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Metalloproteinases (MPs) belong to the superfamily of zinc endopeptidases, which are called metzincins. Three families of MPs have been studied in healthy and diseased conditions in humans. The first study on MPs was published in 1962, and following that, several studies characterized their activity and their effect on health and disease. Several diseases have been related to MPs, such as cardiovascular disease, cancer, inflammatory diseases, gynecological disorders, and others. Moreover, tissue inhibitors of metalloproteinases (TIMPs) have been widely studied, and drugs and artificial molecules that could target MP activity have been evaluated. MPs are relevant to public health because of their role in several diseases and, most of all, their role as biomarkers that also impact the quality of life and the psychosocial dimension of affected patients. In this context, new pathways to precision health and precision medicine have been opened in the area of MPs. This review describes, from the initial studies, the complex dimensions of MPs and related issues centered on health and disease dimensions.

Plankton organisms are fundamental components of the earth’s ecosystem. Zooplankton feeds on phytoplankton and is predated by fish and other aquatic animals, being at the core of the aquatic food chain. On the other hand, Phytoplankton has a crucial role in climate regulation, has produced almost 50% of the total oxygen in the atmosphere and it’s responsible for fixing around a quarter of the total earth’s carbon dioxide. Importantly, plankton can be regarded as a good indicator of environmental perturbations, as it can react to even slight environmental changes with corresponding modifications in morphology and behavior. At a population level, the biodiversity and the concentration of individuals of specific species may shift dramatically due to environmental changes. Thus, in this paper, we propose an anomaly detection-based framework to recognize heavy morphological changes in phytoplankton at a population level, starting from images acquired in situ. Given that an initial annotated dataset is available, we propose to build a parallel architecture training one anomaly detection algorithm for each available class on top of deep features extracted by a pre-trained Vision Transformer, further reduced in dimensionality with PCA. We later define global anomalies, corresponding to samples rejected by all the trained detectors, proposing to empirically identify a threshold based on global anomaly count over time as an indicator that can be used by field experts and institutions to investigate potential environmental perturbations. We use two publicly available datasets (WHOI22 and WHOI40) of grayscale microscopic images of phytoplankton collected with the Imaging FlowCytobot acquisition system to test the proposed approach, obtaining high performances in detecting both in-class and out-of-class samples. Finally, we build a dataset of 15 classes acquired by the WHOI across four years, showing that the proposed approach’s ability to identify anomalies is preserved when tested on images of the same classes acquired across a timespan of years.

Abstract Background Femoropopliteal bypass occlusions are a significant issue in patients with critical limb ischemia and chronic total occlusion of the native superficial femoral artery, which challenges vascular surgeons and interventional radiologists. Performing a secondary femoropopliteal bypass is still considered the standard of care, although it is associated with a higher complication rate and lower patency rate in comparison with primary bypass. Over the past few years, angioplasty has been commonly used, with the development in endovascular technologies, to treat chronic total occlusions of the native superficial femoral artery, with a good technical success rate and clinical prognosis. The purpose of the study is to assess the outcome of endovascular recanalization of chronic total occlusions of the native superficial femoral artery, in patients unfit for surgery with critical limb ischemia after failed femoropopliteal bypass. Results A total of 54 patients were treated. 77.8 % of the conduits were PTFE grafts; the remainder were single-segment great saphenous veins. The most common clinical presentation was rest pain. Technical success was achieved in 51 (94.4 %) of 54 limbs. Angiographically, 77.8 % of the lesions were TASC II category D, while 22.2 % were TASC II category C. The average length of the native SFA lesions was 26.8 cm. Clinical success, with improved Rutherford classification staging, followed each case of technical success. The median follow-up value was 5.75 years (IQR, 1.5–7). By Kaplan-Meier survival analysis, primary patency rates were 61 % (± 0.07 SE) at 1 year and 46 % (± 0.07 SE) at 5 years. Secondary patency rates were 93 % (± 0.04 SE) at 1 year and 61 % (± 0.07 SE) at 5 years. Limb salvage rates were 94 % (± 0.03 SE) at 1 year and 88 % (± 0.05 SE) at 5 years. Conclusions The endovascular recanalization of chronic total occlusions (CTO) of the native superficial femoral artery (SFA) after a failed femoropopliteal bypass is a safe and effective therapeutic option in patients unfit for surgery with critical limb ischemia.

Massimo Bellini,1 Ginevra Berti,1 Leonilde Bonfrate,2 Flavia Ciranni,1 Agostino Di Ciaula,2 Mirko Di Ruscio,3 Alessandra Dell’Era,4,5 Christian Lambiase,1 Antonino Noto,2 Andrea Pancetti,1 Piero Portincasa,2 Francesco Rettura1 1Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 2Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, Bari, Italy; 3IBD Unit, IRCCS Ospedale Sacro Cuore-Don Calabria, Negrar di Valpolicella, Verona, Italy; 4Department of Biomedical and Clinical Sciences, “Luigi Sacco”, University of Milan, Milan, Italy; 5Gastroenterology and Endoscopy Unit – ASST Fatebenefratelli Sacco, Milan, ItalyCorrespondence: Francesco RetturaGastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyTel +39 50 997411Fax +39 50 997412Email rettura.fra@gmail.comAbstract: Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by recurrent chronic abdominal pain and impaired bowel habits, which affects daily activity and work productivity, and is associated with a significant healthcare economic burden as well as an impaired quality of life and psycho-affective profile. Management of patients is a great challenge for physicians; at the present, the therapeutic strategy aimed to treat the different symptoms, and no medical therapy is proven to modify the natural history of the disease. GELSECTAN® (xyloglucan, pea protein and tannins, xylo-oligosaccharides) is a medical device with both protective and prebiotic actions on the intestinal mucosa, able to restore intestinal permeability and to improve gastrointestinal symptoms, controlling diarrhoea, abdominal pain and bloating in adult patients with irritable bowel syndrome. We report and discuss four cases of different patients with irritable bowel syndrome successfully managed with Gelsectan in the real clinical practice. Literature data, as well as these case reports, show that this device is effective and safe in improving symptoms and bowel habits associated to irritable bowel syndrome; its efficacy and safety were confirmed for the long-term use too. Agents with film-forming protective properties, such as Gelsectan, represent a new alternative therapeutic option for the management of patients with irritable bowel syndrome.Keywords: irritable bowel syndrome, GELSECTAN®, xyloglucan, tannins, xylo-oligosaccharides

Klippel–Trenanauy syndrome (KTS) is a rare genetic disease determined by overexpression of the phosphatidylinositol-4-5-bisphosphate 3 kinase catalytic subunit (PIK3CA) gene. The clinical presentation is characterized by venous and capillary malformations and lymphatic malformation. To date, no definitive treatment has been suggested in order to improve the clinical symptoms related to the developments of a skin wound. In this case, we describe a young man with KTS that developed a severe skin wound in the lower right limb unresponsive to the common treatment but responsive to a treatment with oxygen-ozone therapy, pulsed magnetic fields (diamagnetic treatment), and topical fixed association of cocum caprylate, oleic acid, quercetin, and 18-β glycyrrhetinic acid. This is the first case that supports a multistep approach to treat a rare and severe disease, and we hope that other studies can support our data.

Several factors that underlie health inequality have been studied and defined as the social determinants of health (SDHs). The main SDHs are gender, socioeconomic status (SES), and ethnicity. In this study, disparity was analyzed in the context of vascular diseases (VDs) such as Peripheral Artery Disease (PAD), Chronic Venous Disease (CVD), Abdominal Arterial Aneurysm (AAA), and Carotid Stenosis (CS). This article aims to provide a comprehensive overview of the published evidence of the SDHs in VDs. For this purpose, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Published articles using the Scopus and ScienceDirect databases were searched. The criteria for the articles’ inclusion/exclusion were decided using a modified PICOTS framework. For the selected articles, the data sheets were organized in such a way to extract all data of potential relevance. Our findings showed that in VDs, gender, SES, and ethnicity are very important, with some specific problems for VDs analyzed. In conclusion, having detected the presence of SDHs that act negatively on VDs, a model based on action items for the SDHs associated with VDs was proposed.

Eighty-five Egyptian mummies belonging to different dynastic periods and collected in a number of Italian museums, have been censed and submitted for paleopathological research. In most cases the presence of bandages required the application of X- rays and computed axial tomography (CAT). Fifty-two mummies have been studied in situ with Xrays; twelve with CAT scanning. Technical problems kept us from investigating eleven of the censed mummies. In a few cases it was possible to perform autopsies, endoscopy, or histological studies. The mummies submitted for X- rays were divided into two groups: The first group thirty-six mummies studied by the team of Paleopathology-Egyptology of the University of Pisa were studied for the first time. The second group was composed of twenty-six mummies studied elsewhere in Italy. Those results also have been included in the Anubi Project database.

The crypt of the church of the «Saints Jesus and Mary» of Borgo Cerreto, a village near Spoleto (Umbria, central Italy), revealed the natural mummy of a soldier, dated at the first of the 19th century. The inferior half of the right thigh showed a large circular dressing. X-ray evidenced a comminuted fracture of the inferior third of the right femoral diaphysis, with the presence of small metallic fragments. A medication still in situ was present under the dressing. The wound of oval shape (2 x 1.6 cm in size), the comminuted fracture of the diaphysis and the tiny metallic fragments prove that we are in the presence of a gunshot wound. The size of the wound, well adapting to the 16 mm gauge of the military gun balls of the first half of the 19th century, allowed us to identify it with a typical bullet-hole.

Plankton organisms are fundamental components of the earth's ecosystem. Zooplankton feeds on phytoplankton and is predated by fish and other aquatic animals, being at the core of the aquatic food chain. On the other hand, Phytoplankton has a crucial role in climate regulation, has produced almost 50% of the total oxygen in the atmosphere and it's responsible for fixing around a quarter of the total earth's carbon dioxide. Importantly, plankton can be regarded as a good indicator of environmental perturbations, as it can react to even slight environmental changes with corresponding modifications in morphology and behavior. At a population level, the biodiversity and the concentration of individuals of specific species may shift dramatically due to environmental changes. Thus, in this paper, we propose an anomaly detection-based framework to recognize heavy morphological changes in phytoplankton at a population level, starting from images acquired in situ. Given that an initial annotated dataset is available, we propose to build a parallel architecture training one anomaly detection algorithm for each available class on top of deep features extracted by a pre-trained Vision Transformer, further reduced in dimensionality with PCA. We later define global anomalies, corresponding to samples rejected by all the trained detectors, proposing to empirically identify a threshold based on global anomaly count over time as an indicator that can be used by field experts and institutions to investigate potential environmental perturbations. We use two publicly available datasets (WHOI22 and WHOI40) of grayscale microscopic images of phytoplankton collected with the Imaging FlowCytobot acquisition system to test the proposed approach, obtaining high performances in detecting both in-class and out-of-class samples. Finally, we build a dataset of 15 classes acquired by the WHOI across four years, showing that the proposed approach's ability to identify anomalies is preserved when tested on images of the same classes acquired across a timespan of years. [ABSTRACT FROM AUTHOR]

Flavocoxid is a blended extract containing baicalin and catechin with potent antioxidant and anti-inflammatory properties due to the inhibition of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) enzymes, nuclear factor-κB (NF-κB), tumor necrosis factor (TNF)-alpha, and the mitogen-activated protein kinases (MAPKs) pathways. This phase 1/2 study was designed to assess the safety and tolerability of flavocoxid in patients with Duchenne muscular dystrophy (DMD). Thirty-four patients were recruited: 17 were treated with flavocoxid at an oral dose of 250 or 500 mg, according to body weight, for one year; 17 did not receive flavocoxid and served as controls. The treatment was well tolerated and nobody dropped out. Flavocoxid induced a significant reduction in serum interleukin (IL)-1 beta and TNF-alpha only in the group of DMD boys on add-on therapy (flavocoxid added to steroids for at least six months). The decrease in IL-1 beta was higher in younger boys. The serum H2O2 concentrations significantly decreased in patients treated with flavocoxid alone with a secondary reduction of serum glutathione peroxidase (GPx) levels, especially in younger boys. The exploratory outcome measures failed to show significant effects but there was a trend showing that the younger boys who received treatment were faster at performing the Gowers’ maneuver, while the older boys who received treatment were faster at doing the 10-m walk test (10MWT). Therefore, a double-blind, placebo-controlled study for at least two/three years is warranted to verify flavocoxid as a steroid substitute or as add-on therapy to steroids.

Background: Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects.Methods: We examined blood smear of 26 LOPD patients. We evaluated 10 treated and 16 untreated LOPD patients. Among the latter group, 7 patients later initiated ERT and were tested again 6 months after start. Blood smear was also sampled from 82 controls and 19 patients with other muscle glycogenoses (MGSDs). PAS staining was used to evaluate: (1) presence of lymphocytes with glycogen-filled vacuoles, (2) quantification of vacuolated lymphocytes.Results: We found that PAS-positive lymphocytes were significantly higher in LOPD patients than in controls or other MGSDs (p < 0.05 and p < 0.001, respectively). ROC curve for discriminating between untreated LOPD patients and controls yielded an AUC of 1.00 (95%CI 1.00–1.00; p < 0.0001). PAS-positive lymphocyte cutoff level of >10 yielded sensitivity of 100% (95%CI 78–100%), specificity of 100% (95%CI 96–100%), and positive predictive value of 100%. Patients studied before and after ERT showed a dramatic decrease of PAS-positive vacuolated lymphocytes number (p = 0.016). In other MGSDs, PAS-positive lymphocytes were significantly lower that untreated LOPD patients but higher than controls.Conclusions: Our data suggest that the Blood Smear Examination (BSE) for PAS-positive lymphocytes quantification could be used as a simple and sensitive test for a quick screening of suspected Pompe disease. The quantification of vacuolated lymphocytes appears to be also a valuable tool for monitoring the efficacy of treatment in LOPD patients.

Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.

Klippel–Trenanauy syndrome (KTS) is a rare genetic disease determined by overexpression of the phosphatidylinositol-4-5-bisphosphate 3 kinase catalytic subunit (PIK3CA) gene. The clinical presentation is characterized by venous and capillary malformations and lymphatic malformation. To date, no definitive treatment has been suggested in order to improve the clinical symptoms related to the developments of a skin wound. In this case, we describe a young man with KTS that developed a severe skin wound in the lower right limb unresponsive to the common treatment but responsive to a treatment with oxygen-ozone therapy, pulsed magnetic fields (diamagnetic treatment), and topical fixed association of cocum caprylate, oleic acid, quercetin, and 18-β glycyrrhetinic acid. This is the first case that supports a multistep approach to treat a rare and severe disease, and we hope that other studies can support our data. [ABSTRACT FROM AUTHOR]

Several factors that underlie health inequality have been studied and defined as the social determinants of health (SDHs). The main SDHs are gender, socioeconomic status (SES), and ethnicity. In this study, disparity was analyzed in the context of vascular diseases (VDs) such as Peripheral Artery Disease (PAD), Chronic Venous Disease (CVD), Abdominal Arterial Aneurysm (AAA), and Carotid Stenosis (CS). This article aims to provide a comprehensive overview of the published evidence of the SDHs in VDs. For this purpose, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Published articles using the Scopus and ScienceDirect databases were searched. The criteria for the articles' inclusion/exclusion were decided using a modified PICOTS framework. For the selected articles, the data sheets were organized in such a way to extract all data of potential relevance. Our findings showed that in VDs, gender, SES, and ethnicity are very important, with some specific problems for VDs analyzed. In conclusion, having detected the presence of SDHs that act negatively on VDs, a model based on action items for the SDHs associated with VDs was proposed. [ABSTRACT FROM AUTHOR]

Background: Femoropopliteal bypass occlusions are a significant issue in patients with critical limb ischemia and chronic total occlusion of the native superficial femoral artery, which challenges vascular surgeons and interventional radiologists. Performing a secondary femoropopliteal bypass is still considered the standard of care, although it is associated with a higher complication rate and lower patency rate in comparison with primary bypass. Over the past few years, angioplasty has been commonly used, with the development in endovascular technologies, to treat chronic total occlusions of the native superficial femoral artery, with a good technical success rate and clinical prognosis. The purpose of the study is to assess the outcome of endovascular recanalization of chronic total occlusions of the native superficial femoral artery, in patients unfit for surgery with critical limb ischemia after failed femoropopliteal bypass. Results: A total of 54 patients were treated. 77.8 % of the conduits were PTFE grafts; the remainder were single-segment great saphenous veins. The most common clinical presentation was rest pain. Technical success was achieved in 51 (94.4 %) of 54 limbs. Angiographically, 77.8 % of the lesions were TASC II category D, while 22.2 % were TASC II category C. The average length of the native SFA lesions was 26.8 cm. Clinical success, with improved Rutherford classification staging, followed each case of technical success. The median follow-up value was 5.75 years (IQR, 1.5–7). By Kaplan-Meier survival analysis, primary patency rates were 61 % (± 0.07 SE) at 1 year and 46 % (± 0.07 SE) at 5 years. Secondary patency rates were 93 % (± 0.04 SE) at 1 year and 61 % (± 0.07 SE) at 5 years. Limb salvage rates were 94 % (± 0.03 SE) at 1 year and 88 % (± 0.05 SE) at 5 years. Conclusions: The endovascular recanalization of chronic total occlusions (CTO) of the native superficial femoral artery (SFA) after a failed femoropopliteal bypass is a safe and effective therapeutic option in patients unfit for surgery with critical limb ischemia. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by recurrent chronic abdominal pain and impaired bowel habits, which affects daily activity and work productivity, and is associated with a significant healthcare economic burden as well as an impaired quality of life and psycho-affective profile. Management of patients is a great challenge for physicians; at the present, the therapeutic strategy aimed to treat the different symptoms, and no medical therapy is proven to modify the natural history of the disease. GELSECTAN® (xyloglucan, pea protein and tannins, xylo-oligosaccharides) is a medical device with both protective and prebiotic actions on the intestinal mucosa, able to restore intestinal permeability and to improve gastrointestinal symptoms, controlling diarrhoea, abdominal pain and bloating in adult patients with irritable bowel syndrome. We report and discuss four cases of different patients with irritable bowel syndrome successfully managed with Gelsectan in the real clinical practice. Literature data, as well as these case reports, show that this device is effective and safe in improving symptoms and bowel habits associated to irritable bowel syndrome; its efficacy and safety were confirmed for the long-term use too. Agents with film-forming protective properties, such as Gelsectan, represent a new alternative therapeutic option for the management of patients with irritable bowel syndrome. [ABSTRACT FROM AUTHOR]

Background: Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects. Methods: We examined blood smear of 26 LOPD patients. We evaluated 10 treated and 16 untreated LOPD patients. Among the latter group, 7 patients later initiated ERT and were tested again 6 months after start. Blood smear was also sampled from 82 controls and 19 patients with other muscle glycogenoses (MGSDs). PAS staining was used to evaluate: (1) presence of lymphocytes with glycogen-filled vacuoles, (2) quantification of vacuolated lymphocytes. Results: We found that PAS-positive lymphocytes were significantly higher in LOPD patients than in controls or other MGSDs (p < 0.05 and p < 0.001, respectively). ROC curve for discriminating between untreated LOPD patients and controls yielded an AUC of 1.00 (95%CI 1.00–1.00; p < 0.0001). PAS-positive lymphocyte cutoff level of >10 yielded sensitivity of 100% (95%CI 78–100%), specificity of 100% (95%CI 96–100%), and positive predictive value of 100%. Patients studied before and after ERT showed a dramatic decrease of PAS-positive vacuolated lymphocytes number (p = 0.016). In other MGSDs, PAS-positive lymphocytes were significantly lower that untreated LOPD patients but higher than controls. Conclusions: Our data suggest that the Blood Smear Examination (BSE) for PAS-positive lymphocytes quantification could be used as a simple and sensitive test for a quick screening of suspected Pompe disease. The quantification of vacuolated lymphocytes appears to be also a valuable tool for monitoring the efficacy of treatment in LOPD patients. [ABSTRACT FROM AUTHOR]

Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment. [ABSTRACT FROM AUTHOR]