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Abstract Despite the global vaccination campaigns, certain patient groups remain highly vulnerable to SARS-CoV-2 and are at high risk for unfavorable COVID-19 outcomes. As previously shown by our group and a more recent report by Chang Su and coworkers, patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT) represent one of such high-risk populations. This is due to the underlying disease-related immunodeficiency, suboptimal response to vaccines, heavy exposure to dexamethasone, and the use of high-dose melphalan prior to the ASCT procedure. Contracting SARS-CoV-2 and developing COVID-19 during the ASCT procedure remain high-risk events for these patients. It is then crucial to maintain and implement all appropriate strategies to prevent COVID-19 breakthroughs in this clinical setting. This might include targeted pre- and post-exposure prophylaxis with monoclonal antibodies, based on the circulation and prevalence of different SARS-CoV-2 variants/subvariants, and the prompt use of antivirals if, despite prophylaxis, MM patients develop COVID-19 during the transplantation procedure. We emphasize the importance of regularly monitoring MM patients for SARS-CoV-2 infection at all stages of the ASCT procedure. This is crucial to promptly implement measures to reduce the risk of unfavorable COVID-19 outcomes during the current post-pandemic phase.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs’ ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs’ efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

Bing–Neel syndrome (BNS) is a rare condition that may occur in patients with Waldenstrom macroglobulinemia (WM) and is caused by lymphoplasmacytic infiltration into the central nervous system. BNS is an extramedullary manifestation of WM which may present with various neurological signs and symptoms that make the diagnosis difficult to achieve. We present a case of BNS in a 60-year-old patient diagnosed 6 years after recovering from Waldenstrom’s macroglobulinemia. We observed the patient for a secondary generalized focal motor seizure. Unenhanced brain CT revealed slight hyperdensity of left parietal subarachnoid spaces. The MRI of the brain and spinal cord showed leptomeningeal enhancement in both parietal lobes. The presence of monoclonal bands (light chain k and IgM) was found in cerebrospinal fluid, leading to the diagnosis of BNS. The patient started treatment with ibrutinib and remains clinically stable during a 1-year follow-up. However, the MRI showed the appearance of a new subcortical left parietal lesion. BNS is an extremely rare presentation of WM that should be recognized and considered early in the presence of unexplained neurological symptoms in patients with a history of WM, even if the patient appears to have recovered.

Meningitis is the infection of the meninges, which are connective tissue membranes covering the brain, and it most commonly affects the leptomeninges. Clinically, meningitis may present with fever, neck stiffness, altered mental status, headache, vomiting, and neurological deficits. Encephalitis is an infection of the brain, which usually presents with fever, altered mental status, neurological deficits, and seizure. Meningitis and encephalitis are serious conditions which could also coexist, with high morbidity and mortality, thus requiring prompt diagnosis and treatment. Imaging plays an important role in the clinical management of these conditions, especially Magnetic Resonance Imaging. It is indicated to exclude mimics and evaluate the presence of complications. The aim of this review is to depict imaging findings of the most common meningitis and encephalitis.

Abstract Background Nivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies. Methods The frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients. Results Circulating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (

O autor, radioterapeuta do S.N.C., foi incumbido por seu Diretor, Dr. Mário Kroeff, de estudar o "radon'', importante agente radioterópico. Após ter conseguido bolsa de estudos por intermédio do "Institute of Interamerican Affairs'' permaneceu nos EE UU. da América durante um ano e dois mêses. Durante essa estada, frequentou o "Memorial Hospital" onde ao lado dos físicos L. Marinelli e G. Failla, familiarizou-se no manejo da aparelhagem, no modo de captação, acondicionamento e dosagem das células de "radon". Na Universidade de Colúmbia, seguiu o curso sôbre "física das irradiações" ministrado pela Dra. E. Quimby. Acompanhou durante três mêses o Serviço de Radioterapia do "Billings Hospital" e do "Hines Hospital'', respectivamente sob a orientação dos Drs. Anna Hamann e Harry Slobodin. Visitou em Chicago o "Tumor Institute'' do Dr. Max Cutler e a fábrica de aparêlhos de Raios X da General Electric. Em Nova lorque frequentou ainda, durante três mêses, o Serviço de Radioterapia do "Presbyterian Hospital'', chefiado pelo Dr. Maurice Lens.

Trabalho apresentado por ocasião da 1ª Jornada Brasileira de Radiologia. Nas três primeiras décadas, que se seguiram à descoberta dos raios X e do radium dezenas de pessoas pagaram com a vida o tributo, devido à super-exposição aqueles tipos de irradiações. Isto porque, não conhecendo bem os perigos a que se expunham, trabalhavam os pioneiros da radioterapia com meios insuficientes de proteção. Hoje em dia, graças aos notáveis trabalhos de Failla, Quimby, Taylor, Evans e Braestrup além de outros, onde são descritos os meios de proteção adequada para os raios X e radium, podem os médicos e técnicos trabalhar durante muito tempo com as irradiações sem sofrer os seus efeitos nocivos.

A presente publicação visa apresentar um caso de Sarcoma de Ewing primitivo de costela, mostrando o resultado obtido pela roentgenterapia. O interesse principal desta observação reside nas seguintes razões: 1) localização das mais raras; 2) eficiência dos Raios X no seu tratamento, pois que além do desaparcimento do tumor, houve regeneração óssea total.

O autor teceu considerações em torno do Tumor de Ewing, discorrendo sôbre sua histogênese. Apresentou uma estatística de 11 casos, sendo que todos tiveram confirmação anatomo-patológica. Foi descrita a triade sintomatológica desta enfermidade que consiste em: dôr, tumor e febre. O aspecto raãioãiagnóstico desses tumores foi estudado, assim como foram apresentadas reproduções de radiografias. As caracteristicas anátomo-patológicas do Sarcoma de Ewing foram apresentadas. Técnicas de tratamento pela radioterapia foram descritas. A dose tumor nos casos pré-operatórios variou entre 1.200 a 1.600 r. Nos casos com finalidade curativa oscilou entre 3.000 a 4.200 r. Nos 10 casos tratados, o resultado terapêutico foi o seguinte: dos 7 tratados pela radioterapia, 2 acham-se vivos e livres de sintomas, sendo que 1 já apresenta sobrevida de 5 anos e 10 mêses, e 0 outro apresenta sobrevida de 10 mêses; os 5 restantes faleceram de metástases generalizadas. Os 3 casos tratados pela cirurgia faleceram, sendo que a maior sobrevida obtida foi de 1 ano e 3 mêses. Pela experiência que tivemos com os nossos casos, achamos que a radioterapia deve constituir sempre a terapêutica ideal para tratamento dos tumores de Ewing. A cirurgia só será indicada nos casos em que o tumor se localize nos membros e em que não se consiga hospitalização para imobilização do doente durante o tratamento pela roentgenterapia.

Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic cancer originating from the malignant transformation of plasmacytoid dendritic cell precursors. This malignancy progresses rapidly, with frequent relapses and a poor overall survival rate, underscoring the urgent need for effective treatments. However, diagnosing and treating BPDCN have historically been challenging due to its rarity and the lack of standardized approaches. The recognition of BPDCN as a distinct disease entity is recent, and standardized treatment protocols are yet to be established. Traditionally, conventional chemotherapy and stem cell transplantation have been the primary methods for treating BPDCN patients. Advances in immunophenotyping and molecular profiling have identified potential therapeutic targets, leading to a shift toward CD123-targeted immunotherapies in both clinical and research settings. Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. However, the therapeutic effectiveness of CD123-targeting treatments needs improvement through innovative approaches and combinations of treatments with other anti-leukemic drugs. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

Os autores designam como linfoma as seguintes afecções: Bryll Symmers (linfoma macrofolicular), doença de Hodgkin, retículo-sarcoma e linfosarcoma. Apresentam classificações para os linfomas e leucemias. Para o diagnóstico, além dos meios semióticos clássicos, são analisados os exames subsidiários: anatomia patológica, exames hematológicos e exame radiológico. De todos os elementos diagnósticos apresentados, são estudados com mais detalhe, a eletroforese e o mielograma, por constituirem assunto de grande atualidade. Os vários achados de mielogramas para os linfomas e leucemias, são descritos. O traçado eletroforético é estudado com detalhe. Neste trabalho são apresentados dois tipos de aparelhos: a) Kern LK 30, tipo Tiselius que determinado a eletroforese em mínimas quantidades de sôro; b) tipo Wieland Fischer, cuja migração faz-se no papel de filtro. Apresentam ainda resultados eletroforéticos nos diversos tipos de linfomas e leucemias. Os autores apresentam quadro próprio, no qual dividem o tratamento em 4 grupos distintos, que são: — Tratamento pelas irradiações. Il Tratamento quimioterapico. III — Tratamento cirúrgico. IV — Tratamento auxiliar. Ao relatarem com minúcia o tratamento pelas irradiações, além de tecerem considerações sôbre a terapêutica com os isótopos radioativos, analisam as várias técnicas roentgenterápicas, assim como, suas indicações no tratamento destas afecções. O tratamento quimioterápico é dividido em 4 grupos: substâncias radiomiméticas, substâncias citotóxicas, substâncias anti-metabólicas e hormônios. Neste capítulo são analisadas e relatadas as doses das principais drogas usadas no combate a estas enfermidades. Como tratamento auxiliar, os autores, apresentam considerações e emitem suas experiências sôbre: exo sanguíneo transfusão, transfusão e antibióticos. O prognóstico é apresentado com detalhe. Os autores citam casos de leucemia granulocítica crônica, linfosarcoma, retículo-sarcoma e doença de Hodgkin com sobrevida além de 5 anos após tratamento pelos Raios X e pela quimioterapia. O trabalho é ilustrado com farta documentação, constando de fotografias de doentes, fotografias de estruturas microscópicas, quadros esquemáticos e apresentação de radiografias.

Relatório apresentado em Painel, sobre o Tema Oficial, "Tratamento do Câncer do Faringe", por ocasião do VI Congresso Internacional de Câncer, realizado em São Paulo, em 29 de julho de 1954.

Os AA. demonstraram o grande valor que a cintilografia cerebral desempenha no diagnóstico dos tumores primitivos e metastáticos. Em casuística de 109 exames realizados encontraram 36 casos de neoplasias malignas. O trabalho foi ilustrado com diversas figuras.

Abstract Background To date, there is no information on the safety and efficacy of the novel anti-sarbecoviruses monoclonal antibody sotrovimab administered, as a post-exposure prophylactic measure, during the aplastic phase of autologous stem cell transplantation (ASCT). Methods We describe the outcomes of a Multiple Myeloma (MM) patient, who was threateningly exposed to the Omicron (B.1.1.529) SARS-CoV-2 variant, two days after having received a myeloablative regimen of high-dose melphalan. The patient fulfilled all CDC criteria for prolonged close contacts with an index patient who tested positive for a molecular nasopharyngeal swab (Omicron; B.1.1.529) soon after admission to the ward. Given the high risks of morbidity and mortality in the case of COVID-19 developing during the aplastic phase of transplantation, we adopted a post-exposure prophylaxis intervention based on intravenous (i.v.) sotrovimab. Results Sotrovimab (500 mg i.v.) was administered at day + 2 from stem cells reinfusion, i.e. 4 days after myeloablative chemotherapy, and at day + 5 from the last close contact with the Omicron-positive index case. The patient was fully protected from SARS-CoV-2 infection throughout his clinical course and remained molecularly negative at the day + 30 from the transplant. We compared times to engraftment and transplant-related toxicities of the sotrovimab-treated patient with the last 15 MM patients transplanted at our Centre, evidencing no unexpected safety signals, infusion-related reactions, or alarming effects on engraftment kinetics. Conclusions We have shown here for the first time that administration of sotrovimab during the pre-engraftment phase of ASCT is effective, safe, and not associated with delays in hemopoietic recovery. As compared to MM patients who received the same myeloablative conditioning regimen, the patient given sotrovimab during the aplastic phase did not show any significant differences in engraftment kinetics and toxicity outcomes. Post-exposure prophylaxis with sotrovimab may represent a valuable approach in the stem cell transplantation setting for patients with high-risk exposure to a confirmed COVID-19 case sustained by highly infectious SARS-CoV-2 variants escaping the vaccine-derived immunity due to antigenic shifts in the spike proteins.

Acinetobacter baumannii (Ab) is an opportunistic Gram-negative pathogen intrinsically resistant to many antimicrobials. The aim of this retrospective study was to describe the imaging features on chest X-ray (CXR) and computed tomography (CT) scans in hospitalized patients with multidrug-resistant (MDR) Ab pneumonia. CXR and CT findings were graded on a three-point scale: 1 represents normal attenuation, 2 represents ground-glass attenuation, and 3 represents consolidation. For each lung zone, with a total of six lung zones in each patient, the extent of disease was graded using a five-point scale: 0, no involvement; 1, involving 25% of the zone; 2, 25–50%; 3, 50–75%; and 4, involving >75% of the zone. Points from all zones were added for a final total cumulative score ranging from 0 to 72. Among 94 patients who tested positive for MDR Ab and underwent CXR (males 52.9%, females 47.1%; mean age 64.2 years; range 1–90 years), 68 patients underwent both CXR and chest CT examinations. The percentage of patients with a positive CT score was significantly higher than that obtained on CXR (67.65% > 35.94%, p-value = 0.00258). CT score (21.88 ± 15.77) was significantly (p-value = 0.0014) higher than CXR score (15.06 ± 18.29). CXR and CT revealed prevalent bilateral abnormal findings mainly located in the inferior and middle zones of the lungs. They primarily consisted of peripheral ground-glass opacities and consolidations which predominated on CXR and CT, respectively.

Introduction:. Autonomic nervous system activity in cirrhotic portal hypertension is linked to hyperdynamic circulation. Heart rate variability (HRV) is a validated noninvasive method to assess the sympathovagal balance. To investigate the correlation between HRV parameters and degree of portal hypertension, we studied a cohort of patients with cirrhosis accounting for etiology and treatments. Patients and Methods:. In this cross-sectional, observational cohort study, 157 outpatients of both sex with nonalcoholic cirrhosis were assessed by upper gastrointestinal endoscopy to search for esophagogastric varices. Twenty-four-hour electrocardiogram Holter monitoring with 3 HRV parameters measurement [SD of the NN intervals, root mean square successive difference of NN intervals, and SD of the averages of NN intervals (SDANN)] according to time-domain analysis were performed in all patients. Sixteen patients with large esophagogastric varices underwent measurements of the HVPG and assessment of HRV parameters at baseline and after 45 days on carvedilol. Results:. The liver dysfunction, expressed by Child-Pugh class or MELD score, was directly related to root mean square successive difference of NN intervals and inversely related to SDANN. Presence of ascites was inversely related to SDANN and to SD of the NN intervals. Treatment with carvedilol had an inverse relation with SDANN. Presence and size of esophagogastric varices had an inverse relation to SDANN and SD of the NN intervals. Upon multivariate analysis the associations between SDANN and Child-Pugh class, size of varices and ascites were confirmed. In the subgroup of 16 patients undergoing HVPG measurement, pressure gradient was unrelated to heart rate and HRV parameters. Conclusions:. Time-domain HRV parameters in patients with cirrhosis, confirm the autonomic nervous system alteration, and their correlation to the degree of portal hypertension suggesting a role of the ANS in hepatic decompensation.

Non-traumatic thoracic aorta emergencies are associated with significant morbidity and mortality. Diseases of the intimomedial layers (aortic dissection and variants) have been grouped under the common term of acute aortic syndrome because they are life-threatening conditions clinically indistinguishable on presentation. Patients with aortic dissection may present with a wide variety of symptoms secondary to the pattern of dissection and end organ malperfusion. Other conditions may be seen in patients with acute symptoms, including ruptured and unstable thoracic aortic aneurysm, iatrogenic or infective pseudoaneurysms, aortic fistula, acute aortic thrombus/occlusive disease, and vasculitis. Imaging plays a pivotal role in the patient’s management and care. In the emergency room, chest X-ray is the initial imaging test offering a screening evaluation for alternative common differential diagnoses and a preliminary assessment of the mediastinal dimensions. State-of-the-art multidetector computed tomography angiography (CTA) provides a widely available, rapid, replicable, noninvasive diagnostic imaging with sensitivity approaching 100%. It is an impressive tool in decision-making process with a deep impact on treatment including endovascular or open surgical or conservative treatment. Radiologists must be familiar with the spectrum of these entities to help triage patients appropriately and efficiently. Understanding the imaging findings and proper measurement techniques allow the radiologist to suggest the most appropriate next management step.

Background: The clinical presentation of acute myocarditis (AM) is widely variable, ranging from a subclinical disease to an infarct-like syndrome. Cardiac magnetic resonance (CMR) has become the reference non-invasive diagnostic tool for suspected AM, allowing the identification of the various hallmarks of myocardial inflammation (edema, fibrosis, and hyperemia). The aim of the study was to investigate any differences in morphological, functional, and tissue characterization CMR parameters between infarct-like AM in patients with unobstructed coronary arteries and non-infarct-like AM, diagnosed according to the original Lake-Louise Criteria (LLC); Methods: We retrospectively selected 39 patients diagnosed with AM according to LLC, divided into 2 groups according to the clinical presentation: infarct-like in group 1 patients and non-infarct-like in group 2 patients. CMR morphologic, functional, and tissue characterization parameters were analyzed and compared. Results: In group 1, CMR tissue characterization parameters were mainly altereda in septal location with mesocardial myocardial involvement; in group 2, CMR tissue characterization parameters were mainly altered in a lateral location with subepicardial myocardial involvement mainly at the mid-cavity. No significant differences in morphological or functional parameters were observed between the two study groups. Conclusions: Our results showed differences in the localization and distribution of myocardial tissue damage assessed by CMR among forms of AM accompanied by an infarct-like clinical presentation compared with non-infarct-like presentations of AM. The mechanisms underlying the different preferential sites of damage observed in our study are not known, and we do not exclude the possibility of their prognostic implications.

Abstract Background Overweight and obese patients with solid tumors receiving anti-programmed cell death-1 (PD-1)/PD-ligand-1(PD-L1) immune checkpoint inhibitors exhibit improved survival and higher risk of immune-related adverse events (irAEs) than those with a normal body mass index (BMI). In classic Hodgkin lymphoma (cHL), the impact of BMI on survival and immune-related toxicity is unknown. We evaluated for the first time associations of BMI with survival and irAEs in patients with relapsed/refractory (RR)-cHL undergoing PD-1 blockade. Methods Data from a multicenter study on 133 patients treated with the anti-PD1 antibody nivolumab (July 2015–December 2016) were retrieved from a prospective database. Progression-free (PFS), overall survival (OS), incidence and severity of irAEs according to BMI categories were estimated by Kaplan–Meier method, landmark-analyses and Cox regressions. Results Patients, mostly males (63%, n = 84) with a median age of 35 years (range, 15–82), advanced stage (75%), B symptoms (63%), bulky disease (24%), a median of 4 previous treatments (range, 1–9), received a median of 18 nivolumab doses (range, 1–57). No statistically significant differences across BMI subgroups emerged as to PFS, with 1-year rates of 67.1% for both normal weight (n = 66; 49.6%) and overweight (n = 31; 23.3%) patients. Underweight (n = 12; 9%) and obese (n = 24; 18%) patients had a 1-year PFS of 54.5% and 49%, respectively. In survival analyses, BMI either as a continuous (P = 0.5) or categorical (P for trend = 0.63) variable failed to associate with PFS. Response rates and time-to-response did not cluster in any BMI subset. No BMI-related differences in OS emerged across normal, overweight and obese patients but underweight patients had the worst survival. Occurrence of irAEs of whatever severity did not statistically associate with BMI. Conclusions In patients with RR-cHL receiving nivolumab, no statistically significant differences emerged in response rates, PFS and OS across BMI categories of normal weight, overweight and obese. Overweight/obese patients did not display an increased risk of irAEs. The exquisite sensitivity to anti-PD-1 antibodies, the unique cytokine milieu and effector pathways triggered by nivolumab in cHL, may represent biologic ‘equalizers’ counteracting the immunoregulatory effects of adiposity. Differently from solid tumors, BMI is not associated with treatment efficacy and immune-related toxicity and does not represent a predictive tool for PD-1-targeted immunotherapies in cHL.

Abstract Aims We sought to compare the effects of furosemide + hypertonic saline solution (HSS) treatment in patients with acute decompensated heart failure in comparison with furosemide alone and the response in a compensated state after an acute saline load with regard to serum levels of heart failure biomarkers. Methods and results We enrolled 141 patients with acute decompensated heart failure with reduced ejection fraction admitted to our Internal Medicine ward from March 2017 to November 2019. A total of 73 patients were randomized to treatment with i.v. high‐dose furosemide plus HSS, whereas 68 patients were randomized to i.v. high‐dose furosemide alone. Patients treated with furosemide plus HSS compared with controls treated with furosemide alone showed a comparable degree of reduction in the serum levels of interleukin (IL)‐6, soluble suppression of tumorigenicity 2 (sST2), and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in the ‘between‐group’ analysis. Nevertheless, patients treated with high‐dose furosemide + HSS showed significantly higher absolute delta values of IL‐6 (2.3 ± 1.2 vs. 1.7 ± 0.9, P

Abstract Background Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age. Aims The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices. Methods We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection. Results 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance. Discussion Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot.

We run logit models to explain the variability of Pinus radiata structural lumber in 71 second and third unpruned logs. The response variable was the proportion of lumber with a static modulus of elasticity greater or equal than 8 GPa, pMSG8+, and the explanatory variables were log volume, branch index, largest branch, log internode index, wood basic density, and acoustic velocity. The average pMSG8+ volume was 44,30 % and 36,18 % in the second and third log respectively. Ten models were selected based on meeting statistical assumptions, their goodness of fit, and the statistical significance of their parameters. The best models (R2 - adj. > 0,75) included acoustic velocity (AV) as explanatory variable, which explained 56,25 % of the variability of pMSG8+. Models without AV presented goodness of fit ranging from 0,60 to 0,75 (R2 - adj.), and variables with the highest weight to explain the variability of pMSG8+ were volume, followed by wood basic density, branch index, and largest branch. It is possible to model pMSG8+ from log variables even when acoustic velocity is not available; however, this requires wood basic density models calibrated for the Pinus radiata growing zone.

Abstract Background We report an unusual case of infective colitis by Yersinia enterocolitica complicated by microliver abscesses mimicking multiple liver metastases in a 79 yr old female without any risk factors for bacteriaemia by this pathogen. Case presentation The patient was admitted to the Internal Medicine with Stroke Care ward of University Policlinico “P. Giaccone” in Palermo because of the appearance of diarrhoea. After the antimicrobial treatment for infective colitis, the clinicians observed a persistently increased white blood cells (WBC) count and multiple hepatic lesions; after having excluded any neoplastic disease and inflammatory bowel disease (IBD), blood cultures positive for Y. enterocolitica allowed to establish the final diagnosis was infective micro liver abscesses consequent to infective colitis due to Y. enterocolitica, which were successfully treated with cefixime and doxycycline. Conclusions This case report should make clinicians reflect on how complex the differential diagnosis between microliver abscesses and metastasis could be and the possibility of bacteriaemia by Y. enterocolitica even without iron overload conditions.

Abstract Patients with non-hodgkin lymphomas (NHL) represent a population of special interest during the current Coronavirus disease-19 (COVID-19) pandemics. NHLs are associated with disease- and treatment-related immunodeficiencies which may generate unusual COVID-19 dynamics and pose unique management challenges. We report the unusual clinical course of COVID-19 in a patient with mantle cell lymphoma (MCL) exposed to nine doses of Rituximab shortly before infection with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). He had a prolonged asymptomatic phase, with negative molecular and antibody testing for SARS-CoV-2, followed by a rapidly progressive evolution to severe COVID-19. Despite detection of viral RNA overlapped with first symptoms occurrence, anti-SARS-CoV-2 antibodies displayed an asynchronous pattern, with IgG first appearing 2 days after RNA positivity and IgM never being detected throughout the entire clinical course. While disease-associated immune derangements and/or previous treatments involving anti-CD20 antibodies might have contributed to COVID-19 dynamics in our patient, data suggests that antibody testings, without concurrent molecular assessment for SARS-CoV-2, may turn inadequate for monitoring of MCL patients, and in general NHL patients heavily exposed to anti-CD20 antibodies, during the current pandemics. We suggest that repeated molecular testing of nasopharyngeal swab should be implemented in these subjects despite a negative serology and absence of symptoms of SARS-CoV-2 infection. For the same reasons, a customized strategy needs to be developed for patients exposed to anti-CD20 antibodies, based on different features and mechanism of action of available SARS-CoV-2 vaccines and novel vaccinomics developments.

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

Abstract Background Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage. Aims We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes. Methods Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose­ lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels. Results At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy. Conclusions Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.

Ischemic stroke occurs under a variety of clinical conditions and has different pathogeneses, resulting in necrosis of brain parenchyma. Stroke pathogenesis is characterized by neuroinflammation and endothelial dysfunction. Some of the main processes triggered in the early stages of ischemic damage are the rapid activation of resident inflammatory cells (microglia, astrocytes and endothelial cells), inflammatory cytokines, and translocation of intercellular nuclear factors. Inflammation in stroke includes all the processes mentioned above, and it consists of either protective or detrimental effects concerning the “polarization” of these processes. This polarization comes out from the interaction of all the molecular pathways that regulate genome expression: the epigenetic factors. In recent years, new regulation mechanisms have been cleared, and these include non-coding RNAs, adenosine receptors, and the activity of mesenchymal stem/stromal cells and microglia. We reviewed how long non-coding RNA and microRNA have emerged as an essential mediator of some neurological diseases. We also clarified that their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. To date, we do not have adequate tools to control pathophysiological processes associated with stroke. Our goal is to review the role of non-coding RNAs and innate immune cells (such as microglia and mesenchymal stem/stromal cells) and the possible therapeutic effects of their modulation in patients with acute ischemic stroke. A better understanding of the mechanisms that influence the “polarization” of the inflammatory response after the acute event seems to be the way to change the natural history of the disease.

Abstract Background PD-1 blocking agents, such as nivolumab, have demonstrated clear anti-tumor effects and clinical benefits in a subset of patients with advanced malignancies. Nonetheless, more efforts are needed to identify reliable biomarkers for outcome, to correctly select patients who will benefit from anti-PD-1 treatment. The aim of this study was to investigate the role of peripheral CD8+T cells expressing CD73, involved in the generation of the immune suppressive molecule adenosine, in predicting outcome after nivolumab treatment in advanced melanoma patients. Methods PBMCs from 100 melanoma patients treated with nivolumab were collected at National Cancer Institute “G. Pascale” of Naples. Frequencies of CD8+ lymphocytes phenotypes were assessed by flow cytometry at baseline before nivolumab treatment, along with clinical characteristics and blood count parameters. Healthy controls (n = 20) were also analysed. Percentages of baseline T cells expressing PD-1 and CD73 were correlated with outcome after nivolumab treatment. Results Melanoma patients presented a lower frequency of total circulating CD8+ lymphocytes than control subjects (p = 0.008). Patients with low baseline percentage of circulating CD8+PD-1+CD73+ lymphocytes (

(1) Background: Consolidation therapy is an emerging strategy for patients with relapsed/refractory (RR) Hodgkin Lymphoma (HL) at high risk of failing salvage autologous stem cell transplantation (ASCT). (2) Objectives: To assess the safety and effectiveness of PD1-blockade consolidation for these high-risk patients. (3) Design: Multi-center retrospective analysis. (4) Methods: We identified 26 patients given anti-PD1 consolidation, from June 2016 to May 2020. (5) Results: Patients displayed the following risk factors: refractory disease (69%), relapse < 12 months from upfront therapy (15%), ≥2 lines of salvage therapy (73%), extranodal disease (65%). Nineteen patients (73%) had ≥3 of these factors. In addition, 16 patients (61%) also displayed PET-positive (Deauville ≥ 4) disease before ASCT. Treatment-related adverse events (TRAEs), never graded > 3, occurred in 12 patients (46.15%) and mainly included skin rashes (41.7%), transaminitis (33.3%), and thyroid hypofunction (25%). Patients completed a median of 13 courses (range 6–30). At a median follow-up of 25.8 months post-ASCT, the median progression-free (PFS) was 42.6 months, with a 2-year PFS and overall survival rates of 79% and 87%, respectively. (6) Conclusions: Post-ASCT consolidation with anti-PD1 is feasible and effective. Further studies are warranted to define the optimal treatment length and patients’ subsets more likely to benefit from this approach.

The “Blood pressure levels, clinical features and markers of subclinical cardiovascular Damage of Asthma patients” (BADA) study is aimed at defining the cardiovascular risk profile and the markers of subclinical and clinical vascular and cardiac damage in asthmatic patients. Very few studies have assessed asthmatic patients without concomitant heart disease through a transthoracic echocardiogram. The goal of the present study is to investigate the prevalence of morphology and/or function changes in the cardiac chambers of a sample of 86 patients with chronic asthma, referred to the dedicated outpatient unit of the Division of Respiratory Diseases of the AOUP “P. Giaccone” of the University of Palermo, and the results obtained were compared with those of a control group without respiratory or cardiovascular diseases. Patients with asthma showed a marked and widespread involvement of the four cardiac chambers compared with the controls: enlargement of the two atria, greater left ventricular remodeling with interventricular septal thickening, increased indexed left ventricular mass with a significantly greater percentage of patients with overt left ventricular hypertrophy, worse left ventricular diastolic function proven by the significant difference in the E/A ratio, and worse right ventricular systolic function with global right ventricular dysfunction estimated by the Myocardial Performance Index (Tei Index). Multivariate regression analysis, after adjustment for essential hypertension, hypertension severity, diabetes, Body Mass Index, and creatinine clearance, seems to indicate that the indexed left ventricular mass, right atrial volume, and right ventricular Tei index (but not left ventricular hypertrophy) correlate significantly with asthma, severe asthma, and FEV1 (and to a lesser extent with asthma duration). No correlation is apparent between inhaled therapy (ICS, SABA) and myocardial involvement. These results seem to confirm that a more in-depth cardiovascular evaluation in patients with chronic respiratory disease allows the identification of unrecognized cardiovascular involvement. A transthoracic echocardiogram performed in asthmatic patients without clinically overt signs or symptoms of cardiovascular impairment has identified some features indicative of an early subclinical cardiac impairment not found in the control group. These findings, considering also the higher frequency of hypertension in the asthma group, deserve further validation in the future.

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.35– 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15–1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0–2 and 3–5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.

Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study.

Medical imaging is required for a complete clinical evaluation to identify lung involvement or pulmonary embolism during SARS-CoV-2 infection or pulmonary and cardiovascular sequelae. Contrast media (CM) have undoubtedly been useful in clinical practice due to their ability to improve medical imaging in COVID-19 patients. Considering their important use, especially in hospitalized COVID-19 patients, and that increased use of a medical tool could also be associated with its deeper knowledge, we chose to explore if new information emerged regarding CM safety profiles. We analyzed all Individual Case Safety Reports (ICSRs) validated by Campania Pharmacovigilance Regional Centre from 1 January 2018 to 31 December 2021 and reported a CM (ATC code V08) as a suspected drug. We compared CM-related reporting between 2 years before (period 1) and 2 years during (period 2) the COVID-19 pandemic. From our analysis, it emerged that, during the COVID-19 pandemic, CM-related ADR reporting decreased, but a significant increase in reporting of serious cases emerged. Serious ADRs were mainly related to iodinated CM (V08A ATC) compared to magnetic resonance imaging CM (V08C ATC). Cutaneous and respiratory disorders were the most frequently reported in both periods. No new or unknown ADRs were reported in the overall study period.

Abstract Introduction In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Aims To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles. Methods Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci. Results Between November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1_A interactions. Conclusion Our findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of “proinflammatory” genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke.

Few data are available regarding the effectiveness of anti-SARS-CoV-2 vaccine in immunocompromised patients. Vaccination may have a suboptimal efficacy in this population, in particular if patients are exposed to anti-B-cell therapy. We report the virological and clinical characteristics of a patient with follicle center lymphoma under bimonthly maintenance therapy with obinutuzumab, an anti-CD20 monoclonal antibody. Despite three doses of BNT162b2 vaccine, the patient was infected by the SARS-CoV-2 Omicron variant. After an initial period of clinical and molecular remission due to early therapy with sotrovimab, the patient experienced a fatal relapse sustained by the same viral strain.

Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point of view of cardio- and cerebrovascular risk, two complementary diseases. Beyond shared aspects such as inflammation and oxidative stress, there are multiple molecular mechanisms by which they feed off each other: chronic hyperglycemia and advanced glycosylation end-products (AGE) promote ‘accelerated atherosclerosis’ through the induction of endothelial damage and cellular dysfunction. These diseases impact the vascular system and, therefore, the risk of developing cardio- and cerebrovascular events is now evident, but the observation of this significant correlation has its roots in past decades. Cerebrovascular complications make diabetic patients 2–6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke, they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization, and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.

There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.

Background: Our aim was to assess the safety and efficacy of transcatheter embolization in the treatment of post-partum bleedings. Methods: In a single institution, the outcome of 15 patients who underwent transarterial embolization (TAE) for post-partum hemorrhages (PPH) were retrospectively reviewed. Eleven patients presented with hemodynamic instability requiring blood transfusion (73%) and four patients were hemodynamically stable (27%). Arterial embolization was performed with gelatin sponge, particles, and coils. Results: Mean follow-up time was 21.2 months (range 12–48 months). Technical success rate was 100%. The overall clinical success rate was 100%. No major complications that required intensive care treatment were registered during or after the procedures. No patient required emergency surgery and subsequent hysterectomy. During follow-up, four patients became pregnant after transcatheter arterial embolization and delivered full-term, healthy infants. Conclusions: TAE is a safe method that allows for the avoidance of surgery and hysterectomy for uncontrollable PPH; a future normal pregnancy after embolization may be hypothesized.

Abstract Background No study evaluated vascular health markers in subjects with non-alcoholic fatty liver disease (NAFLD) through a combined analysis of reactive hyperemia peripheral arterial tonometry (RH-PAT) and arterial stiffness indexes. Aim of the study We aimed to assess whether NAFLD and its histological severity are associated with impairment of arterial stiffness and RH-PAT indexes in a mixed cohort of patients with biopsy-proven NAFLD. Materials and methods The Kleiner classification was used to grade NAFLD grade. Pulse wave velocity (PWV) and augmentation index (Aix) were used as markers of arterial stiffness, whereas endothelial function was assessed using reactive hyperemia index (RHI). The mini-mental state examination (MMSE) was administered to test cognitive performance. Results 80 consecutive patients with biopsy-proven NAFLD and 83 controls without fatty liver disease. NAFLD subjects showed significantly lower mean RHI, higher mean arterial stiffness indexes and lower mean MMSE score. Multivariable analysis after correction for BMI, dyslipidaemia, hypertension, sex, diabetes, age and cardiovascular disease showed that BMI, diastolic blood pressure and RHI are significantly associated to NAFLD. Simple linear regression analysis showed among non-alcoholic steatohepatitis (NASH) subjects a significant negative relationship between ballooning grade and MMSE and a significant positive association between Kleiner steatosis grade and augmentation index. Conclusions Future research will be addressed to evaluate the relationship between inflammatory markers and arterial stiffness and endothelial function indexes in NAFLD subjects. These study will evaluate association between cardiovascular event incidence and arterial stiffness, endothelial and cognitive markers, and they will address the beneficial effects of cardiovascular drugs such as statins and ACE inhibitors on these surrogate markers in NAFLD subjects.

Objective: Several epidemiological studies suggest that the preservation of the physiological circadian rhythm of blood pressure or its disruption affects the extent of the organ damage developed by the patient. If we classify the circadian rhythm of blood pressure into four nocturnal profiles, significant differences emerge in terms of organ damage burden and prognosis: reverse dippers have the worst prognosis while dippers and mild dippers fall into an intermediate risk range. The risk profile of extreme dippers is still debated, and the available data are very conflicting and inconclusive. Starting from this gap of knowledge, we aimed to evaluate, retrospectively, in a cohort of hypertensive subjects, the degree of cardiac involvement in relation to the different nocturnal blood pressure profiles. Methods: We retrospectively evaluated 900 patients with essential hypertension, of whom 510 met our study criteria. We graded the 510 patients in relation to the percentage of reduction in mean systolic blood pressure (SBP) at night-time compared with day-time, considering this as a continuous variable, and then compared the extreme quintiles with each other and with the middle quintile (considered as reference). Results: Patients with less (or no) reduction in nocturnal SBP (reverse dipper) showed a higher level of organ damage and comorbidities. With regard to echocardiographic indexes, patients with maximum nocturnal pressure reduction (extreme dipper) showed a lower level of remodeling and/or impairment of E/e’ ratio, Right Atrium Area, Basal Right Ventricular Diameter, Inferior Vena Cava Average Diameter, and Tricuspidal Anular Plane Systolic Excursion compared also with hypertensive patients with a physiological nocturnal pressure reduction, even after correction for the main confounders. Conclusions: These data suggest that extreme dippers may constitute the subgroup of hypertensive patients with the lowest 24-h pressure load and, therefore, less cardiac remodeling.

Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.

Several studies link cardiovascular diseases (CVD) with unhealthy lifestyles (unhealthy dietary habits, alcohol consumption, smoking, and low levels of physical activity). Therefore, the strong need for CVD prevention may be pursued through an improved control of CVD risk factors (impaired lipid and glycemic profiles, high blood pressure, and obesity), which is achievable through an overall intervention aimed to favor a healthy lifestyle. Focusing on diet, different recommendations emphasize the need to increase or avoid consumption of entire classes of food, with only partly known and only partly foreseeable consequences on the overall level of health. In recent years, the ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome, and although the beneficial effects on weight loss and glucose metabolism seems to be well established, the effects of a prolonged KD on the ability to perform different types of exercise and the influence of KD on blood pressure (BP) levels, both in normotensives and in hypertensives, are not so well understood. The objective of this review is to analyze, on the basis of current evidence, the relationship between KD, regular physical activity, and BP.

Abstract Previous reports have investigated the impact of age on D-Dimer testing in elderly individuals with suspected deep vein thrombosis (DVT), but data on the age-related diagnostic value of D-dimer in a sample covering a broad age range are limited. The present study determined age-specifically the diagnostic accuracy of D-dimer and compared it to C-reactive protein (CRP), a marker of inflammation, in 500 patients with suspected DVT from the VTEval project (NCT02156401). Sensitivity of D-dimer was lower in patients 0.05). In conclusion, these data outline a clinically-relevant limitation of D-dimer testing among younger patients with suspected DVT indicating a necessity for age-adapted cut-off values. Further research is required to decrypt the role of inflammation in the pathophysiology and diagnosis of venous thrombosis.

The number of everyday interconnected devices continues to increase and constitute the Internet of Things (IoT). Things are small computers equipped with sensors and wireless communications capabilities that are driven by energy constraints, since they use batteries and may be required to operate over long periods of time. The majority of these devices perform data collection. The collected data is stored on-line using web-services that, sometimes, operate without any special considerations regarding security and privacy. The current work proposes a modified hash-chain authentication mechanism that, with the help of a smartphone, can authenticate each interaction of the devices with a REST web-service using One Time Passwords (OTP) while using open wireless networks. Moreover, the proposed authentication mechanism adheres to the stateless, HTTP-like behavior expected of REST web-services, even allowing the caching of server authentication replies within a predefined time window. No other known web-service authentication mechanism operates in such manner.

The improved knowledge of pathogenetic mechanisms underlying lymphomagenesis and the discovery of the critical role of tumor microenvironments have enabled the design of new drugs against cell targets and pathways. The Food and Drug Administration (FDA) has approved several monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) for targeted therapy in hematology. This review focuses on the efficacy results of the currently available targeted agents and recaps the main ongoing trials in the setting of mature B-Cell non-Hodgkin lymphomas. The objective is to summarize the different classes of novel agents approved for mature B-cell lymphomas, to describe in synoptic tables the results they achieved and, finally, to draw future scenarios as we glimpse through the ongoing clinical trials. Characteristics and therapeutic efficacy are summarized for the currently approved mAbs [i.e., anti-Cluster of differentiation (CD) mAbs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and bispecific antibodies] as well as for SMIs i.e., inhibitors of B-cell receptor signaling, proteasome, mTOR BCL-2 HDAC pathways. The biological disease profiling of B-cell lymphoma subtypes may foster the discovery of innovative drug strategies for improving survival outcome in lymphoid neoplasms, as well as the trade-offs between efficacy and toxicity. The hope for clinical advantages should carefully be coupled with mindful awareness of the potential pitfalls and the occurrence of uneven, sometimes severe, toxicities.

Alzheimer's disease (AD) is the most frequent age-associated dementia with no treatments that can prevent or slow its progression. Since age is by far the major risk factor for AD, there is a strong rationale for an alternative approach to drug discovery based upon the biology of aging. Phenotypic screening assays that reflect multiple, age-associated neurotoxicity pathways rather than single molecular targets can identify compounds that have therapeutic efficacy by targeting aspects of aging that contribute to AD pathology. And, while the suitability of any single assay can be questioned, a combination of assays can make reliable predictions about the neuroprotective effects of compounds in vivo. Therefore, our lab has developed a combination of phenotypic screening assays that are ideally suited not only to identify novel neuroprotective compounds for the treatment of AD but also their target pathways, thereby potentially providing new therapeutic targets for disease treatment. Using these assays, we screened a large library of extracts from plants with identified pharmacological uses. Analysis of one of these extracts from the plant Yerba santa (Eriodictyon californicum) identified the flavanone sterubin as the active component and further studies showed it to be a potent neuroprotective and anti-inflammatory compound. Keywords: Oxidative stress, Ferroptosis, Glutathione, Inflammation, Nrf2, ATF4

Background Inflammatory bowel disease (IBD) is characterized by a low prevalence of traditional risk factors, an increased aortic pulse‐wave velocity (aPWV), and an excess of cardiovascular events. We have previously hypothesized that the cardiovascular risk excess reported in these patients could be explained by chronic inflammation. Here, we tested the hypothesis that chronic inflammation is responsible for the increased aPWV previously reported in IBD patients and that anti‐TNFa (anti‐tumor necrosis factor‐alpha) therapy reduce aPWV in these patients. Methods and Results This was a multicenter longitudinal study. We enrolled 334 patients: 82 patients with ulcerative colitis, 85 patients with Crohn disease, and 167 healthy control subjects matched for age, sex, and mean blood pressure, from 3 centers in Europe, and followed them for 4 years (range, 2.5–5.7 years). At baseline, IBD patients had higher aPWV than controls. IBD patients in remission and those treated with anti–TNFa during follow‐up experienced an aortic destiffening, whereas aPWV increased in those with active disease and those treated with salicylates (P=0.01). Disease duration (P=0.02) was associated with aortic stiffening as was, in patients with ulcerative colitis, high‐sensitivity C‐reactive protein during follow‐up (P=0.02). All these results were confirmed after adjustment for major confounders. Finally, the duration of anti–TNFa therapy was not associated with the magnitude of the reduction in aPWV at the end of follow‐up (P=0.85). Conclusions Long‐term anti–TNFa therapy reduces aPWV, an established surrogate measure of cardiovascular risk, in patients with IBD. This suggests that effective control of inflammation may reduce cardiovascular risk in these patients.

Epiploic appendagitis is a relatively rare disease characterized by an inflammation of fat-filled serosal outpouchings of the large intestine, called epiploic appendices. Diagnosis of epiploic appendagitis is made challenging by the lack of pathognomonic clinical features and should therefore be considered as a potential diagnosis by exclusion first of all with appendicitis or diverticulitis which are the most important causes of lower abdominal pain. Currently, with the increasing use of ultrasound and computed tomography in the evaluation of acute abdominal pain, epiploic appendagitis can be diagnosed by characteristic diagnostic imaging features. We present a case of epiploic appendagitis with objective of increasing knowledge of this disease and its diagnostic imaging findings, in order to reduce harmful and unnecessary surgical interventions.

Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.