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Mario Cozzolino,1 Andrea Galassi,1 Ferruccio Conte,1 Michela Mangano,1 Luca Di Lullo,2 Antonio Bellasi1,3 1Department of Health Sciences, Renal Division, University of Milan, ASST Santi Paolo e Carlo, San Paolo Hospital, Milan, 2U.O.C. Nefrologia e Dialisi, Ospedale L. Parodi Delfino, Colleferro, Roma, 3Sant’Anna Hospital, ASST-Lariana, Como, Italy Abstract: Secondary hyperparathyroidism (SHPT), a very frequent, severe, and worsening complication of chronic kidney disease, is characterized by high serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and disturbances in mineral metabolism. Clinically, SHPT shows renal osteodystrophy, vascular calcification, cardiovascular damage, and fatal outcome. Calcium-sensing receptor (CaSR) is the main physiological regulator of PTH secretion; its activation by calcium rapidly inhibits PTH. Another important player in regulating mineral metabolism is vitamin D receptor (VDR), which is under the influence of vitamin D and influences the intestinal absorption of calcium and phosphate, PTH gene expression, and bone calcium mobilization. Serum phosphate levels influence fibroblast growth factor 23 (FGF-23) production, a phosphatonin that modulates serum phosphate reabsorption, PTH synthesis, and vitamin D production. Current therapeutic approaches consist of 1) phosphate intake control by diet or phosphate binders, 2) vitamin D by VDR activation, and 3) calcimimetic agents that activate CaSR. Recently, a new long-acting peptide (etelcalcetide) belonging to the calcimimetics class was approved for intravenous use in hemodialysis patients with SHPT. Etelcalcetide binds directly to CaSR, by a sulfide bond, inhibiting the production and secretion of PTH by parathyroid glands. After intravenous administration in rats, etelcalcetide is quickly distributed to the tissues and eliminated by kidneys, while in uremic animals the nonrenal excretion is only 1.2%. In hemodialysis patients, the treatment itself is the main route of elimination. Etelcalcetide in hemodialysis patients with SHPT was more effective than placebo and cinacalcet, with a PTH reduction of >30% in 76% of patients with etelcalcetide versus 10% with placebo. Particular attention was paid to the safety of the drug; the most common adverse event was asymptomatic blood calcium reduction, similar to cinacalcet, while gastrointestinal symptoms were less frequent. This promising new drug available for better control of SHPT will, together with drugs already in use, optimize the treatment to normalize the biochemical parameters. Keywords: secondary hyperparathyroidism, CKD-MBD, calcimimetic, dialysis

Abstract The anomaly known as a bifid rib is difficult to quantify in bioarchaeological collections not only because of its rarity in the population itself (less than 1.5%), but also because of vulnerability to postmortem damage of this part of the skeleton as well as similarity to other developmental anomalies, which can lead to its misidentification. This work presents five cases of rib bifurcation (from four individuals) from four different populations living in Kujawy region in north-central Poland from the Neolithic until the Early Modern Era. Morphological analyses are matched by a paleoradiological investigation. Furthermore, this study endeavours to summarize all known cases of rib bifurcation in archaeological collections and discuss the correctness of the diagnoses. Additionally, criticism of the arguments allegedly proving the presence of naevoid basal cell carcinoma syndrome (NBCCS, Gorlin-Goltz syndrome) in the archaeological populations based on available photographic data of bifurcated ribs and associated anomalies is made. Finally, a new proposal for the classification of this anomaly in osteological material is presented.

Abstract The concept of resilience has changed over time and nowadays it refers to the positive adaptation to life adversities, rather than to the absence of a pathological response normally occurring in susceptible people. Based on our previous data showing that the exposure to the chronic mild stress (CMS) paradigm differently affected bioenergetics in the ventral hippocampus of vulnerable and resilient animals, here we investigated whether resilience is a stable trait or if the energetic strategy set in motion to sustain resilience unveils a vulnerability feature in a more dynamic situation. To this aim, vulnerable and resilient rats after 6 weeks of CMS were subjected to a further acute, unfamiliar restraint stress (ARS) and metabolomic studies were conducted in the ventral hippocampus. We observed that exposure to a single novel challenge negatively affects the fuel utilization of resilient animals. Indeed, while they increase glycolysis to sustain the non-hedonic phenotype when exposed to CMS, they shift to fatty acid β-oxidation after ARS, as vulnerable animals following CMS, suggesting that the energy strategy that guarantees resilience is fragile and can be negatively modified by a different environmental condition. These results suggest that strengthening resilience to foster individuals to bounce back from stressful life events may represent a strategy to decrease vulnerability or prevent the risk of relapsing to a pathological state.

Objetivo: analisar os fatores associados a hospitalização em unidade de terapia intensiva (UTI) por síndrome respiratória aguda grave em decorrência da COVID-19 e de outros vírus respiratórios em crianças paranaenses de 0 a 5 anos nos anos de 2020 a 2022. Método: Estudo transversal, realizado a partir dos dados secundários disponibilizados no Sistema de Informação de Vigilância Epidemiológica da Gripe. Para análise utilizou-se a regressão de Poisson com variância robusta, para as variáveis respostas (hospitalização em UTI COVID-19, UTI por outros vírus respiratórios e óbitos) e variáveis independentes (faixa etária, uso de suporte ventilatório, presença de comorbidades e fatores de risco). Resultados: foram hospitalizadas 17.995 crianças, sendo 265 em UTI COVID-19 e 2.994 em UTI não COVID-19 por outros patógenos. A média de idade foi de 1,9 anos e 2,2 anos respectivamente. A raça cor/branca e o sexo masculino foi predominante em ambos os grupos. Foram registrados 184 óbitos por COVID-19, e 83 óbitos considerados por outras causas. O uso de suporte ventilatório esteve associado a todos os desfechos, a presença de comorbidades estiveram associados a necessidade de UTI independentemente do agente etiológico. Conclusão: A necessidade de suporte ventilatório esteve associada a maior hospitalização em UTI como o óbito. Crianças acometidas por SARS-CoV-2 não apresentam maior chance de ser hospitalizada em UTI frente aquelas com outros patógenos respiratórios, mas tiveram maiores chances de vir a óbito.

A osteoartrose é um distúrbio crônico, deteriorando a cartilagem articular e estruturas periarticulares, sendo uma grande causa de dor articular nos felinos senis. Gatos frequentemente desenvolvem artroses devido ao envelhecimento, obesidade e sedentarismo, fatores comuns em cativeiro. Assim, pode-se considerar que artroses em felinos selvagens são desencadeadas pelos mesmos fatores, considerando a fisiologia do gato doméstico (Felis catus) como similar aos demais membros da família Felidae. Este trabalho objetivou relatar um caso de osteoartrose lombossacra em uma leoa (Panthera leo). O animal de 20 anos de idade, do Parque Ecológico de Americana – SP, apresentava sinais de apatia e hiporexia, sendo encaminhado para o Hospital Veterinário da Faculdade de Americana (FAM), onde foram realizados exames de check-up. Não havia alterações em hemograma, enquanto no bioquímico foram observados leve hipoalbuminemia e grande aumento de amilase. Na ultrassonografia, rins apresentaram contornos sutilmente irregulares. Na endoscopia, havia hiperemia em vias respiratórias e nódulos polipoides em nasofaringe. Na laringe, foram observadas úlceras bilaterais em região subglótica e, em brônquios, malácia e fratura de anéis brônquicos. Na radiografia, foram vistos processos de mineralização das articulações esternocondrais e luxação xifoide. Na coluna vertebral, havia presença de entesófitos em vértebras, pontes anquilosantes, opacificação de forame intervertebral, perda de definição de facetas articulares, remodelamento de corpos vertebrais e estruturas puntiformes de radiopacidade mineral sobrepondo processos espinhosos. Conclui-se, portanto, que pela proximidade genética e evolutiva, deve-se atentar aos sinais de artrose em felinos selvagens, pois assim como ocorre em felinos domésticos, os fatores predisponentes comumente presentes em ambiente cativo, juntamente com a idade avançada, podem desencadear a osteoartrose.

Acknowledging the increasing urgency of climate change, many local administrations, in Italy as well as abroad, are currently elaborating their own adaptation strategy. A key step of this process is understanding the current climate, past variability and ongoing trends. Combined with the analysis of vulnerable and exposed elements, it supports the identification of key climatic impacts and risks for the territory and the elaboration of future scenarios. Several climatic datasets are available for this purpose, ranging from station observations to interpolated products and to model reanalyses, each with its own features. The study aimed to shed light on these differences and thus help practitioners make better, more informed decisions. Three gridded datasets, offering global, European and national coverage, were compared to derive a local characterization of mean climatic features, recent trends and climate extremes for the Marche Region (Central Italy). The assessment was based on temperature and precipitation variables from the global reanalysis ERA5-Land, the European observation dataset E-OBS, and the high-resolution reanalysis dynamically downscaled for Italy VHR-REA_IT. The analysis showed that large-scale products such as E-OBS and ERA5-Land can still represent a robust complement for adaptation planning. However, important limitations in describing spatial and temporal patterns need to be properly accounted for in the decision-making process. Only an integrative approach based on a multi-source data evaluation would properly address the multi-faceted aspects of climate variability on a regional scale, derive a more comprehensive analysis of past and current conditions and better manage the underlying uncertainty.

Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a role in initiation and progression of CRC, and shapes anti-tumor immune responses but how responsiveness of the immune system to the intestinal microbiota may contribute to sexual dimorphism of CRC is largely unknown. We studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n = 184 male and female CRC patients through high-dimensional single-cell flow cytometry and 16S rRNA gene sequencing. We functionally tested the immune system-microbiome interactions in in-vivo and in-vitro models of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating invariant Natural Killer T (iNKT) cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of β-glucuronidase activity are distinctive traits characterizing the gut microbiome of female patients affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. Our results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer.

Introducción: Van Eck y cols. dividieron la estructura del intercóndilo en tres tipos: tipo A, U y W. El primero asociado a mayor impingement y riesgo de lesión de LCA primario o plástica. El objetivo de este estudio es analizar la reproducibilidad intra e interobservador de la clasificación de Van Eck mediante resonancia magnética. Materiales y métodos: se evaluaron setenta imágenes de resonancia magnética de rodilla realizadas en nuestra institución, presentadas en dos tiempos. Se utilizó el índice de Kappa de Cohen (k) para evaluar la reproducibilidad intra e interobservador. Resultados: la fiabilidad intraobservador para el referente 1 fue de k: 0.71, mientras que para el segundo referente fue de k: 0.83. Se obtuvo, en promedio, una concordancia buena a muy buena según los niveles de Landis y Koch. En tanto, la concordancia interobservador obtuvo un k: 0.39 promedio, lo que nos habla de una correlación débil. Todos los resultados fueron estadísticamente significativos p

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

In 1950 on Mount Zlatý kůň (‘Golden Horse’) in modern-day Czech Republic a system of caves was discovered. During many years of research in this area, human and animal osteological remains have been excavated, among which the most interesting ones were nine fragments of a female skull, now dated to ca. 43,000 yrs BP which are one of the earliest known anatomically modern humans in Eurasia. The aim of this research was to use purely digital techniques to: (1) to reconstruct the skull based on the 3D data of preserved fragments, (2) to approximate the probable appearance of the female it belonged to, and (3) to analyze the calculated shape of the reconstructed mandible and volume of the neurocranium in the context of similarities and differences with other representatives of the genus Homo. Computer techniques used in this research constitute a new, original approach to the problem of 3D analyses and may be useful primarily in bioarchaeological sciences, where metric analyses of the most valuable bone artifacts are often severely limited due to the incompleteness of the material available for research. The digital techniques presented here may also contribute significantly to the field of surgery, with the possibility of being adapted for applications in cranial prosthetics and post-traumatic reconstructive surgery.

This study investigates the practices and rules of Genoese gilding, drawing insights from a 16th-century manuscript containing regulations for gold leaf production. Employing X-ray and ion beam techniques, we quantitatively assess the manuscript’s gold leaf thickness without destructive sampling. Artisanal goldbeater-produced leaves of different thicknesses, applied with a guazzo or mordant technique, served as standards. Further analysis of samples with unknown thickness from the furniture of Palazzo Spinola di Pellicceria in Genoa (Italy) has confirmed the method’s applicability to practical cases. External beam Rutherford backscattering spectrometry (RBS) and particle-induced X-ray emission (PIXE) analyses were carried out using 3 MeV protons at the LABEC accelerator laboratory in Florence. A linear relationship between Gold Lα peak yield and leaf thickness, as measured by RBS, has been established for optimal calibration of portable or hand-held X-Ray fluorescence (XRF) instrumentation for in situ measurements. Moreover, the caratage of the gold foil preserved in the manuscript has been assessed.