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Background: Acquired brain injury (ABI), especially to the right hemisphere, can result in difficulty using or understanding prosodic contours in speech. Prosody is used to convey emotional connotation or linguistic intent and includes pitch, loudness, rate, and voice quality. A disorder in the comprehension or production of prosody is known as aprosodia; despite the communication disability caused by prosodic disorders, the assessment and treatment of aprosodia following ABI has received scant attention. Aims: The aim of this scoping review is to gather and synthesise useful knowledge on aprosodia and provide therapists with an exhaustive document in order to guide clinical decision-making encouraging active identification and treatment of this disorder. Methods & Procedures: This scoping review, conducted in accordance with PRISMA-ScR guidelines, investigated the existing literature concerning the assessment and treatments of linguistic and affective aprosodia in adult patients after ABI. A systematic search in four electronic databases (PubMed, CINAHL, Web of Science, ScienceDirect) was conducted for articles written in English, French, or Italian published between 1970 and 2020. After all evaluative criteria were applied, 15 articles were included for final review. Outcomes & Results: Results show the presence of six assessment tools for affective aprosodia and five evaluation tools targeting affective and linguistic prosody. Assessment of aprosodia is generally accomplished through acoustic and perceptual approaches. Current treatments for prosodic disorders focus on expressive aprosodia and have applied mostly two different approaches: imitative and cognitive-linguistic methods. Conclusion & Implications: Findings suggest that aprosodia can be assessed by therapists through various techniques and may be amenable to behavioural treatments. Nevertheless, although there are several assessment tools available, no one currently offers a comprehensive assessment that incorporates an ecological dimension. It therefore seems necessary to continue research in this direction. The rehabilitation of receptive prosody abilities also remains to be explored.

Abstract Background Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment. In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy. Methods/Design Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests. Discussion This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies. Trial Registration Current Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21

New intervention tools for severely damaged kidneys are in great demand to provide patients with a valid alternative to whole organ replacement. For repairing or replacing injured tissues, emerging approaches focus on using stem and progenitor cells. Embryonic kidneys represent an interesting option because, when transplanted to sites such as the renal capsule of healthy animals, they originate new renal structures. Here, we studied whether metanephroi possess developmental capacity when transplanted under the kidney capsule of MWF male rats, a model of spontaneous nephropathy. We found that six weeks post-transplantation, renal primordia developed glomeruli and tubuli able to filter blood and to produce urine in cyst-like structures. Newly developed metanephroi were able to initiate a regenerative-like process in host renal tissues adjacent to the graft in MWF male rats as indicated by an increase in cell proliferation and vascular density, accompanied by mRNA and protein upregulation of VEGF, FGF2, HGF, IGF-1 and Pax-2. The expression of SMP30 and NCAM was induced in tubular cells. Oxidative stress and apoptosis markedly decreased. Our study shows that embryonic kidneys generate functional nephrons when transplanted into animals with severe renal disease and at the same time activate events at least partly mimicking those observed in kidney tissues during renal regeneration. [ABSTRACT FROM AUTHOR]

Background: Despite new therapeutic approaches have improved the prognosis of newborns with retinopathy of prematurity (ROP), an unfavourable structural and functional outcome still remains high. There is high pressure to develop new drugs to prevent and treat ROP. There is increasing enthusiasm for anti-VEGF drugs, but angiogenic inhibitors selective for abnormal blood vessels would be considered as an optimal treatment. In an animal experimental model of proliferative retinopathy, we have recently demonstrated that the pharmacological blockade of beta-adrenoreceptors improves retinal neovascularization and blood retinal barrier breakdown consequent to hypoxia. The purpose of this study is to evaluate the propranolol administration in preterm newborns suffering from a precocious phase of ROP in terms of safety and efficacy in counteracting the progression of retinopathy. Methods/Design: Preterm newborns (gestational age at birth lower than 32 weeks) with stage 2 ROP (zone II-III without plus) will be randomized, according to their gestational age, to receive propranolol added to standard treatment (treatment adopted by the ETROP Cooperative Group) or standard treatment alone. Propranolol will be administered until retinal vascularization will be completely developed, but not more than 90 days. Forty-four participants will be recruited into the study. To evaluate the safety of propranolol administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of propranolol, the progression of the disease, the number of laser treatments or vitrectomies, the incidence of retinal detachment or blindness, will be evaluated by serial ophthalmologic examinations. Visual function will be evaluated by means of behavioural standardized tests. Discussion: This pilot study is the first research that explores the possible therapeutic role of beta blockers in ROP. The objective of this research is highly ambitious: to find a treatment simple, inexpensive, well tolerated and with few adverse effects, able to counteract one of the major complications of the prematurity. Any favourable results of this research could open new perspectives and original scenarios about the treatment or the prevention of this and other proliferative retinopathies. Trial Registration: Current Controlled Trials ISRCTN18523491; ClinicalTrials.gov Identifier NCT01079715; EudraCT Number 2010-018737-21. [ABSTRACT FROM AUTHOR]

Thermotolerant Campylobacter spp. are frequently the cause of human gastroenteritis and have assumed more importance in Italy following the increased consumption of raw milk. Our objectives were to determine the prevalence and genotypes of Campylobacter spp. in dairy herds and to investigate the possible sources of bulk milk contamination. Bulk milk from dairy herds (n = 282) was cultured for Campylobacter spp. and Enterobacteriaceae. At three Campylobacter jejuni-positive farms, bovine feces, pigeon intestines, milk, and water points were also investigated. Isolates were identified by PCR and genotyped using multilocus sequence typing (MLST). C. jejuni was detected in 34 (12%) bulk milk samples. The strains belonged to 14 sequence types, and the most common clonal complexes were CC-21, CC-48, and CC-403. No association was demonstrated between the presence of C. jejuni and high levels of Enterobacteriaceae in bulk milk. At the three farms examined, C. jejuni was isolated from bovine feces (25/82 [30.5%]), pigeon intestines (13/60 [21.7%]), bulk milk (10/24 [41.7%]), and water points (4/16 [25%]). MLST revealed lineages that were common between milk and bovine feces but distinct between cattle and pigeons. In one herd, C. jejuni with the same genotype was isolated repeatedly from bulk milk and a cow with an udder infection. Our results showed a high prevalence of C. jejuni in bulk milk and suggested that udder excretion, in addition to fecal matter, may be a route of bulk milk contamination. MLST analysis indicated that pigeons are probably not relevant for the transmission of C. jejuni to cattle and for milk contamination. [ABSTRACT FROM AUTHOR]

Abstract: ST1968, a novel hydrophilic camptothecin analogue of the 7-oxyiminomethyl series, is characterised by the formation of stable DNA–topoisomerase I cleavable complex and by a promising profile of antitumour activity. The present study was designed to extend preclinical evaluation of the novel camptothecin in human squamous cell carcinoma (SCC) models. ST1968 exhibited an impressive activity with a high cure rate in SCC models. ST1968 produced 100% of complete response without evidence of regrowth in tumours characterised by susceptibility to drug-induced apoptosis (FaDu, A431 and A2780). In contrast to irinotecan, ST1968 still showed an excellent, persisting activity in models less susceptible to apoptosis induction (KB, Caski and SiHa), in which drug treatment elicited a persistent DNA damage response, as documented by phosphorylation of p53, RPA-2 and histone H2AX, resulting in delayed apoptosis and senescence. This behaviour was associated with a marked cellular/tumour drug accumulation. In conclusion, ST1968 exhibited an outstanding antitumour activity superior to that of irinotecan against SCC. A high intracellular accumulation, resulting in fast apoptosis or DNA damage persistence, appeared to be a critical determinant of SCC sensitivity to ST1968. [Copyright &y& Elsevier]

Thyroid hormone (TH) signaling is a universal regulator of metabolism, growth, and development. Here, we show that TH-TH receptor (TH-TR) axis alterations are critically involved in diabetic nephropathy-associated (DN-associated) podocyte pathology, and we identify TRα1 as a key regulator of the pathogenesis of DN. In ZSF1 diabetic rats, T3 levels progressively decreased during DN, and this was inversely correlated with metabolic and renal disease worsening. These phenomena were associated with the reexpression of the fetal isoform TRα1 in podocytes and parietal cells of both rats and patients with DN and with the increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In diabetic rats, TRα1-positive cells also reexpressed several fetal mesenchymal and damage-related podocyte markers, while glomerular and podocyte hypertrophy was evident. In vitro, exposing human podocytes to diabetes milieu typical components markedly increased TRα1 and DIO3 expression and induced cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, the maladaptive cell cycle induction/arrest, and TRα1-ERK1/2-mediated hypertrophy. Strikingly, T3 treatment reduced TRα1 and DIO3 expression and completely reversed all these alterations. Our data show that diabetic stress induces the TH-TRα1 axis to adopt a fetal ligand/receptor relationship pattern that triggers the recapitulation of the fetal podocyte phenotype and subsequent pathological alterations.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially lethal monogenic human disorder. There is currently no cure for ADPKD. The mechanistic complexity of the disease, the absence of animal models that can faithfully mimic the disease, as well as the lack of functional human in vitro assays for compound testing, have made drug discovery for PKD very difficult. We recently developed an engineering platform that allowed us to generate polycystic tubules using patients' own cells to test drug efficacy and discover potential new pharmacological treatments for PKD. Here we describe an engineering platform that enables the generation of custom-made polycystic tubules using patients' own cells for modeling PKD and testing drug efficacy., (© 2019 Elsevier Inc. All rights reserved.)

Novel methods in developmental biology and stem cell research have made it possible to generate complex kidney tissues in vitro that resemble whole organs and are termed organoids. In this chapter we describe a technique using suspensions of fully dissociated mouse kidney cells to yield organoids that can become vascularized in vivo and mature and display physiological functions. This system can be used to produce fine-grained human-mouse chimeric organoids in which the renal differentiation potential of human cells can be assessed. It can also be an excellent method for growing chimeric organoids in vivo using human stem cells, which can differentiate into specialized kidney cells and exert nephron-specific functions. We provide detailed methods, a brief discussion of critical points, and describe some successfully implemented examples of the system.

The lack of engineering systems able to faithfully reproduce complex kidney structures in vitro has made it difficult to efficiently model kidney diseases and development. Using polydimethylsiloxane (PDMS) scaffolds and a kidney-derived cell line we developed a system to rapidly engineer custom-made 3D tubules with typical renal epithelial properties. This system was successfully employed to engineer patient-specific tubules, to model polycystic kidney disease (PKD) and test drug efficacy, and to identify a potential new pharmacological treatment. By optimizing our system we constructed functional ureteric bud (UB)-like tubules from human induced pluripotent stem cells (iPSCs), and identified a combination of growth factors that induces budding morphogenesis like embryonic kidneys do. Finally, we applied this assay to investigate budding defects in UB-like tubules derived from a patient with a PAX2 mutation. Our system enables the modeling of human kidney disease and development, drug testing and discovery, and lays the groundwork for engineering anatomically correct kidney tissues in vitro and developing personalized medicine applications., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three-dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption. Exploiting this technology, we mixed human amniotic fluid stem cells with mouse embryonic kidney cells to establish three-dimensional chimeric organoids that engrafted in vivo and grew to form vascularized glomeruli and tubular structures. Human cells contributed to the formation of glomerular structures, differentiated into podocytes with slit diaphragms, and internalized exogenously infused BSA, thus attaining in vivo degrees of specialization and function unprecedented for donor stem cells. In conclusion, human amniotic fluid stem cell chimeric organoids may offer new paths for studying renal development and human podocyte disease, and for facilitating drug discovery and translational research., (Copyright © 2016 by the American Society of Nephrology.)

The application of cell-based therapies in regenerative medicine is gaining recognition. Here, we show that human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal cells, can be reprogrammed into renal proximal tubular-like epithelial cells using cell-free extracts. Streptolysin-O-permeabilized BMSCs exposed to HK2-cell extracts underwent morphological changes-formation of "domes" and tubule-like structures-and acquired epithelial functional properties such as transepithelial-resistance, albumin-binding, and uptake and specific markers E-cadherin and aquaporin-1. Transmission electron microscopy revealed the presence of brush border microvilli and tight intercellular contacts. RNA sequencing showed tubular epithelial transcript abundance and revealed the upregulation of components of the EGFR pathway. Reprogrammed BMSCs integrated into self-forming kidney tissue and formed tubular structures. Reprogrammed BMSCs infused in immunodeficient mice with cisplatin-induced acute kidney injury engrafted into proximal tubuli, reduced renal injury and improved function. Thus, reprogrammed BMSCs are a promising cell resource for future cell therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The shortage of transplantable organs provides an impetus to develop tissue-engineered alternatives. Producing tissues similar to immature kidneys from simple suspensions of fully dissociated embryonic renal cells is possible in vitro, but glomeruli do not form in the avascular environment. Here, we constructed renal organoids from single-cell suspensions derived from E11.5 kidneys and then implanted these organoids below the kidney capsule of a living rat host. This implantation resulted in further maturation of kidney tissue, formation of vascularized glomeruli with fully differentiated capillary walls, including the slit diaphragm, and appearance of erythropoietin-producing cells. The implanted tissue exhibited physiologic functions, including tubular reabsorption of macromolecules, that gained access to the tubular lumen on glomerular filtration. The ability to generate vascularized nephrons from single-cell suspensions marks a significant step to the long-term goal of replacing renal function by a tissue-engineered kidney.

Human amniotic fluid stem (hAFS) cells, a novel class of broadly multipotent stem cells that share characteristics of both embryonic and adult stem cells, have been regarded as promising candidate for cell therapy. Taking advantage by the well-established murine model of acute kidney injury (AKI), we studied the proregenerative effect of hAFS cells in immunodeficient mice injected with the nephrotoxic drug cisplatin. Infusion of hAFS cells in cisplatin mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival. Human AFS cells engrafted injured kidney predominantly in peritubular region without acquiring tubular epithelial markers. Human AFS cells exerted antiapoptotic effect, activated Akt, and stimulated proliferation of tubular cells possibly via local release of factors, including interleukin-6, vascular endothelial growth factor, and stromal cell-derived factor-1, which we documented in vitro to be produced by hAFS cells. The therapeutic potential of hAFS cells was enhanced by cell pretreatment with glial cell line-derived neurotrophic factor (GDNF), which markedly ameliorated renal function and tubular injury by increasing stem cell homing to the tubulointerstitial compartment. By in vitro studies, GDNF increased hAFS cell production of growth factors, motility, and expression of receptors involved in cell homing and survival. These findings indicate that hAFS cells can promote functional recovery and contribute to renal regeneration in AKI mice via local production of mitogenic and prosurvival factors. The effects of hAFS cells can be remarkably enhanced by GDNF preconditioning.

Because cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib.