Ultrasound Guidance in Paravertebral Injections of Oxygen-Ozone: Treatment of Low Back Pain

Background: Paravertebral injection of ozone is an established clinical practice for the treatment of Low Back Pain (LBP). The role of Ultrasound Guidance (USG) in mini invasive procedures has become important in many clinical practice thanks to the greater precision this technique can add. As matter of fact, a large volume of ozone in a single administration may have some adverse or side effects. In this study we wanted to verify if the use of USG in Oxygen/ Ozone (O2/O3) infiltrations could allow the administration of a smaller volume of gas mixture, increasing the safety and the comfort of the procedure itself, obtaining however similar or better results in pain decrease. Methods: We compared two groups of 25 patients affected by LBP, undergoing 10 infiltrations of O2/O3, by using USG (group U) or only anatomical landmarks (group AL). Pain intensity, by calculating Visual Analogical Scale (VAS) difference before and after the treatment, and the discomfort were evaluated in both groups. Results: The mean of the VAS before the treatment was 6.44 in group U and 6.48 in group AL. The mean of the VAS after the treatment was 2.22 in group U and 3.04 in group AL. The mean of discomfort rate was 2.84 in group U and 5.44 in group AL. The number of patients with unbearable discomfort was 0 in group U and 7 in group AL. Conclusions: As many other treatment, also paravertebral injections of O2/O3 benefits of the advantages of the US device which makes this treatment safer and more accurate

The closing of forensic psychiatric hospitals in Italy: determinants, current status and future perspectives: a scoping review

Introduction. Italy is the only country in the world to have closed forensic psychiatric hospitals and converted to fully-residential services. The international interest around this reform has not been matched by research. This scoping review aims to report the determinants of the reform, the most updated information on how the system operates, its benefits and its challenges. We further aim to discuss the implications for policy, research and practice. Methods. 1. Selection of relevant sources through electronic search on four databases, Google, relevant printed materials and personal communication with practitioners currently working in REMS. 2. Study quality monitoring. 3. Data extraction onto NVivo 4. Data synthesis through content analysis. Results. 43 papers were selected for inclusion in our review. Two main themes were identified: 1. Historical chronology of the closure of forensic psychiatric hospitals; 2. The current model of residential forensic psychiatric care. Conclusions. The closing down of Italian forensic psychiatric hospitals represented a fundamental step for human rights. Further work is required to improve the current service, including potential reforming of the penal code, improved referral/admission processes and consistent monitoring to reduce service inequality across regions. Further research is crucial to test the effectiveness of the Italian model of care against traditional ones

Secretome protein signature of human pancreatic cancer stem-like cells

Emerging research has demonstrated that pancreatic ductal adenocarcinoma (PDAC) contains a sub-population of cancer stem cells (CSCs) characterized by self-renewal, anchorage-independent-growth, long-term proliferation and chemoresistance. The secretome analysis of pancreatic CSCs has not yet been performed, although it may provide insight into tumour/microenvironment interactions and intracellular processes, as well as to identify potential biomarkers. To characterize the secreted proteins of pancreatic CSCs, we performed an iTRAQ-based proteomic analysis to compare the secretomes of Panc1 cancer stem-like cells (Panc1 CSCs) and parental cell line. A total of 72 proteins were found up-/down-regulated in the conditioned medium of Panc1 CSCs. The pathway analysis revealed modulation of vital physiological pathways including glycolysis, gluconeogenesis and pentose phosphate. Through ELISA immunoassays we analysed the presence of the three proteins most highly secreted by Panc1 CSCs (ceruloplasmin, galectin-3, and MARCKS) in sera of PDAC patient. ROC curve analysis suggests ceruloplasmin as promising marker for patients negative for CA19-9.Overall, our study provides a systemic secretome analysis of pancreatic CSCs revealing a number of secreted proteins which participate in pathological conditions including cancer differentiation, invasion and metastasis. They may serve as a valuable pool of proteins from which biomarkers and therapeutic targets can be identified. Biological significance: The secretome of CSCs is a rich reservoir of biomarkers of cancer progression and molecular therapeutic targets, and thus is a topic of great interest for cancer research. The secretome analysis of pancreatic CSCs has not yet been performed. Recently, our group has demonstrated that Panc-CSCs isolated from parental cell line by using the CSC selective medium, represent a model of great importance to deepen the understanding of the biology of pancreatic adenocarcinoma. To our knowledge, this is the first proteomic study of pancreatic CSC secretome. We performed an iTRAQ-based analysis to compare the secretomes of Panc1 CSCs and Panc1 parental cell line and identified a total of 43 proteins secreted at higher level by pancreatic cancer stem cells. We found modulation of different vital physiological pathways (such as glycolysis and gluconeogenesis, pentose phosphate pathway) and the involvement of CSC secreted proteins (for example 72 kDa type IV collagenase, galectin-3, alpha-actinin-4, and MARCKS) in pathological conditions including cancer differentiation, invasion and metastasis. By ELISA verification we found that MARCKS and ceruloplasmin discriminate between controls and PDAC patients; in addition ROC curve analyses indicate that MARCKS does not have diagnostic accuracy, while ceruloplasmin could be a promising marker only for patients negative for CA19-9.We think that the findings reported in our manuscript advance the understanding of the pathways implicated in tumourigenesis, metastasis and chemoresistance of pancreatic cancer, and also identify a pool of proteins from which novel candidate diagnostic and therapeutic biomarkers could be discovered

Exceptional Response in BRAF p.V600E-Mutant Enteric-Type Adenocarcinoma of the Lung With Cutaneous Spread: A Case Report

Background: Enteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis. Case presentation: An 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing. Conclusions: We reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation

Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bi‑directionally convert into cancer stem cells

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when metastatic events have occurred. Cancer stem cells (CSCs) play an important role in tumor initiation, metastasis, chemoresistance and relapse. A growing number of studies have suggested that CSCs exist in a dynamic equilibrium with more differentiated cancer cells via a bi‑directional regeneration that is dependent on the environmental stimuli. In this investigation, we obtain, by using a selective medium, PDAC CSCs from five out of nine PDAC cell lines, endowed with different tumorsphere‑forming ability. PDAC CSCs were generally more resistant to the action of five anticancer drugs than parental cell lines and were characterized by an increased expression of EpCAM and CD44v6, typical stem cell surface markers, and a decreased expression of E‑cadherin, the main marker of the epithelial state. PDAC CSCs were able to re‑differentiate into parental cells once cultured in parental growth condition, as demonstrated by re‑acquisition of the epithelial morphology, the decreased expression levels of EpCAM and CD44v6 and the increased sensitivity to anticancer drugs. Finally, PDAC CSCs injected into nude mice developed a larger subcutaneous tumor mass and showed a higher metastatic activity compared to parental cells. The present study demonstrates the ability to obtain CSCs from several PDAC cell lines and that these cells are differentially resistant to various anticancer agents. This variability renders them a model of great importance to deeply understand pancreatic adenocarcinoma biology, to discover new biomarkers and to screen new therapeutic compounds

Dietary restriction for the treatment of Meniere’s disease

Meniere's disease (MD) is an idiopathic inner ear disorder characterized by spontaneous recurrent vertigo, fluctuating sensorineural hearing loss (SNHL), aural fullness and tinnitus. Endolymphatic hydrops (EH) of the inner ear is currently considered the pathophysiological mechanisms that underlies typical symptoms of MD. MD diagnosis is based on the criteria of the Baràny Society. There are many therapeutic options for MD, but none is considered effective by the scientific community. The first-line treatment commonly includes dietary modification, as low salt diet and reduction of alcohol and caffeine daily intake. Although some studies showed a positive effect of these dietary restrictions, even in the prevention of recurrences, currently there is no uniform consensus on their usefulness. New dietary approach, such SPC-flakes, are being evaluated: further assessments will be needed to validate their use in clinical practice

Proteomic analysis of pancreatic cancer stem cells: Functional role of fatty acid synthesis and mevalonate pathways

Recently, we have shown that the secretome of pancreatic cancer stem cells (CSCs) is characterized by proteins that participate in cancer differentiation, invasion, and metastasis. However, the differentially expressed intracellular proteins that lead to the specific characteristics of pancreatic CSCs have not yet been identified, and as a consequence the deranged metabolic pathways are yet to be elucidated. To identify the modulated proteins of pancreatic CSCs, iTRAQ-based proteomic analysis was performed to compare the proteome of Panc1 CSCs and Panc1 parental cells, identifying 230 modulated proteins. Pathway analysis revealed activation of glycolysis, the pentose phosphate pathway, the pyruvate-malate cycle, and lipid metabolism as well as downregulation of the Krebs cycle, the splicesome and non-homologous end joining. These findings were supported by metabolomics and immunoblotting analysis. It was also found that inhibition of fatty acid synthase by cerulenin and of mevalonate pathways by atorvastatin have a greater anti-proliferative effect on cancer stem cells than parental cells. Taken together, these results clarify some important aspects of the metabolic network signature of pancreatic cancer stem cells, shedding light on key and novel therapeutic targets and suggesting that fatty acid synthesis and mevalonate pathways play a key role in ensuring their viability

GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis

Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine–threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in an in vivo mouse model of lung fibrosis and in vitro using different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy

Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT). METHODS: We examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy. RESULTS: PDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes. CONCLUSIONS: Tumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance

Forensic mental health in Europe: some key figures

Purpose. While the number of forensic beds and the duration of psychiatric forensic psychiatric treatment have increased in several European Union (EU) states, this is not observed in others. Patient demographics, average lengths of stay and legal frameworks also differ substantially. The lack of basic epidemiological information on forensic patients and of shared indicators on forensic care within Europe is an obstacle to comparative research. The reasons for such variation are not well understood. Methods. Experts from seventeen EU states submitted data on forensic bed prevalence rates, gender distributions and average length of stay in forensic in-patient facilities. Average length of stay and bed prevalence rates were examined for associations with country-level variables including Gross Domestic Product (GDP), expenditure on healthcare, prison population, general psychiatric bed prevalence rates and democracy index scores. Results. The data demonstrated substantial differences between states. Average length of stay was approximately ten times greater in the Netherlands than Slovenia. In England and Wales, 18% of patients were female compared to 5% in Slovenia. There was a 17-fold difference in forensic bed rates per 100,000 between the Netherlands and Spain. Exploratory analyses suggested average length of stay was associated with GDP, expenditure on healthcare and democracy index scores. Conclusion. The data presented in this study represent the most recent overview of key epidemiological data in forensic services across seventeen EU states. However, systematically collected epidemiological data of good quality remain elusive in forensic psychiatry. States need to develop common definitions and recording practices and contribute to a publicly available database of such epidemiological indicators