Background & Aims Excess fatty acid oxidation and generation of reactive carbonyls with formation of advanced lipoxidation endproducts (ALEs) is involved in nonalcoholic steatohepatitis (NASH) by ...triggering inflammation, hepatocyte injury, and fibrosis. This study aimed at verifying the hypothesis that ablation of the ALE-receptor galectin-3 prevents experimental NASH by reducing receptor-mediated ALE clearance and downstream events. Methods Galectin-3-deficient ( Lgals3−/− ) and wild type ( Lgals3+/+ ) mice received an atherogenic diet or standard chow for 8 months. Liver tissue was analyzed for morphology, inflammation, cell and matrix turnover, lipid metabolism, ALEs, and ALE-receptors. Results Steatosis was significantly less pronounced in Lgals3−/− than Lgals3+/+ animals on atherogenic diet. NASH, invariably detected in Lgals3+/+ mice, was observed, to a lower extent, only in 3/8 Lgals3−/− mice, showing less inflammatory, degenerative, and fibrotic phenomena than Lgals3+/+ mice. This was associated with higher circulating ALE levels and lower tissue ALE accumulation and expression of other ALE-receptors. Up-regulation of hepatic fatty acid synthesis and oxidation, inflammatory cell infiltration, pro-inflammatory cytokines, endoplasmic reticulum stress, hepatocyte apoptosis, myofibroblast transdifferentiation, and impaired Akt phosphorylation were also significantly attenuated in Lgals3−/− animals. Galectin-3 silencing in liver endothelial cells resulted in reduced Nε -carboxymethyllysine-modified albumin uptake and ALE-receptor expression. Conclusions Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic ALE accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis. It also reduced up-regulation of lipid synthesis and oxidation causing less fat deposition, oxidative stress, and possibly insulin resistance. These data suggest that galectin-3 is a major receptor involved in ALE uptake by the liver.
Introduction SARS-CoV-2 infection has been associated with the onset or persistence of symptoms in the long-term after the acute infection is resolved. This condition known as Post-COVID, might be ...particularly severe and potentially life-threatening. However, little is known on the impact of post-COVID condition on mortality. Aim of the present study is to assess and quantify Post-COVID deaths in Italy in years 2020 and 2021, based on an analysis of death certificates. Methods Data from the Italian National Cause of Death Register were analyzed. ICD-10 code U09.9, released by the World Health Organization in September 2020, was used to identify the ‘Post-COVID’ condition. Numbers of post-COVID deaths from October 2020 to December 2021 were analyzed. Rates of post-COVID deaths were calculated for the year 2021. Results Between October 2020 and December 2021, 4,752 death certificates reporting post-COVID condition were identified. Of these, 14.9% ( n = 706) occurred between October and December 2020 and 85.1% ( n = 4,046) in 2021. In 46.0% of post-COVID-related deaths, the underlying cause of death was COVID-19. Other frequent underlying causes were heart disease (14.3% of cases), neoplasms (9.2%), cerebrovascular diseases (6.3%) and Alzheimer’s disease and other dementias (5.5%). The mortality rate related to post-COVID conditions in year 2021 was 5.1 deaths per 100 thousand inhabitants and it increased with increasing age. Men showed a higher mortality rate than women (4.3 deaths per 100 thousand in women and 6.0 deaths per 100 thousand in men). Discussion Post-COVID conditions contributed to a substantial number of deaths in Italy. Strategies to identify the population at risk of severe long-term consequences of SARS-CoV-2 infection and interventions aimed at reducing this risk must be developed.
In adult population, Growth Hormone Deficiency (GHD) is a complex clinical condition with heterogeneity of causes and duration. Growth Hormone (GH) replacement therapy has beneficial effects ...entailing a chronic and expensive use. Therefore, entity, appropriateness and standardization of GHD treatment need to be accurately analysed. In Italy, the epidemiological surveillance on somatropin therapy is entrusted to the National Register of Growth Hormone Therapy (Registro Nazionale degli Assuntori dell'Ormone della Crescita-RNAOC) by the Italian Regulation, in accordance of which the RNAOC-database is collecting the notifications of somatropin prescriptions.
Aim of this study is to analyse data on somatropin-treated adult population communicated to the RNAOC by the specialist centres of 15 Italian regions and 2 autonomous provinces.
From 2011 to 2019, the somatropin-treated adults were 970 with 4061 examinations (1.21 ± 0.33 visits/year). The diagnoses were: hypopituitarism (n = 579); hypophysectomy (n = 383); and congenital GHD (n = 3). Five subjects were addressed with diagnoses not included in the regulation. The starting posology of somatropin was 0.320 (± 0.212) mg/day, 0.292 (± 0.167) mg/day in male and 0.360 (± 0.258) in female patients, with 7 administrations/week in 70.31% of the prescriptions. The differences in posology by gender persisted at 10th year of the follow-up. Starting dosage was higher in patients diagnosed with adult GHD before the age of 30 (0.420 ± 0.225 mg/day), with a progressive decrease of the dosage during the follow-up.
This is the first report on adult GH treatment, describing numbers, diagnoses, and pharmaceutical prescriptions associated to somatropin therapy in a large cohort of Italian GHD-adults.
In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal ...cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM) and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG) was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.
Müller cell activation is an early finding in diabetic retinopathy (DR), but its physiopathologic role in the disease is still unclear, especially in the early phases. We investigated on Müller glial ...activation in primary rat retinal cultures, exposed to High Glucose (HG), and in retinas from streptozotocin (stz)-induced diabetic rats. First of all, we checked if the presence of Müller glia influenced HG neurotoxicity. In mixed glial/neuronal retinal cultures, a single HG administration (sHG) for 48 h induced activation of Müller glia, in absence of neuronal damage. In contrast, in pure neuronal cultures, a marked neurotoxic effect was detected, suggesting that in this cell model Müller glia protect neurons from HG neurotoxicity. To better mimic the diabetic milieu, where retinal cells are constantly bathed in hyperglycemic fluid, and to further characterize astrocytic neuroprotective ability, mixed retinal cultures were exposed to repeated daily replacement of HG (rHG). In this paradigm, starting from 48 h, increased apoptosis and synaptic loss were observed, even in the presence of Müller cells. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whose activation triggers a prosurvival pathway, was increased by sHG, while it was down-regulated by rHG, suggesting that ERK1/2 activation is involved in neuroprotection. Consistently, in presence of ERK1/2 inhibitor PD98059, sHG exerted a proapoptotic effect also in glial/neuronal retinal cultures. In line with the in vitro data, early changes in diabetic retinas from stz-injected rats included Müller cell activation and increased pERK1/2 levels, but no signs of neuronal damage. These results suggest that, in the early phases of DR, Müller glial activation does not contribute to neurodegeneration, but may indeed have a neuroprotective activity against HG-induced neurotoxicity through a mechanism involving pERK1/2.
•The diabetic milieu is not toxic for retinal neurons in presence of Müller glia.•Müller glia neuroprotection against diabetic milieu depends on ERK1/2 activation.•Early activation of Müller glia in diabetes is not associated with neuronal damage.
Despite the growing clinical relevance of Long-COVID, there is minimal information available on the organizational response of health services to this condition.
A national online survey of centers ...providing assistance for Long-COVID was implemented. Information collected included date of start of activity, target population, mode of assistance and of referral, type and number of specialists available, diagnostic and instrumental tests, use of telemedicine and of specific questionnaires.
Between February and May 2022, 124 centers completed the survey. Half of them were situated in northern Italy. Most (88.9%) provided assistance through either outpatient visits or day hospital services. Eleven (8.9%) assisted pediatric patients. Access to centers included scheduled visits for previously hospitalized patients (67.7%), referral from primary care (62.1%), from other specialists (46.8%), and, less commonly, from other services. Almost half of the centers (46.3%) started their activity early in the pandemics (March-September 2020). Almost all (93.5%) communicated with primary care physicians, and 21.8% used telemedicine tools. The mean number of patients followed was 40 per month (median 20, IQR 10-40). In most cases, the center coordinator was a specialist in respiratory diseases (30.6%), infectious diseases (28.2%), or internal medicine (25.0%). At least half of the centers had specialistic support in cardiology, respiratory diseases, radiology, infectious diseases, neurology and psychology, but roughly one quarter of centers had just only one (14.5%) or two (9.7%) specialists available. The clinical assessment was usually supported by a wide range of laboratory and instrumental diagnostics and by multidimensional evaluations.
Most of the centers had an articulate and multidisciplinary approach to diagnosis and care of Long-COVID. However, a minority of centers provided only single or dual specialistic support. These findings may be of help in defining common standards, interventions and guidelines that can reduce gaps and heterogeneity in assistance to patients with Long-COVID.
A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, ...commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients.
Recombinant human growth hormone (rhGH) is an approved and effective treatment for short children born small for gestational age (SGA). Prevalence of children eligible for treatment as SGA is ...reported to be 1:1800. The latest data from the National Registry of Growth Hormone therapy (RNAOC) showed that the number of children treated with SGA indication is still small (prevalence 0.37/100,000) and these children are significantly less reported than those treated for growth hormone deficiency (GHD), although GHD prevalence is 1:4000-1:10,000. This means that many short children born SGA are still not properly identified, and therefore not treated with rhGH, or misdiagnosed as GHD. This article provides some practical tools for the identification of children eligible for rhGH treatment.
ABSTRACT
We previously showed that mice lacking galectin‐3/AGE‐receptor 3 develop accelerated diabetic glomerulopathy. To further investigate the role of galectin‐3/AGE‐receptor function in the ...pathogenesis of diabetic renal disease, galectin‐3 knockout (KO) and coeval wild‐type (WT) mice were injected for 3 months with 30 μg/day of Nε‐carboxymethyllysine (CML)‐modified or unmodified mouse serum albumin (MSA). Despite receiving equal doses of CML, KO had higher circulating and renal AGE levels and showed more marked renal functional and structural changes than WT mice, with significantly higher proteinuria, albuminuria, glomerular, and mesangial area and glomerular sclerosis index. Renal 4‐hydroxy‐2‐nonenal content and NFκB activation were also more pronounced in KO‐CML vs. WT‐CML. Kidney mRNA levels of fibronectin, laminin, collagen IV, and TGF‐β were up‐regulated, whereas those of matrix metalloproteinase‐2 and ‐14 were down‐regulated, again more markedly in KO‐CML than WT‐CML mice. Basal and CML‐induced RAGE and 80K‐H mRNA levels were higher in KO vs. WT mice. MSA injection did not produce any significant effect in both genotypes. The association of galectin‐3 ablation with enhanced susceptibility to AGE‐induced renal disease, increased AGE levels and signaling, and altered AGE‐receptor pattern indicates that galectin‐3 is operating in vivo as an AGE receptor to afford protection toward AGE‐dependent tissue injury.
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