Neuroactive steroids and diabetic complications in the nervous system.

Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.

Built-up area and population density: Two Essential Societal Variables to address climate hazard impact.

Scientists use Essential Climate Variables to understand and model the Earth's climate. Complementary to the Climate Variables this paper introduces global built-up area and population density, referred to as Essential Societal Variables, that can be used to model human activities and the impact of climate induced hazards on society. Climate impact scenarios inform policy makers on current and future risk and on the cost for mitigation and adaptation measures. The global built-up area and global population densities are generated from Earth observation image archives and from national population census data in the framework of the Global Human Settlement Layer (GHSL) project. The layers are produced with fine granularity for four epochs: 1975, 1990, 2000 and 2015, and will be updated on a regular basis with open satellite imagery. The paper discusses the relevance of global built-up area and population density for a number of policy areas, in particular to understand regional and global urbanization processes and for use in operational crisis management and risk assessment. The paper also provides examples of global statistics on exposure to natural hazards based on the two ESVs and their use in policy making. Finally, the paper discusses the potential of using population and built-up area for developing indicators to monitor the progress in Agenda 2030 including the Sustainable Development Goals (SDGs).

Axon diameter and axonal transport: In vivo and in vitro effects of androgens.

Testosterone is a sex hormone involved in brain maturation via multiple molecular mechanisms. Previous human studies described age-related changes in the overall volume and structural properties of white matter during male puberty. Based on this work, we have proposed that testosterone may induce a radial growth of the axon and, possibly, modulate axonal transport. In order to determine whether this is the case we have used two different experimental approaches. With electron microscopy, we have evaluated sex differences in the structural properties of axons in the corpus callosum (splenium) of young rats, and tested consequences of castration carried out after weaning. Then we examined in vitro the effect of the non-aromatizable androgen Mibolerone on the structure and bidirectional transport of wheat-germ agglutinin vesicles in the axons of cultured sympathetic neurons. With electron microscopy, we found robust sex differences in axonal diameter (males>females) and g ratio (males>females). Removal of endogenous testosterone by castration was associated with lower axon diameter and lower g ratio in castrated (vs. intact) males. In vitro, Mibolerone influenced the axonal transport in a time- and dose-dependent manner, and increased the axon caliber as compared with vehicle-treated neurons. These findings are consistent with the role of testosterone in shaping the axon by regulating its radial growth, as predicted by the initial human studies.

Pharmacology and toxicology of xylazine: quid novum?

The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for human use but is commonly used in veterinary medicine due to its sedative and muscle-relaxant properties. Cases of human intoxication due to accidental or voluntary use have been reported since the 1980s. However, reports of adulteration of illicit opioids (heroin and illicit fentanyl) with xylazine have been increasing all over Western countries. In humans, xylazine causes respiratory depression, bradycardia, and hypotension-posing individuals, using xylazine-adulterated opioids. We present a narrative review of the latest intoxication cases related to xylazine, to bring awareness to readers and also to help pathologists to detect and deal with xylazine cases.

Fatal acute lung injury after balloon valvuloplasty in a dog with pulmonary stenosis.

A one-year-old French Bulldog was referred for the management of a severe form of pulmonary valve stenosis (PS) complicated by right-sided congestive heart failure. Echocardiography showed severe valvular PS with right ventricular concentric hypertrophy, dilatation and severe right atrial enlargement. A pulmonary balloon valvuloplasty (PBV) was performed with a balloon-to-pulmonary annulus ratio of 1.36. Echocardiography immediately after PBV showed a significant reduction in right atrial and ventricular size, improved opening and mobility of the pulmonary valve leaflets, and a 75% reduction in the pulmonary pressure gradient from 158 mmHg pre-operative to 40 mmHg post-operative. The dog recovered well from anesthesia, but 2 h later, it suddenly showed severe respiratory distress. Focus cardiac ultrasound showed increased left cardiac size with echocardiographic signs of high left ventricular filling pressure. Bedside lung ultrasound showed diffuse numerous-to-confluent B lines, compatible with a severe alveolar-interstitial syndrome. The dog was treated with furosemide, helmet continuous positive airway pressure, and then mechanical ventilation but without success. At post-mortem evaluation, histological examination of the lung showed diffuse, severe broncho-alveolar edema with mixed leukocyte, fibrin, and red blood cell infiltrate. Moreover, severe congestion and multifocal alveolar hemorrhages were evident. All findings were compatible with fatal acute lung injury after PBV secondary to pulmonary reperfusion-ischemia injury and increased pulmonary capillary hydrostatic pressure. Based on the present case, acute lung injury should be considered as a rare but serious complication of PBV.

Histopathological markers for the diagnosis of anaphylactic death.

The postmortem diagnosis of anaphylactic death may be frustrating when victims are not hospital patients, even more so when they are recovered dead. The frequent lack of specific morphological findings in such cases means that diagnosis by the forensic pathologist must rely solely on exclusion criteria or circumstantial evidence. However, a diagnostic approach based on case history, analysis of circumstances, available clinical and necropsy findings, as well as toxicology, histopathology and biohumoral data, often allows demonstration of the cause of death. Some useful reflections on microscopic morphological data have come from two recent cases, where thorough data collection provided a reasonably certain diagnosis of anaphylactic death and systemic inflammatory response syndrome-related cardiac arrest, respectively. In both cases tissue histopathology proved crucial, since histochemical (GIEMSA) and immunohistochemical analysis (CD117 and tryptase) documented a large number of mast cells in tissues, particularly the laryngeal wall, and a discrepancy between cells positive for GIEMSA and tryptase and those positive for CD117. Staining for CD117 was also detected in cells with dendrite morphology and in a subpopulation of small lymphocytes with incised nuclei. The morphological findings of these cases are discussed, especially those obtained with immunohistochemistry, and the need for the latter data to be interpreted by experienced medical staff in the framework of a thorough analysis of all the data collected is highlighted.

SARS-CoV-2 identification in lungs, heart and kidney specimens by transmission and scanning electron microscopy.

From two COVID-19-related deaths, samples of lung, heart and kidney were collected and processed for Transmission and Scanning Electron Microscopy (TEM and SEM) with the aim of identifying the virus. Virions of SARS-CoV-2 were found in all tissues by TEM and SEM, corroborating the hypothesis that the virus enters the cells of different organs. This is the first report identifying SARS-CoV-2 in different human tissues by TEM and SEM.

A global cloud free pixel- based image composite from Sentinel-2 data.

Large-scale land cover classification from satellite imagery is still a challenge due to the big volume of data to be processed, to persistent cloud-cover in cloud-prone areas as well as seasonal artefacts that affect spatial homogeneity. Sentinel-2 times series from Copernicus Earth Observation program offer a great potential for fine scale land cover mapping thanks to high spatial and temporal resolutions, with a decametric resolution and five-day repeat time. However, the selection of best available scenes, their download together with the requirements in terms of storage and computing resources pose restrictions for large-scale land cover mapping. The dataset presented in this paper corresponds to global cloud-free pixel based composite created from the Sentinel-2 data archive (Level L1C) available in Google Earth Engine for the period January 2017- December 2018. The methodology used for generating the image composite is described and the metadata associated with the 10 m resolution dataset is presented. The data with a total volume of 15 TB is stored on the Big Data platform of the Joint Research Centre. It can be downloaded per UTM grid zone, loaded into GIS clients and displayed easily thanks to pre-computed overviews.

Closure of an unusual morphology patent ductus arteriosus with a covered stent in a dog.

Patent ductus arteriosus (PDA) with unusual morphology was diagnosed in a 3-year-old German shepherd presented for exercise intolerance. Two interventional PDA closure procedures with various Amplatzer devices and one surgical ligation were attempted to close the PDA. However, PDA closure failed with both methods due to the unusual morphology and the severe enlarged ductus ampulla. Therefore, the patient underwent an aortic covered stent placement, and successful closure of the PDA was achieved. Eight months after the procedure, the dog was free of clinical signs and no residual flow was identified through the PDA on transthoracic echocardiography. Moreover, computed tomography angiography demonstrated correct stent positioning, with no evidence of thrombus formation, damage to the stent, nor any aortic wall abnormalities. Aortic covered stent placement is a viable option in dogs with unusual PDA morphology.

Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury.

A satisfactory management to ensure a full restoration of peripheral nerve after trauma is not yet available. Using an experimental protocol, in which crush injury was applied 1 cm above the bifurcation of the rat sciatic nerve for 20 s, we here demonstrate that the levels of neuroactive steroids, such as pregnenolone and progesterone (P) metabolites (i.e. dihydroprogesterone, DHP, and tetrahydroprogesterone, THP) present in injured sciatic nerve were significantly decreased. On this basis, we have focused our attention on DHP and its direct precursor, P, analyzing whether these two neuroactive steroids may have neuroprotective effects on biochemical, functional and morphological alterations occurring during crush-induced degeneration-regeneration. We demonstrate that DHP and/or P counteract biochemical alterations (i.e. myelin proteins and Na(+),K(+)-ATPase pump) and stimulate reelin gene expression. These two neuroactive steroids also counteract nociception impairment, and DHP treatment significantly decreases the up-regulation of myelinated fibers' density occurring in crushed animals. Altogether, these observations suggest that DHP and P (i.e. two neuroactive steroids interacting with progesterone receptor) may be considered protective agents in case of nerve crush injury.

Study of inelastic nuclear interactions of 400 GeV/c protons in bent silicon crystals for beam steering purposes.

Inelastic nuclear interaction probability of 400 GeV/c protons interacting with bent silicon crystals was investigated, in particular for both types of crystals installed at the CERN Large Hadron Collider for beam collimation purposes. In comparison to amorphous scattering interaction, in planar channeling this probability is ∼ 36 % for the quasi-mosaic type (planes (111)), and ∼ 27 % for the strip type (planes (110)). Moreover, the absolute inelastic nuclear interaction probability in the axial channeling orientation, along the ⟨ 110 ⟩ axis, was estimated for the first time, finding a value of 0.6 % for a crystal 2 mm long along the beam direction, with a bending angle of 55 µ rad. This value is more than two times lower with respect to the planar channeling orientation of the same crystal, and increases with the vertical angular misalignment. Finally, the correlation between the inelastic nuclear interaction probability in the planar channeling and the silicon crystal curvature is reported.

Use of an implantable pump for controlled subcutaneous insulin delivery in healthy cats.

The aim of this study was to examine the safety and reliability of a research-grade implantable pump for controlled delivery of insulin glargine in cats. For this purpose, a small telemetrically controlled drug delivery pump with a refillable reservoir was implanted into the subcutaneous tissues of the dorsal neck in 10 clinically healthy cats. The reservoir was filled with insulin glargine, and the pump was programmed to deliver four boluses of 0.25 IU/kg, 2-3 weeks apart. As a control, insulin glargine (0.25 IU/kg) was injected SC. Blood glucose and plasma insulin glargine concentrations were measured before each bolus and SC injection and for 8 h afterward. Cats were monitored for signs of discomfort. Pumps were easily implanted and well tolerated by all cats. The experiment was completed in five of 10 cats. In four, the pump failed because of technical reasons; another cat developed severe hypoglycaemia attributable to insulin leakage. Overall, plasma insulin glargine increased after six of eight (75%) initial boluses and after one of 16 (6%) successive boluses. Glucose decreased after seven of eight (88%) initial boluses and after four of 16 (25%) successive boluses. Only the first bolus significantly increased plasma insulin glargine (P = 0.008) and decreased glucose (P = 0.008). Of 20 SC injections, 10 (50%) increased plasma insulin glargine (P <0.001) and 12 (60%) decreased glucose (P <0.001). The pump did not cause discomfort in cats, but life-threatening hypoglycaemia occurred in one. Frequent device problems suggest that the pump needs improvements. Because successive boluses did not increase plasma insulin glargine, this type of insulin may not be appropriate with the pump.

Membrane-type matrix metalloproteinase-9 activity in placental tissue from patients with pre-existing and gestational diabetes mellitus.

The activity of matrix metalloproteinase (MMP)-9 was evaluated in placental tissue from healthy subjects (controls) and from patients with gestational and pre-existing diabetes mellitus (GDM and PDM, respectively). Compared with controls, MMP-9 activity was greater in placental tissue from patients with PDM and lower in placental tissue from patients with GDM. The modulatory role of nitric oxide (NO) and reactive oxygen species (ROS) on MMP-9 activity in placental tissue was evaluated. In healthy placenta, NO synthase inhibitors diminished MMP-9 activity, whereas NO donors enhanced it. The addition of xanthine/xanthine oxidase or hydrogen peroxide to placental incubates enhanced MMP-9 activity, while the addition of superoxide dismutase (SOD) diminished it. In placental tissue from patients with PDM, MMP-9 activity was stimulated by NO and by ROS. In placental tissue from patients with PDM, concentrations of nitrates/nitrites and thiobarbituric acid-reactive substances (TBARS) were enhanced, whereas SOD activity was decreased, suggesting that elevated concentrations of NO and ROS may be related to the enhanced MMP-9 concentrations found in these tissues. In placenta from GDM patients, in which a diminished concentration of MMP-9 were detected, nitrate/nitrite concentrations were increased, but placental MMP-9 activity did not change in the presence of either NO donors or inhibitors. The activity of MMP-9 in placental tissue from patients with GDM was stimulated by ROS donor systems and was inhibited by the addition of SOD; however, TBARS and SOD concentrations were unchanged in these tissues compared with controls. These findings demonstrate that placental MMP-9 activity is modulated by NO and ROS and that, in diabetic pathology, NO and ROS may determine changes in MMP-9 activity, which are probably involved in the structural and functional abnormalities of diabetic placental tissue.

[Neonatal sepsis and perinatal risk factors]. / Sepsi neonatale e fattori di rischio perinatali.

Numerous studies have identified perinatal risk factors of neonatal sepsis. Some authors have attempted to develop a score system and have shown that babies with septicemia usually had a significantly higher score than healthy newborns and infants with other diseases. The aim of our study is to verify the validity of a scoring method based on the following items: maternal disease; e.g. diabetes, severe toxemia, infection; rupture of the membranes more than 24 hours before the delivery; foul-smelling amniotic fluid; complicated delivery; Apgar score less than 7; umbilical catheterization; respiratory distress and other neonatal diagnoses leading to operative procedures. We have evaluated four groups of babies, full-term AGA and SGA and preterm AGA and SGA, 84 with septicemia, 105 with other diseases and 210 healthy newborn infants. None of the perinatal risk factors or neonatal diseases was sufficiently predictive of neonatal septicemia. Only the incidence of umbilical catheterization was significantly higher (p less than 0.01) in preterm AGA (37.1%) and SGA (64.7%) babies with septicemia than in preterm healthy AGA (2.8%) and SGA (7.7%) babies; on the contrary, no statistical differences were found between preterm AGA (37.1%) and SGA (64.7%) infants with septicemia and preterm AGA (42.8%) and SGA (66.6%) infants with other neonatal diseases. A score of 1 was assigned for each of the considered items. In the full-term infants a score of 1 or less was found in 100% of the healthy infants. A score of 2-3 was found in 26% of the septicemic infants and in 42% of the infants with other diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Intracranial hemorrhage in congenital factor II deficiency]. / Emorragia endocranica nel deficit congenito del fattore II.

A case of congenital defect of factor II is reported. It concerns a newborn with a not traumatic haematoma due to congenital hypoprothrombinaemia, which is rarely described in scientific literature.

[Possible pathogenetic factors in hypocalcemia of low birth weight newborn infants (author's transl)]. / L'ipocalcemia del neonato di basso peso: aspetti etiopatogenetici.

The Authors studied the possible pathogenetic factors in hypocalcemia of 66 low birth weight healthy newborn infants, 28 preterm and 38 small for gestational age babies. To clarify the pathogenesis of neonatal hypocalcemia, the Authors determined daily in the first week of life serum calcium, phosphorus and magnesium concentrations, the serum natrium and kalium level and E.A.B. on capillary blood. Total serum proteins was determined on the 2nd and on the 7th day of age. The incidence of hypocalcemia was 25.7% for all considered babies: 32.1% for preterm infants and 21% for small for gestational age babies. The hypocalcemia of preterm babies appears early during the first three days of life and it results not correlated with the serum phosphorus and the serum magnesium concentrations. On the contrary the small for gestational age babies show a "late" hypocalcemia directly related with an elevated serum concentration of phosphorus and with a reduced serum magnesium level. Both the preterm and the small for gestational age newborn infants had asymptomatic hypocalcemia and the orally administration of high doses of calcium gluconate 10% was able to normalize rapidly the serum calcium level.

[Neonatal sepsis caused by coagulase-negative staphylococci]. / Sepsi neonatale da stafilococchi coagulasi-negativi.

All cases of neonatal bacteremia occurring at Neonatal Department of Pediatric Clinic, Catholic University of Rome, from January 1976 to December 1983 were examined retrospectively. Twenty-seven (30%) newborn infants with positive blood cultures for coagulase-negative staphylococcus were identified. Seven (25.9%) of the 27 infants were born at term, 4 AGA and 3 SGA; mean birth weight was 2,804 gm (range 2,280-3,670). All of these neonates had clinical evidence and laboratory signs of sepsis, and one had the cerebrospinal-fluid culture positive for coagulase-negative staphylococcus. In the remaining 20 infants (74.1%) the mean birth weight was 1,445 gm (range 810 - 2,400) and mean gestational age was 32 weeks (range 27 - 36). In 15 of the 20 preterm infants clinical signs of septicemia were associated with positive blood culture, and sixty percent of these had received an umbilical artery catheter. An half of coagulase-negative staphylococci isolated from our neonatal sepsis were DNAse-positive and/or phosphatase-positive and/or mannitol-positive. Two full-term infants, one with Down syndrome and one with cardiac malformation, died at 9 days and at 2 weeks of age, respectively. Three of 15 preterm infants with coagulas-negative staphylococcal septicemia died; deaths were among infants of very low birth weights and immature gestations who had severe respiratory syndrome. These data show that coagulase-negative staphylococcus can be important cause of septicemia in patients with compromised host defenses as newborn infants, and especially in the premature babies receiving invasive procedures.

White matter as a transport system.

There are two ways to picture white matter: as a grid of electrical wires or a network of roads. The first metaphor captures the classical function of an axon as conductor of action potentials (and information) from one brain region to another. The second one points to the important role of axons in a bi-directional transport of biological molecules and organelles between the cell body and synapse. Given the wide variety of such cargoes, a well-functioning axonal transport is critical for a number of processes, including neurotransmission, metabolism and viability of neurons. This selective review will emphasize the need for considering axonal transport when interpreting functional consequences of inter-individual variations in the structural properties of white matter. We start by describing the space occupied by white matter and techniques used in vivo for its characterization. We then provide examples of key features of maturation and aging of white matter, as well as some of the common abnormalities observed in neurodevelopmental and neurodegenerative disorders. Next, we review work that motivated our focus on axonal diameter, and explain the relationships between transport and cytoskeleton within the axon. We will conclude by describing molecular machinery of axonal transport and genes that may contribute to inter-individual variations in axonal diameter and axonal transport.

Neuroprotective effects of progesterone in chronic experimental autoimmune encephalomyelitis.

Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na(+) ,K(+) -ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment.