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Abstract Wilson's disease (WD) is a genetic metabolic disease strictly associated with liver cirrhosis. In this review, the genetic bases of the disease are discussed, with emphasis on the role of ATP7B (the Wilson disease protein) dysfunction as a determinant factor of systemic copper overload. Regarding the different multiple mutations described in WD patients, the peculiarity of Sardinian population is highlighted, Sardinians carrying a rare deletion in the promoter (5′ UTR) of the WD gene. The role of epigenetic changes in the clinical presentation and evolution of liver disease in WD patients is also discussed, nutrition probably representing a relevantly risk factor in WD patients. The role of transmission electron microscopy in the diagnosis of WD-related liver disease is underlined. Mitochondrial changes, increased peroxisomes fat droplets, lipolysosomes and intranuclear glycogen inclusions are reported as the most frequent ultrastructural changes in the liver of WD carriers. The role of histochemical stains for copper is analyzed, and the Timm's method is suggested as the most sensitive one for revealing hepatic copper overload in all stage of WD. The marked variability of the histological liver changes occurring in WD is underlined simple steatosis may represent the only pathological changes, frequently associated with glycogenated nuclei. Mallory-Denk bodies lipogranulomas alcoholic and non-alcoholic fatty liver disease ending with bridging fibrosis and cirrhosis. Finally, the reversal of fibrosis as a possible therapeutic objective in WD is discussed. Graphical abstract This article highlights the molecular mechanisms underlying copper trafficking inside the hepatocyte, focusing on the role of hCtr1 (the copper transporter 1) and the copper metallochaperone Atox1 in copper transfer from the sinusoidal lumen toward the Golgi Apparatus where the ATP7B (Wilson disease protein) is located. Unlabelled Image Highlights • Altered copper metabolism and liver overload • Open questions regarding the relationships between copper storage and liver disease • Morphology role is to identify the structural and ultrastructural aspects. • Liver histology and Wilson disease, non-alcoholic fatty liver disease, viral hepatitis [ABSTRACT FROM AUTHOR]

The liver is a major hematopoietic organ during embryonic and fetal development in humans. Its hematopoietic activity starts during the first weeks of gestation and continues until birth. During this period the liver is colonized by undifferentiated hematopoietic stem cells (HSCs) that gradually differentiate and once mature, enter the circulatory system through the hepatic sinusoids, this process is called hepatic hematopoiesis. The morphology of hepatic hematopoiesis, has been studied in humans through the years, and led to a characterization of all the cell types that make up these phenomena. Studies on murine models also helped to describe the extent of hepatic hematopoiesis at different gestational ages. Using this knowledge, we attempted to describe how hepatic hematopoiesis morphologically evolves as gestation progresses, in human embryos and fetuses. Thus, we observed a total of 32 tissue specimens obtained from the livers of embryos and fetuses at different gestational ages. Basing our observations on the four stages of liver hematopoiesis identified by Sasaki and Sonoda in mice, we also described four consecutive stages of liver hematopoiesis in humans, which resulted to be highly similar to those described in murine models. [ABSTRACT FROM AUTHOR]

• Trace metals have a close relationship with the Haemostatic System. • They can allow to stabilize blood clots. • They can also activate blood coagulation. In this narrative review we report the main relationships between trace metals and the hemostatic system since this aspect has seldom attracted the attention of the scientific community. A basic aspect to be considered is the importance of maintaining the fine control of all trace metals' levels since they have an important impact on the pathophysiology of the hemostatic system. It is worth noting that poor diet habits are responsible for most trace metal deficiencies, while pollution is responsible for dangerous exposure to them with a consequent negative impact on the general population. This appears of paramount importance in planning the implementation of food and nutrient support to ameliorate the hidden hunger and the quality of life of people especially in developing countries and limiting poisons both in the air and food. As it often happens, when damage to certain mechanisms takes a very long time to appear, no attention is paid to the importance of a systematic prevention to avoid late negative outcomes. [ABSTRACT FROM AUTHOR]

The preterm kidney cannot be simply considered as a kidney small in size: as compared to the adult kidney, the developing organ of the preterm infant is characterized by marked differences regarding the architecture and cell components. At macroscopy, fine linear demarcations indenting the renal surface characterize the fetal and preterm kidney. At microscopy, multiple major architectural changes differentiate the developing kidney from the adult one: a large capsule with a high cellularity; the branching ureteric bud, extending from the hilum towards the renal capsule; striking morphological differences among superficial (just born) and deep (more mature) glomeruli; persistence of remnants of the metanephric mesenchyme in the hylum; incomplete differentiation of developing proximal and distal tubules. At cellular level, kidneys of preterm infants are characterized by huge amounts of stem/precursor cells showing different degrees of differentiation, admixed with mature cell types. The most striking difference between the preterm and adult kidney is represented by the abundance of stem/progenitor cells in the former. Multiple stem cell niches may be identified in the preterm kidney, including the capsule, the sub-capsular nephrogenic zone, the cap mesenchyme embracing the ureteric bud tips, the cortical and medullary interstitium, and the hilar zone in proximity of the ureteric origin. The sub-capsular area represents the major stem cell niche in the prenatal kidney. It has been defined "blue strip", due to the scarcity of cytoplasm of the undifferentiated stem/progenitors, which appear as small cells arranged in a solid pattern. All these data taken together, the morphological approach to the analysis of the preterm kidney appears completely different from that typically utilized in kidney biopsies from adult subjects. Such a different structure should be taken into account when evaluating renal function in a preterm infant in clinical practice. Moreover, a better knowledge of molecular biology of the blue strip stem/ progenitor cells could be at the basis of a new "endogenous" regenerative medicine, finalized to maintain and protect the nephrogenic potential of preterm infants till the 36th week of post-conceptional age, allowing them to escape oligonephronia and chronic kidney disease later in life. [ABSTRACT FROM AUTHOR]

Abstract: During the first year of life the infant oral environment undergoes dramatic changes. To investigate how the salivary proteome of human children evolves during infant development we have analyzed whole saliva of 88 children aged between 0 and 48months by a top-down platform based on RP-HPLC–ESI–MS. Children were divided according to their age into five groups (A, 0–6months, N=17; B, 7–12months, N=14; C, 13–24months, N=32; D, 25–36months, N=16; E, 37–48months, N=9). The proteins and peptides analyzed were histatins (histatin-1, histatin-3 1/24), acidic proline-rich proteins, statherin, P-B peptide, and salivary cystatins. Protein and peptide quantification based on the area of the RP-HPLC–ESI–MS extracted ion current peak evidenced that: (i) concentrations of the major salivary proteins/peptides showed a minimum in the 0–6-month-old group and increased with age; (ii) the level of histatin-1 reached a maximum in the 7–12-month-old group, a minimum in the 13–24-month-aged babies and it increased again in the 25–36-month-old group; (iii) S-type cystatins were almost undetectable in the 0–6-month-old group; (iv) P-B peptide concentration greatly increased with age; (v) histatin-3 1/24 and statherin concentrations did not show any age-related variation. Biological significance: The top-down proteomic approach undertaken in this work reveals that the salivary proteome of human children from birth to 48months of age shows important quantitative modifications. The concentrations of the major salivary proteins, with the exception of statherin and histatin-3 1/24, showed a minimum in the 0–6-month-old group when the expression in salivary glands is probably not fully activated. Concentrations of the salivary proteins slowly increased with age, with different trends. Only histatin-1 showed the highest concentration in the 7–12-month-old group, followed by a decrease in the 13–24-month-aged children. This particular trend could be related to the phenomenon of eruption of primary dentition. This study gives a contribution to the knowledge on the physiological variability occurring in human saliva during the early childhood. It could represent a strong and reliable basis for further investigation of saliva to develop diagnostic and prognostic biomarkers. [Copyright &y& Elsevier]

Abstract: The aim of this review is to give a general view on the current status of the role of aluminium in human health and disease. The main aspects of aluminium metabolism in humans are covered, summarizing the state of knowledge on the absorption, distribution, retention and excretion of aluminium, giving particular emphasis to the main metabolic pathways of this metal ion in different organs. Then the pathological consequences of aluminium overload in man, its role in neurodegenerative diseases and the emerging implication of this metal ions in different pathologies are treated. Finally, the function of different chelators utilized in clinical practice in the therapy of aluminium depending diseases is discussed and the latest studies on aluminium chelators are presented. Some emphasis is given to the parallelism between iron and aluminium chelators, and in particular interesting correlations between structural parameters of these two trivalent metal ions are presented. [Copyright &y& Elsevier]

Aim Papillary thyroid carcinoma (PTC) is the most common malignant tumour of the thyroid gland. The immunohistochemical profile of PTC is characterized by immunoreactivity of tumour cells for cytokeratins, thyroglobulin, vimentin, EMA and S100 protein. Recently, the presence of a serum protease inhibitor, alpha-1-antitrypsin (A1AT), has been demonstrated in tumour cells of PTC. The aim of our study was to test immunoreactivity of PTC for another inhibitor of proteases, alpha-1-antichymotrypsin (A1ACT). Methods and results Serial paraffin sections of nine consecutive cases of PTC were tested with anti-A1AT and anti-A1ACT antibodies. No immunoreactivity for A1AT and A1ACT was found in the normal thyroid tissue surrounding each tumour. In seven out of nine cases, tumour cells of PTC showed cytoplasmic immunoreactivity for A1ACT. In two cases, A1ACT was detected even in the nuclei. Immunoreactivity for A1AT was found only in three cases. Two cases of PTC showed no staining for both A1ACT and A1AT. No significant correlation of A1ACT staining was found with various prognostic indices (age of patients, histological pattern, tumour size, presence of regional lymph node metastases). The two cases showing a lack of staining for both A1ACT and A1AT showed a more aggressive clinical behaviour. Conclusions Our preliminary study shows that A1ACT is expressed by tumour cells in a large proportion of papillary carcinomas of the thyroid gland. Its significance remains, to the best of our knowledge, still unknown. The observation of a more aggressive behaviour in the two cases characterized by the absence of immunoreactivity for both A1ACT and A1AT suggests that the presence or absence of protease inhibitors could play a role in controlling tumour progression in PTC. [ABSTRACT FROM AUTHOR]