Search

Globally, agriculture is the largest source of nitrous oxide (N 2 O), a potent greenhouse gas (GHG). A recognised tool to prevent its loss from agricultural soils is the presence of a shallow water table. A four-year lysimeter experiment (2011–2014) was conducted in northeast Italy to investigate how water table levels affect N 2 O emissions after different N fertilisation techniques. Soil surface flux and groundwater-dissolved N 2 O were studied under free drainage and at two shallow water table levels (60 cm and 120 cm) and at two levels of N input (250 and 368 kg N ha −1  y −1 ), using dry manure in 2011 and 2012 and fresh manure in 2013 and 2014. DNA was extracted from soils and quantitative PCR (qPCR) was used to assess the size of nitrifying, denitrifying and N 2 -fixing bacterial communities. at three soil depths. The day after pre-seeding fertiliser incorporation, N 2 O emission started to be detected and continued for two-three weeks; brief measurable emissions also followed top–dressing fertilisation events. Cumulative N 2 O emission measured between 0.97 and 2.33 kg N 2 O-N ha −1  y −1 , corresponding to emission factors from 0.4% to 1.1%. Manure fertilisation significantly affected the N dose only when applied as fresh manure. Water-filled pore space (WFPS) affected daily N 2 O emissions with a significant interaction with fertilisation level. The two N input levels showed differences only when WFPS was >40%, which revealed N availability as key to increased N 2 O emissions at high water content, supposedly by fostering anaerobic denitrification. No significant relationships were observed between peak N 2 O emissions and the values of the temperature or irrigation variables recorded during the experimental observation period. Groundwater dissolved N 2 O-N concentrations measured about 1.7 μg L −1 with some peak variability from nitrate leaching. Quantitative PCR assays demonstrated that shifts in microbial population that can be involved in oxidation processes and heterotrophic denitrification occurred in the soil, even though the contributions of the different N pathways on N 2 O emissions were indistinguishable. Indeed, both nitrifying and denitrifying genes were simultaneously promoted by the high fertilisation input and hindered by the high water table level. Shallow groundwater conditions appeared to reduce N 2 O emissions probably by favouring complete denitrification. These results suggest that in the Po Plain, regulated by the Nitrate Directive, shallow groundwater conditions, with a balanced N input, may mitigate air and water pollution. [ABSTRACT FROM AUTHOR]

Many efforts have been made in Europe to improve the environmental quality of agro-ecosystems. Since the 2000s, agri-environmental measures (AEMs) have been financed and implemented in EU countries, although their beneficial effects are still questioned due to poorly targeted environmental issues and a lack of site-specific payments. Indeed, estimates of AEM outcomes at the territorial level require considerable efforts to consider simultaneously multiple environmental objectives with multiple targets. As a result, a DAYCENT model-GIS platform was developed that integrates multiple types of pedo-climatic and land management information. The aim was to provide a decision support system for spatially evaluating and selecting the best AEMs in terms of soil, water and air quality, when compared with a standard scenario without any adopted measure. Our modelled results showed that in the Veneto Region, north-eastern Italy, the AEMs applied from 2007 to 2013 improved the environmental value of the agro-ecosystems, especially in terms of soil and water quality. Continuous soil cover, reduction of soil disturbance through grasslands, conservation agriculture and cover crops were the best simulated strategies to increase soil organic matter content (+25%) and reduce nitrogen leaching (⿿90%). These strategies were also able to sharply reduce soil water erosion (⿿86%) and as a consequence P loss, in particular in the steep hilly and mountain areas, although their application to arable lands in those landscapes is still rare. In contrast, care should be taken in the long-term regarding an increase in P leaching, since predictions up to +0.15 kg ha ⿿1 y ⿿1 are reached compared to the standard scenario. Finally, greenhouse gas (GHG) emissions (N 2 O and CH 4 ) were reduced mainly due to increased fertilisation efficiency. The proposed method can be a flexible decision support tool for a result-oriented and scientifically-based evaluation of AEMs that may help policy makers to evaluate the most effective measures for increasing the environmental value of agro-ecosystems. [ABSTRACT FROM AUTHOR]

Background: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro.Methods: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays.Results: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01).Conclusion: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo. [ABSTRACT FROM AUTHOR]

Several pesticides have been hypothesized to act as endocrine-disrupting compounds, exhibiting hormonal activity and perturbing normal physiological functions. Among these, especially s-triazine herbicides have received increased attention. Despite being banned in many countries, including the European Union, atrazine is still the world's most widely used herbicide. Despite its discontinued use, considerable concentrations of atrazine and its degradation products, mainly desethylatrazine (DEA) and deisopropylatrazine (DIA), are still found in the environment, including drinking water sources. The aim of this investigation was to study concentrations of especially s-triazine herbicides and major degradation products in drinking water, including spring water, tap water and bottled water in Luxembourg. Spring water (2007/2008/2009, n = 69/69/69), tap water (2008/2009, n = 19/26), and bottled water (2007/2008/2009, n = 5/13/7) were sampled at locations in Luxembourg and investigated for pesticides by LC-ESI-MS/MS. Atrazine was the predominant triazine, detectable in many spring water locations, tap and bottled water, ranging (mean) from 0–57 (9), 0–44 (4), and 0–4 (1) ng l−1, respectively. DEA and DIA in spring water ranged (mean) from 0–120 (19) and 0–27 (3) ng l−1, with higher concentrations from agricultural areas and low molar ratios of DEA:atrazine <0.5 and high ratios of atrazine:nitrate suggesting point-source contamination. Levels (mean) of DEA and DIA in tap water were 0–62 (14) and 0–6 (<1) ng l−1 and in bottled water 0–11 (2) and 0–7 (2) ng l−1. Simazine and other triazines were detected in traces (<5 ng l−1). Thus, the conducted monitoring suggested the presence of low concentrations of s-triazines in raw and finished water, presumably partly due to non-agricultural contamination, with concentrations being below thresholds advocated by the European Union Directive 98/83/EC. [ABSTRACT FROM AUTHOR]

Background: Uterine serous papillary carcinoma (USPC) was an aggressive and chemotherapy resistant variant of endometrial cancer. The authors evaluated the expression of human trophoblast-cell-surface-marker (Trop-2) and the potential of hRS7, a humanized anti-Trop-2 monoclonal antibody, as a novel therapeutic strategy against USPC.Methods: Trop-2 expression was evaluated by immunohistochemistry (IHC) in a total of 23 USPC. Six primary USPC cell lines were assessed by flow cytometry and real-time polymerase chain reaction (PCR) for Trop-2 expression. Sensitivity to hRS7 (Immunomedics, Inc.) antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in standard 5-hour ⁵¹Cr-release assays against primary USPC cell lines.Results: Expression of Trop-2 was found in 15 of 23 (65%) of the tumor tissues tested by IHC and in 50% (3 of 6) of the USPC cell lines tested by real-time PCR and flow-cytometry (Trop-2 expression in USPC versus normal endometrial cells; P < .005). USPC cell lines overexpressing Trop-2, regardless of their intrinsic resistance to natural killer cytotoxicity, were highly sensitive to hRS7-mediated ADCC in vitro (range of killing, 28.2% to 64.4%) (P < .001). Negligible cytotoxicity against USPC was seen in the absence of hRS7 or in the presence of rituximab control antibody (range of killing, 1.1% to 12.4%). Incubation with interleukin-2 (50 IU/mL) in addition to hRS7 further increased the cytotoxic activity against USPC cell lines overexpressing Trop-2 (P = .008).Conclusions: Trop-2 was highly expressed in uterine serous carcinoma at mRNA and protein levels. Primary USPC cell lines are highly sensitivity to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for USPC refractory to standard treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF.Methods: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h (51)Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU ml(-1)).Results: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing+/-s.d., 65.6+/-3.7%, range 57.5-77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC.Conclusion: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities. [ABSTRACT FROM AUTHOR]

Background: The authors investigated the expression of serum amyloid A (SAA) in endometrial endometrioid carcinoma and evaluated its potential as a serum biomarker.Methods: SAA gene and protein expression levels were evaluated in endometrial endometrioid carcinoma and normal endometrial tissues, by real-time polymerase chain reaction (PCR), immunohistochemistry (IHC), and flow cytometry. SAA concentration in 194 serum samples from 50 healthy women, 42 women with benign diseases, and 102 patients including 49 grade 1, 38 grade 2, and 15 grade 3 endometrial endometrioid carcinoma was also studied by a sensitive bead-based immunoassay.Results: SAA gene expression levels were significantly higher in endometrial endometrioid carcinoma when compared with normal endometrial tissues (mean copy number by real-time PCR = 182 vs 1.9; P = .001). IHC revealed diffuse cytoplasmic SAA protein staining in poorly differentiated endometrial endometrioid carcinoma tissues. High intracellular levels of SAA were identified in primary endometrial endometrioid carcinoma cell lines evaluated by flow cytometry, and SAA was found to be actively secreted in vitro. SAA concentrations (microg/mL) had medians of 6.0 in normal healthy women and 6.0 in patients with benign disease (P = .92). In contrast, SAA values in the serum of endometrial endometrioid carcinoma patients had a median of 23.7, significantly higher than those of the healthy group (P = .001) and benign group (P = .001). Patients harboring G3 endometrial endometrioid carcinoma were found to have SAA concentrations significantly higher than those of G1/G2 patients.Conclusions: SAA is not only a liver-secreted protein, but is also an endometrial endometrioid carcinoma cell product. SAA is expressed and actively secreted by G3 endometrial endometrioid carcinoma, and it is present in high concentration in the serum of endometrial endometrioid carcinoma patients. SAA may represent a novel biomarker for endometrial endometrioid carcinoma to monitor disease recurrence and response to therapy. [ABSTRACT FROM AUTHOR]

Background The island of Sardinia features a high incidence of multiple sclerosis (MS) characterized by early age at onset and a progressively increasing trend. The current study was aimed at examining variations in human leukocyte antigen-risk genotypes occurring over time in a cohort of patients. Methods Susceptible and neutral DRB1-DQB1 genotypes were identified in 1660 patients. Age at onset was established in 1436 patients divided into two cohorts, an older cohort (subjects born before 1949, N = 233) and a younger one (subjects born from 1960 to 1989, N = 850). Patients from the older cohort were randomly assigned to patients of the same sex from the younger cohort, matched for age at onset. The final sample included 170 pairs. Logistic conditional analysis was performed to determine the probability of a neutral genotype in both cohorts. Kaplan-Meier analysis was applied to ascertain the influence of predisposing and neutral genotypes in age at onset for both cohorts. Findings The probability of carrying a neutral genotype was 1.76-fold higher in the younger than in the older cohort (P = 0.02) and 3.67-fold higher in men (P = 0.005). Kaplan-Meier analysis revealed an earlier age at onset in patients of the young cohort carrying the predisposing genotype (P = 0.004). Interpretation In the Sardinian population, an environment more prone and propitious to autoimmunity may contribute toward the rising incidence of MS or anticipate overt manifestation of the disease in genetically predisposed subjects. [ABSTRACT FROM AUTHOR]

Background: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients.Methods: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied.Results: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT-PCR=162 vs 2.21; P=0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mug ml(-1)) had a median (95% CIs) of 6.0 (4.0-8.9) in normal healthy females and 6.0 (4.2-8.1) in patients with benign disease (P=0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2-56.2), significantly higher than those in the healthy group (P=0.0005) and benign group (P=0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P=0.0024).Conclusion: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy. [ABSTRACT FROM AUTHOR]

Idiopathic achalasia is a rare disorder of the oesophagus of unknown aetio-pathogenesis characterized by a myenteric inflammation, aperistalsis and insufficient lower oesophageal sphincter relaxation. Vasoactive intestinal peptide (VIP), present in the myenteric plexus, is involved in smooth muscle relaxation and acts as an anti-inflammatory cytokine. The human VIP receptor 1 gene (VIPR1) is highly polymorphic and may play a role in idiopathic achalasia. One hundred and four consecutive patients and 300 random controls from the same geographic area were typed for five SNPs mapping in the VIPR1 gene. Patients with idiopathic achalasia show a significant difference in allele, genotype and phenotype distribution of SNP rs437876 mapping in intron 4. This association, however, was almost entirely due to the group of patients with late disease onset ( P = 0.0005). These results strongly suggest that idiopathic achalasia is a heterogeneous disease with a different aetiology in cases with early or late disease onset. [ABSTRACT FROM AUTHOR]

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B *2705 strongly associated with AS and B *2709 which is not, and show the co-occurrence of the B *2705 allele with a single nucleotide polymorphism (SNP) mapping at 3′-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B *2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a ‘danger’ signal might influence susceptibility to AS.Genes and Immunity (2008) 9, 659–667; doi:10.1038/gene.2008.60; published online 31 July 2008 [ABSTRACT FROM AUTHOR]

Background Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS. Methods Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An "ad hoc" questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment. Results Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m² of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment. Conclusions MITO treatment may affect reproductive capacity in women with MS. Patients of child-bearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA. [ABSTRACT FROM AUTHOR]

We investigated the clinical and MRI effects of mitoxantrone (MITOX) administered to 45 patients during the first five years of highly active relapsing-remitting multiple sclerosis. Differences occurring between the end of treatment and follow-up (clinical mean: 3.6 years; brain MR: 1.8 years) with respect to baseline variables (EDSS, annualized relapse rate, active T2 lesions, new T1 lesions and number of Gd-enhancing lesions) were analysed using parametric and non-parametric tests. One patient developed leukemia four months after the end of the treatment; no other serious adverse events occurred during treatment and the follow-up period. A clinically relevant reduction in the annualized relapse rate (P<0.0001 at end of treatment and P<0.0001 at follow-up) and improvement in the EDSS (P<0.0001 at end of treatment and P=0.0005 at follow-up) was found. At the end of treatment, 53% of patients experienced no increase in active T2 lesions, while 73% showed no increase in the number of new T1 lesions. At follow-up, 41 out of 45 (91%) patients showed a stable MRI pattern and were active-scan free. Despite potential serious adverse events, MITOX may be considered an option in selected patients with very active early MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system of unknown pathogenesis, is a complex disease with a multifactorial etiology determined by both genetic and environmental factors. The pathological entity MS has a wide phenotype, and also the severity of the disease is widely variable. Clinical heterogeneity of the disease might arise from different genotype-phenotype interactions. Results of recent studies and theories about the modifying role of different genes in the course and the severity of MS are here discussed. [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor about the clinical trial focused on the applicability of interferon in treating chronic inflammatory demyelinating polyneuropathy.

Introduction: Cladribine is an oral immune reconstitution therapy for relapsing multiple sclerosis (RMS). Hormonal and immune changes are responsible for the decline of disease activity in the third trimester of pregnancy and disease reactivation in the early post-partum period.We investigate the impact of pregnancy on disease activity in women with MS who conceived after cladribine treatment. Methods: We recruited women of childbearing age with relapsing–remitting MS (RRMS) who became pregnant or not after being treated with cladribine. For both groups, demographic, clinical and radiological data were collected 1 year before and after treatment during a mean follow-up of 3.53 years. We compared disease activity over time between groups using variance analysis for repeated measures. Results: 48 childbearing women were included. 25 women had a pregnancy after a mean of 1.75 years from the first treatment cycle. Women with or without pregnancy did not differ in demographics or pre-cladribine disease activity. No significant differences in disease activity or EDSS worsening were found between women with or without pregnancy. Discussion: Our findings suggest that pregnancy does not appear to influence disease activity and disability in women previously treated with cladribine; further studies with larger numbers and longer follow-up are needed to confirm this finding. [ABSTRACT FROM AUTHOR]

Plant pathogens face different environmental clues depending on the stage of the infection cycle they are in. Fusarium graminearum infects small grain cereals producing trichothecenes type B (TB) that act as virulence factor in the interaction with the plant and have important food safety implications. This study addresses at the proteomic level the effect of an environmental stimulus (such as the presence of a polyamine like agmatine) possibly encountered by the fungus when it is already within the plant. Because biological diversity affects the proteome significantly, a multistrain (n = 3) comparative approach was used to identify consistent effects caused on the fungus by the nitrogen source (agmatine or glutamic acid). Proteomics analyses were performed by the use of 2D-DIGE. Results showed that agmatine augmented TB production but not equally in all strains. The polyamine reshaped drastically the proteome of the fungus activating specific pathways linked to the translational control within the cell. Chromatin restructuring, ribosomal regulations, protein and mRNA processing enzymes were modulated by the agmatine stimulus as well as metabolic, structural and virulence-related proteins, suggesting the need to reshape specifically the fungal cell for TB production, a key step for the pathogen spread within the spike. Biological significance Induction of toxin synthesis by plant compounds plays a crucial role in toxin contamination of food and feed, in particular trichothecenes type B produced mainly by F. graminearum on wheat. This work describes the level of diversity of 3 strains facing 2 toxin inducing plant derived compounds. This knowledge is of use for the research community on toxigenic Fusarium strains in cereals for understanding the role of fungal diversity in toxin inducibility. This work also suggests that environmental clues that can be found within the plant during infection (like different nitrogen compounds) are crucial stimuli for reshaping the proteome profile and consequently the specialization profiling of the fungus, ultimately leading to very different toxin contamination levels in the plant. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests the prognostic value of spinal cord (SC) pathology in multiple sclerosis (MS). However, the 2021 MAGNIMS-CMSC-NAIMS guidelines don't recommend routine SC MRI for disease monitoring. This study investigates the frequency of new asymptomatic and isolated SC lesions, exploring their potential to predict clinical activity and guide treatment decisions. We enrolled relapsing-remitting MS (RRMS) patients who underwent brain and SC MRI at baseline and after 12 months. New, enlarged, or gadolinium-enhanced (Gd+) lesions on MRI were considered disease activity markers. Clinical relapses and treatment changes observed 3 months after the 12-month MRI were analyzed using regression analysis, evaluating their association with worsening SC findings. A total of 201 RRMS patients (56 males, 27.9%, mean age 42.5 ± 12.1 years, mean EDSS 2.7 ± 1.9) were included. Isolated worsening of T2 lesion burden in the SC occurred in 16 patients (8%), and 12 (6%) had Gd + lesions. Among patients without brain MRI activity (n = 138), regression analysis revealed a significant association between new Gd + SC lesions and clinical relapses within 3 months of the 12-month MRI (p = 0.024). Worsening SC findings (p = 0.021) and SC lesion enhancement (p = 0.046) emerged as key factors influencing disease-modifying therapy changes within 3 months in these patients. Notably, even without clinical symptoms, worsening SC findings significantly predicted treatment changes (p = 0.003). Our findings highlight the independent value of SC MRI findings in MS monitoring. Importantly, isolated and asymptomatic SC worsening significantly impacted treatment decisions. • This study investigated the frequency of new, asymptomatic, and isolated spinal cord (SC) lesions in relapsing-remitting MS (RRMS) patients. • The study aimed to assess the potential of SC lesions for predicting clinical activity and guiding treatment decisions. • This study suggests that SC MRI may aid MS monitoring & treatment decisions beyond brain MRI. [ABSTRACT FROM AUTHOR]

Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS. [ABSTRACT FROM AUTHOR]

Background:We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro.Methods:Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays.Results:High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean±s.e.m.=6.8±0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6±0.8% and 10.7±0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu.Conclusion:Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo. [ABSTRACT FROM AUTHOR]

Background: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu.Methods: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays.Results: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression.Conclusion: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC. [ABSTRACT FROM AUTHOR]

(±)-2-(6-Methoxy-2-naphthyl)propionic acid methyl ester (methyl ester of Naproxen), the precursor of therapeutically important nonsteroidal anti-inflammatory drugs (NSAIDs) was enantioselectively hydrolysed using as biocatalyst Candida rugosa lipase. In research aimed at studing the structure–activity relationship (SAR), NMR spectroscopy methods were employed to identify which Naproxen molecular moiety was essential to the substrate–enzyme interaction. The experimental results, in agreement with previous computer modelling studies and reported kinetic data, gave new information on the enzyme–substrate complex formation in solution. [Copyright &y& Elsevier]

Vagus nerve stimulation (VNS), an adjunctive approach for the treatment of epilepsy, was performed in three multiple sclerosis (MS) patients displaying postural cerebellar tremor (PCT) and dysphagia. Following VNS, improvement of PCT and dysphagia was manifested over a period of two and three months, respectively. In view of the involvement of the main brainstem visceral component of the vagus, the nucleus tractus solitarius (NTS), in modulating central pattern generators (CPGs) linked to both olive complex pathway and swallowing, improvement is likely to be VNS related. The results obtained suggest an additional therapeutic application for VNS and may represent a novel form of treatment in patients with severe MS. [ABSTRACT FROM AUTHOR]

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. Aims: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. Results: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS. [ABSTRACT FROM AUTHOR]

Objective: Aim of the research was to define the quality of life of Italian neurologists and nurses' professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue.Material and Methods: One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis.Results: Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life.Conclusion: The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it. [ABSTRACT FROM AUTHOR]

Background: Little is known about the influence of multiple sclerosis (MS) diagnosis on parenthood attitude in people with MS (pwMS).Objective: To investigate the impact of diagnosis, clinical features and external disease-related influences on parenthood decision-making in Italian pwMS.Methods: A web-based survey was posted on SMsocialnetwork.com to investigate clinical status, parenthood desire, influences on family planning, pregnancy outcomes, abortions and adoptions of pwMS.Results: 33/395 respondents never wanted to become parent because of MS ("anti-parenthood after diagnosis"). 362 declared to be in favor of parenthood. 51% pwMS having a child by the survey time had already received the MS diagnosis at first childbirth. The frequency of a second child in pwMS after diagnosis was 38% compared to 67% in people without yet MS diagnosis. 16% of pwMS were discouraged to become parent after diagnosis, mainly by medical personnel. In 71% of respondents, diagnosis did not delay the decision to become parent and only 39% were counseled by treating physician to plan pregnancy. Patients' distribution according to the clinical phenotype (exclusively relapsing vs exclusively progressive) showed a higher proportion of progressive patients in the "anti-parenthood after diagnosis" subgroup.Conclusion: MS diagnosis impacted dramatically on the life project of 7% of pwMS that decided not to have children because of the disease and in pro-parenthood pwMS impacted especially on having the second child. Only a minority was counseled to plan pregnancy. A worse disease course driving to a progressive phenotype at survey time might have negatively impacted on parenthood desire. [ABSTRACT FROM AUTHOR]

Background and purpose: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. Methods: Patients with relapsing–remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. Results: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. Conclusions: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described. [ABSTRACT FROM AUTHOR]

Background and purpose: Patients with multiple sclerosis (MS) have many pregnancy‐related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity. The aim of this study was to investigate pregnancy planning and outcomes in patients with MS treated with MITO, both before and after the treatment. Methods: Patients with MS previously treated with MITO were recruited. Clinical, demographic and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non‐parametric tests were performed using SPSS 22 software. Results: A total of 238 patients (female/male, 158/80) were included; 106 subjects planned a pregnancy before MITO and 40 after MITO. Of these, respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion and 98 (96%) and 32 (91%) were full‐term pregnancies. A total of 96 patients (40%) planned a pregnancy only before MITO (and not after), whereas 30 (13%) planned a pregnancy only after MITO (and not before) (P < 0.01). A total of 103 patients did not plan a pregnancy before MITO and 198 did not plan a pregnancy after MITO. The reasons included lack of interest or a partner, fear of MS and infertility. All of the babies born were healthy until the end of follow‐up. Conclusions: Mitoxantrone does not affect the ability to conceive or pregnancy outcomes. We found no differences in pregnancies, abortions or miscarriages before and after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the approach taken by neurologists. [ABSTRACT FROM AUTHOR]

Background Several correlations between cognitive impairment (CI), radiologic markers and cognitive reserve (CR) have been documented in MS. Obiective To evaluate correlation between CI and brain volume (BV) considering CR as possibile mitigating factor. Methods 195 relapsing MS patients underwent a neuropsychological assessment using BICAMS. BV was estimated using SIENAX to obtain normalized volume of brain (NBV), white matter (NWV), gray matter (NGV) and cortical gray matter (CGV). CR was estimated using a previously validated tool. Results Pearson test showed a correlation between the symbol digit modality test (SDMT) score and NBV ( r = 0.38; p < 0.000) NGV( r = 0.31; p < 0.000), CGV ( r = 0.35; p < 0.000) and CRI score( r = 0.42; p < 0.000). Linear regression (dependent variable:SDMT) showed a relationship with CR scores ( p = 0.000) and NGV( p < 0.000). A difference was detected between cognitive impaired and preserved patients regarding mean of NBV( p = 0.002), NGV( p = 0.007), CGV( p = 0.002) and CR Scores ( p = 0.007). Anova showed a association between the presence of CI (dependent variable) and the interaction term CRIQ × CGV ( p = 0.004) whit adjustment for age and disability evaluated by EDSS. Conclusions Our study shows a correlation between cognition and BV, in particular gray matter volume. Cognitive reserve is also confirmed as an important element playing a role in the complex interaction to determine the cognitive functions in MS. [ABSTRACT FROM AUTHOR]

Several studies indicated leukocyte telomere length (LTL) as a biomarker of multiple sclerosis (MS) evolution. This study aimed to investigate LTL in women with multiple sclerosis (MS) compared to that in healthy women (HW) across different reproductive phases, and to evaluate its relationship with MS activity. Blood samples were collected from women with MS and HW during the fertile phase, pregnancy, and puerperium. LTL was determined using quantitative fluorescence in situ hybridization (Q-FISH). Blood samples from 68 women with MS (22 during fertile life, 23 during pregnancy, and 23 post-partum) and 52 HW (23 during fertile life, 20 during pregnancy, and 9 post-partum) were analyzed. During pregnancy, LTL in MS women and HW was 84.7 ± 10.5 and 77.6 ± 11.5, respectively (p < 0.005). Regression analysis showed that shorter LTL was associated with pregnancy in HW (p = 0.021); this relationship was not observed in MS women, for whom shorter LTL was related to a higher EDSS (p = 0.036). A longitudinal analysis was performed in eight MS women, showing LTL shortening from pregnancy to puerperium (p = 0.003), which was related to MS reactivation (p = 0.042). Our results highlight the possible associations between LTL, reproductive biological phases, and MS activity after delivery. • Telomere length (TL) is hypothesized to be an indicator of Multiple Sclerosis (MS) evolution. • Beneficial effects of pregnancy on MS activity have been reported. • Conversely, MS reactivation is frequently reported in the post-partum period. • This study evaluated associations between TL, reproductive biological phases, and MS activity. • From pregnancy to puerperium, an LTL shortening was reported, also related to MS reactivation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex chronic disease with an unknown etiology. It is considered an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS) characterized, in most cases, by an unpredictable onset of relapse and remission phases. The disease generally starts in subjects under 40; it has a higher incidence in women and is described as a multifactorial disorder due to the interaction between genetic and environmental risk factors. Unfortunately, there is currently no definitive cure for MS. Still, therapies can modify the disease's natural history, reducing the relapse rate and slowing the progression of the disease or managing symptoms. The limited access to human CNS tissue slows down. It limits the progression of research on MS. This limit has been partially overcome over the years by developing various experimental models to study this disease. Animal models of autoimmune demyelination, such as experimental autoimmune encephalomyelitis (EAE) and viral and toxin or transgenic MS models, represent the most significant part of MS research approaches. These models have now been complemented by ex vivo studies, using organotypic brain slice cultures and in vitro, through induced Pluripotent Stem cells (iPSCs). We will discuss which clinical features of the disorders might be reproduced and investigated in vivo, ex vivo, and in vitro in models commonly used in MS research to understand the processes behind the neuropathological events occurring in the CNS of MS patients. The primary purpose of this review is to give the reader a global view of the main paradigms used in MS research, spacing from the classical animal models to transgenic mice and 2D and 3D cultures. • Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS). • Several preclinical models that reproduce different aspects of the disease are used in MS research. • Transgenic and humanized mice models contribute to the understanding of key pathophysiological mechanisms underlying MS. • The use of in vitro models gives new opportunities and perspectives for the study of MS. [ABSTRACT FROM AUTHOR]

Motor and cognitive disabilities are related to brain atrophy in multiple sclerosis (MS). 'Timed up and go' (TUG) has been recently tested in MS as functional mobility test, as it is able to evaluate ambulation/coordination-related tasks, as well as cognitive function related to mobility. The objective of this study is to evaluate the relationship between brain volumes and TUG performances. Inclusion criteria were a diagnosis of MS and the ability to walk at least 20 m. TUG was performed using a wearable inertial sensor. Times and velocities of TUG sub-phases were calculated by processing trunk acceleration data. Patients underwent to a brain MRI, and volumes of whole brain, white matter (WM), grey matter (GM), and cortical GM (C) were estimated with SIENAX. Sixty patients were enrolled. Mean age was 41.5 ± 11.6 years and mean EDSS 2.3 ± 1.2. Total TUG duration was correlated to lower WM ( ρ = 0.358, p = 0.005) and GM ( ρ = 0.309, p = 0.017) volumes. A stronger association with lower GM volume was observed for intermediate ( ρ = 0.427, p = 0.001) and final turning ( ρ = 0.390, p = 0.002). TUG is a useful tool in a clinical setting as it can not only evaluate patients' disability in terms of impaired functional mobility, but also estimate pathological features, such as grey atrophy. [ABSTRACT FROM AUTHOR]

Background: Amongst Sardinians the human leukocyte antigen (HLA) DRB1-DQB1 haplotypes *15:02-*06:01, *16:01-*05:02, *14:01-4-*05:03 are protective for multiple sclerosis (MS), while *13:03-*03:01, *04:05-*03:01, *03:01-*02:01, *15:01-*06:02 and Mycobacterium avium subspecies paratubercolosis (MAP) are predisposing factors. We studied the correlation between MAP and HLA.Methods: Five hundred thirty-one patients were searched for anti-MAP2694 antibodies, DRB1-DQB1 genotyping was performed. The haplotypes were classified as predisposing, neutral or protective.Results: Anti-MAP2694 were found in 23 % of subjects carrying one protective HLA versus 32 % without (p = 0.04).Conclusions: We showed a lower frequency of Abs in patients with protective HLA. These haplotypes could have a protective role for both MS and MAP. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55-200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45-60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS. [ABSTRACT FROM AUTHOR]

Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % ( p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion-extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the χ 2 test with a standard 2 × 2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Mood disorders are very common among multiple sclerosis (MS) patients, but their frequency in patients with progressive course (PMS) has not been adequately researched. Our study aimed to determine the frequency of mood disorders among patients with PMS compared with those with relapsing-remitting MS (RMS) and to explore the associations with disability and disease duration. The study included consecutive outpatients affected by MS according the 2010 revised Mc Donald diagnostic criteria. Psychiatric diagnoses were determined according to DSM-IV by psychiatrists using structured interview tools (ANTAS-SCID). Demographic and clinical data of patients were also collected. Disease courses were defined according to the re-examined phenotype descriptions by the Committee and MS Phenotype Group. Intergroup comparisons were performed by Chi-square test, while logistic regression analysis was performed to assess possible factors associated with mood disorders. In total, 240 MS patients (167 women) were enrolled; of these, 18 % (45/240) had PMS. The lifetime DSM-IV major depression diagnosis (MDD) was established in 40 and 23 % of the PMS and RMS patients, respectively. Using logistic regression analysis, the presence of MDD was independent from disease duration and disability and dependent on PMS course ( P = 0.02; OR 2.2). Patients with PMS presented with MDD more frequently than those with RMS, independently from disease duration and physical disability. These findings highlight the importance of considering mood disorders, especially MDD, in the management of PMS patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a long-lasting neurological disease with onset in young adult age. Patients with MS are less active than healthy people, and their sedentary lifestyle might lead to secondary diseases or worsening of symptoms, disability and quality of life. In the study, we evaluated the attitude of physical activity (PA) of a group of MS patients and the differences in practice PA before and after the diagnosis. A randomly recruited group of patients with MS fulfilled a questionnaire about their attitudes towards PA before the onset and after the diagnosis of the disease. Clinical and demographic data were recorded. Out of 118 patients, 37 % practiced PA only before the diagnosis, 9 % only after and 52 % during both periods. After the diagnosis, 64 % of participants noted some negative differences in PA, in particular less physical resistance and worsening of symptoms, and 38 % stopped PA. However, patients referred benefits from PA after diagnosis. Individual exercises rather than group activities were preferred after diagnosis. Only 26 % of patients knew that adapted PA existed and the differences between adapted PA and classic physiotherapy. We observed a reduction in the practice of PA in patients after the diagnosis of MS, in particular for disease-related reasons. Nevertheless, active patients referred benefits from PA. It is important to know the point of view of patients towards developing individualized training programs. In this way, it could be possible to achieve more benefits from PA and reduce the negative effects. [ABSTRACT FROM AUTHOR]

The present study aims to describe the evolution of teriflunomide use for multiple sclerosis (MS) in the clinical setting, in particular for naïve patients and young women. Predictors of treatment response were also investigated. This was an independent, retrospective, real-world monocentric study. We analysed the use of teriflunomide from 2016 to 2020 in patients categorized as naïve or switchers, and assessed the variations in its use in men and women by age group. Clinical and MRI data of treated patients were evaluated, and NEDA-3 status at 24 and 36 months was defined. Determinants of therapeutic response were examined using regression analysis. The study included 319 MS patients exposed to teriflunomide [209 women (65.5%)]. Of these, 67 (21%) were naïve and 252 (79%) were switchers. A 20% increase of teriflunomide use in the naïve group in the past two years, particularly in 2020, the first year of global Sars-Cov-2 spread, was observed. An increase of teriflunomide use of more than 10% in young women under age 45 was also reported. NEDA-3 status was calculated for 204 patients after 24 months and was achieved in 120 (58.8%) of these ones. NEDA-3 was also achieved in 92/160 (56.8%) patients at 36 months. A lower ARR in the two years prior to teriflunomide treatment (p = 0.026), lower baseline age (p = 0.05), and lower EDSS score (p = 0.009) were associated with achievement of the NEDA-3. Our study confirms a major evolution in teriflunomide use in clinical settings, particularly for naïve patients and young women. • Teriflunomide use has progressively increased for treatment of Multiple Sclerosis (MS). • In the last two years, we described a 20% and 10% increase of its use in naïve patients and young women. • The efficacy goal of NEDA-3 at 24 and 36 months was achieved in more than 55% patients. • An adequate shared decision-making process is necessary to identify the best candidate patient. [ABSTRACT FROM AUTHOR]

Background:Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts.Methods:Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival.Results:Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean±s.e.m. IC50=0.0056±0.0006 μM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean±s.e.m. IC50=0.563±0.092 μM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017).Conclusions:Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted. [ABSTRACT FROM AUTHOR]

Background The purpose is to measure the worsening of the Quality of Life (QoL) in people with Multiple Sclerosis (MS) and the concomitant role of co-morbid Major Depressive Disorder (MDD) and Bipolar Disorder (BD), the latter not yet studied even though it was found strictly associated with MS. Methods Cases: 201 consecutive-MS-patients. Controls: 804 sex-and-age-matched subjects without MS, randomly selected from an epidemiological database study. Psychiatric diagnoses according to DSM-IV were determined by physicians using structured interview tools (ANTAS-SCID). Bipolar Spectrum Disorders were identified by Mood Disorders Questionnaire (MDQ). QoL was measured by SF-12. Results MS was the strongest determinant in worsening the QoL in the overall sample. Both MDD and BD type-II lifetime diagnoses were significantly associated with a poorer quality of life in the total sample as in cases of MS. In MS the impairment of the QoL attributable to BD type-II was even greater than that in MDD. Limitations The MS diagnosis was made differently in cases and controls. Although this may have produced false negatives in controls, it would have reinforced the null hypothesis (no role of MS in worsening the QoL); therefore, it does not invalidate the study. Conclusions MDD as well BD type-II are co-determinants in worsening QoL in MS. Clinicians should consider depressive symptoms as well as the hypomanic and mixed components in MS. Additional research is required to confirm our results and further clarify the manner in which BD and the mixed symptoms of BD type-II may affect awareness of both the underlying disease and psychiatric component and finally to what extent they impact treatment adherence with the available therapies for MS. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim was to determine the risk of Mood Disorders (MD), particularly Bipolar Disorders (BD), in Multiple Sclerosis (MS) using standardized psychiatric diagnostic tools. Methods: Case–control study. Cases: 201 consecutive-patients with MS. Controls: 804 sex- and age-matched subjects without MS, randomly selected from a database concurrently used for an epidemiological study on the MD prevalence in the community. Psychiatric diagnoses according to DSM-IV were determined by physicians using structured interview tools (ANTAS-SCID). Results: Compared to controls, MS patients had a higher lifetime prevalence of DSM-IV Major Depressive Disorders (MDD; P<0.0001), BD I (P=0.05), BD II (P<0.0001) and Cyclothymia (P=0.0001). As people with MS had a higher risk of depressive and bipolar spectrum disorders, ratio MDD/bipolar spectrum disorders was lower among cases (P<0.005) indicating a higher association with Bipolar Spectrum Disorders and MS. Limitations: MS diagnosis was differently collected in cases and controls. Even if this might have produced false negatives in controls, it would have reinforced the null hypothesis of no increased risk for MD in MS; therefore, it does not invalidate the results of the study. Conclusions: This study was the first to show an association between BD and MS using standardized diagnostic tools and a case–control design. The results suggest a risk of under-diagnosis of BD (particularly type II) in MS and caution in prescribing ADs to people with depressive episodes in MS without prior excluding BD. The association between auto-immune degenerative diseases (like MS) and BD may be an interesting field for the study of the pathogenic hypothesis. [Copyright &y& Elsevier]

The article presents a study on the epidemiology and clinical features of mycobacterium avium subspecies paratuberculosis (MAP) and multiple sclerosis (MS) in Sardinia, Italy. It mentions the association of the pathogenic bacterium with the autoimmune disease in the region. It also notes its possible influence through MS treatment and steroids.

Background:We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen.Methods:We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours.Results:Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs.Conclusion:SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy. [ABSTRACT FROM AUTHOR]