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Background and purpose: Although Labrune syndrome is a well-known disorder characterized by a typical neuroradiological triad, namely leukoencephalopathy, intracranial calcifications and cysts, there are no reports of systemic involvement in this disorder. This paper attempts to describe a peculiar clinical manifestation related to a novel mutation in the SNORD118 gene. Methods: Clinical examination, brain and total-body imaging, and neurophysiological and ophthalmological investigations were performed. Amplification of the SNORD118 gene and Sanger sequencing were integrated to investigate potential causative mutations. Results: A 69-year-old woman, with a long history of episodes of vertigo and gait imbalance, was referred to our hospital for progressive cognitive and motor deterioration. Computed tomography and magnetic resonance imaging disclosed diffuse bilateral leukoencephalopathy in periventricular and deep white matter, widespread calcifications and numerous cysts in the brain, liver, pancreas and kidneys. The genetic analysis revealed two biallelic variants in the SNORD118 gene, one of which is novel (n.60G>C). Conclusions: This is the first report of adult-onset Labrune syndrome with an unusual systemic involvement presenting a novel mutation in the SNORD118 gene.

Multiple System Atrophy (MSA) is a rare neurodegenerative disease, clinically defined by a combination of autonomic dysfunction and motor involvement, that may be predominantly extrapyramidal (MSA-P) or cerebellar (MSA-C). Although dementia is generally considered a red flag against the clinical diagnosis of MSA, in the last decade the evidence of cognitive impairment in MSA patients has been growing. Cognitive dysfunction appears to involve mainly, but not exclusively, executive functions, and may have different characteristics and progression in the two subtypes of the disease (i.e., MSA-P and MSA-C). Despite continued efforts, combining in-vivo imaging studies as well as pathological studies, the physiopathological bases of cognitive involvement in MSA are still unclear. In this view, the possible link between cardiovascular autonomic impairment and decreased cognitive performance, extensively investigated in PD, needs to be clarified as well. In the present study, we evaluated a cohort of 20 MSA patients (9 MSA-P, 11 MSA-C) by means of a neuropsychological battery, hemodynamic assessment (heart rate and arterial blood pressure) during rest and active standing and bedside autonomic function tests assessed by heart rate variability (HRV) parameters and sympathetic skin response (SSR) in the same experimental session. Overall, global cognitive functioning, as indicated by the MoCA score, was preserved in most patients. However, short- and long-term memory and attentional and frontal-executive functions were moderately impaired. When comparing MSA-P and MSA-C, the latter obtained lower scores in tests of executive functions and verbal memory. Conversely, no statistically significant difference in cardiovascular autonomic parameters was identified between MSA-P and MSA-C patients. In conclusion, moderate cognitive deficits, involving executive functions and memory, are present in MSA, particularly in MSA-C patients. In addition, our findings do not support the role o

COVID-19 and preeclampsia (preE) share the ANG-II mediated endothelial dysfunction, resulting from a significant dysregulation of RAS and an imbalanced proportion of anti-angiogenic and pro-angiogenic soluble plasmatic factors. Of note, an increased incidence of preE has been reported among COVID-19-infected mothers compared to the general pregnant population. The two most promising angiogenic markers are the soluble fms-like tyrosine kinase receptor-1 (sFlt-1), the major antiangiogenic factor, and the placental growth factor (PlGF), a powerful angiogenic factor. Since these markers have proven useful in the prediction, diagnosis, and severity of preE, this study aimed to evaluate their maternal serum levels in pregnancies complicated by SARS-CoV-2 infection and to assess their potential use to guide the management of these women. A retrospective analysis of SARS-CoV-2-positive pregnant women was performed. The serum levels of sFlt-1 and PlGF were collected at the diagnosis of SARS-CoV-2 infection at the hospital, before the beginning of steroid/hydroxychloroquine and/or antithrombotic therapy. The sFlt-1/PlGF ratio was stratified using cut-off values clinically utilized in the diagnosis and prediction of preE (low < 38, intermediate 38–85/110* and high >85/110*, * if before or after the 34th week of gestation). A total of 57 women were included, of whom 20 (35%) had signs and symptoms of COVID-19 at hospital presentation and 37 (65%) were asymptomatic. None were vaccinated. The mean gestational age at diagnosis of SARS-CoV-2 infection was 32 weeks in symptomatic patients and 37 weeks and 5 days in asymptomatic ones (p = 0.089). sFlt-1 serum levels were higher in SARS-CoV-2 positive asymptomatic patients compared to women with COVID-19 related symptoms (4899 ± 4357 pg/mL vs. 3187 ± 2426 pg/mL, p = 0.005). sFlt-1/PlGF at admission was <38 in 18 of the 20 symptomatic women (90%) compared to 22 (59%) of the asymptomatic patients (p = 0.018). Of note, two of th

Globalization caused a shift in trial locations towards low-middle income countries, raising ethical concerns. These include the risk that conditions primarily affecting children in these countries will be neglected in favor of those affecting developed countries. We analyzed 253 published and 69 ongoing pharmacological RCTs performed in Latin America between 2000 and 2015 involving exclusively children. While over 50% of the previously highly investigated diseases were no longer priorities, other diseases acquired greater attention in recent years. Brazil and Mexico resulted as the most active countries. A large gap remains between the real needs of children in these countries and scientific research.

Item does not contain fulltext, Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile and immunohistochemistry analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions. In post-IM specimens, the pathological response and tumor apoptosis were tightly associated with T-cell infiltration, thus suggesting the presence of an ongoing anti-tumor response, which was further confirmed by in vitro functional assays with CD3+ T cells isolated from an IM-responding FS-DFSP lesion. The integration of targeted therapies with immune therapies is currently under investigation to achieve longer tumor control. Our data outline the in situ immunological effects of IM and classify IM-treated FS-DFSP as potentially sensitive to immunotherapy, thus providing the rationale for further investigations of combination treatment for this soft-tissue sarcoma.

Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile and immunohistochemistry analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions. In post-IM specimens, the pathological response and tumor apoptosis were tightly associated with T-cell infiltration, thus suggesting the presence of an ongoing anti-tumor response, which was further confirmed by in vitro functional assays with CD3+ T cells isolated from an IM-responding FS-DFSP lesion. The integration of targeted therapies with immune therapies is currently under investigation to achieve longer tumor control. Our data outline the in situ immunological effects of IM and classify IM-treated FS-DFSP as potentially sensitive to immunotherapy, thus providing the rationale for further investigations of combination treatment for this soft-tissue sarcoma.

Myths and folklore, as expressions of popular beliefs, provide valuable information on medical knowledge in earlier times. Fairy tales have often recounted occupational maladies throughout the ages and also provide some insight into the toxic effects of certain metals, such as mercury. Much historical information can be gleaned from unexpected sources, and as such, fairy tales should be more carefully scrutinized by contemporary researchers with an interest in the historical origins of workplace injury and disease.

In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels. Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.

Purpose: To investigate the risk of illnesses in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type and complications. Methods: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, Slovenia) were followed prospectively for 17,484 and 17,206 person-months and asked to report any spontaneous complaint requiring medical attention (illness), its type and complications (hospitalization, absence from work or school, medical action). Risk assessment was done by actuarial methods, relative risks (RR), and 95% confidence intervals (CIs). Results: During the study period 644 patients (68%) and 504 controls (56%) reported an illness (p<0.0001); 30% were seizure related. The cumulative probability of illness at 12 and 24 months was 49 and 86% in the cases and 39 and 75% in the controls (p<0.0001). The largest differences regarded disorders affecting the nervous system (NS) (RR, 3.3; 95% CI, 2.3-4.2) and ear, nose, and throat (ENT) (RR, 1.3; 95% CI, 1.0-1.6). In patients with epilepsy, an NS illness was more likely to be followed by hospital admission, work absence, or medical intervention. All risks were significantly reduced after excluding seizure-related events. Conclusions: Patients with epilepsy are at higher risk of NS and ENT illnesses and complications than the general population. However, the risk of illness is significantly reduced when seizure-related events are excluded

Purpose: To investigate the risk of accidents in a cohort of patients with epilepsy and in matched nonepilepsy controls, by type, circumstances, and complications. Methods: A total of 951 children and adults with idiopathic, cryptogenic, or remote symptomatic epilepsy and 904 matched controls seen in secondary and tertiary centers in eight European countries (England, Estonia, Germany, Italy, the Netherlands, Portugal, Russia, and Slovenia) were followed up prospectively for 17,484 and 17,206 person-months and asked to report any accident requiring medical attention, its site, and complications. Risk assessment was done by using actuarial methods, relative risks (RRs), and 95% confidence intervals (CIs). Results: During the study period, 199 (21%) patients and 123 (14%) controls reported an accident (p < 0.0001); 24% were seizure related. The cumulative probability of accidents at 12 and 24 months was 17 and 27% in the cases and 12 and 17% in the controls. The risk was highest for concussions (RR, 2.6; 9.5% CI, 1.2-5.8), abrasions (RR, 2.1; 95% CI, 1.1-4.0), and wounds (RR, 1.9; CI, 1.2-3.1). Domestic accidents prevailed in both groups, followed by street and work accidents, and were more common among cases. Compared with controls, patients with epilepsy reported more hospitalization, complications, and medical action. Disease characteristics associated with an increased risk of accidents included generalized epilepsy (concussions), active epilepsy, and at least monthly seizures (abrasions). Most risks decreased, becoming nonsignificant after excluding seizure-related events. Conclusions: Patients with epilepsy are at higher risk of accidents and their complications. However, the risk was substantially lower after exclusion of seizure-related events.

Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30(+) lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30(+) lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4(+)Foxp3(+) or PD1(+) subpopulations and CD4(-)CD8(-) T cells. CD30(+) T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30(+) lymphocytes at those sites associate positively with melanoma progression.

Interleukin-2 has been shown to stimulate cortisol secretion in man. Owing to its immunosuppressive properties, an increase in cortisol levels during interleukin-2 cancer immunotherapy could potentially counteract induced activation of the antitumor immune response. Few data are available about cortisol secretion secondary to prolonged interleukin-2 administration. To investigate the problem, we evaluated cortisol circadian rhythms in 7 consecutive metastatic small cell lung cancer patients who received interleukin-2 subcutaneously for 4 weeks (daily dose: 6 x 10(6) x IU/m2). Venous blood samples were drawn at 8.00 a.m., 4.00 p.m. and 12.00 p.m., before interleukin-2, and after each week until the end of the cycle. Beta-endorphin levels were also measured on the same samples. Four patients were evaluated during a second interleukin-2 cycle. Mean cortisol levels increased during interleukin-2 therapy, but were significantly higher than those seen in basal conditions after the first week of treatment. Moreover, cortisol peaks observed during the second cycle of therapy were not significantly different from those seen during the first cycle. Mean beta-endorphin levels increased in response to interleukin-2 administration, but the increase did not reach statistical significance. The early cortisol rise progressively decreased as treatment continued. This suggests that the interleukin-2-induced cortisol rise has no relevant clinical importance in antagonizing the activation of an effective antitumor immune response during cancer immunotherapy with interleukin-2

Il tema della governace e' stato declinato nella specifica tematica delle ipotesi di valutazione. Per giungere alla valutazione della goverance si e' creato un modello in grado di restituire un rating sulla goverance confrontandolo con analoghe metodologie e indicatori utilizzate da agenzie di valutazione gia' note in campo internazionale.

I crack economico-finanziari evidenziatisi nel mondo anglosassone e, successivamente, in Italia e in Europa nonché la crisi finanziaria attuale hanno, ulteriormente, evidenziato l’importanza del passaggio da una shareholder view ad una stakeholder view. Obiettivo dell’impresa non deve essere la “creazione di valore per gli azionisti” ma per tutti gli interlocutori sociali. Molte sono le variabili aziendali da controllare e trasformare per cercare di attuare tale obiettivo. Una “buona governance” aziendale, punto focale per garantire una migliore amministrazione e gestione delle imprese e per ottenere, di conseguenza, una performance positiva, viene vista sempre più come variabile fondamentale per offrire maggiori garanzie di tutela a tutti gli interlocutori dell’impresa. Proprio per tale ragione la nostra ricerca si focalizzerà sull’implementazione ed analisi di, quello che noi riteniamo possa essere, uno strumento fondamentale per poter fornire una migliore analisi della bontà della governance ovvero il “Corporate Governance rating”. La ricerca si propone, dopo un’analisi dello stato dell’arte nell’ambito della Corporate governance in Italia, di introdurre un modello di rating che applicato alle aziende italiane evidenzi una possibile relazione tra una buona governance e performance aziendali quest’ultime influenzate sia da fattori esogeni come l’ambiente esterno sia da fattori legati a scelte di governo economico. Inizialmente si effettuerà un’analisi storica della struttura e delle stabilità degli assetti proprietari nelle imprese osservando, in particolare, quanto un sistema proprietario stabile nel lungo periodo possa incidere favorevolmente sulla governance aziendale. Si procederà evidenziando i principali sistemi di corporate governance possibili secondo la legislazione italiana e adottati dalle principali aziende in Italia. Nell’ambito dell’analisi empirica si svilupperà un nuovo modello di rating della Corporate Governance che, partendo dai modelli

Glucose-regulated stress protein gp96 is known to be involved in the host response to pathogens and to cancer. Our study explored the relationships between gp96 and human blood plasmacytoid dendritic cells (pDC) and proved that gp96 directly targets pDC by a receptor-dependent interaction. Competition studies identified CD91 as a gp96 receptor on pDC, and laser confocal imaging indicated that CD91 triggering was followed by gp96 endocytosis and trafficking into early endosomes and later into the endoplasmic reticulum compartment. Using two alternative Abs, we showed that human blood pDC reproducibly expressed CD91, although different levels of expression were detectable among the analyzed donors. Moreover, CpG-matured pDC displayed CD91 receptor up-regulation that correlated with an increased gp96 binding. Functionally, gp96-pDC interaction activated the NF-kappaB pathway, leading to the nuclear translocation of the NF-kappaB complex. gp96-treated pDC maintained an immature phenotype, while they down-modulated the release of IL-8, suggesting an anti-inflammatory role of this pathway, and they strongly up-regulated the cell surface expression of the gp96 receptor CD91. CpG-matured or gp96-treated pDC, expressing high levels of the gp96 receptor CD91, antagonized the gp96-induced activation of monocyte-derived dendritic cells in terms of cell surface phenotype and cytokine production. Altogether, these results suggest that gp96-pDC interaction might represent an active mechanism controlling the strength of the immune response to free, extracellular available gp96; this mechanism could be particularly relevant in wounds and chronic inflammation.

Udgivelsesdato: 1998-null, Several T cell-recognized epitopes presented by melanoma cells have been identified recently. Despite the large array of epitopes potentially available for clinical use, it is still unclear which of these antigens could be effective in mediating anti-tumor responses when used as a vaccine. Preliminary studies showed that immunization of melanoma patients with epitopes derived from proteins of the MAGE family may result in significant clinical regressions. However, no sign of systemic immunization could be observed in peripheral blood of treated patients. Conversely, significant immunization (detected as increased antigen-specific CTL activity in peripheral blood) was obtained by vaccinating HLA-A2.1+ melanoma patients with the immunodominant epitope (residues 27-35) of the differentiation antigen MART-1, but this immunization was not accompanied by a significant clinical response. To implement immunotherapeuties capable of significantly impacting disease outcome, it is necessary to identify the potential mechanisms responsible for the failure of some antigens to mediate significant anti-tumor responses in vivo. In the case of the MART-1(27-35) epitope, we hypothesize that one of these mechanisms may be related to the existence of natural analogs of this peptide in other human normal proteins.

The increase in IL-2 receptor serum levels is one of the most typical changes in immune parameters during IL-2 cancer immunotherapy. To better define the effects of prolonged IL-2 injection on SIL-2R levels, we evaluated 7 advanced small cell lung cancer patients who received IL-2 subcutaneously at a daily dose of 9 x 10(6) IU/m2/12h for two days followed by 3 x 10(6) IU/m2/12h for 18 days (5 days/week for 4 weeks). Moreover, four patients were also evaluated during the second IL-2 cycle. Venous blood samples were drawn before and at weekly intervals during IL-2 therapy. Mean SIL-2R serum levels rapidly increased with the start of IL-2 injection, and they were significantly higher than the baseline levels throughout the immunotherapy cycle. The increase in mean SIL-2R levels was higher in patients with progressive disease than in those with response or stable disease, but the difference was not significant. Finally, the increase in mean SIL-2R concentrations during the second IL-2 cycle was not significantly different from that seen during the first one. The present study confirms that IL-2 administration determines an evident increase in SIL-2R levels; moreover, it would demonstrate that re-exposure to IL-2 after a rest period does not induce a more pronounced SIL-2R release