Simulation modelling for groundwater safety in an overexploitation situation: the Maggiore Valley context (Piedmont,Italy)

The Maggiore Valley well field plays a fundamental role in supplying drinking water to a large territory of the Piedmont (north-western Italy). However, an increasing demand for water has led to the overexploitation of the groundwater resources. This situation has caused a progressive drawdown of the piezometric level (locally, up to 0.8 m/year), a spatial reduction in the artesian zone, localised land subsidence and damage to wells. The main purpose of this study was the development of a groundwater flow model of the area for analysing the aquifer response to various pumping strategies. Initially, the groundwater flow simulation (achieved by the application of the MODFLOW code) was calibrated satisfactorily. Then, the groundwater response to four scenarios was simulated to explore the best option to mitigate the problem. In three of the scenarios, a withdrawal reduction of 110 l/s was simulated, whilst considering various relocation options for extraction within the well field. The fourth scenario simulated a withdrawal reduction of 150 l/s; this option also assumed a supplementary water supply from the Monferrato Aqueduct, located north of the study area. All the simulations provided an increase in the piezometric level; in some instances, up to 30 m. Based on these simulations, the most promising management strategy for the Maggiore Valley well field would seem to be the option using a supplementary feed from the Monferrato Aqueduct. In this instance, the predicted piezometric level rise would be up to 25 m; this option also precludes the need for drilling additional wells.     

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called “gut-liver-brain axis” involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with “neuroCD”.     

Fascial Innervation: A Systematic Review of the Literature

Currently, myofascial pain has become one of the main problems in healthcare systems. Research into its causes and the structures related to it may help to improve its management. Until some years ago, all the studies were focused on muscle alterations, as trigger points, but recently, fasciae are starting to be considered a new, possible source of pain. This systematic review has been conducted for the purpose of analyze the current evidence of the muscular/deep fasciae innervation from a histological and/or immunohistochemical point of view. A literature search published between 2000 and 2021 was made in PubMed and Google Scholar. Search terms included a combination of fascia, innervation, immunohistochemical, and different immunohistochemical markers. Of the 23 total studies included in the review, five studies were performed in rats, four in mice, two in horses, ten in humans, and two in both humans and rats. There were a great variety of immunohistochemical markers used to detect the innervation of the fasciae; the most used were Protein Gene Marker 9.5 (used in twelve studies), Calcitonin Gene-Related Peptide (ten studies), S100 (ten studies), substance P (seven studies), and tyrosine hydroxylase (six studies). Various areas have been studied, with the thoracolumbar fascia being the most observed. Besides, the papers highlighted diversity in the density and type of innervation in the various fasciae, going from free nerve endings to Pacini and Ruffini corpuscles. Finally, it has been observed that the innervation is increased in the pathological fasciae. From this review, it is evident that fasciae are well innerved, their innervation have a particular distribution and precise localization and is composed especially by proprioceptors and nociceptors, the latter being more numerous in pathological situations. This could contribute to a better comprehension and management of pain.     

Quantifying the relevance and stage of disease with the Tau image technique

Discusses a complementary diagnostic imaging technique based on infrared functional imaging. It is concluded that the Tau images obtained with our method provide a large amount of information. The method, in fact, correctly depicts the ill and symptomatic situation; moreover, it is able to identify the surface projection onto the skin of the damaged areas and, by means of the evaluated value of the Tau time, the stage of the disease. Additionally, it is possible to evaluate the evolution of the clinical situation following a rehabilitation therapy and to quantitatively compare the different Tau images recorded at different times.     

Random mutagenesis of the cAMP chemoattractant receptor, cAR1, of Dictyostelium. Evidence for multiple states of activation

cAMP receptor 1 (cAR1) of Dictyostelium couples to the G protein G2 to mediate activation of adenylyl and guanylyl cyclases, chemotaxis, and cell aggregation. Other cAR1-dependent events, including receptor phosphorylation and influx of extracellular Ca2+, do not require G proteins. To further characterize signal transduction through cAR1, we performed random mutagenesis of the third intracellular loop (24 amino acids), since the corresponding region of other seven helix receptors has been implicated in the coupling to G proteins. Mutant receptors were expressed in car1(-) cells and were characterized for G protein-dependent and -independent signal transduction. Our results demonstrate that cAR1 is remarkably tolerant to amino acid substitutions in the third intracellular loop. Of the 21 positions where amino acid substitutions were observed, one or more replacements were found that retained full biological function. However, certain alterations resulted in receptors with reduced ability to bind cAMP and/or transduce signals. There were specific signal transduction mutants that could undergo cAMP-dependent cAR1 phosphorylation but were impaired either in coupling to G proteins, in G protein-independent Ca2+ influx, or in both pathways. In addition, there were general activation mutants that failed to restore aggregation to car1(-) cells and displayed severe defects in all signal transduction events, including the most robust response, cAMP-dependent cAR1 phosphorylation. Certain of these mutant phenotypes were obtained in a complementary study, where the entire region of cAR1 from the third to the seventh transmembrane helices was randomly mutagenized. Considered together, these studies indicate that the activation cycle of cAR1 may involve a number of distinct receptor intermediates. A model of G protein-dependent and -independent signal transduction through cAR1 is discussed.     

Pitfalls in the economic evaluation of thrombolysis in myocardial infarction. The impact of national differences in the cost of thrombolytics and of differences in the efficacy across patient subgroups

BACKGROUND: The economic evaluation of the results of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Artery (GUSTO) trial found that recombinant tissue plasminogen activator is more cost-effective than streptokinase for the treatment of acute myocardial infarction. AIM: We evaluated the impact on a cost effectiveness analysis, of the differences in the cost of thrombolytics among countries and of differences in efficacy across patient subgroups. METHODS: We considered the crude costs of streptokinase and recombinant tissue plasminogen activator in Germany, Italy, the United Kingdom, and the United States of America, and the 30-day mortality found in the GUSTO trial. We calculated the incremental costs for each life saved when streptokinase is substituted by recombinant tissue plasminogen activator. We also calculated the incremental costs for each life saved for two protocols implying a selective use of streptokinase and recombinant tissue plasminogen activator (age-selective protocol: recombinant tissue plasminogen activator in patients < or = 75 years, streptokinase in older patients; site-selective protocol: recombinant tissue plasminogen activator in anterior acute myocardial infarction, streptokinase in non-anterior acute myocardial infarction). RESULTS: The incremental costs for each life saved when streptokinase is substituted by recombinant tissue plasminogen activator in all GUSTO patients vary greatly among countries: the incremental costs for each life saved are 31%, 45%, and 97% higher in Germany, Italy, and the United States of America compared to the United Kingdom. The use of a site-selective protocol implies a halved cost-effectiveness ratio compared to the use of recombinant tissue plasminogen activator in all cases of acute myocardial infarction. CONCLUSIONS: (1) The cost-efficacy of recombinant tissue plasminogen activator vs streptokinase in acute myocardial infarction varies greatly among countries due to differences in the cost of drugs. (2) A selective use of thrombolytics for some sites of infarction is more cost-effective than the exclusive use of recombinant tissue plasminogen activator.     

Storage-time effects on olive oil DNA assessed by Amplified Fragments Length Polymorphisms

In this study Amplified Fragments Length Polymorphisms (AFLPs) analysis was applied on DNA extracted from different monovarietal olive oils. The aim was to study how the length of storage after milling of the oil can affect the use of DNA as an analyte for molecular traceability. Results, all assessed by statistical analyses, showed that the authentication of olive oil with molecular methods should be performed within a month from olive oil production. After this period, a significant decrease of quality of DNA extracted from olive oil was observed, with a consequent loss of information, that can affect the reliability of the results.     

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.     

Self‐Immobilizing Precatalysts: Norbornene‐Bridged Zirconium ansa‐Metallocenes

We report here the synthesis of new tethered biscyclopentadienyl and bisindenyl zirconocenes, bearing one unsaturation on the interannular bridge, and their use as self‐immobilizing catalysts. They proved to be active catalysts towards ethylene polymerization in solution, with activities comparable to those displayed by commercial rac‐Et(Ind)₂ZrCl₂. When tested as self‐polymerization catalysts under suitable experimental conditions, they gave colored precipitates that, once reactivated with MAO, were significantly active in ethylene polymerization, although lower than those of the corresponding catalytic systems in solution. The molecular weights of the produced polymers were similar to those obtained with the same catalysts in solution, but their distribution resulted to be broader, with values typical of heterogeneous catalytic systems. From ¹³C NMR studies we had the first spectroscopic evidence of the actual incorporation of a metallocene of this type into a polymeric chain.