Early application of ipsilateral cathodal-tDCS in a mouse model of brain ischemia results in functional improvement and perilesional microglia modulation

Early stroke therapeutic approaches rely on limited options, further characterized by a narrow therapeutic time window. In this context, the application of transcranial direct current stimulation (tDCS) in the acute phases after brain ischemia is emerging as a promising non-invasive tool. Despite the wide clinical application of tDCS, the cellular mechanisms underlying its positive effects are still poorly understood. Here, we explored the effects of cathodal tDCS (C-tDCS) 6 h after focal forelimb M1 ischemia in Cx3CR1GFP/+ mice. C-tDCS improved motor functionality of the affected forelimb, as assessed by the cylinder and foot-fault tests at 48 h, though not changing the ischemic volume. In parallel, histological analysis showed that motor recovery is associated with decreased microglial cell density in the area surrounding the ischemic core, while astrocytes were not affected. Deeper analysis of microglia morphology within the perilesional area revealed a shift toward a more ramified healthier state, with increased processes' complexity and a less phagocytic anti-inflammatory activity. Taken together, our findings suggest a positive role for early C-tDCS after ischemia, which is able to modulate microglia phenotype and morphology in parallel to motor recovery

Surgical Treatment Strategies and Prognosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC is the fifth most common cause of mortality worldwide and the third cancer related cause and is responsible for about 1 million deaths yearly [1]. The ageadjusted worldwide incidence is 5.5-14.9 per 100.000 population. In some areas of the world, such as sub-Saharan Africa and Southeast Asia, HCC represents the first cause of cancer death with an incidence of 52 per 100.000. Furthermore, in Europe and USA, HCC incidence has progressively raised in the past decade representing a burden problem. HCC is one of the few cancers for which a number of risk factors are known in great detail [2, 3]. HCC is almost always (80%) associated with cirrhosis, at least in developed countries, and chronic hepatitis C and B infection, alcoholic cirrhosis and haemocromatosis are some of the established risk factors [4]. The metabolic syndrome related to hypertension, central obesity, diabetes and obesity has been identified as a new risk factor. As a result, screening programs have developed, with the use of ultrasound and \u3b1-fetoprotein (AFP), with a hope to increase the chances of diagnosing small HCC and unltimately increase the rate of curability. Definitive diagnosis relies on the demonstration of a typical vascular pattern per liver imaging techniques (triple-phase CT-scan or MRI) of tumors larger than 2 cm with arterial hypervascularity and venous wash- out. Nodules, smaller than 2 cm, should be rechecked every six months or, if highly suspect, subjected to needle biopsy. It\u2019s likely that the study of tumor-specific tissue markers with prognostic value could introduce a systematic use of needle biopsy. Over the past 20 years, surgical treatment of hepatocellular carcinoma has seen an immense boost and improvement, with good survival outcomes and reduced morbidity and mortality.Liver resection (LR) and orthotopic liver transplantation (OLT) and ablative therapies are now considered the only potentially curative treatments for this cancer. LR has achieved improvement in survival within the past decade as a result of advances in diagnosis, surgical management of HCC and perioperative care. However, the long-term prognosis remains poor, and the 5-year overall survival rate ranges between 33% and 44%, with a 5-year cumulative recurrence rate of 80% to 100%. OLT could be viewed as the optimal treatment for HCC that is accompanied by advanced cirrhosis because of the widest possible resection margins for tumour and for a definitive cure of cirrhosis and its related complications. OLT for HCC performed within well-defined oncologic criteria (Milan criteria \u201creference\u201d) has shown long-term results comparable with those of transplantation for non-HCC patients. However, the critical shortage of available donated organs, together with the increasing number of patients awaiting transplantation, makes this therapeutic option available to only a small percentage of patients. Owing to the limited organ supply, many liver transplant centers usually make a selection to resect patients with compensated liver cirrhosis, defined as Child\u2013Pugh A chronic liver disease and resectable tumor and to reserve transplantation for those with impaired liver function (Child-Pugh class B-C) and small oligonodular HCC considered within the currently accepted criteria for transplantation. Radiofrequency and microwave ablation are relatively new percutaneous techniques in clinical use for HCC, that can produce tumour necrosis. Complete response rates are high in large series if tumour is less that 3 cm in diameter. This chapter will consider the main surgical techniques for the treatment of HCC in the light of the major guidelines currently available and of personal experience. Also, we will review HCC prognostic factors, and the particular situation of \u201clarge\u201d HCC and the strategy for liver tumours located at the hepato-caval confluence

Platinum, Palladium and Rhodium deposition to the Prunus laurus cerasus leaf surface as an indicator of the vehicular traffic pollution in the city of Varese area. An easy and reliable method to detect PGEs released from automobile catalytic converters

Background, aim, and scope The widespread use of some Platinum Group Elements (PGE) as catalysts to minimize emission of pollutants from combustion engines produced a constantly growing increase of the concentration of these elements in the environment; their potential toxicological properties explain the increasing interest in routine easy monitoring. We have found that leaves of Prunus laurus cerasus are efficient collectors of particulate with a dimension < 60-80 \u3bcm, and a simple and reliable procedure was developed to reveal traces of platinum, palladium and rhodium released from automotive catalysts. The analysis of the dust deposited on the foliage is a direct indicator of traffic pollution. Materials and methods Leaves of prunus laurus cerasus were washed by sonication in a mixture of water and 2 propanol and the washings, to be discarded, were separated by centrifugation to yield typically 0.05-1.2 g of dust that, after mineralization, were directly submitted to Atomic Absorption analysis. Results Comparison of the 2007 and 2004-5 results showed a dramatic reduction of the platinum levels and revealed that palladium is now the main component of this traffic related pollution. Discussion The results are consistent with the increasing diffusion of cars with a diesel engine whose catalysts are made up of Pt and/or Pd alone, and gives a significant insight into the recent evolution in catalyst design that replaces platinum for palladium. Conclusion The proposed analytical procedure is simple, with short preparation times, and greatly reduces matrix effects so that atomic absorption spectroscopy can easily detect the three noble metals at the ng/g level in the dust. Recommendation and perspectives The results clearly show that Pd concentrations have increased over time, and must be cause of concern

Advances in understanding large-scale responses of the water cycle to climate change

Globally, thermodynamics explains an increase in atmospheric water vapor with warming of around 7%/°C near to the surface. In contrast, global precipitation and evaporation are constrained by the Earth's energy balance to increase at ∼2–3%/°C. However, this rate of increase is suppressed by rapid atmospheric adjustments in response to greenhouse gases and absorbing aerosols that directly alter the atmospheric energy budget. Rapid adjustments to forcings, cooling effects from scattering aerosol, and observational uncertainty can explain why observed global precipitation responses are currently difficult to detect but are expected to emerge and accelerate as warming increases and aerosol forcing diminishes. Precipitation increases with warming are expected to be smaller over land than ocean due to limitations on moisture convergence, exacerbated by feedbacks and affected by rapid adjustments. Thermodynamic increases in atmospheric moisture fluxes amplify wet and dry events, driving an intensification of precipitation extremes. The rate of intensification can deviate from a simple thermodynamic response due to in‐storm and larger‐scale feedback processes, while changes in large‐scale dynamics and catchment characteristics further modulate the frequency of flooding in response to precipitation increases. Changes in atmospheric circulation in response to radiative forcing and evolving surface temperature patterns are capable of dominating water cycle changes in some regions. Moreover, the direct impact of human activities on the water cycle through water abstraction, irrigation, and land use change is already a significant component of regional water cycle change and is expected to further increase in importance as water demand grows with global population

Frequency and type of domestic injuries among children during COVID-19 lockdown: what changes from the past? An Italian multicentre cohort study

: Accidents are the main cause of injury in children, more than half events happen at home. Aims of this study were to assess if SARS-CoV-2 lockdown influence emergency department (ED) visits due to children domestic accident (DAs) and to identify factors associated with hospitalization. This was a multicentre, observational, and retrospective cohort study involving 16 EDs in Italy and enrolling children (3-13&nbsp;years) receiving a visit in ED during March-June 2019 and March-June 2020. Risk factors for hospitalization were identified by logistic regression models. In total, 8860 ED visits due to domestic accidents in children occurred before (4380) and during (4480) lockdown, with a mean incidence of DA of 5.6% in 2019 and 17.9% in 2020 (p &lt; 0.001) (IRR: 3.16; p &lt; 0.001). The risk of hospitalization was influenced by the type of occurred accident, with fourfold higher for poisoning and twofold lower risk for stab-wound ones. In addition, a higher risk was reported for lockdown period vs 2019 (OR: 1.9; p &lt; 0.001), males (OR: 1.4; p &lt; 0.001), and it increased with age (OR: 1.1; p &lt; 0.001).&nbsp; &nbsp; Conclusions: The main limitation of this study is the retrospective collection of data, available only for patients who presented at the hospital. This does highlight possible differences in the total number of incidents that truly occurred. In any case, the COVID-19 lockdown had a high impact on the frequency of DAs and on hospitalization. A public health campaign aimed at caregivers would be necessary to minimize possible risks at home. What is Known: • In Italy, domestic accidents are the second leading cause of paediatric mortality after cancer. • During the first SARS-CoV-2 lockdown in 2020, a sharp decrease in the total number of Emergency Departments visits for all causes was observed, both in children and in adults. What is New: • During the first SARS-CoV-2 lockdown in 2020, domestic accidents involving children increased threefold from the previous year. • Higher risk of hospitalization was showed in minors accessing during 2020 vs 2019, in males than in females and&nbsp;it increased with advancing age. Considering the type of injury, a significant higher risk of hospitalization for poisoning was observed

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: a translational study

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients