Symmetric Aromatic Amidoalkylations of Triphenylenes.

Triphenylene derivatives are highly investigated for their electronic, supramolecular and photophysical properties, but the direct modification of the central aromatic core is particularly challenging especially in the internal positions 1, 4, 5, 8, 9, and 12. Herein we present an efficient alkylation method of 2,3,6,7,10,11-hexasubstituted triphenylene derivatives leading to tris-alkylated C3-symmetric derivatives in good yields using N-(hydroxymethyl)carboxamide or N-(alkoxylmethyl)carboxamide alkylating agents.

A ß-Glucosyl Sterol Probe for in†situ Fluorescent Labelling in Neuronal Cells to Investigate Neurodegenerative Diseases.

A ß-glucosyl sterol probe bearing a terminal alkyne moiety for fluorescent tagging enables the investigation of the neuronal and intracellular localization of this class of compounds involved in neurodegenerative diseases. The compound showed localization in the neuronal cells, with marked differences in the uptake and metabolism leading to enhanced persistence with respect to the un-glycosylated sterol analogue. In addition, a different impact was observed towards lysosomes, with the simple sterol probe showing the enlargement of the lysosome structures, while the ß-glucosyl sterol was less capable to alter the morphology of this specific organelle.

Substrate Selectivity Imparted by Self-Assembled Molecular Containers and Catalysts.

Recent trends in catalysis are devoted to mimicking some peculiar features of enzymes like site selectivity, through functional group recognition, and substrate selectivity, through recognition of the entire surface of the substrate. The latter is a specific feature of enzymes that is seldomly present in homogeneous catalysis. Supramolecular catalysis, thanks to the self-assembly of simple subunits, enables the creation of cavities and surfaces whose confinement effects drive the preferential binding of a substrate among others with consequent substrate selectivity. The topic is an emerging field that exploits recognition phenomena to discriminate the reagents based on their size and shape. This review deals this cutting-edge field of research covering examples of supramolecular self-assembled molecular containers and catalysts operating in organic as well as aqueous media, with special emphasis for catalytic systems dealing with direct competitive experiments involving two or more substrates.

Is Micellar Catalysis Green Chemistry?

Many years ago, twelve principles were defined for carrying out chemical reactions and processes from a green chemistry perspective. It is everyone's endeavor to take these points into account as far as possible when developing new processes or improving existing ones. Especially in the field of organic synthesis, a new area of research has thus been established: micellar catalysis. This review article addresses the question of whether micellar catalysis is green chemistry by applying the twelve principles to micellar reaction media. The review shows that many reactions can be transferred from an organic solvent to a micellar medium, but that the surfactant also has a crucial role as a solubilizer. Thus, the reactions can be carried out in a much more environmentally friendly manner and with less risk. Moreover, surfactants are being reformulated in their design, synthesis, and degradation to add extra advantages to micellar catalysis to match all the twelve principles of green chemistry.

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions.

The hexameric resorcin[4]arene capsule as a self-assembled organocatalyst promotes a series of reactions like the carbonyl-ene cyclization of (S)-citronellal preferentially to isopulegol, the water elimination from 1,1-diphenylethanol, the isomerization of α-pinene and ß-pinene preferentially to limonene and minor amounts of camphene. The role of the supramolecular catalyst consists in promoting the protonation of the substrates leading to the formation of cationic intermediates that are stabilized within the cavity with consequent peculiar features in terms of acceleration and product selectivity. In all cases the catalytic activity displayed by the hexameric capsule is remarkable if compared to many other strong Brønsted or Lewis acids.

Focus on Key Issues in Immune Thrombotic Thrombocytopenic Purpura: Italian Experience of Six Centers.

Immune-mediated thrombotic thrombocytopenic purpura is a rare and challenging hematological disease caused by the antibody anti-ADAMTS13. Though the mortality rate has decreased considerably in recent years, fatalities still remain unacceptable. This study aimed at further adding to the existing knowledge of this medical challenge. We enrolled 89 consecutive patients observed in six Italian centers (from 8 August 2013 to 28 May 2021) with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura. Clinical information and blood parameters were collected for all patients. We describe clinical manifestations and laboratory data, possible risk factors and the therapeutic management of first episodes or relapses. A total of 74 first episodes and 19 relapses (median 3 years (interquartile range (IQR): 2-7)) were recorded. Seventy percent of patients enrolled at the first episode showed neurological signs and/or symptoms. All the patients enrolled at the first episode were treated with plasma exchange (median = 12; IQR: 8-19.5) and methylprednisolone (1 mg/kg/day). Rituximab (375 mg/m2 weekly for four weeks) and caplacizumab were given to 15 (20.2%) and 2 patients (2.6%), respectively. We observed an overall mortality of 5.4% in the follow-up (median 60 months; IQR: 36.0-103.5). All fatalities occurred after a diagnostic delay. Present data point to the importance of the early detection of factors mostly associated with poor outcomes. It is likely that use of caplacizumab could improve the prognosis in those patients.

Emergency Medicine Cases in Underwater and Hyperbaric Environments: The Use of in situ Simulation as a Learning Technique.

INTRODUCTION: Hyperbaric chambers and underwater environments are challenging and at risk of serious accidents. Personnel aiming to assist patients and subjects should be appropriately trained, and several courses have been established all over the world. In healthcare, simulation is an effective learning technique. However, there have been few peer-reviewed articles published in the medical literature describing its use in diving and hyperbaric medicine. METHODS: We implemented the curriculum of the Master's degree in hyperbaric and diving medicine held at the University of Padova with emergency medicine seminars created by the faculty and validated by external experts. These seminars integrated traditional lectures and eight in situ simulation scenarios. RESULTS: For the hyperbaric medicine seminar, simulations were carried out inside a real hyperbaric chamber at the ATIP Hyperbaric Treatment Centre, only using air and reproducing compression noise without pressurization to avoid damages to the manikins. The four scenarios consisted of hyperoxic seizures, pneumothorax, hypoglycemia, and sudden cardiac arrest. Furthermore, we added a hands-on session to instruct participants to prepare an intubated patient undergoing hyperbaric oxygen treatment with a checklist and simulating the patient transfer inside and outside the hyperbaric chamber. The diving medicine seminar was held at the Y-40 The Deep Joy pool in Montegrotto Terme (Italy), also involving SCUBA/breath-hold diving (BHD) instructors to rescue subjects from the water. These diving medicine scenarios consisted of neurologic syndrome ("taravana/samba") in BHD, drowning of a breath-hold diver, pulmonary barotrauma in BHD, and decompression illness in a SCUBA diver. CONCLUSION: With this experience, we report the integration of simulation in the curriculum of a teaching course in diving and hyperbaric medicine. Future studies should be performed to investigate learning advantages, concept retention, and satisfaction of participants.

Extremely Old Patients Hospitalized in Internal Medicine: What about Their Anemia?

In western countries, about half of the hospitalized patients are anemic. Generally, these patients are old, often with multiple diseases, and anemia worsens the prognosis, finally increasing the risk of death. We describe a monocentric observational study that evaluates 249 consecutive adult patients (160 women and 89 men) with anemia admitted in the internal medicine department over five months. They represent 71.5% of all patients admitted in the study period. Demographic, historical, and clinical data, laboratory tests, duration of hospitalization, readmission at 30 days, and death were recorded. Patients were stratified by age (75-84=old, >85 years=oldest-old), anemia severity, and etiology of anemia. Anemia was found in 67.5% of old and in 77.2% of oldest-old patients. In 37% of old and 32% of oldest-old patients, anemia was mild, in 43% old and 59% of oldest-old moderate and in 20% old and 9% of oldest-old severe in agreement with WHO criteria. Moderate anemia was significantly more common in the oldest-old (p=0.01). The causes of anemia were iron deficiency in 10.6% of patients, other deficiencies in 2.8%, chronic diseases in 38.2%, hematologic neoplasms in 6.1%, multifactorial in 24.1%, and undetermined in 19.9%. The oldest-old have a higher frequency of multifactorial anemia (p=0.04), while hematologic neoplasms were more common in old patients (p=0.03). Most patients with undetermined anemia had mild/moderate forms. An anti-anemic treatment, mainly blood transfusion, was adopted in 100% of oldest-old patients and in 60% of old (p= 0.04). Anemia (and/or its treatment) was reported in the discharge letter in 19% of old and in 28.2% of oldestold patients. From a general point of view, physicians seem to disregard anemia in the context of more important pathologic conditions. In oldest-old patients, multifactorial anemia seems to be considered only "one more cause of disability." When borderline anemia occurs, even if it can represent a relevant adverse condition in frailty, it is poorly considered.

PAR-4/Ca2+-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. METHODS: In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. RESULTS: We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. CONCLUSIONS: These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.

Admission criteria for a cardiovascular short stay unit: a retrospective analysis on a pilot unit.

Rapid intensive observation (RIO) units have been created to guarantee high standards of care in a sustainable health-care system. Within short stay units (SSUs), which are a subgroup of RIOs, only rapidly manageable patients should be admitted. Physicians are unable to predict the length of stay (LOS) as objective criteria to make such a prediction are missing. A retrospective observational study was carried out to identify the objective criteria for admission within a cardiovascular care-oriented SSU. Over a period of 317 days, 340 patients (age 69.4 ± 14.7 years) were admitted to a pilot SSU within our internal medicine department. The most frequent diagnoses were chest pain (45.9%), syncope (12.9%), and supraventricular arrhythmias (11.2%). The median LOS was 4 days (quartile 1:3; quartile 3:7). Predictors of LOS ≤ 96 h were age < 80, hemoglobin > 115 g/L, estimated glomerular filtration rate > 45 mL/min/1.73 m2, Charlson Comorbidity Index < 3, Barthel Index > 40, diagnosis of chest pain, syncope, supraventricular arrhythmias, or acute heart failure. The HEART (history, ECG, age, risk factors, troponin) score was found to be excellent in risk stratification of patients admitted for chest pain. Blood tests and anamnestic variables can be used to predict the LOS and thus SSU admission. The HEART score may help in the classification of patients with chest pain admitted to an SSU.

Life-Saving Procedures Performed While Wearing CBRNe Personal Protective Equipment: A Mannequin Randomized Trial.

INTRODUCTION: Chemical-biological-radiological-nuclear-explosive (CBRNe) are complex events. Decontamination is mandatory to avoid harm and contain hazardous materials, but can delay care. Therefore, the stabilization of patients in the warm zone seems reasonable, but research is limited. Moreover, subjects involved in biological events are considered infectious even after decontamination and need to be managed while wearing personal protective equipment (PPE), as seen with Ebola and COVID-19 pandemic. With this simulation mannequin trial, we assessed the impact of CBRNe PPE on cardiopulmonary resuscitation and combat casualty care procedures. METHODS: We compared procedures performed by emergency medicine and anesthesiology senior residents, randomized in 2 groups (CBRNe PPE vs. no PPE). Chest compression (CC) depth was defined as the primary outcome. Time to completion was calculated for the following: tourniquet application; tension pneumothorax needle decompression; peripheral venous access (PVA) and intraosseous access positioning; and drug preparation and administration. A questionnaire was delivered to evaluate participants' perception. RESULTS: Thirty-six residents participated. No significant difference between the groups in CC depth (mean difference = 0.26 cm [95% confidence interval = -0.26 to 0.77 cm, P = 0.318]), as well as for CC rate, CC complete release, and time for drugs preparation and administration was detected. The PPE contributed to significantly higher times for tourniquet application, tension pneumothorax decompression, peripheral venous access, and intraosseous access positioning. The residents found simulation relevant to the residencies' core curriculum. CONCLUSIONS: This study suggests that cardiopulmonary resuscitation can be performed while wearing PPE without impacting quality, whereas other tasks requiring higher dexterity can be significantly impaired by PPE.Trial Registration Number: NCT04367454, April 29, 2020 (retrospectively registered).

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

A novel RUNX1 mutation with ANKRD26 dysregulation is related to thrombocytopenia in a sporadic form of myelodysplastic syndrome.

Aging is associated with a higher risk of developing malignant diseases, including myelodysplastic syndromes, clonal disorders characterised by chronic cytopenias (anaemia, neutropenia and thrombocytopenia) and abnormal cellular maturation. Myelodysplastic syndromes arising in older subjects are influenced by combinations of acquired somatic genetic lesions driving evolution from clonal haematopoiesis to myelodysplastic syndromes and from myelodysplastic syndromes to acute leukaemia. A different pattern of mutations has been identified in a small subset of myelodysplastic syndromes arising in young patients with familial syndromes. In particular, dysregulation of ANKRD26, RUNX1 and ETV6 genes plays a role in familial thrombocytopenia with predisposition to myelodysplastic syndromes and acute leukaemia. Whether these genes affect thrombopoiesis in sporadic myelodysplastic syndrome with thrombocytopenia is still undefined. Thirty-one myelodysplastic syndromes subjects and 27 controls subjects were investigated. Genomic DNA was used for mutation screening (ETV6, RUNX1, 5'UTR ANKRD26 genes). Functional studies were performed in the MEG-01-akaryoblastic cell line. We found four novel variants of RUNX1 gene, all in elderly myelodysplastic syndromes subjects with thrombocytopenia. Functional studies of the variant p.Pro103Arg showed no changes in RUNX1 expression, but the variant was associated with deregulated high transcriptional activity of ANKRD26 in MEG-01 cells. RUNX1 variant p.Pro103Arg was also associated with increased viability and reduced apoptosis of MEG-01, as well as impaired platelet production. Our findings are consistent with dysregulation of ANKRD26 in RUNX1 haploinsufficiency. Lack of repression of ANKRD26 expression may contribute to thrombocytopenia of subjects with sporadic myelodysplastic syndromes.

Histology of the spleen in immune thrombocytopenia: clinical-pathological characterization and prognostic implications.

OBJECTIVE: Immune thrombocytopenia (ITP) is an acquired disorder, characterized by immune-mediated platelet destruction. The spleen plays a key pathogenic role in ITP and splenectomy is a valuable second-line therapy for this disease. Little is known on ITP spleen histology and response to splenectomy is unpredictable. This study aims to characterize ITP spleen histology and assess possible predictors of splenectomy outcome. METHODS: A series of 23 ITP spleens were retrospectively assessed for the following histological parameters: density of lymphoid follicles (LFs), marginal zones (MZs), T helper and cytotoxic T cells; presence of reactive germinal centers (GCs); width of perivascular T cell sheaths; and red pulp features. Clinical and histological data were matched with postsplenectomy platelet counts to assess their prognostic relevance. RESULTS: Three histological patterns were documented: a hyperplastic white pulp pattern, a non-activated white pulp pattern (lacking GCs), and a white pulp-depleted pattern. Poor surgical responses were associated with presplenectomy high-dose steroid administration, autoimmune comorbidities and low T follicular helper cell density. The combination of such parameters stratified patients into different splenectomy response groups. The removal of accessory spleens was also associated with better outcome. CONCLUSION: ITP spleens are histologically heterogeneous and clinical-pathological parameters may help predict the splenectomy outcome.

Platelet-Derived Microparticles Bearing PF4 and Anti-GAGS Immunoglobulins in Patients with Sepsis.

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients (p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients' sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.

Testing the vibrational exciton and the local mode models on the instructive cases of dicarvone, dipinocarvone, and dimenthol vibrational circular dichroism spectra.

The vibrational circular dichroism (VCD) spectra of dicarvone (1), dipinocarvone (2), and dimenthol (3) have been recorded in the range 900-3200 cm-1 , encompassing the mid-infrared (mid-IR), the CO stretching, and the CH-stretching regions. For compound 3 also, the fundamental and the first overtone OH stretching regions have been investigated by IR/NIR absorption and VCD. Density functional theory (DFT) calculations allow one to interpret the IR and VCD spectra and to confirm the configuration/conformational studies previously conducted by X-ray diffraction. The most intense VCD signals are associated with the vibrational normal modes involving symmetry-related groups close to the CC bond connecting covalently the two molecular units. The vibrational exciton (VCDEC) model is fruitfully tested on the VCD data of compounds 1 and 2 for the spectroscopic regions at ~1700 cm-1 , and the local mode model is tested on compound 3 at ~3500 and ~6500 cm-1 . For compounds 1 and 2 also, ECD spectra are reported, and the exciton mechanism is tested also there, and connections to the VCDEC model are examined.

Prevalence and Causes of Anemia in Hospitalized Patients: Impact on Diseases Outcome.

Anemia is extremely common in hospitalized patients who are old and often with multiple diseases. We evaluated 435 consecutive patients admitted in the internal medicine department of a hub hospital and 191 (43.9%) of them were anemic. Demographic, historic and clinical data, laboratory tests, duration of hospitalization, re-admission at 30 days and death were recorded. Patients were stratified by age (<65, 65-80, >80 years), anemia severity, and etiology of anemia. The causes of anemia were: iron deficiency in 28 patients, vitamin B12 and folic acid deficiencies in 6, chronic inflammatory diseases in 80, chronic kidney disease in 15, and multifactorial in 62. The severity of the clinical picture at admission was significantly worse (p < 0.001), length of hospitalization was longer (p < 0.001) and inversely correlated to the Hb concentration, re-admissions and deaths were more frequent (p 0.017) in anemic compared to non-anemic patients. A specific treatment for anemia was used in 99 patients (36.6%) (transfusions, erythropoietin, iron, vitamin B12 and/or folic acid). Anemia (and/or its treatment) was red in the discharge letter only 54 patients. Even if anemia is common, in internal medicine departments scarce attention is paid to it, as it is generally considered a "minor" problem, particularly in older patients often affected by multiple pathologies. Our data indicate the need of renewed medical attention to anemia, as it may positively affect the outcome of several concurrent medical conditions and the multidimensional loss of function in older hospitalized patients.

Antithrombotic prophylaxis for surgery-associated venous thromboembolism risk in patients with inherited platelet disorders. The SPATA-DVT Study.

Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery.