Uneven Linguistic Outcome in Extremely Preterm Children.

One primary problem in extremely preterm children is the occurrence of atypical language development. The aim of this study was to explore the components of language (articulatory phonetics, lexicon and syntax) in comprehension and production in extremely preterm children between the 4th and 5th year of age. The language section of the Preschool Neuropsychological Test was administered to 20 extremely preterm monolingual Italian children (GA < 28 weeks) and to a control sample of 40 full term children (GA > 37 weeks), matched for age and non-verbal IQ. Language comprehension was fully efficient in all of the components that we assessed. In the tasks of language production the clinical sample fared much worse than their age and IQ matched controls and the differences were highly significant (p < .001). Language acquisition in extremely preterm children may follow uneven developmental trajectories: language comprehension can be spared in the face of a selective impairment of language production at the level of articulatory phonetics and syntax.

Neuroprotection as a Potential Therapeutic Perspective in Neurodegenerative Diseases: Focus on Antiepileptic Drugs.

Neuroprotection is conceived as one of the potential tool to prevent or slow neuronal death and hence a therapeutic hope to treat neurodegenerative diseases, like Parkinson's and Alzheimer's diseases. Increase of oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation have been identified as main causes of neuronal death and adopted as targets to test experimentally the putative neuroprotective effects of various classes of drugs. Among these agents, antiepileptic drugs (AEDs), both the old and the newer generations, have shown to exert protective effects in different experimental models. Their mechanism of action is mediated mainly by modulating the activity of sodium, calcium and potassium channels as well as the glutamatergic and GABAergic (gamma-aminobutyric acid) synapses. Neurological pathologies in which a neuroprotective action of AEDs has been demonstrated in specific experimental models include: cerebral ischemia, Parkinson's disease, and Alzheimer's disease. Although the whole of experimental data indicating that neuroprotection can be achieved is remarkable and encouraging, no firm data have been produced in humans so far and, at the present time, neuroprotection still remains a challenge for the future.

Evaluation of risk of symptomatic cytomegalovirus reactivation in myeloma patients treated with tandem autologous stem cell transplantation and novel agents: a single-institution study.

The introduction of proteasome inhibitors and/or immunomodulators in the treatment of myeloma has led to an increase in viral infections, particularly in the Herpesviridae family. Previous studies about the risk of cytomegalovirus (CMV) reactivation after autologous stem cell transplantation (ASCT) have examined the clinical outcome after the first ASCT; however, only 1 study to date has investigated the risk of CMV reactivation after a second transplantation. To address this issue, we performed a retrospective chart review on 78 consecutive myeloma patients (median age 56 years) who underwent a tandem non-CD34(+) selected ASCT after induction treatment with either conventional chemotherapy (n = 42) or with novel agents (n = 36), respectively. All subjects had been mobilized and conditioned with cyclophosphamide plus granulocyte colony-stimulating factor and melphalan alone, respectively. CMV DNA load in the blood has been determined by polymerase chain reaction in the case of a clinical suspicion of CMV reactivation; therefore, routine monitoring was not performed. Considering the outcome of both the first and the second transplantations, we observed a total of 13 episodes of symptomatic CMV reactivation (13/156, 8%), in 12 subjects (12/78, 15%), all successfully treated. Eight subjects experienced a CMV reactivation after the first ASCT (8/78, 10%); however, only 1 of them (1/8, 12%) experienced a CMV reactivation after the second transplantation. Conversely, 4 CMV reactivations (6%) were observed after the second transplantation in the group of 70 patients who did not experience a CMV reactivation after the first ASCT. No statistically significant difference was observed between first and second ASCT (8/78, 10% vs. 5/78, 6%; P = 0.767). Univariate analysis showed that a pre-transplant treatment with novel agents was the only baseline factor significantly associated with the occurrence of post-ASCT CMV symptomatic reactivation after the first transplant (odds ratio [OR]: 9.897; 95% confidence interval [CI]: 1.154-84.840; P = 0.021) but not after the second transplant (OR: 5.125; 95% CI: 0.546-48.119; P = 0.115). No end-organ disease or primary infection was documented. Our data suggest that second transplantation does not increase the risk of CMV reactivation in our patient population, when compared with the first one, and confirm the role of a pre-transplant treatment with novel agents as a risk factor for CMV symptomatic reactivation.

Intercellular crosstalk mediated by tunneling nanotubes between central nervous system cells. What we need to advance.

Long-range intercellular communication between Central Nervous System (CNS) cells is an essential process for preserving CNS homeostasis. Paracrine signaling, extracellular vesicles, neurotransmitters and synapses are well-known mechanisms involved. A new form of intercellular crosstalk mechanism based on Tunneling Nanotubes (TNTs), suggests a new way to understand how neural cells interact with each other in controlling CNS functions. TNTs are long intercellular bridges that allow the intercellular transfer of cargoes and signals from one cell to another contributing to the control of tissue functionality. CNS cells communicate with each other via TNTs, through which ions, organelles and other signals are exchanged. Unfortunately, almost all these results were obtained through 2D in-vitro models, and fundamental mechanisms underlying TNTs-formation still remain elusive. Consequently, many questions remain open, and TNTs role in CNS remains largely unknown. In this review, we briefly discuss the state of the art regarding TNTs identification and function. We highlight the gaps in the knowledge of TNTs and discuss what is needed to accelerate TNTs-research in CNS-physiology. To this end, it is necessary to: 1) Develop an ad-hoc TNTs-imaging and software-assisted processing tool to improve TNTs-identification and quantification, 2) Identify specific molecular pathways involved into TNTs-formation, 3) Use in-vitro 3D-CNS and animal models to investigate TNTs-role in a more physiological context pushing the limit of live-microscopy techniques. Although there are still many steps to be taken, we believe that the study of TNTs is a new and fascinating frontier that could significantly contribute to deciphering CNS physiology.

GFAP serves as a structural element of tunneling nanotubes between glioblastoma cells and could play a role in the intercellular transfer of mitochondria.

Tunneling nanotubes (TNTs) are long F-actin-positive plasma membrane bridges connecting distant cells, allowing the intercellular transfer of cellular cargoes, and are found to be involved in glioblastoma (GBM) intercellular crosstalk. Glial fibrillary acid protein (GFAP) is a key intermediate filament protein of glial cells involved in cytoskeleton remodeling and linked to GBM progression. Whether GFAP plays a role in TNT structure and function in GBM is unknown. Here, analyzing F-actin and GFAP localization by laser-scan confocal microscopy followed by 3D reconstruction (3D-LSCM) and mitochondria dynamic by live-cell time-lapse fluorescence microscopy, we show the presence of GFAP in TNTs containing functional mitochondria connecting distant human GBM cells. Taking advantage of super-resolution 3D-LSCM, we show the presence of GFAP-positive TNT-like structures in resected human GBM as well. Using H2O2 or the pro-apoptotic toxin staurosporine (STS), we show that GFAP-positive TNTs strongly increase during oxidative stress and apoptosis in the GBM cell line. Culturing GBM cells with STS-treated GBM cells, we show that STS triggers the formation of GFAP-positive TNTs between them. Finally, we provide evidence that mitochondria co-localize with GFAP at the tip of close-ended GFAP-positive TNTs and inside receiving STS-GBM cells. Summarizing, here we found that GFAP is a structural component of TNTs generated by GBM cells, that GFAP-positive TNTs are upregulated in response to oxidative stress and pro-apoptotic stress, and that GFAP interacts with mitochondria during the intercellular transfer. These findings contribute to elucidate the molecular structure of TNTs generated by GBM cells, highlighting the structural role of GFAP in TNTs and suggesting a functional role of this intermediate filament component in the intercellular mitochondria transfer between GBM cells in response to pro-apoptotic stimuli.

Hepatitis C virus infection prevalence and liver dysfunction in a cohort of B-cell non-Hodgkin's lymphoma patients treated with immunochemotherapy.

Several studies have reported a higher prevalence of hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin's lymphoma (NHL) than in the general population. Treatment for NHL includes the use of chemotherapeutic agents such as cytotoxic drugs, corticosteroids, and rituximab, which can be immunosuppressive and hepatotoxic. While reactivation of hepatitis B virus (HBV) when undergoing immunosuppressive therapy for haematological malignancies is a well-documented complication, data on HCV reactivation or liver function impairment after chemotherapy for NHL are controversial. From January 2006 to December 2009, 207 consecutive NHL patients treated with chemotherapy without rituximab (CHOP) or with rituximab (R-CHOP) were observed; screening for HCV infection and baseline liver function tests were performed in all patients. The prevalence of HCV infection was 9.2%. This prevalence is higher than that observed in the general population in Italy (3%). Among the HCV-infected subjects, the incidence of hepatitis flares was 26.3% vs 2.1% among the HCV-uninfected individuals. Although less frequent and less severe than in HBV-infected subjects, liver dysfunction can occur as a consequence of rituximab-containing regimens in HCV-infected patients with NHL. In the cases considered in this study, no patient treated with chemotherapy without rituximab developed hepatitis flares. The frequency and the severity of this complication vary in different reports. Therefore, we recommend the assessment of liver function and the screening of all patients with NHL for HCV infection before starting chemotherapy; we also recommend monitoring of liver function tests and HCV-RNA serum levels during treatment.

Concomitant MPZ and MFN2 Gene Variants and Charcot Marie Tooth Disease in a Boy: Clinical and Genetic Analysis-Literature Review.

Charcot- Marie- Tooth (CMT) disease includes a group of clinically and genetically heterogeneous neuropathic disorders with an estimated frequency of 1 on 2.500 individuals. CMTs are differently classified according to the age of onset, type of inheritance, and type of inheritance plus clinical features. For these disorders, more than 100 genes have been implicated as causal factors, with mutations in the PMP22 being one of the most common. The demyelinating type (CMT1) affects more than 30% of the CMTs patients and manifests with motor and sensory dysfunctions of the peripheral nervous system mainly starting with slow progressive weakness of the lower extremities. We report here a 12 year- old boy presenting with typical features of CMT1 type, hearing impairment, and inguinal hernia who at the next-generation sequence analysis displayed a concomitant presence of two variants: the c.233 C>T p.Ser 78Leu of the MPZ gene (NM_000530.6) characterized as pathogenetic and the c.1403 G>A p.Arg 468His of the MFN2 gene (NM_014874.3) characterized as VUS. Concomitant variant mutations in CMTs have been uncommonly reported. The role of these gene mutations on the clinical expression and a literature review on this topic is discussed.

Analysis of Risk Factors for a Low Immune Response to Messenger RNA COVID-19 Vaccine in Kidney Transplant Recipients and Differences Between Second and Third Dose.

BACKGROUND: The efficacy of the response to SARS-CoV-2 vaccination in kidney transplant recipients is low. The aim of our study was to evaluate the risk factors correlated with the low antibody response and whether there was an improvement between the second and the third dose. METHODS: A prospective study was conducted on 176 kidney transplant recipients who received the second and the third dose of the anti-SARS-CoV-2 mRNA Comirnaty vaccine. We evaluated the seroconversion process after administration of the second and the third dose and assessed a possible correlation with age, time between transplant and vaccination, and type of immunosuppressive therapy. RESULTS: A total of 98 of the 176 patients (55.7%) responded positively after the inoculation of the second dose and according to the multivariable logistic regression analysis the lack of seroconversion was independently associated with patient age ≥60 (P = .025; odds ratio [OR], 2.094), time since transplant of 1 to 3 months (P = .032; OR, 2.118), and triple therapy (P = .044; OR, 2.327). After the vaccine third dose, the seroconversion increased to 62.5%, and it was negatively influenced by calcineurin inhibitor use (12/21, 57.1% vs 71/78, 91.0%, P = .0006) and triple therapy (13/21, 61.9% vs 72/78, 92.3%, P = .0014). The median of antispike antibody response significantly increased from 18.5 IU/mL after the second dose to 316.9 IU after the third dose (P < .0001). CONCLUSIONS: We demonstrated a correlation between older age and shorter distance from the transplant and triple immunosuppressive therapy with the lack of seroconversion. We noticed a significant improvement in antibody response by a third dose of messenger RNA vaccine.

[Bio-ecological control of chronic liver disease and encephalopathy]. / Controllo bio-ecologico della cirrosi epatica e dell'encefalopatia.

Minimal encephalopathy was originally associated with chronic liver disease but is increasingly associated with most other chronic diseases and particularly with diabetes and also chronic disorders in other organs: kidneys, lungs, thyroid and with obesity. It is increasingly with dramatically increased and more or less permanent increase in systemic inflammation, most likely a result of Western lifestyle. Frequent physical exercise and intake of foods rich in vitamins, antioxidants, fibres, lactic acid bacteria etc in combination with reduction in intake of refined and processed foods is known to reduce systemic inflammation and prevent chronic diseases. Some lactic acid bacteria, especially Lb paracasei, lb plantarum and pediococcus pentosaceus have proven effective to reduce inflammation and eliminate encephalopathy. Significant reduction in blood ammonia levels and endotoxin levels were reported in parallel to improvement of liver disease. Subsequent studies with other lactic acid bacteria seem to demonstrate suppression of inflammation and one study also provides evidence of clinical improvement.

Embolization of the renal artery before graft nephrectomy: a comparing study to evaluate the possible benefits.

The graft nephrectomy is burdened by immunological and surgical complications. The main surgical complications of graft nephrectomy are hemorrhage, infections, vascular injury and death. The mortality is high, with percentages varying between 1.3 and 38%. Therefore, graft nephrectomy should be recommended only in selected cases. We conducted a retrospective study, comparing the data of 26 patients undergoing an allograft nephrectomy (2009-2013), without embolization of the renal artery (NO EMBO group) with the data of 40 patients undergoing an allograft nephrectomy (2014-2019), with embolization of the renal artery (EMBO group). We included only graft nephrectomies performed at least 6 months after transplantation. The patients included in the study were consecutive because until 2013 we did not perform the embolization of the renal graft artery. Afterwards, from 2014, instead, we routinely carry out embolization to all patients to be subjected to graft nephrectomy. We, therefore, wanted to analyze whether this surgical approach compared to the previous technique can lead to an improvement in morbidity and mortality, reducing the risk of bleeding and operating times. The examination of our data highlights that embolization of renal artery reduces the operating times of the explant, in addition the group subjected to embolization had less changes in hemoglobinemia and less blood loss.

Ultrashort high energy electron bunches from tunable surface plasma waves driven with laser wavefront rotation.

We propose to use ultrahigh intensity laser pulses with wave-front rotation (WFR) to produce short, ultraintense surface plasma waves (SPW) on grating targets for electron acceleration. Combining a smart grating design with optimal WFR conditions identified through simple analytical modeling and particle-in-cell simulation allows us to decrease the SPW duration (down to a few optical cycles) and increase its peak amplitude. In the relativistic regime, for Iλ_{0}^{2}=3.4×10^{19}W/cm^{2}µm^{2}, such SPW are found to accelerate high charge (few 10 s of pC), high energy (up to 70 MeV), and ultrashort (few fs) electron bunches.

Alkaline phosphatase (alp) levels in multiple myeloma and solid cancers with bone lesions: Is there any difference?

INTRODUCTION: Bone involvement in Multiple Myeloma results from increased osteoclast formation and activity that occurs in proximity to myeloma cells. The role of Alkaline Phosphatse (ALP) in this process and the diagnostic significance of plasma levels in patients with MM are unclear. AIM: To compare plasma ALP levels in patients with MM and solid cancers and metastatic lesions to the bone. RESULTS: In this observational retrospective study we enrolled 901 patients were enrolled: 440 patients (49%) with Multiple Myeloma, 461 (51%) with solid cancers. All 901 patients had bone lesions. Among patients with Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. This difference is independent of stage, number and type of bone lesions. CONCLUSION: This study suggests that plasma ALP has a different clinical significance in MM than in other neoplasms and could be used as a discriminating marker in presence of bone lesions. In particular, lower or normal values, should suggest further investigations such as urinary and serum electrophoresis, associated with bone marrow aspirate in case of the presence of a monoclonal component, in order to confirm or exclude a MM diagnosis.

Hyperhomocysteinemia recurrence in levodopa-treated Parkinson's disease patients.

BACKGROUND: Patients with Parkinson's disease (PD) and chronically treated with L-DOPA exhibit, in a percentage of 10-30%, supra-physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper-homocysteinemic PD patients, the time of hyper-tHcy recurrence after discontinuation of 1-month folate supplementation given to normalize plasma tHcy levels. METHODS: Plasma tHcy, cobalamin and folate were assayed before and after 1-month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontinuation in 29 PD patients (16M/13F, mean age 69.4 +/- 6.9 years) stabilized on a mean L-DOPA dose of 509.4 +/- 312.1 mg/day. RESULTS: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2-month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper-tHcy. CONCLUSIONS: One-month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper-homocysteinemic PD patients. Following folate discontinuation, hyper-tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper-homocysteinemic patients with PD.

Ab initio calcineurin inhibitor-based monotherapy immunosuppression after liver transplantation reduces the risk for Pneumocystis jirovecii pneumonia.

At the Tor Vergata University of Rome, ab initio calcineurin inhibitor-based monotherapy immunosuppression (IS) is the standard of treatment after liver transplantation (LT). As the net state of IS determines the onset of Pneumocystis jirovecii pneumonia (PCP), we hypothesized that, in the presence of weak impairment of the immune function, as determined by the above-mentioned IS, the host is not overexposed to the risk for PCP and consequently the specific anti-PCP prophylaxis is unnecessary. In a single-cohort descriptive study, we retrospectively investigated the incidence of PCP in 203 LT patients who did not receive anti-PCP prophylaxis because they were under monotherapy IS. The primary endpoint of the study was the incidence of PCP during the first 12 months following LT; secondary endpoints were the incidence of acute rejection requiring additional IS and of CMV infection. No cases of PCP were recorded. The incidence of CMV and acute rejection was 3.9% and 0.9%, respectively. Our data suggest that monotherapy IS after LT may nullify the risk for PCP even in the absence of any specific prophylaxis.

Allen: A High-Level Trigger on GPUs for LHCb.

We describe a fully GPU-based implementation of the first level trigger for the upgrade of the LHCb detector, due to start data taking in 2021. We demonstrate that our implementation, named Allen, can process the 40 Tbit/s data rate of the upgraded LHCb detector and perform a wide variety of pattern recognition tasks. These include finding the trajectories of charged particles, finding proton-proton collision points, identifying particles as hadrons or muons, and finding the displaced decay vertices of long-lived particles. We further demonstrate that Allen can be implemented in around 500 scientific or consumer GPU cards, that it is not I/O bound, and can be operated at the full LHC collision rate of 30 MHz. Allen is the first complete high-throughput GPU trigger proposed for a HEP experiment.

Fatal hemorrhage in two renal graft recipients with multi-drug resistant Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa (PA) infections occurring after renal transplantation (RT) represent a potentially life-threatening complication. We present 2 cases of early death following RT in which PA was transmitted, possibly from the donor to the recipients, despite preoperative cultures that were negative. The donor had developed PA-related bilateral pneumonia while in the intensive care unit. However, after appropriate antibiotic therapy, no signs of infection were present at the time of organ retrieval and cultures were negative. Both recipients received a renal graft from the same donor and developed multi-drug resistant (MDR)-PA infections with bacterial phenotypes and resistances similar to the donor. The first recipient died 9 days after RT from rupture of a false aneurysm of the external iliac artery, caused by a fully thickened PA-related arteritis. The second recipient died postoperatively on day 10 after rupture of an aneurysm in the right vertebral artery. Our experience shows that MDR-PA infection early after RT may be a catastrophic event. Specific anti-PA antibiotic therapy in RT patients during the perioperative period is recommended in the case of PA infection in the donor, even after apparent successful therapy with negative cultures.

Soluble proteome investigation of cobalt effect on the carotenoidless mutant of Rhodobacter sphaeroides.

AIMS: To investigate the surviving capability of Rhodobacter sphaeroides under phototrophic conditions in the presence of high cobalt concentration and its influence on the photosynthetic apparatus biosynthesis. METHODS AND RESULTS: Cells from R. sphaeroides strain R26.1 were grown anaerobically in a medium containing 5.0 mmol l(-1) cobalt ions and in a control medium. Metal toxicity was investigated comparing the soluble proteome of Co(2+)-exposed cells and cells grown in control medium by two-dimensional gel electrophoretic analysis. Significant changes in the expression level were detected for 43 proteins, the majority (35) being up-regulated. The enzyme porphobilinogen deaminase (PBGD) was found down-regulated and its activity was investigated. CONCLUSIONS: The up-regulated enzymes mainly belong to the general category of proteins and DNA degradation enzymes, suggesting that part of the catabolic reaction products can rescue bacterial growth in photosynthetically impaired cells. Furthermore, the down-regulation of PBGD strongly indicates that this key enzyme of the tetrapyrrole and bacteriochlorophyll synthesis is directly involved in the metabolic response. SIGNIFICANCE AND IMPACT OF THE STUDY: Data and experiments show that the cobalt detrimental effect on the photosynthetic growth of R. sphaeroides is associated with an impaired expression and functioning of PBGD.

FTO rs9939609 Gene Polymorphism and Obesity: Lack of Association in Kidney Transplantation.

The fat mass and obesity-associated (FTO) gene is one of the most important obesity susceptibility genes. Some FTO gene polymorphisms have been associated with obesity, diabetes, and hypertension, all conditions for which, after transplant, there is increased susceptibility, due to effects of immunosuppressive regimens. To evaluate whether FTO could be a candidate for targeted preventive intervention in the transplant setting, we investigated whether the common genetic variation, FTO rs9939609T>A, could affect weight gain and risk of cardiovascular complications in kidney transplantation. METHODS: In 198 kidney transplant recipients, FTO rs9939609 was investigated in association with body mass index (BMI)/obesity and with other clinical markers of posttransplant risk, then monitored up to 5 years after transplantation. Genotyping was performed using an allelic discrimination method on a real-time polymerase chain (PCR) system. Associations were analyzed using the chi-square test; differences between genotypes were examined with analysis of variance or Kruskal-Wallis test; tests for repeated measures and a general linear model analysis controlling for age and gender were also utilized. RESULTS: Allele and genotype frequencies of FTO rs9939609 in recipients (T/T, 29.8%; T/A, 49.0%; A/A, 21.2%; A, 45.7%; T, 54.3%) reflect those present in healthy Caucasian populations. In the face of pre-/posttransplant differences in total cholesterol, triglycerides, or fasting glucose, results did not show significant changes in these factors among genotypes either before or after transplantation. CONCLUSION: This study highlights a lack of association of FTO rs9939609T>A genotypes and posttransplant weight gain, plasma lipids, and fasting blood glucose in kidney transplantation.

Clinical operational tolerance after kidney transplantation: a short literature review.

The clinical era of solid organ transplantation started with a renal transplantation (RT) performed between identical twins in Boston in 1954. The patient did not receive any immunosuppression, thus representing the very first case of operational tolerance (Tol). However, more than half a century later, we must admit the inadequacy of our knowledge regarding such a fundamental aspect of transplant immunology, as demonstrated by the fact that Tol has never been achieved in an intention-to-treat protocol. Herein we aim to shortly review the worldwide experience on clinical operational Tol after RT. Thus far, reports on successful cases of Tol after RT have been anecdotal: the largest series included no more than 10 individuals. We will understand that Tol can develop even in the presence of either HLA mismatches or blood group incompatibility at baseline, in the presence of anti-HLA antibodies during follow-up, as well as in patients having experienced acute rejection. Despite the lack of robust evidence, the fact that Tol is often accidentally discovered by transplant physicians during follow-up in noncompliant patients justifies the hypothesis that the real number of Tol cases might be much higher than currently reported.