Mesoglycan: Clinical Evidences for Use in Vascular Diseases

Vascular glycosaminoglycans (GAG) are essential components of the endothelium and vessel wall and have been shown to be involved in several biologic functions. Mesoglycan, a natural GAG preparation, is a polysaccharide complex rich in sulphur radicals with strong negative electric charge. It is extracted from porcine intestinal mucosa and is composed of heparan sulfate, dermatan sulfate, electrophoretically slow-moving heparin, and variable and minimal quantities of chondroitin sulfate. Data on antithrombotic and profibrinolytic activities of the drug show that mesoglycan, although not indicated in the treatment of acute arterial or venous thrombosis because of the low antithrombotic effect, may be useful in the management of vascular diseases, when combined with antithrombotics in the case of disease of cerebral vasculature, and with antithrombotics and vasodilator drugs in the case of chronic peripheral arterial disease. The protective effect of mesoglycan in patients with venous thrombosis and the absence of side effects, support the use of GAG in patients with chronic venous insufficiency and persistent venous ulcers, in association with compression therapy (zinc bandages, multiple layer bandages, etc.), elastic compression stockings, and local care, and in the prevention of recurrences in patients with previous DVT following the standard course of oral anticoagulation treatment

Treatment of hemophilia: a review of current advances and ongoing issues

Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection.

OBJECTIVES: To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. METHODS: This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. RESULTS: In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251 (27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. CONCLUSIONS: SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. © 2020 International Society of Ultrasound in Obstetrics and Gynecology

Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus

Multimodal and Multiscale Deep Neural Networks for the Early Diagnosis of Alzheimer’s Disease using structural MR and FDG-PET images

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1–3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer’s disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly

Budd-Chiari syndrome in a paroxysmal nocturnal hemoglobinuria patient with previous cerebral venous thrombosis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal stem cell disorder characterized by intravascular hemolytic anemia that results from the clonal expansion of hematopoietic stem cells harboring somatic mutations in an X-linked gene, termed PIG-A (phosphatidylinositol glycan class A). PIG-A mutations block glycosylphosphatidylinositol (GPI) anchor biosynthesis, resulting in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis, leading to the release of free hemoglobin, which contributes to many of the clinical manifestations of PNH including fatigue, pain, esophageal spasm and possibly serious thrombotic episodes [1]. Allogeneic hematopoietic stem cell transplantation is the only curative therapy for PNH. The complement inhibitor eculizumab, a humanized monoclonal antibody against C5, that inhibits terminal complement activation, recently approved in the US, has been shown to reduce hemolysis, decrease the erythrocyte transfusion requirements and the risk for thrombosis, and to improve quality of life of PNH patients [2, 3]. Major morbidity and mortality with PNH are often ascribed to the development of venous thromboembolism (VTE) [1–6], and several patients have recurrent thromboses [7]. VTE in PNH patients occur mostly at unusual sites. Data from a recent review report hepatic vein thrombosis, leading to Budd-Chiari syndrome (BCS), as the most frequent (40.7%) thrombotic complication, accounting for the majority of deaths [8], followed by cerebral vein and sinus thromboses, superior sagittal sinus being the most frequently involved site [8]. Inherited thrombophilia may increase the risk of serious thromboembolic events in PNH patients [9]. In patients experiencing VTE, early anti-thrombotic therapy (heparin, thrombolysis) aimed to limit the extension of thrombosis, or to dissolve formed thrombi, should improve the prognosis of this severe complication. PNH patients suffering from VTE should be treated with anticoagulant drugs indefinitely [1]. Thrombocytopenia often complicates PNH, and this issue must be addressed when an anticoagulation management plan is formulated [1]. Recurrent, life-threatening thrombosis merits consideration for bone marrow transplantation (BMT) [1]. Over the past few years significant advances in other therapeutic approaches, such as transjugular intrahepatic portosystemic shunt (TIPS), have contributed to the improvement of survival in this setting [8]. We report the case of a 29-year-old woman, R. D. The family history was negative for VTE and cardiovascular disease. She was a non-smoker. And had been slightly overweight since childhood. When she was 19 years old, an isolated moderate thrombocytopaenia (50,000/mmc) was detected although in the absence of bleeding. As idiopathic thrombocytopaenia was diagnosed, she was treated with long-term steroids, with an improvement in the platelet count (120,000/mmc). At the age of 27, while on oral contraceptives for 3 months, she experienced a sudden occurrence of headache and visual loss, followed by seizures and coma. A computed tomography (CT scan) showed multiple cerebral venous thromboses. Screenings A. Tufano (&) N. Macarone Palmieri E. Cimino A. M. Cerbone Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy e-mail: [email protected] F. Alfinito Division of Hematology, Federico II University of Naples, Via S. Pansini, 5, 80131 Naples, Italy 123 Intern Emerg Med (2009) 4:75–77 DOI 10.1007/s11739-008-0182-7for congenital (antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A mutation, C677T MTHFR variant) and acquired (Lupus anticoagulant, antiphospholipid antibodies) thrombophilic abnormalities were negative. At that time, according to the available clinical records, she did not receive anticoagulant drugs, and symptoms improved after diuretics and steroid administration. Two years later, when she was 29 years of age, the patient was admitted to our hospital for recurrent abdominal pain, fever and pancytopaenia (WBC 4,000/mmc; Hb 9 g/dl; platelets 61,000/mmc). Steroid treatment had been withdrawn some weeks before the admission. Laboratory testing confirmed anaemia (9.8 g/dl) and a low platelet count (60,000/mmc), and also showed an increased LDH (1605 IU/L) ALP (137 IU/L) and cGT (112 IU/L) levels and reduced haptoglobin. An abdominal CT scan showed hepatic and splenic enlargement with ascites and signs of hepatic outflow obstruction, consistent with a Budd-Chiari syndrome (Fig. 1). Lupus anticoagulant and antiphospholipid antibodies were still negative. Homocysteine levels were normal. Cytofluorimetric investigation of peripheral blood cell immunophenotype showed abnormalities of complement regulatory proteins, consistent with the diagnosis of PNH [10]: 80% of red blood cells were CD59 deficient, 90% of granulocytes lacked CD 68b and 95% of monocytes did not show CD14 on cell membrane. Almost all hemopoesis was clonal. Bone marrow aspirate showed dysplastic features. Because of the thrombocytopenia, and while the patient was under evaluation for BMT, treatment with oral anticoagulants was delayed, and therapy with full-dose enoxaparin (100 IU/Kg bid) was started. Progressive splenic enlargement and bone marrow failure resulted in further reduction of the platelet count over the following three months (30,000/mmc); therefore, heparin dosage was reduced to 100 IU/Kg/d in order to avoid hemorrhagic complications. Six months later she experienced recurrent abdominal pain and ascites, compatible with a recurrence of the Budd-Chiari syndrome, and fatal hepatic failure. Her severe clinical condition hampered surgical or radiologic therapeutic approaches. Another PNH patient with a history of cerebral venous thrombosis and Budd-Chiari syndrome is described in a case-report published in 2005 [11]. The authors present the case of a 26-year-old man with a previous diagnosis of apparently idiopathic cerebral vein thrombosis, who developed hepatic venous thrombosis, and who had laboratory tests suggestive of PNH 9 months later. This patient underwent a TIPS, but experienced 1 month later an episode of stent blockage treated with balloon dilatation and restenting. In conclusion, our case report highlights that PNH should be considered in patients with venous thrombosis at unusual sites, especially if associated with haemocromocytometric abnormalities. Antithrombotic treatment in this setting is mandatory, but a careful risk-to-benefit ratio evaluation should be taken into account. A TIPS procedure may be a useful therapeutic option for PNH patients with Budd-Chiari syndrome, but caution is needed to prevent stent occlusion