Frontal lobe metabolic alterations in autism spectrum disorder: a 1H-magnetic resonance spectroscopy study.

Recently, neuroimaging studies were performed using 1H-magnetic resonance spectroscopy (1H-MRS), revealing a quantitative alteration of neurochemicals (such as neurotransmitters and metabolites) in several brain regions of patients with autism spectrum disorder (ASD). The involvement of the frontal lobe in the neurobiology of ASD has long been documented in the literature. Therefore, the aim of this study was to analyze the alterations of N-acetylaspartate/creatine (NAA/Cr) and choline/Cr (Cho/Cr) ratios in the frontal lobe subcortical white matter (WM) in ASD patients, in order to reveal any alteration of metabolites that might be the expression of specific clinical features of the disorder

A Frontline Approach With Peripherally Inserted Versus Centrally Inserted Central Venous Catheters for Remission Induction Chemotherapy Phase of Acute Myeloid Leukemia: A Randomized Comparison

BACKGROUND: The incidence of peripherally inserted central catheter (PICC)-related adverse events has been uncertain in the setting of acute myeloid leukemia (AML) compared with the incidence of centrally inserted central catheter (CICC) adverse events. PATIENTS AND METHODS: We conducted a monocentric, randomized trial of patients with previously untreated AML. Of the 93 patients, 46 had received a PICC and 47 had received a CICC as frontline intravascular device. Thereafter, all patients underwent intensive chemotherapy for hematologic remission induction. The primary endpoint was catheter-related (CR)-bloodstream infection (BSI) and venous thrombosis (VT) rate. The secondary endpoints catheter malfunction, catheter removal, and patient overall survival. RESULTS: The CR-BSI and CR-VT rate in the PICC and CICC groups was 13% and 49%, respectively, with a difference of 36 percentage points (relative risk for CR-BSI or CR-VT, 0.266; P = .0003). The CR-BSI incidence was 1.4 and 7.8 per 1000 catheters daily in the PICC and CICC groups, respectively. Among the CR thromboses, the symptomatic VT rate was 2.1% in the PICC group and 10.6% in the CICC group. In the CICC group, 16 of the 47 patients (34%) had the catheter removed for BSI (n = 5), septic thrombophlebitis (n = 4), VT (n = 2), or malfunction (n = 5) a median of 7 days after insertion. In the PICC group, only 6 of the 46 patients (13%) required catheter removal for VT (n = 2) or malfunction (n = 4). At a median follow-up of 30 days, 6 patients in the CICC group died of CR complications versus none of the patients in the PICC group (P = .012). Using PICCs, the reduction in BSI and symptomatic VT decreased mortality from CR infection and venous thromboembolism. In contrast, the CICC approach led to early catheter removal mostly for difficult-to-treat infectious pathogens. CONCLUSION: Our data have confirmed that BSI and symptomatic VT are the major complications affecting frontline central intravascular device-related morbidity in the leukemia setting. The use of a PICC is safer than that of a CICC and maintains the effectiveness for patients with AML undergoing chemotherapy, with an approximate fourfold lower combined risk of infection or thrombosis at 30 days

Whole transcriptome profiling of Late-Onset Alzheimer's Disease patients provides insights into the molecular changes involved in the disease

Alzheimer's Disease (AD) is the most common cause of dementia affecting the elderly population worldwide. We have performed a comprehensive transcriptome profiling of Late-Onset AD (LOAD) patients using second generation sequencing technologies, identifying 2,064 genes, 47 lncRNAs and 4 miRNAs whose expression is specifically deregulated in the hippocampal region of LOAD patients. Moreover, analyzing the hippocampal, temporal and frontal regions from the same LOAD patients, we identify specific sets of deregulated miRNAs for each region, and we confirm that the miR-132/212 cluster is deregulated in each of these regions in LOAD patients, consistent with these miRNAs playing a role in AD pathogenesis. Notably, a luciferase assay indicates that miR-184 is able to target the 3'UTR NR4A2 - which is known to be involved in cognitive functions and long-term memory and whose expression levels are inversely correlated with those of miR-184 in the hippocampus. Finally, RNA editing analysis  reveals a general RNA editing decrease in LOAD hippocampus, with 14 recoding sites significantly and differentially edited in 11 genes. Our data underline specific transcriptional changes in LOAD brain and provide an important source of information for understanding the molecular changes characterizing LOAD progression

Hepatic Lysosomal Acid Lipase and lipophagy in the progression of NAFLD

Lysosomal Acid Lipase (LAL) is an acidic enzyme that degrades cholesterol-ester and triglyceride inside lysosomes. Both genetic LAL deficiency and non-alcoholic fatty liver disease (NAFLD) are featured by lipid accumulation in hepatocyte leading to steatosis and eventually liver failure. Recently, a deficit in blood LAL activity was found in NAFLD patient (1). Lipophagy plays a pivotal role in degradation of lipids in the liver and consists in autophagic sequestration of lipid droplets and their degradation inside lysosomes by LAL (2). p62 serves as an autophagy/lipophagy receptor for selective autophagy and accumulates when the autophagy is blocked. We aimed to evaluate the hepatic expression of LAL in NAFLD patients and healthy subjects and to verify its association with histopathological features. Furthermore, we aimed to compare LAL levels with autophagic flux and lysosomal compartment status (LAMP1-positive vesicles). LAL expression was reduced in NAFLD patients with respect to healthy subjects (

Daily On-Line Set-Up Correction in 3D-Conformal Radiotherapy: Is It Feasible?

Aims and background The aim of this report was to investigate the feasibility in terms of treatment time prolongation of an on-line no-action level correction protocol, based on daily electronic portal image verification. Methods and study design The occupation of a linear accelerator (LINAC) delivering 3-D conformal treatments was monitored for two weeks (from Monday to Friday, 10 working days). An electronic portal image device I-View (Elekta, UK) was used for setup verification. Single-exposure portal images were acquired daily using the initial 8 monitor units delivered for each treatment field. Translational deviations of isocenter position larger than 5 mm or 7 mm, for radical or palliative treatments, respectively, were immediately corrected. In order to estimate the extra workload involved with the on-line protocol, the time required for isocenter check and table correction was specifically monitored. Results Forty-eight patients were treated. In all, 482 fractions had electronic portal images taken. Two hundred and forty-five setup corrections were made (50.8% of all fractions). The occupation of the LINAC lasted 106 h on the whole. Twelve h and 25 min (11.7% of LINAC occupation time) were spent for portal image verification and setup correction. On the average, 4.3 fractions per hour were carried out. Conclusions When used by trained therapists, ideally, portal imaging may be carried out before each fraction, requiring approximately 10% of LINAC occupation time

Efficiency of plasmapheresis: a comparison of three Italian Centres

Background. In order to support the economic and financial sustainability of the Italian health system, there is a need to define technically and economically efficient strategies that assure the self-sufficient apheretic production of plasma. Material and methods. Process and product costs at the Casa del Donatore (CD) in Bologna were determined on the basis of costing models used at Verona's Inter-hospital Department of Transfusional Medicine (IDTM) by academics from the University of Turin and those used at the Marche Regional IDTM by academics from Marche Polytechnic University. During the first phase, data was collected concerning donors, biological screening tests, the number of units produced/discarded, the materials used (individual pharmacy codes and related final expenditure), human resources (number, professional status, time involved, the number of activities per day, percentage productivity), equipment, and general costs. During the second phase, direct costs were verified and the costs common to the units produced were attributed using the functional principle. Results. The overall cost of a litre of plasma collected by means of apherisis (about \u20ac 280) was similar at the three centres, but there were differences in their cost structures that could be attributed to organisational choices, economic factors and/or structural variables. Plasmapheresis accounts for 24% of the plasma collected in Marche and the CD, but 17% of that collected in Verona, whereas the donation index is lower in the CD (1.8) than in the other two centres (2.2). The annual donor screening tests are substantially similar, but there are some differences in their timing (at the time of screening candidate donors or at the time of first donation). There are also some differences in the use of tests that are not required by law but are carried out in order to protect donors and recipients. The working times in three centres are similar, but personnel costs vary because of their different retribution policies. Discussion. Comparing the cost determinants at each centre made it possible to highlight changes that each can make in order to improve efficiency, and may lay the basis for doing the same in other organisational contexts

Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver

Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity

An 1H NMR study of the cytarabine degradation in clinical conditions to avoid drug waste, decrease therapy costs and improve patient compliance in acute leukemia

Cytarabine, the 4-amino-1-(β-D-arabinofuranosyl)-2(1H)-pyrimidinone, (ARA-C) is an antimetabolite cytidine analogue used worldwide as key drug in the management of leukaemia. As specified in the manufacturers' instructions, once the components-sterile water and cytarabine powder-are unpackaged and mixed, the solution begins to degrade after 6 hours at room temperature and 12 hours at 4°C. To evaluate how to avoid wasting the drug in short-term, low-dose treatment regimens, the reconstituted samples, stored at 25°C and 4°C, were analyzed every day of the test week by reversed-phase HPLC and high-field NMR spectroscopy. All the samples remained unchanged for the entire week, which corresponds to the time required to administer the entire commercial drug package during low-dose therapeutic regimens. The drug solution was stored in a glass container at 4°C in an ordinary freezer and drawn with sterile plastic syringes; during this period, no bacterial or fungal contamination was observed. Our findings show that an cytarabine solution prepared and stored in the original vials retains its efficacy and safety and can, therefore, be divided into small doses to be administered over more days, thus avoiding unnecessary expensive and harmful waste of the drug preparation. Moreover, patients who require daily administration of the drug could undergo the infusion at home without need to go to hospital. The stability of the aliquots would help decrease hospitalization costs

Liposomal doxorubicin supercharge-containing front-line treatment in patients with advanced-stage diffuse large B-cell lymphoma or classical Hodgkin lymphoma: Preliminary results of a single-centre phase II study

We evaluated the impact of liposomal doxorubicin (NPLD) supercharge-containing therapy on interim fluorodeoxyglucose positron emission tomography (interim-FDG-PET) responses in high-risk diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma (c-HL). In this phase II study (2016-2021), 81 adult patients with advanced-stage DLBCL (n = 53) and c-HL (n = 28) received front-line treatment with R-COMP-dose-intensified (DI) and MBVD-DI. R-COMP-DI consisted of 70 mg/m2 of NPLD plus standard rituximab, cyclophosphamide, vincristine and prednisone for three cycles (followed by three cycles with NPLD de-escalated at 50 mg/m2 ); MBVD-DI consisted of 35 mg/m2 of NPLD plus standard bleomycin, vinblastine and dacarbazine for two cycles (followed by four cycles with NPLD de-escalated at 25 mg/m2 ). Patients underwent R-COMP-DI and MBVD-DI with a median dose intensity of 91% and 94% respectively. At interim-FDG-PET, 72/81 patients (one failed to undergo interim-FDG-PET due to early death) had a Deauville score of ≤3. At end of treatment, 90% of patients reached complete responses. In all, 20 patients had Grade ≥3 adverse events, and four of them required hospitalisation. At a median 21-months of follow-up, the progression-free survival of the entire population was 77.3% (95% confidence interval 68%-88%). Our data suggest that the NPLD supercharge-driven strategy in high-risk DLBCL/c-HL may be a promising option to test in phase III trials, for improving negative interim-FDG-PET cases incidence