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Background: Nailfold videocapillaroscopy (NVC) is a feasible method that allows the observation of the microvascular changes that mark the course of systemic sclerosis (SSc). In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages and microthromboses, is a good indicator of the steady-state level and overtime changes of disease activity (DA) in SSc., Objectives: To verify whether high NEMO scores, which mirror a very active microvascular derangement in the fingers, may be associated with the subsequent development of ischaemic digital ulcers (IDUs)., Methods: The NEMO score was assessed at baseline (T0) in 98 patients with SSc, all classified according to the ACR-EULAR criteria. Of them, 90 were females, 48 had the limited and 50 had the diffuse cutaneous variant of SSc. Afterwards, the patients were closely followed up for 2 years, and the appearance of new IDUs recorded at any time of the follow-up. The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the subsequent development of IDUs., Results: During the follow-up, 38 out of 98 patients developed one or more IDUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (95% CI 11.0-21.5) and 4.5 (95% CI 4.0-6.0), respectively, p < 0.0001]. The ROC curve derived from different T0-NEMO score values had an AUC of 0.79 (95% CI 0.69-0.86, p < 0.0001). A NEMO score of ≥ 12 had a sensitivity of 83.3% (95% CI 71.5-91.7) and a specificity of 63.2% (95% CI 46.0-78.2), with positive (P) and negative (N) predictive (PV) values of 58.9% (95% CI 44.7-72.2) and 85.6% (71.8-94.4), respectively. A NEMO score of ≥ 16 had a sensitivity of 95.0% (95% CI 86.1-99.0) and a NPV of 93.4% (77.5-99.2)., Conclusions: Being a valid tool to measure DA levels in SSc, the NEMO score also appears to be closely related to the subsequent development of IDUs in this disease.

Background: In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard., Aim of the Study: To verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes., Patients and Methods: The NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4-56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other., Results: NEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations (p < 0.0001 in all cases with the exception of the correlation with EScSG values at T1 (p < 0.03)). The values of the two composite DA indices were also strictly related to each other in both T0 and T1 observations (p < 0.0001). Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p < 0.0001 in both cases). Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen's k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively)., Conclusions: NEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

Introduction: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS., Methods and Analyses: Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc., Methods: Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination., Results: The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p < 0.0001), and it was the only one among the NVC variables that gave a significant contribution in a logistic model where the ESSG score represented the dependent variable. ROC curve analysis confirmed that the NEMO score had the best performance in measuring DA. The AUC of the NEMO score was significantly greater than the AUCs obtained by plotting the sensitivity and specificity of the number of GCs and the mean nCs (p < 0.0001 in all cases). The NEMO score values that showed the best sensitivity-specificity balance in capturing patients with a relevant DA level were slightly higher in the Naples cohort than in the Milan cohort., Conclusions: This study confirms that the presence of a certain number of MHEs and MTs in NVC may be considered a strong warning signal of a current phase of DA in patients with SSc.

With an eye on the sequence of two Indian papers concurrently published in Diabetes Therapy, this paper analyzes skin differences among races and points to a lack of organized structured education sessions as the main cause of the high prevalence of lipodystrophy (LD) and consequent poor metabolic control. Only half of all insulin-treated patients reach their therapeutic targets worldwide. The factors involved in this are manifold, including the choice of overlong and repeatedly reused needles, as well as a failure to systematically rotate injection sites, all of which lead to skin LD. Regularly issued guidelines and expert recommendations provide suggestions about how to correct poor injection techniques, but LD still occurs at a high rate and is associated with poor metabolic control, a high risk of complications, frequent severe hypoglycemic episodes, and huge health and social costs. Poor knowledge of subcutaneous tissue anatomy and the physiological response to insulin injection by both health care personnel and patients may contribute to this problem. Moreover, differences in body structure among the races present in our multiethnic societies must be taken into account when choosing needle length and shooting technique in order to avoid accidental intramuscular injections.

Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL.We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers.Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated.Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib.In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.

In the setting of acute pulmonary embolism (PE), pulmonary infarction is deemed to occur primarily in individuals with compromised cardiac function.The current study was undertaken to establish the prevalence of pulmonary infarction in patients with acute PE, and the relationship between infarction and: age, body height, body mass index (BMI), smoking habits, clot burden, and comorbidities.The authors studied prospectively 335 patients with acute PE diagnosed by computed tomographic angiography (CT) in 18 hospitals throughout central Italy. The diagnosis of pulmonary infarction on CT was based on Hampton and Castleman's criteria (cushion-like or hemispherical consolidation lying along the visceral pleura). Multivariable logistic regression was used to model the relationship between covariates and the probability of pulmonary infarction.The prevalence of pulmonary infarction was 31%. Patients with infarction were significantly younger and with significantly lower prevalence of cardiovascular disease than those without (P < 0.001). The frequency of infarction increased linearly with increasing height, and decreased with increasing BMI. In logistic regression, the covariates significantly associated with the probability of infarction were age, body height, BMI, and current smoking. The risk of infarction grew with age, peaked at approximately age 40, and decreased afterwards. Increasing body height and current smoking were significant amplifiers of the risk of infarction, whereas increasing BMI appeared to confer some protection.Our data indicate that pulmonary infarction occurs in nearly one-third of the patients with acute PE. Those with infarction are often young and otherwise healthy. Increasing body height and active smoking are predisposing risk factors.

Objectives: This study sought to evaluate the impact of arterial duct (AD) stenting in promoting catch-up growth of hypoplastic pulmonary artery (PA) tree in congenital heart disease with duct-dependent pulmonary circulation (CHD-DPC)., Background: Significant and balanced PA growth following AD stenting has already been consistently reported in the literature. However, no data are so far available about the role of this approach in severe PA hypoplasia, which significantly impacts the risk of surgical repair., Methods: Pre-surgical angiographic PA evaluation was performed in 45 patients with confluent PAs submitted to neonatal AD stenting as palliation of CHD-DPC. PA growth was evaluated as Nakata Index and McGoon ratio as well as individual PA z-score changes, both in the whole population and according to the original vessel size (Nakata Index <100 mm(2)/m(2), Group I [n = 15] vs. Nakata Index >100 mm(2)/m(2), Group II [n = 30])., Results: Control angiography was performed 7.5 ± 6.5 months (median 6 months) after duct stenting, showing significant and balanced PA growth. The Nakata Index increased from 143 ± 73 mm(2)/m(2) to 270 ± 88 mm(2)/m(2) (124 ± 118%, p < 0.0001); left PA z-score from -0.7 ± 1.7 to 1.0 ± 1.4; right PA z-score from -0.6 ± 1.3 to 1.2 ± 1.3 (p < 0.0001 for both comparisons). Group I showed a greater increase of global PA growth (Nakata Index increase 227 ± 141% vs. 72 ± 57%, p < 0.001) as compared with Group II. Final PA size did not significantly differ between the groups (246 ± 105 mm(2)/m(2) vs. 282 ± 78 mm(2)/m(2), p = NS)., Conclusions: Percutaneous AD stenting is highly effective in promoting a significant and balanced catch-up growth of diminutive PAs, being therefore advisable in this subset of patients as a reliable alternative to surgical palliation., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM)., Methods: We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines., Results: In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets., Conclusions: CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Purpose: To evaluate long-term keratoconus stability after corneal crosslinking (CXL) with riboflavin., Methods: In this prospective study, 57 eyes of 55 patients with progressive keratoconus, consecutively treated with ultraviolet A (UVA) - riboflavin CXL, were examined with the corneal topographer Pentacam, the biometer IOLMaster and the analyzer of corneal biomechanics Ocular Response Analyzer before and during a 24 months follow-up after CXL., Results: Twenty-four months after CXL, there was a significant improvement in best corrected visual acuity (BCVA) (P<0.01), a significant decrease in corneal thinnest point (CTP), keratometry readings at the keratoconus apex (K max), and corneal volume (CV) (P<0.01), and a significant increase in axial eye length (AL) (P=0.01). No significant changes in anterior chamber volume (ACV) and depth (ACD), (P=0.8), corneal hysteresis (CH) (P=0.16) and corneal resistance factor (CRF) (P=0.06) were found. However, in the subgroup of patients with decreased K max readings 24 months after treatment, both CH and CRF showed a significant reduction (P<0.01)., Conclusion: In the first month after the procedure, CXL induces a reduction in corneal volume. During the 24 months follow-up the cornea tends to recover its original volume with a persistence of the CXL efficacy., (Copyright © 2013 Spanish General Council of Optometry. Published by Elsevier Espana. All rights reserved.)

Background: Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2., Case Presentation: A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion., Conclusions: We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2 allele in both affected family members may reflect the active state of the normally silenced maternal IGF2 copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.

Objectives: Self-injury (SI) is defined as a behavioral disturbance consisting of a deliberate harm to one's own body without suicidal intent, it is not uncommon and ranges in severity from simple nail-biting to more extreme forms of self-mutilation. The head neck region may be the target of such lesions. SI is associated with several medical conditions, of which it can represent the first clinical sign. Aim of this paper is to describe a series of oral SI, giving special emphasis to the clinical findings, etiology and the management of lesions., Material and Methods: A total of 19 patients with oral SI were prospectively examined; attention was paid to the occurrence and characterization of oral lesions. The management of the lesion also varied depending on the patient medical history, on the etiology of the psychiatric behavior, and on the severity, frequency, and method of inflicting injury. Periodic examinations were performed (after two weeks, three months and six months) and registered., Results: All the patients healed gradually and healing was conditioned by the disease underlying. The treatment consisted of behavior modification in 11 cases, pharmacological treatment in 11 cases, psychotherapy in 2 cases, mouth guard in 9 cases, surgery in 2 cases, extractions in 1 case., Conclusions: Oral SI are uncommon in the clinical practice. They may be associated with a known disease or may be the consequence of this, but often they may be the first sign of a psychiatric disorder.

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

Background: Many asthmatic women complain of symptom exacerbations in particular periods, i.e. during pregnancy and menstrual cycles (perimenstrual asthma: PMA)". The goal of this study was to study the effect of the luteal and follicular phases of the menstrual cycle on bronchial reactivity (BR) in a group of asthmatic women., Methods: For this purpose, 36 pre-menopausal women were enrolled and underwent testing for resting pulmonary function, measurement of the diffusing capacity of the lung for carbon monoxide (DLCO), and airway responsiveness to methacholine in the follicular and luteal phases of their menstrual cycles. We also measured plasma hormone levels and levels of cyclic adenosine monophosphate (cAMP; a mediator of bronchial smooth muscle contraction) and testosterone in induced sputum samples., Results: Our study showed that about 30% of the asthmatic women had decreased PC20FEV1.0 in the follicular phase of menstrual cycle with a significant correlation between PC20FEV1.0 and serum testosterone levels. Moreover, marked increases in sputum testosterone levels (mean=2.6-fold increase) together with significant increases in sputum cAMP concentrations (mean=3.6-fold increases) were observed during the luteal phase of asthmatic patients, suggesting that testosterone contributes to the pathophysiology of PMA. We excluded the possibility that testosterone directly inhibits phosphodiesterase (PDE) activity as incubating PDE with testosterone in vitro did not reduce PDE catalytic activity., Conclusions: In conclusion, our data show that PC20FEV1.0 was decreased in the follicular phase of the menstrual cycle in about 30% of women and was associated with lower cAMP levels in sputum samples, which may contribute to bronchoconstriction. Our results also suggest a link between PMA and testosterone levels. However, whether these findings are of clinical significance in terms of the management of asthma or asthma worsening during the menstrual cycle needs further investigation.

Objective: To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes., Research Design and Methods: In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1., Results: During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect., Conclusions: Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes., (© 2014 by the American Diabetes Association.)

Background: Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR)., Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR., Conclusion: This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer cells and identifies new potential targets in the therapeutic approach to human cancers.

Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.

This retrospective study was performed to verify the efficacy and safety of Onabotulinumtoxin A (BTX-A) in treating children with neurogenic bladder (NB) secondary to myelomeningocele (MMC) with detrusor overactivity/low compliance. From January 2002 to June 2011, 47 patients out of 68 with neuropathic bladder were selected (22 females, 25 males, age range 5-17 years; mean age 10.7 years at first injection). They presented overactive/poor compliant neurogenic bladders on clean intermittent catheterization, and were resistant or non compliant to pharmacological therapy. Ten patients presented second to fourth grade concomitant monolateral/bilateral vesicoureteral reflux (VUR). All patients were incontinent despite catheterization. In the majority of patients Botulinum-A toxin was administered under general/local anesthesia by the injection of 200 IU of toxin, without exceeding the dosage of 12 IU/kg body weight, diluted in 20 cc of saline solution in 20 sites, except in the periureteral areas. Follow-up included clinical and ultrasound examination, urodynamics performed at 6, 12 and 24 weeks, and annually thereafter. Seven patients remained stable, 21 patients required a second injection after 6-9 months and 19 a third injection. VUR was corrected, when necessary, in the same session after the BT-A injection, by 1-3 cc of subureteral Deflux®. Urodynamic parameters considered were leak point pressure (LPP), leak point volume (LPV) and specific volume at 20 cm H(2)O pressure. The results were analyzed using the Wilcoxon test. All patients experienced a significant 66.45% average increase of LPV (Wilcoxon paired rank test = 7169 × 10(-10)) and a significant 118.57% average increase of SC 20 (Wilcoxon paired rank test = 2.466 × 10(-12)). The difference between preoperative and postoperative LPP resulted not significant (Wilcoxon paired rank test = 0.8858) No patient presented severe systemic complications; 38/47 patients presented slight hematuria for 2-3 days. Two patients had postoperative urinary tract infection. All patients were hospitalized for 24 h with catheterization. Thirty-eight out of 47 patients achieved dryness between CIC; nine patients improved their incontinence but still need pads. Ten patients have resumed anticholinergic agents. Our results suggest that the use of BTX-A is safe and effective in patients with MMC with a positive effect on their dryness and quality of life.

Background: Sudden cardiac death (SCD) is common in patients with Emery-Dreifuss muscular dystrophy (EDMD) and is attributed to the development of life-threatening arrhythmias that occur in the presence of normal left ventricular systolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D) and JTc dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with Emery-Dreifuss muscular dystrophy with preserved systolic and diastolic cardiac function., Material/methods: The study involved 36 EDMD patients (age 20 ± 12, 26 M) and 36 healthy subjects used as controls, matched for age and sex. Heart rate, QRS duration, maximum and minimum QT and JT interval, QTc-D and JTc-D measurements were performed., Results: Compared to the healthy control group, the EDMD group presented increased values of QTc-D (82.7 ± 44.2 vs. 53.1 ± 13.7; P=0,003) and JTc-D (73.6 ± 32.3 vs. 60.4 ± 11.1 ms; P=0.001). No correlation between QTc dispersion and ejection fraction (R=0.2, P=0.3) was found., Conclusions: Our study showed a significant increase of QTc-D and JTc-D in Emery-Dreifuss muscular dystrophy patients with preserved systolic and diastolic cardiac function.

The authors investigated the efficacy of a lifestyle educational program, organized in small group meetings, in improving the outcome of a nonpharmacologic intervention. One hundred and eighty-eight hypertensive patients with stable blood pressure (BP) levels and drug therapy in the previous 6 months were randomly divided into educational care (EC) and usual care (UC) groups. They were followed at 3-month intervals up to 2 years. In addition to the visits in an outpatient clinic, patients in the EC program participated in small group meetings in order to improve their knowledge of the disease and reinforce their motivation for treatment. At baseline, EC and UC groups were similar for age, sex, body mass index (BMI), blood pressure (BP) levels, and pharmacologic treatment. Patients in the EC group had significantly reduced total energy, total and saturated fats, and sodium intake. Physical activity was significantly increased in the EC group as well. At the end of the 1-year follow-up, BMI (P<.001), visceral fat (P<.001), and BP (P<.001) were significantly lower in the EC group compared with the UC group. Pharmacologic treatment during the study was similar for all classes of drugs apart from diuretics whose dose was higher in the UC group at the end of the study., (© 2012 Wiley Periodicals, Inc.)

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.

Aim: The aim was to evaluate the safety and efficacy of the "cross-cylinder" technique in the correction of astigmatism., Setting and Design: A prospective interventional study from a university eye department was conducted., Material and Methods: The photoastigmatic refractive keratectomy (PARK) using the "cross-cylinder" technique was performed in 102 eyes of 84 patients with at least 0.75 D of astigmatism. The study population was divided into two groups: in the first group the preoperative astigmatic power ranged from -0.75 D to -3.00 D (group 1), in the second group it ranged from -3.25 D to -6.00 D (group 2). Group 1 included 82 eyes of 67 patients (29 males and 38 females) with a mean cylinder power of -1.90 ± 0.63 D, group 2 included 20 eyes of 17 patients (13 males and 4 females) with a mean cylinder power of -4.28 ± 0.76 D. All eyes were targeted for emmetropia. The results were evaluated using Calossi's vector analysis method. Six-month postoperative outcomes are presented., Results: Six months after PARK the mean sphere for the entire cohort was +0.28 ± 0.75 D (range +2.5 to -2 D), the mean cylindrical power was +0.33 ± 0.51 D (range +2.5 to -1.25 D) and the mean spherical equivalent refraction was +0.73 ± 0.81 D (range +1.75 to -2 D)., Conclusions: The cross-cylinder technique may be safely used with predictable results for the correction of astigmatism.

Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population.

Herbal products are increasingly used, mainly in chronic liver disease. Extracts of milk thistle, Silymarin and silybin, are the most prescribed natural compounds, with different indications, but with no definitive results in terms of clinical efficacy. This review analyzes the available studies on the effects of the purified product silybin, both as a free and a conjugated molecule, on liver cells or on experimentally induced liver damage, and in patients with liver disease. We searched PUBMED for articles pertaining to the in vitro and in vivo effects of silybin, its antifibrotic, anti-inflammatory, and antioxidant properties, as well as its metabolic effects, combined with the authors' own knowledge of the literature. Results indicate that the bioavailability of silybin phytosome is higher than that of silymarin and is less influenced by liver damage; silybin does not show significant interactions with other drugs and at doses < 10 g/d has no significant side effects. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin; previous human studies were insufficient for confirming the clinical efficacy in chronic liver disease, while ongoing clinical trials are promising. On the basis of literature data, silybin seems a promising drug for chronic liver disease.

We have investigated whether an oxygen/ozone (95%O2/5%O3) mixture would have potential against the formation of experimental postsurgical peritoneal adhesions. In two groups of rats, one control intraperitoneally injected with 3 mL/rat of O2 and one intraperitoneally injected with oxygen/ozone mixture (3 mL/rat equivalent to 300 μg/kg ozone), we induced a midline laparotomy and an enterotomy at the level of the ileum to encourage the formation of peritoneal adhesions. Samples were taken from the parietal peritoneal tissue to assess the formation of adhesions 0 and 10 days after the surgical procedure and to assess the levels of ubiquitin and 20S proteasome. We found decreased formation of postsurgical peritoneal adhesions after treatment of the rats with 300 μg/kg ozone associated with a decreased levels of ubiquitin and 20S proteasome subunit within the adhered tissue. Oxygen/ozone mixture is potentially useful for approaching the post-surgical peritoneal adhesions, and the UPS system is involved in this.

A 55-year-old man with myotonic dystrophy underwent phacoemulsification with IOL implantation in the right eye.3 months after surgery, the patient showed a decreased visual acuity and an intraocular pressure (IOP) of 30 mmHg. Slit lamp examination showed a dense fibrosis of the anterior capsule with capsulorexis' shrinkage. Gonioscopy showed a closed angle. After a YAG laser iridotomy no decrease in the IOP was detected; following surgical peeling of the anterior capsule, the slit lamp showed a distended capsular bag. A YAG laser posterior capsulotomy was performed, without decrease in the IOP. Myotonic patients need to be closely followed up after cataract surgery, because in case of CBS development a prompt posterior capsulotomy could avoid more severe complications.

In this study we used a biocomplex constructed from dental pulp stem/progenitor cells (DPCs) and a collagen sponge scaffold for oro-maxillo-facial (OMF) bone tissue repair in patients requiring extraction of their third molars. The experiments were carried out according to our Internal Ethical Committee Guidelines and written informed consent was obtained from the patients. The patients presented with bilateral bone reabsorption of the alveolar ridge distal to the second molar secondary to impaction of the third molar on the cortical alveolar lamina, producing a defect without walls, of at least 1.5 cm in height. This clinical condition does not permit spontaneous bone repair after extraction of the third molar, and eventually leads to loss also of the adjacent second molar. Maxillary third molars were extracted first for DPC isolation and expansion. The cells were then seeded onto a collagen sponge scaffold and the obtained biocomplex was used to fill in the injury site left by extraction of the mandibular third molars. Three months after autologous DPC grafting, alveolar bone of patients had optimal vertical repair and complete restoration of periodontal tissue back to the second molars, as assessed by clinical probing and X-rays. Histological observations clearly demonstrated the complete regeneration of bone at the injury site. Optimal bone regeneration was evident one year after grafting. This clinical study demonstrates that a DPC/collagen sponge biocomplex can completely restore human mandible bone defects and indicates that this cell population could be used for the repair and/or regeneration of tissues and organs.

Archaeological, anthropological and pathological data suggest that thirteen skeletons found in a house at the Pompeii archaeological site, dated to 79 A.D., belong to one family. To verify this and to identify the relationships between these individuals, we analyzed DNA extracted from bone specimens. Specifically, hypervariable segment 1 (HVS1) of the human mitochondrial DNA (mtDNA) control region was amplified in two overlapping polymerase chain reactions and the sequences were compared to the revised Cambridge Reference Sequence. As independent controls, other polymorphic sites in HVS1, HVS2 and in the coding region were analyzed. We also amplified some short tandem repeats of the thirteen specimens. This study revealed that six of the thirteen individuals are indeed closely related.

Arterial tortuosity syndrome is a rare connective tissue disorder characterized by elongation and tortuosity of large elastic arteries resulting in multiple vascular stenoses. This article reports on a novel hybrid transcatheter-surgical strategy to treat bilateral peripheral pulmonary artery stenoses due to this syndrome. Operation consisted of stent implantation by midline sternotomy and reductive reconstruction of the proximal pulmonary arteries. This approach resulted in right ventricular overload relief and sudden improvement of the patient's clinical condition.

High blood pressure (BP) is one of the crucial determinants of the metabolic syndrome (MS). The extent to which MS, diagnosed according to the criteria of the International Federation of Diabetes, impacts on cardiovascular organ damage, independently of BP, is debated. Three hundred and forty hypertensive patients and 100 normotensive controls underwent the following procedures: (1) physical examination and resting BP measurements, (2) 24 h ambulatory BP monitoring, (3) laboratory routine examination, (4) echocardiography, (5) carotid ultrasonography and (6) ankle-brachial BP index. The syndrome was found in 104 of the 340 hypertensive patients (30.6). In comparison to those without MS, those with MS had significantly higher prevalence of left ventricular (LV) hypertrophy by mass/height(2.7) criteria (46 vs 42%, P<0.01) but not by LV mass/body surface criteria (30 vs 31%); the ratio between early-to-late peak velocities of the LV filling waves (E/A) was higher (E/A=0.99+/-0.14 vs 0.89+/-0.15, P<0.01) and left atrium was larger (3.8+/-0.3 vs 3.5+/-0.5 cm, P<0.01). Both hypertensive groups had significantly greater LVM and carotid intima-media thickness than normotensives, without between-group-difference. In this hypertension outpatient clinic almost one-third hypertensive patients have MS. They show a deterioration in structure and function of the heart in comparison to hypertensive patients without MS, but no difference was detected in the carotid and peripheral arterial circulation.

Aim: To investigate the relationship among the number of platelets and plasma levels of S-nitrosothiols (S-NO), nitrite, total non-protein SH (NPSH), glutathione (GSH), cysteine (CYS), malondialdehyde (MDA), 4-hydroxininenal (4HNE), tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-6 in patients with chronic hepatitis C (CH)., Methods: In vitro the aggregation of platelets derived from controls and CH patients was evaluated before and after the addition of adenosine diphosphate (ADP) and collagen, both in basal conditions and after incubation with nitrosoglutathione (GSNO)., Results: In vivo, S-NO plasma levels increased significantly in CH patients and they were significantly directly correlated with platelet numbers. Patients with platelet counts < 150000/microL, had a smaller increase in S-NO, lower levels of GSH, CYS, NPSH, TNFalpha, and IL-6, and higher levels of nitrite, MDA, and 4-HNE relative to those of patients with platelet counts > 150000/microL. In vitro, the ADP and collagen aggregation time was increased in platelets from patients and not from controls; in addition, platelets from CH patients but not from controls also showed a latency time after exposure to collagen., Conclusion: The incubation of platelets with GSNO improved the percentage aggregation and abolished the latency time.

Several studies have recognized the strong impact that the acute myocardial infarctions (AMI) have on the morbidity and mortality of patients affected by cardiovascular diseases. Still open, however, is the field concerning the mediators and the pathways involved in the etiology of this cardiovascular event. The present review would support the relatively new discovered role that the polymorphonuclear leukocytes (PMNs) have in the pathogenesis of the AMI, through a brief analysis of past and ongoing research. Particularly, it is reviewed here the possibility that inhibition of the activity of PMNs and inhibition of the signaling pathways related to their activity may result useful in AMI and may improve the prognosis of this pathology. This review, indeed, presents and discusses new data on one of the lipid kinase, the phosphoinositide 3-kinase gamma (PI3Kg), and its role in neutrophil recruitment during AMI.

Objective: To study the cardiac geometric changes after transcatheter closure of large atrial septal defects (ASDs) according to patient age at the time of the procedure., Design: Prospective echocardiographic follow-up study., Setting: Tertiary referral centre., Patients and Intervention: 25 asymptomatic patients younger than 16 years (median 8 years; group 1) and 21 asymptomatic adults (median 38 years; group 2) underwent percutaneous closure of large ASD with the Amplatzer septal occluder device (mean 25 (SD 7) mm)., Main Outcome Measures: Cardiac remodelling was assessed by M mode and two dimensional echocardiography one and six months after ASD closure., Results: By six months, right atrial volume decreased from 31 (15) to 19 (5) ml/m(2) (p < 0.001) and right ventricular (RV) transverse diameter decreased from 29.8 (8.6) to 23.2 (5.6) mm/m(2) (p < 0.001). Conversely, left atrial volume did not change significantly (from 18 (6) to 20 (6) ml/m(2), NS) and left ventricular (LV) transverse diameter increased from 27.8 (6.4) to 31.8 (7.3) mm/m(2) (p < 0.05). Ventricular remodelling resulted in an RV:LV diameter ratio decrease from 1.1 (0.2) to 0.7 (0.1) (p < 0.001). The magnitude and time course of cardiac remodelling did not differ significantly between the age groups. Indeed, right atrial volume decreased by 33 (26)% versus 37 (23)%, RV diameter decreased by 26 (10)% versus 20 (13)%, LV diameter increased by 17 (15)% versus 15 (10)%, and RV:LV diameter ratio decreased by 36 (8)% versus 27 (15)% in groups 1 and 2, respectively., Conclusions: Cardiac remodelling after percutaneous ASD closure seems to be independent of the patient's age at the time of the procedure up to early adulthood. Thus, postponing ASD closure for a few years may be a reasonable option for potentially suitable asymptomatic children.

The association between large, left-sided patent ductus arteriosus and severe, peripheral, right pulmonary artery stenosis with no other cardiac malformation is an unreported condition that might be misdiagnosed as pulmonary hypertension due to long-standing ductal shunt. A 57-year-old man with supposed hypertensive patent ductus arteriosus underwent confirmatory cardiac catheterization. At angiography, a severe pre-hilar right pulmonary artery stenosis (peak pressure gradient, 65 mmHg) was found to complicate the hemodynamic picture of a moderate-to-large patent ductus arteriosus (QP/QS, 1.7:1), by causing pulmonary hypertension (mean pressure, 65 mmHg) and left-to-right pulmonary flow imbalance. Both lesions were treated in a single procedure of right pulmonary artery stenting and patent ductus arteriosus closure, after which the pulmonary artery pressure significantly decreased (mean, 35 mmHg). In our opinion, a thorough hemodynamic evaluation followed by pulmonary angiography should be mandatory before proceeding to patent ductus arteriosus closure in the adult patient who has "hypertensive" ductus, in whom possible associated malformations can be missed due to a poor echocardiographic window.

Brucellosis is endemic in the Mediterranean area. In spite of the false negative results, the standard agglutination test remains the routine test for the diagnosis of brucellosis in southern Italy. We present a case of a patient with undulant fever and erythema nodosum-like skin lesions, with negative serum agglutination test, but isolated positivity of the ELISA test for anti-Brucella IgM. A diagnosis of brucellosis for this patient was supported by the anamnestic and clinical data, and by the response to therapy. This case and a review of the literature urge us to consider the ELISA test indispensable for the serological diagnosis of brucellosis.

Background: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-kappaB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1beta. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1beta and airway hyperresponsiveness., Methods: We have examined the effect of passive sensitization on IL-1beta mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 microM), were used to quantify IL-1beta mRNA. Other tissues were used to study the effect of EFS (3-10-25 Hz)., Results: Mean IL-1beta mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1beta mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues., Conclusion: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1beta mRNA expression and responsiveness to EFS of passively sensitized bronchi.

1. Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide ligand for a specific G-protein coupled receptor, the N/OFQ peptide receptor (NOP). The N/OFQ-NOP receptor system has been reported to play an important role in pain, anxiety and appetite regulation. In airways, N/OFQ was found to inhibit the release of tachykinins and the bronchoconstriction and cough provoked by capsaicin. 2. Here we evaluated the effects of NOP receptor activation in bronchoconstriction and airway microvascular leakage induced by intraesophageal (i.oe.) hydrochloric acid (HCl) instillation in rabbits. We also tested the effects of NOP receptor activation in SP-induced plasma extravasation and bronchoconstriction. 3. In anesthetized New Zealand rabbits bronchopulmonary function (total lung resistance (R(L)) and dynamic compliance (C(dyn))) and airway microvascular leakage (extravasation of Evans blue dye) were evaluated. 4. Infusion of i.oe. HCl (1 N) led to a significant increase in bronchoconstriction and plasma extravasation in the main bronchi and trachea of rabbits pretreated with propranolol, atropine and phosphoramidon. 5. Bronchoconstriction and airway microvascular leakage were inhibited by N/OFQ (3-30 microg kg(-1) i.v.) in a dose-dependent manner. The NOP receptor agonist [Arg14,Lys15]N/OFQ mimicked the inhibitory effect of N/OFQ, being 10-fold more potent, UFP-101, a peptide selective NOP receptor antagonist, blocked the inhibitory effects of both agonists. 6. Under the same experimental conditions, N/OFQ and [Arg14,Lys15]N/OFQ did not counteract the bronchoconstriction and airway microvascular leakage induced by substance P. 7. These results suggest that bronchoconstriction and airway plasma extravasation induced by i.oe. HCl instillation are inhibited by activation of prejunctional NOP receptors.

Gynaecologic oncology day surgery deals primarily with the diagnosis of endometrial, cervical, vulvar and vaginal tumors. Conscious sedation is an important technique used in gynaecologic oncology day surgery. It is often associated with regional anaesthesia. The goals of conscious sedation are to provide effective pain control with complete safety, reduction of the recovery time, of the infection risk and cost. Since the consequences of the immunosuppressive effects of the opiates and the surgical stress could lead to an increased susceptibility to post-operative infections and a possible lack of immunological defence in the cancer patients, we investigated the possibility of eliminating the administration of opiates during minor operations in gynaecologic oncology day surgery. In this study, 400 patients, aged between 35 and 77 years, underwent surgery using sedation at the day hospital annexed to the Gynaecology and Obstetrics Department of the 2nd University of Naples, Italy. The patients were randomized into two equal study groups, according to a computer-generated randomised list. All patients were seen by the consultant anaesthetist three days before surgery. In all cases, during surgery, we monitored the main vital parameters such as ECG, HR and RR, BT, BP and SO. The drugs commonly used were: opioids, hypnotics and benzodiazepines, associated or not, with local anaesthetics. By using these drugs, pain and anxiety were reduced, sedation and amnesia were accomplished. In our experience, conscious sedation seems to be the best choice in gynaecologic oncology day surgery because it presents low toxicity, is short acting and readily reversible, has a low cost and, finally, because it is more comfortable for the patients. Moreover, it is possible to eliminate the administration of opiates during conscious sedation for less invasive surgical procedures.

In middle-age hypertensives from the Gubbio Population Study, we evaluated the relationship between blood pressure (BP) control over a long time and the prevalence of left ventricular hypertrophy (LVH). A population survey was performed in 1982-1985 and repeated in 1989-1992. During the second survey, subjects in the age range 40-60 years were invited to undergo an M-mode echocardiographic examination. A total of 487 subjects who participated in both surveys are included in the present analysis. Some of them (294) were normotensive (Group 1), 110 were hypertensive but had never taken antihypertensive drugs (Group 2), 47 hypertensives on drugs were in good BP control (Group 3) and 36 hypertensives on drugs had uncontrolled hypertension (Group 4). BP values at the 1989-1992 examination were, respectively, 122/77, 145/86, 124/78 and 153/91 mmHg, while 7 years earlier were 122/77, 133/84, 136/85 and 152/95 mmHg. Despite normal BP levels in Group 3, left ventricular mass index (LVMi, g/m(2.7)) was greater than in normotensives (42.4+/-10, 46.6+/-13, 47.0+/-10, 51.9+/-15 g/m(2.7)). Accordingly, the prevalence of LVH (LVMi >51 g/m(2.7)) was 18, 26.4, 36.7 and 50% in groups 1-4, respectively. The 193 hypertensives were, thereafter, divided according to BP control (ie <140/90 mmHg) on both surveys (1983-1985 and 1989-1992): 27 hypertensives with optimal BP levels on both visits also had a ventricular mass similar to normotensives and significantly lower than the other hypertensives (LVMi 44.6+/-11.6 vs 48.5+/-13.2, P<0.001). In conclusion, these findings indicate that hypertensive patients with BP values at levels similar to those in normotensives for a long period do not increase their left ventricular mass in comparison to subjects with normal BP levels.

Kaposi's sarcoma (KS) of the tongue is extremely rare in immunocompetent patients. We report a case of KS of the tongue associated with a median rhomboid glossitis. The main clinical, pathological and immunohistochemical features allowed the differential diagnosis.

Human Fibrin Glue (HFG) is made of two components contained in separate vials: a freeze dried concentrate of clotting proteins, mainly fibrinogen, Factor XIII and fibronectin (the sealant) and freeze dried thrombin (the catalyst). The first component is reconstituted with an aprotinin solution that inhibits tissue fibrinolysis. The second component (thrombin), available in 500 I.U. concentration, is dissolved with calcium chloride. It is so a set of substances involved in the hemostatic process and in the wound healing, conferring to the product the following important properties: hemostatic and sealing action, through the strengthening of the last step of the physiological coagulation; biostimulation, which favors the formation of new tissue matrix. The indications for the use of human fibrin sealant are numerous and present in all the surgical branches. A randomized controlled trial of 50 patients undergoing hernia repair according to Lichtenstein's technique under local anesthesia was performed. Patients had concurrent coagulopathies as a consequence of liver disease or long-term treatment with anticoagulants for ischemic heart disease or cardiac rhythm disturbances. Coagulopathies were defined according to the following criteria: prothrombin time < 10.5 seconds, activated partial thromboplastin time < 21 seconds, and fibrinogen < 230 mg/dL. Patients were randomized in a 1:1 ratio with (group A) or without (control group B) use of human fibrin glue: Postoperative hemorrhagic complications were significantly reduced in group A (4%) compared with group B (24%). This study showed that human fibrin glue is effective in preventing local hemorrhagic complications after inguinal hernia repair in patients with concurrent coagulation disorders.

Background: In vitro studies have demonstrated that interleukin (IL)-1beta decreases insulin and DNA contents in pancreatic islet beta cells, causing structural damage, that it is toxic to cultured human islet beta cells and that it is able to induce apoptosis in these cells., Materials and Methods: Isolated rat islets of Langerhans were exposed in vitro to interleukin (IL)-1beta and either the imidazoline compound RX871024 (RX) or/and M40403, an Mn-containing superoxide dismutase mimetic (MnSODm)., Results: Insulin secretion, on days 1, 2 and 3 after challenge with 3 ng/ml of IL-1beta, was almost abolished and this was accompanied by an early increase in MnSOD activity. By days 2 and 3, SOD activities were lower than those of untreated controls and NO significantly increased by day 2. Moreover, IL-1beta induced a significant increase in MnSOD transcripts, while iNOS mRNA appeared by days 2 and 3 when MnSOD mRNA was absent. RX blocked all toxic effects of IL-1beta by maintaining insulin secretion and islet beta cell phenotype, including the inhibition of nonspecific proteins and of iNOS induction. In contrast, the MnSODm, failed to counteract iNOS induction as well as the reduced insulin secretion., Conclusions: In summary, our findings stress that IL-1beta-induced suppression of insulin secretion may be related to iNOS induction in beta cells and that RX can reverse this effect, by maintaining insulin secretion. Oppositely, the MnSODm is not able to restore IL-1beta-suppressed insulin secretion. Hence, imidazoline compounds may protect beta cells against damage caused by IL-1beta-induced free oxygen and nitrogen radicals.

Ancient DNA (aDNA) samples extracted from the bone remains of six equids buried by the Vesuvius eruption in 79 AD were investigated to test pre-amplification and enzymatic repair procedures designed to enhance the rescue of nuclear genes. The extracts, which proved all positive for Equidae mtDNA amplification, proved positive only four times out of 18 when tested for single-copy Equidae nuclear genes (epsilon globin, p53 and gamma interferon). Pre-amplification did not change the number of retrieved aDNA sequences but 10 times out of 14 enzymatic repair restored the amplifiability of the genes analysed, proving that repair increases the rate of successful rescue from 22 to alpha(lambda)mu(omicron)sigma(tau) 80%. These findings support the hypothesis that some of these cross-linked aDNA molecules, which are not completely separated when DNA is extracted under denaturing conditions, become homoduplex substrates for Pol I and/or T4 ligase action upon renaturation. aDNA authenticity is proved by the homology of the nucleotide sequences of loci tested to the corresponding modern Equidae sequences. Data also indicate that cross-linked homoduplex molecules selected by denaturation of the extract are repaired without any chimera formation. The general features of aDNA amplification with and without denaturation and enzymatic repair are discussed.

Seminal vesicle protein IV (SV-IV) is a secretory anti-inflammatory, procoagulant, and immunomodulatory protein produced in large amounts by the seminal vesicle epithelium of the rat under the strict transcriptional control of androgen. In particular, this protein was shown to possess the ability to markedly inhibit in vivo the humoral and cell-mediated immune responses of mice to nonbacterial cellular antigens (sheep erythrocytes and spermatozoa). We report data that demonstrate that in mice treated with SV-IV and infected with Salmonella enterica serovar Typhimurium, SV-IV is able to downregulate some important immunological and biochemical parameters that serovar Typhimurium normally upregulates in these animals. This event did not correlate with a lower bacterial burden but was associated with a markedly increased one (300%). Furthermore, the treatment of mice with SV-IV alone also produced a significant increase in the rate of mortality among serovar Typhimurium-infected animals. The mechanism underlying these phenomena was investigated, and the strong immunosuppression produced by SV-IV in serovar Typhimurium-infected mice was suggested to be the basis for the increased rate of mortality. The SV-IV-mediated immunosuppression was characterized by a decrease in the humoral and cell-mediated immune responses, altered lymphocyte-macrophage interaction, downregulation of cytokine and inducible nitric oxide synthase gene expression, inhibition of macrophage phagocytosis and intracellular killing activities, and absence of apoptosis in the splenocyte population of SV-IV- and serovar Typhimurium-treated mice. The immunosuppressive activity of SV-IV was specific and was not due to aspecific cytotoxic effects. SV-IV-specific receptors (K(d) = 10(-8) M) occurring on the macrophage and lymphocyte plasma membranes may be involved in the molecular mechanism underlying the SV-IV-mediated immunosuppression. Some results obtained by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay also revealed a functional impairment of mitochondria (a decrease in mitochondrial dehydrogenase activity), thus indicating the possible implication of these organelles in the immunosuppressive process.