuppressive regimen based on tacrolimus and steroids with induction therapy with alemtuzumab was safe, with excellent long-term results for combined LKT.

In some recent hypotheses, the ovary has been indicated as a source of insulin-like growth factor (IGF)-I, with synthesis regulated from local steroidal and non-steroidal substances. We measured IGF-I concentrations in both serum and follicular fluid of women undergoing in-vitro fertilization (IVF) and embryo transfer, in both induced and spontaneous cycles. It was found that serum and follicular IGF-I concentrations were correlated with follicular morphology, oocyte maturity, steroid concentrations and clinical characteristics of IVF cycles. In addition, we measured IGF-I concentrations in both peripheral and ovarian circulation to gain further detailed information on the contribution of the ovary to IGF-I production. The results of our study support the hypothesis that follicular IGF-I is probably derived by diffusion from peripheral circulation and that local production appears unlikely.

The relationship between neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases and post-operative morbidity still has to be clarified. Data from 242 patients undergoing hepatectomy for colorectal liver metastases, judged resectable at first observation, were reviewed and their clinical outcome was related to neo-adjuvant chemotherapy (125 patients). Selection biases were outlined and properly handled by means of propensity score analysis. Post-operative death was 1.2% and morbidity 40.9%. Pre-operative chemotherapy was only apparently related to higher morbidity (P = 0.021): multivariate analysis identified extension of hepatectomy and intra-operative blood loss as independent prognostic variables (P

Background The American Cancer Society's Active for Life is a worksite wellness program that encourages employees to be physically active. This paper reports the experience of implementing Active for Life in a worksite setting and its longer-term impact on physical activity. Context The Active for Life intervention was provided to employees at Group Health Cooperative, a nonprofit health care system in the Pacific Northwest with 9800 employees. Methods Posters, newsletters, health fairs, and site captains promoted enrollment in Active for Life. Interventions included goal-setting, self-monitoring, incentives, and team competition. Preprogram and postprogram changes in physical activity were assessed at baseline, 10 weeks, and 6 months. Consequences Active for Life was offered to 3624 employees, and 1167 (32%) enrolled; 565 (48%) completed all three surveys. At 10 weeks, all physical activity measures increased significantly. The proportion of employees meeting the guideline of the Centers for Disease and Control and Prevention for physical activity increased from 34% to 48% (P < .01). At the 6-month follow-up, the frequency of exercising enough to work up a sweat (P < .01) remained significantly increased, but other measures of physical activity declined toward baseline. Interpretation A 10-week worksite program implemented at multiple facilities increased physical activity by the end of the intervention, but these changes were not sustained over time. Future interventions might include extending the length of the program, repeating the program, or adding larger economic incentives over time. Any such alternative models should be carefully evaluated, using a randomized design if possible.

Objective To determine the occurrence of carpal tunnel syndrome (CTS) and ulnar neuropathy at the elbow (UNE) in a cohort of floor cleaners and to check differences between workers with and without CTS. Methods All female floor cleaners of three major hospitals in Tuscany (Italy) were contacted. Clinical and electrophysiological severity of CTS and UNE were evaluated with standardized scales and symptoms were assessed with the self-administered Boston Questionnaire (BQ); demographic and non-occupational factors and durations of current and previous occupations were recorded. Univariate analysis of risk factors was performed in workers with and without CTS. Logistic regression was used to evaluate the capacity of independent variables to predict CTS. Results Out of a total of 179 cleaners, 145 (81%)—mean age 39.6 years (20–64 years)—were enrolled in the study; 70 (48%) had CTS (diagnosis based on clinical and electrophysiological findings). BQ symptom and hand function scores were anomalous in 108 (74%) and 84 (58%) subjects, respectively. UNE was detected in 7/103 women. Univariate analysis showed that cleaners with CTS were older, had greater BMI and longer exposure to cleaning with previous employers than those without CTS. In the logistic regression, the only predictor of CTS was cleaning with previous employers (O.R. 12.1, 95% CI 3–49.9). Conclusions These results indicate a high occurrence of CTS in floor cleaners; UNE is less frequent than CTS, presumably due to repetitive movements that stress wrists more than elbows. The only predictive factor of CTS was cleaning as an occupation with previous employers. Therefore, the actual risk factor for CTS could not be cleaning per se, but how this job is performed.

The valuation of human costs is a necessity, but this task poses many problems of method. A team made of a philosopher, a psychologist and a physician has been working with economist researchers in order to look into the meaning that the preferences announced at the time of the inquiries on human costs by QALY methods could assume. These methods are often used to obtain a valuation of the impact of a health attack on people's quality of life. The methods--in the frame of the argument assumed by the economic theory on well-being--hypothesize that people's choices depend mainly on cognitive work. The qualitative interviews show that the psychological construction process for the announced preferences largely overlap this frame. In this paper the authors hastily tackle the factors which have an effect on the preferences. They conclude that the QALY methods don't seem to be able to assess the quality of life nori to valuate the damage that the quality of life could include.

BACKGROUND: In human reproduction, embryo implantation is complex and poorly understood. At present, no single markers are used in routine treatment to assay biochemical functions of the human embryo. Soluble human leukocyte antigen-G (sHLA-G) could be considered a possible marker of embryo developmental potential. It is localized primarily on the extravillous trophoblast, making this antigen a potential mediator of immune interaction at the maternal-fetal interface during gestation. METHODS: Soluble-HLA-G levels were evaluated by an enzyme-linked immunosorbent assay (ELISA) employing monoclonal antibody MEM-G9. It was evaluated in 318 media of single embryo cultures. We correlated the presence of sHLA-G with embryo morphology and the pregnancy obtained in that treatment cycle. RESULTS: No correlation was found between embryo morphology and sHLA-G levels. Pregnancy was observed only when the medium of at least one transferred embryo contained sHLA-G. In 26 out of 66 patients, none of the obtained embryos showed any detectable sHLA-G molecules and no pregnancy occurred. CONCLUSIONS: From our results, we propose sHLA-G as a potential marker of embryo development: the sHLA-G ELISA can be a useful biochemical assay in addition to embryo morphology in embryo selection for transfer in IVF treatment if there are other embryos with the same morphology.

Alterations of p53 are one of the most common molecular changes found in all types of lung tumors, suggesting a crucial role for p53 in bronchial carcinogenesis. However, the prognostic significance of p53 abnormalities in lung cancer patients is still unclear. By using genetic and immunohistochemical methods we have found p53 alterations in 40 of 53 (75%) primary, resected non-small cell lung cancer. A strong association (P = 0.0015) was found between deletions on chromosome region 17p13.3 and p53 mutations suggesting that loss of the wild-type p53 allele might be necessary for tumorigenesis. Correlations to clinicopathological parameters showed that p53 alterations (structural aberration of the gene and/or nuclear accumulation of the protein) are significantly linked with metastatic involvement of hilar and mediastinal lymph nodes (P < 0.01). Since the latter are well established prognostic factors for non-small cell lung cancer, p53 aberrations may also be a predictor of tumor aggressiveness.

Interleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-beta1 (TGF-beta) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was undertaken to further elucidate the biochemical basis of the functional interaction between these two cytokines and to define the site of TGF-beta action on the signaling pathway activated by IL-12. Our data indicate that TGF-beta induced an inhibition of interferon-gamma (IFN-gamma) production without affecting the IL-12Rbeta1 and IL-12Rbeta2 subunits mRNA expression by activated T cells. We further show that TGF-beta has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF-beta was found to significantly inhibit IL-12-induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indicated that TGF-beta induced a decrease in IL-12-induced STAT4 DNA binding activity in T lymphocytes. This study suggests that TGF-beta influences IL-12 responsiveness at least in part by inhibiting early signaling events essential to gene induction in IL-12-activated T cells.

Fifty-two sporadic primary non-small-cell lung carcinomas (NSCLC) were examined for microsatellite instability. Six different microsatellite markers localized on chromosomes 2, 5, 8, 10, 11 and 17 were used. Genomic instability was observed in 35% (18/52) of NSCLC at single or multiple loci. The tumors were also analyzed for p53-gene mutations by PCR-SSCP analysis. Polynucleotide stretch frameshift mutations of TGFbetaRII (transforming-growth-factor-beta receptor II), IGFIIR (insuline growth-factor II receptor) and BAX genes were also analyzed. RER+ (replication-error-positive) tumors appear not to be affected by a higher rate of point mutations in coding sequences: no correlation was found between microsatellite instability and point mutations in the p53 gene, and the RER+ tumors showed no alterations in stretches of nucleotide inside TGFbetaRII, BAX or IGFIIR.

Bronchioloalveolar carcinoma (BAC) is a particular type of adenocarcinoma of the lung which accounts for up to 9 per cent of pulmonary malignancies. The aetiology and pathogenesis of this unique neoplastic disease are still unclear. Three histological subtypes of BAC have been recognized: mucinous, non-mucinous, and sclerosing. Of these, mucinous and sclerosing BAC have a worse prognosis than non-mucinous tumours. The different morphological patterns and clinical outcomes of the subtypes of BAC suggest differences in their biological behaviour. Previous reports have shown that the mucinous form of BAC is characterized by constant mutations at codon 12 of the K-ras gene, whereas the other two histotypes show a frequency of K-ras mutations which is not different from that observed in conventional lung adenocarcinomas. The present study of a series of 51 BACs, previously investigated for K-ras gene mutations, has evaluated the status of two other genes, p53 and FHIT, known to be frequently altered in non-small cell lung cancer. Loss of heterozygosity at microsatellite-containing loci located within the FHIT gene was observed in 22 (43 per cent) BACs. The distribution of FHIT gene abnormalities was not statistically different in the three histological subtypes. p53 mutations were present in 13 (32 per cent) non-mucinous/sclerosing BACs, while no mutations were seen in mucinous tumours (P = 0.039). Correlations with clinicopathological parameters showed that p53 mutations in BACs are associated with more aggressive tumours. No correlations were observed between FHIT or K-ras gene abnormalities and clinicopathological data. In conclusion, these results indicate that FHIT alterations are frequently involved in BAC tumourigenesis and that genetic changes in the p53 and K-ras genes can distinguish between different histotypes of BAC.

Epidemiologic data have strongly indicated that cigarette smoking is linked to the development of lung cancer. However, little is known of the molecular targets of carcinogens contained in tobacco smoke. To identify genetic lesions characteristic of tobacco damage, we undertook a molecular analysis of microsatellite alterations within the FHIT gene and FRA3B, as well as at an independent locus on chromosome 10, D10S197, in lung tumors from heavy smokers and in tumors from never smokers. Loss of heterozygosity affecting at least one locus of the FHIT gene was observed in 41 of 51 tumors in the smokers group (80%) but in only 9 of 40 tumors in nonsmokers (22%). The comparison between the frequency of losses in FHIT in smokers and nonsmokers was statistically significant (P = 0.0001), whereas no difference in loss of heterozygosity rate was observed at D10S197 locus. These findings suggest that FHIT is a candidate molecular target of carcinogens contained in tobacco smoke.

The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the six NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P = 0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.

Previous studies in animal models indicated an autocrine/paracrine action of endothelin-1 (ET-1) in the ovary. We now report evidence on the presence of ET-1 in human ovary during reproductive life. Immunohistochemical and in situ hybridization studies demonstrated a positive signal into cytoplasm of granulosa cells (GC) of follicles at different growth stages. The concentration of ET-1-like immunoreactivity (ET-1-LI) was also measured by a specific RIA in human follicular fluid (FF). FF samples were obtained from women in an in vitro fertilization program undergoing gonadotropin stimulation (group A; n = 24) or no treatment (group B; n = 7). The mean (+/-SD) ET-1-LI FF level in group A (4.85 +/- 2.06 pg/mL) was significantly higher than that in group B (1.29 +/- 0.43 pg/mL; P0.01), whereas the corresponding mean plasma levels were not significantly different and were not correlated to respective FF values. Our results indicate for the first time the presence of ET-1 and its messenger ribonucleic acid in the GC of the human ovary. The higher ET-1-LI levels found in the FF from women undergoing gonadotropin treatment suggest a modulation by gonadotropins and/or ovarian steroids of ET-1 production by GC.

In this study we have investigated responsiveness to progesterone in spermatozoa from a group of unselected male partners of couples undergoing in-vitro fertilization (IVF). We evaluated progesterone-stimulated intracellular Ca2+ ([Ca2+]i) and percentage increase in acrosome reaction in the same sperm sample used for oocyte inseminations. [Ca2+]i was measured with a fluorimetric method, while the acrosome reaction was assessed using a fluorescent probe (fluorescein isothiocyanate-labelled peanut lectin). The average percentage [Ca2+]i as well as the rate of increase in the frequency of acrosome reaction following progesterone challenge were significantly lower (P < 0.005) in the group of patients with a fertilization rate < 50%. In addition, significant correlations between the fertilization rate and the progesterone-stimulated [Ca2+]i and acrosome reaction increases (r = 0.78 and r = 0.79 respectively) were observed. Furthermore, in cases of fertilization failure, no increase of [Ca2+]i or acrosome reaction was observed in response to progesterone with the exception of one case. Our results indicate that [Ca2+]i and acrosome reaction increases in response to progesterone can be of value in the prediction of sperm fertilizing ability. As the two parameters were significantly correlated to each other (r = 0.86), the two assays have similar IVF predictive value and might be used interchangeably as a diagnostic tool in the assignment of male patients to the different kinds of assisted fertilization techniques.

Eighteen patients affected by laparoscopically confirmed endometriosis were randomly assigned to three different schedules of treatment with gonadotropin-releasing hormone agonist (GnRH-a) (goserelin depot formulation 3.6 mg) every 28 days for 6 months. Six women received the first implant in early follicular phase, 4 in late luteal phase and 8 in 3rd and 17th day from onset of menses. Pretreatment and posttreatment laparoscopic score, performed according to the American Fertility Society scoring system, were compared; a significant reduction in the extent of disease was observed in each group investigated (A and C: p < 0.01; B: p < 0.05). In each treatment group after the second GnRH-a implant the mean levels of estrone-3-glucuronide (E1-3G), daily measured in early morning urine specimens during the control cycle and the first three months of therapy, were suppressed to menopausal women range. In group B during the 2nd and 3rd month of therapy, the urinary mean levels of E1-3G were significantly lower than in group A and C. In conclusion the different goserelin depot administration schedules gave similar laparoscopic improvement, in spite of the first GnRH-a administration in luteal phase allowed a more marked estrogenic suppression.

A polymerase chain reaction-single strand conformation polymorphism assay was used to assess p53 mutations in 148 invasive breast carcinomas, selected on the basis of their histotype. They comprised 56 lobular, 47 ductal, 19 mucinous, 18 medullary, and 8 papillary carcinomas. The distribution of p53 mutations was significantly different (P = 0.006) in the histotypes examined: mutations were frequent in medullary (39%) and ductal (26%), less common in lobular (12%), and absent in mucinous and papillary carcinomas. The frequency of mutations in the exon 5 of the p53 gene was significantly higher in medullary carcinomas than in the other histotypes: 5 (63%) of the mutations found in exon 5 were observed in medullary carcinomas (P = 0.012). One hundred twenty-two tumors from the total were also examined by immunohistochemistry for p53 overexpression using antibody PAb 1801. A specific immunostaining in neoplastic cells was present in 12 tumors. A strong correlation (P0.001) was observed between p53 mutations and nuclear accumulation of the p53 protein: 10 tumors were scored positive for both p53 mutation and overexpression. However, in 9 cases having a mutated p53 gene we failed to find a positive immunoreaction. A significant association (P = 0.01) was present between mutations in the p53 gene and high proliferative activity of the tumors determined by immunohistochemistry with monoclonal antibody Ki-67. Moreover, a significantly higher expression of the Ki-67 antigen was found in medullary carcinomas compared to the other histotypes. Our findings indicate that in invasive breast carcinomas structural abnormalities of the p53 gene are mainly seen in medullary and ductal tumors and that the other histological types, especially those associated with a high level of differentiation and favorable prognosis, show a very low incidence of p53 mutations.

The mutant human cell line 11.1 is unresponsive to interferon alpha. Here we describe the genetic complementation of this mutant and the identification and cloning of the wild-type gene that corrects the defect. Using transfection with genomic DNA in conjunction with a powerful back-selection, we isolated a cosmid that reverts the mutant phenotype of 11.1 cells. The cosmid encodes a single message whose level is greatly reduced in mutant cells. Complementary DNAs were cloned and found to be virtually identical to tyk2, a human mRNA encoding a non-receptor protein tyrosine kinase of previously unknown function. This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes.

The aim of this work is to compare transabdominal and transvaginal ultrasound measurement of ovarian size and follicular number and diameter during cycles of ovulation induction for assisted reproduction technologies. We included in our study fourty patients undergoing a controlled ovarian stimulation: the ultrasound monitoring of multiple follicular growth was performed by the same operator, with both transabdominal and transvaginal route, during the follicular phase of the cycle, until the day of human chorionic gonadotrophin (hCG) administration; in ten women was compared transabdominal and transvaginal evaluation of total number of recruited follicles5 mm in size on day -4, on day -2 and on the hCG administration day (day 0); moreover in all the patients transabdominal and transvaginal measurement of the mean follicular diameter of leading follicle and the mean ovarian diameters on hCG injection day was compared.

Investigated the impact of childhood chronic illness within a family context. We interviewed 30 mothers of 6- to 14-year-old children with asthma or diabetes and 30 mothers of healthy children of the same age and sex. Family functioning, extrafamilial social support available to mothers, and child life stress events were examined in relation to the children's psychological adjustment and illness events. The mothers of asthmatic children reported a greater number of internalizing behavior problems in their children, perceived their own social support as less adequate, and reported a greater number of stressful events. Regression analyses demonstrated that family functioning, maternal social support, and chronic illness were significantly related to the psychological adjustment of the child. The importance of family functioning and resources available to the family, such as social support, are discussed as protective influences in coping with childhood chronic illness.

A family study of psychiatric diagnoses was performed in 29 children of bipolar patients and 37 children of normal controls, ages 6-17. There were no differences in major or minor affective diagnoses between the patient and control groups, but there was an increase of non-specific diagnoses in the patient group. Using DSM-III criteria, 10% of patients' children and 14% of controls' children had had at least one episode of major depression. This suggests that major depression in children is not familially related to adult bipolar major affective disorder. The observed prevalence of depression in childhood is increased when both direct interview of children and interview of parents are performed.

The authors examined the personal resources (social problem-solving ability, internal locus of control, self-esteem, and self-perceived competence) and social resources (social network structure and support) in 23 children of patients with bipolar affective disorder (probands) and 33 children of normal control parents. Positive resource profiles were related to psychiatric well-being in the offspring. Nondisordered probands, in particular, demonstrated a strikingly positive profile of personal resources as well as a wide range of peer, sibling, and other kin supporters. Disordered probands had a strikingly negative set of personal resources and a relatively greater reliance on nonkin adult supporters. The absence of a supportive best friend was associated with affective disorder across offspring groups.

Summary A number of social skill training approaches have been devised for remediating peer relationship difficulties in children and adolescents. One recently developed approach, focusing on interpersonal cognitive problem solving (IPCS) skills, is described. ICPS training studies are also reviewed. Despite the pervasive methodological problems that characterize this literature, ICPS training appears to be effective as a remediation strategy with maladjusted youngsters, and as a secondary prevention strategy with children ‘at risk’. While initial findings with nonclinical groups have been less encouraging, available follow-up data suggest that ICPS training may be efficacious as a primary prevention strategy, as well. Several suggestions are offered for improving the methodology of future training studies, while important issues and problems are highlighted for future investigation.

The correlates of social and academic competence were investigated in 9-14 yr old children. Factor analysis of multiple measures of cognitive functioning, excluding IQ identified three dimensions: (1) Social Comprehension; (2) Cognitive Efficiency and (3) Divergent Thinking. The social comprehension dimension was derived from measures of humor and social cognition. Although strongly related to IQ, Social Comprehension still had a substantial unique relation to social competence in a school setting, as assessed by teachers and peers. While this dimension was the best predictor of social competence, IQ was by far the most powerful predictor of academic competence.

A comparative study between MAR test and IBT in 142 seminal samples is presented by the authors and their concordance with TAT and SIT is also evaluated. In particular the interest of IBT for the evaluation of involved immunoglobulinic classes is stressed.

Responses of 2-5-year-old children to angry adult behavior were examined as a function of parental report of marital distress, history of interparent verbal hostility, and history of interparent physical hostility. A trained actor engaged the child's mother in an emotionally expressive verbal exchange while the child played in the same room. The exchange was standardized and consisted of a 7-episode sequence of shifting background conditions (no emotion, friendly, no emotion, angry, no emotion, reconciliation, no emotion). Preoccupation with anger, expressed concern and support-seeking, and accepting of social responsibility (e.g., providing physical or verbal comfort to the mother) were greater in response to background anger than in response to prosocial conditions. The parents' marital adjustment was positively associated with expressed concern and support-seeking by children in response to anger. Form and degree of marital conflict interacted with age and sex in predicting children's response to anger as well. In particular, children whose parents engaged in physical aggressiveness showed increased preoccupation, concern and support-seeking, and social responsibility responses with increasing age. Implications of these findings for the study of the effects of marital discord on children are discussed.

Previous research suggests that elderly people utilize fewer coping strategies than younger people. Some researchers suggest that these quantitative changes reflect decreases in the use of maladaptive strategies; others contend that they reflect decreases in the use of adaptive strategies by older adults. The present article reports the findings of three studies of coping in older people, two addressing coping with health problems, and the other addressing coping with moving. In all three studies, the number of self-reported coping strategies decreases with age. Results do not support the idea that decreases in the number of strategies imply decrements in the quality of coping, however: in two studies, age was unrelated to the effectiveness of strategies, in the third, effectiveness ratings were higher for older subjects. The need for evaluation of specific outcomes of coping strategies is discussed, along with the need for task-specific measurement of coping. It is proposed that decreases in the number of coping strategies reflect improved coping efficiency, rather than a deterioration of adaptational skills.

The determination of the concentrations of estrone-3-glucuronide, pregnanediol-3-glucuronide and luteinizing hormone has been performed in early morning urine samples of 14 normal menstruating women using a timed and measured volume urine collection procedure. In order to investigate the variability of the urinary hormonal concentrations due to day-to-day differences in diuresis, the absolute hormonal concentrations have been corrected either for the urinary creatinine excretion or for the volume of urine voided during the night. The results demonstrate that both correction factors are able to reduce substantially the coefficient of variation values in comparison to the absolute hormonal concentrations. The urinary test of ovarian function has been performed in 11 infertile women affected by luteal insufficiency using the same procedure, and the hormonal profiles showed some alterations in both estrone-3-glucuronide and pregnanediol-3-glucuronide concentrations in comparison to the hormonal profiles of the normal subjects. Such alterations were significant in the single subject when integrated values of the hormonal data in defined time intervals were investigated.

In this study we have compared the results of autoagglutination, IgM M.A.R.-test, seric S.I.T. and seric T.A.T. in 75 men with normal seminal parameters belonging to sub-fertile couples in whom the only evident anomaly was the presence of negative or doubtful P.C.T. We compared a tight correlation between IgG M.A.R.-test and autoagglutination (IgG M.A.R.-test clinically positive in 82.8% of subjects with positive spermagglutination); between seric S.I.T. and IgG M.A.R.-test (S.I.T. positive in 58.3% of subjects with IgG M.A.R.-test clinically positive); between seric T.A.T. and IgM M.A.R.-test (T.A.T. positive in 69.4% of subjects with positive IgG M.A.R.-test). Such results proved the reliability of IgG M.A.R.-test as a screening test in the determination of male autoimmunization. Moreover, the possibility that they were the cases in which only the local antisperm activity was shown, underlines the necessity not to limit immunological research to only seric antibody titrations. The analyses of the types of mixed agglutination present in cases of positive IgG M.A.R.-test make us suspect that a quota of the agglutination type emh was due to the impossibility with such type of test to specify adequately the zones of G.R. sperm interaction involved in the formation of mixed agglutinates.

The Authors report their own experience and results using different approaches to oocyte pick-up and gamete transfer for gamete intrafallopian transfer (GIFT). The overall pregnancy rate of GIFT is 35.86% (66 pregnancies on 184 cases of GIFT). The Protocol I (Laparoscopic oocyte retrieval and gamete transfer) is presently the more used and gives better clinical results (pregnancy rate of 37.7%); in the Author's opinion, the protocols III (echographic pick-up + IVF + laparoscopic delayed zygote intrafallopian transfer (ZIFT), and VII (Laparotomic pick-up and transfer) are interesting complementary techniques for GIFT.