Loss of C9orf72 Function Impairs the Peripheral Neuromuscular System and Anticipates Symptoms in ALS Mice.

Hexanucleotide repeat expansions in the C9orf72 gene is the prevalent genetic cause of ALS, causing neurodegeneration through two gain-of-function mechanisms due to the accumulation of RNA foci and dipeptide-repeat proteins, and a loss-of-function mechanism due to C9orf72 protein reduction. The loss-of-function has never been examined in the peripheral compartment of neuromuscular system, precociously affected by ALS. In this work we observed that C9orf72 is expressed by Schwann cells and skeletal muscle in mice and the constitutive ablation of C9orf72 leads to mild muscle denervation, alterations of autophagy, increased immune cell infiltration and inflammation in muscle and peripheral nerve, typical features of ALS. Moreover, demyelination, activation of Schwann cells in a repair mode and autoimmunity were found in peripheral nerves of C9orf72-/- mice. Evidence demonstrates that the loss-of-function synergizes with other toxic stimuli to induce neurodegeneration. Moreover, C9orf72 mutation often occurs in combination with other ALS or FTD-linked genes, suggesting oligogenicity of ALS. Therefore, to verify whether the C9orf72 loss-of-function could act as ALS modulator, we investigated the effect of C9orf72 constitutive ablation in SOD1G93A mice, the best characterized model of ALS. We found that the C9orf72 loss-of-function anticipated the onset of symptoms exacerbating denervation, autophagy impairment and inflammation in muscle, and enhancing axonal transport disruption in SOD1G93A mice. Conversely, increased anti-inflammatory gliosis in the spinal cord and extended survival were detected in SOD1G93A C9orf72-/- mice. For the first time, in this work we demonstrated that C9orf72 is expressed in the peripheral compartment of neuromuscular system where it is pivotal in maintaining the homeostasis. Despite the C9orf72 ablation had detrimental effects on this district and anticipated the symptom onset in ALS mice, unexpectedly it prolonged their lifespan. This suggests that reducing the C9orf72 expression in the later phase of the disease, for example through antisense oligonucleotides, might have a therapeutic relevance

Validation study of WindTrax reverse dispersion model coupled with a sensitivity analysis of model-specific settings

In last years, atmospheric dispersion models have reached considerable popularity in environmental research field. In this regard, given the difficulties associated to the estimation of emission rate for some kind of sources, and due to the importance of this parameter for the reliability of the results, Backward dispersion models may represent promising tools. In particular, by knowing a measured downwind concentration in ambient air, they provide a numerical value for the emission rate. This paper discusses a critical validation of the WindTrax Backward model: the investigation does not only deal with the strict reliability of the model but also assesses under which conditions (i.e. stability class, number, and location of the sensors) the model shows the greatest accuracy. For this purpose, WindTrax results have been compared to observed values obtained from available experimental datasets. In addition, a sensitivity study regarding model-specific parameters required by WindTrax to replicate the physics and the random nature of atmospheric dispersion processes is discussed. This is a crucial point, since, for these settings, indications on the numerical values to be adopted are not available. From this study, it turns out that the investigated model specific settings do not lead to a significant output variation. Concerning the validation study, a general tendency of the model to predict the observed values with a good level of accuracy has been observed, especially under neutral atmospheric conditions. In addition, it seems that WindTrax underestimates the emission rate during unstable stratification and overestimates during stable con-ditions. Finally, by the definition of alternative scenarios, in which only a portion of the concentration sensors was considered, WindTrax performance appears better than acceptable even with a small number of concen-tration sensors, as long as the positioning is in the middle of the plume and not in the strict vicinity of the source

Considerazioni Critiche e di Prospettiva sulle Misure Provvisorie della Corte Internazionale Di Giustizia nel Caso Gambia c. Myanmar

L’ordinanza adottata dalla Corte internazionale di giustizia il 23 gennaio 2020, in risposta alla richiesta di misure provvisorie presentata nell’ambito della controversia Gambia c. Myanmar e relativa alla presunta violazione della Convenzione per la prevenzione e la repressione del delitto di genocidio, contiene diversi spunti interessanti che, probabilmente, incideranno sulla prosecuzione del giudizio. Il presente scritto esamina le questioni procedurali e sostanziali che emergono dalla medesima. Quanto agli aspetti procedurali, ci si soffermerà, in particolare, sul locus standi dinnanzi alla Corte di uno Stato non direttamente leso da violazioni di obblighi erga omnes partes e sulle prospettive di umanizzazione dei presupposti per l’adozione di misure cautelari in casi aventi ad oggetto gravi violazioni dei diritti umani. Quanto agli aspetti sostanziali, si verificherà l’inquadrabilità degli atti che il Gambia imputa a Myanmar nella fattispecie di genocidio, sotto il profilo dell’elemento oggettivo, della qualificabilità della popolazione Rohingya come gruppo protetto e, infine, degli ostacoli che si presentano ai fini della prova dell’elemento soggettivo, costituito dall’intento di distruggere in tutto o in parte un gruppo protetto. Nelle conclusioni si esamineranno gli sviluppi recenti e le prospettive relative alla prosecuzione del giudizio.The paper examines the procedural and substantial aspects of the order on the preliminary measures adopted by the International Court of Justice on 23 January 2020 in the Gambia v. Myanmar case

Long-term follow-up of patients with Bartter syndrome type I and II

Background. Little information is available on a long-term follow-up in Bartter syndrome type I and II. Methods. Clinical presentation, treatment and long-term follow-up (5.0-21, median 11years) were evaluated in 15 Italian patients with homozygous (n = 7) or compound heterozygous (n = 8) mutations in the SLC12A1 (n = 10) or KCNJ1 (n = 5) genes. Results. Thirteen new mutations were identified. The 15 children were born pre-term with a normal for gestational age body weight. Medical treatment at the last follow-up control included supplementation with potassium in 13, non-steroidal anti-inflammatory agents in 12 and gastroprotective drugs in five patients. At last follow-up, body weight and height were within normal ranges in the patients. Glomerular filtration rate was <90mL/min/1.73m2 in four patients (one of them with a pathologically increased urinary protein excretion). In three patients, abdominal ultrasound detected gallstones. The group of patients with antenatal Bartter syndrome had a lower renin ratio (P < 0.05) and a higher standard deviation score (SDS) for height (P < 0.05) than a previously studied group of patients with classical Bartter syndrome. Conclusions. Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10years. Gallstones might represent a new complication of antenatal Bartter syndrom

Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer's and Parkinson's diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression

Pericardial rather than epicardial fat is a cardiometabolic risk marker: an MRI vs echo study

Several studies using echocardiography identified epicardial adipose tissue (EPI) as an important cardiometabolic risk marker. However, validation compared with magnetic resonance imaging (MRI) or computed tomography has not been performed. Moreover, pericardial adipose tissue (PERI) has recently been shown to have some correlation with cardiovascular disease risk factors. The aims of this study were to validate echocardiographic analyses compared with MRI and to evaluate which cardiac fat depot (EPI or PERI) is the most appropriate cardiovascular risk marker. METHODS: Forty-nine healthy subjects were studied (age range, 25-68 years; body mass index, 21-40 kg/m(2)), and PERI and EPI fat depots were measured using echocardiography and MRI. Findings were correlated with MRI visceral fat and subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, insulin, glucose, and 10-year coronary heart disease risk. RESULTS: Most cardiac fat was constituted by PERI (about 77%). PERI thickness by echocardiography was well correlated with MRI area (r = 0.36, P = .009), and independently of the technique used for quantification, PERI was correlated with body mass index, waist circumference, visceral fat, subcutaneous fat, blood pressure, insulin sensitivity, triglycerides, cholesterol, glucose, and coronary heart disease risk. On the contrary, EPI thicknesses correlated only with age did not correlate significantly with MRI EPI areas, which were found to correlate with age, body mass index, subcutaneous fat, and hip and waist circumferences. CONCLUSIONS: Increased cardiac fat in the pericardial area is strongly associated with features of the metabolic syndrome, whereas no correlation was found with EPI, indicating that in clinical practice, PERI is a better cardiometabolic risk marker than EPI

Broad-Spectrum Inhibition of HIV-1 by a Monoclonal Antibody Directed against a gp120-Induced Epitope of CD4

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1

Leaving and returning to the parental home during COVID times in France, Italy, Germany, Spain, and the United Kingdom

BACKGROUND: During the first year of the COVID pandemic, many European young adults abandoned or delayed their plans to achieve housing autonomy, especially those facing vulnerable employment conditions and in contexts with limited welfare state provision for the young population. OBJECTIVE: The present study contributes to this body of knowledge by examining plans and behaviours associated with leaving the parental home among young individuals (aged 18 to 34) in five European countries, more than one year after the onset of the epidemic at the beginning of 2020. METHOD: Drawing on data from two waves of a cross-sectional survey conducted in May and November 2021 as part of the Youth Project, we investigate the various ways in which the living arrangements of young individuals, such as exiting or returning to the parental home, have evolved in response to the pandemic, in alignment with or in contrast to their pre-pandemic intentions. To achieve this, we employ both multinomial and logit models. RESULTS: We find that the subjective perception of economic vulnerability during the ongoing recession continues to have a negative impact on the intention to obtain or maintain housing autonomy, especially in Italy and Spain

Long-term follow-up of patients with Bartter syndrome type I and II

BACKGROUND: Little information is available on a long-term follow-up in Bartter syndrome type I and II. METHODS: Clinical presentation, treatment and long-term follow-up (5.0-21, median 11 years) were evaluated in 15 Italian patients with homozygous (n = 7) or compound heterozygous (n = 8) mutations in the SLC12A1 (n = 10) or KCNJ1 (n = 5) genes. RESULTS: Thirteen new mutations were identified. The 15 children were born pre-term with a normal for gestational age body weight. Medical treatment at the last follow-up control included supplementation with potassium in 13, non-steroidal anti-inflammatory agents in 12 and gastroprotective drugs in five patients. At last follow-up, body weight and height were within normal ranges in the patients. Glomerular filtration rate was <90 mL/min/1.73 m(2) in four patients (one of them with a pathologically increased urinary protein excretion). In three patients, abdominal ultrasound detected gallstones. The group of patients with antenatal Bartter syndrome had a lower renin ratio (P < 0.05) and a higher standard deviation score (SDS) for height (P < 0.05) than a previously studied group of patients with classical Bartter syndrome. CONCLUSIONS: Patients with Bartter syndrome type I and II tend to present a satisfactory prognosis after a median follow-up of more than 10 years. Gallstones might represent a new complication of antenatal Bartter syndrome