Hyponatremia, hypernatremia and impairment of functional, psychological and sexual domains.

OBJECTIVE: To determine the influence of serum sodium on physical, psychologic and sexual function. METHODS: This is a cross-sectional survey on 3340 community-dwelling men aged 40-79 years from a prospective cohort study in eight European countries, the European Male Ageing Study (EMAS). Participants filled-out the Short Form-36 (SF-36), the Physical Activity Scale for the Elderly (PASE), and the EMAS sexual function questionnaire. For all the analyses, serum sodium corrected for glycaemia ([Na+]G) was used. RESULTS: The relationship between [Na+]G and SF-36 physical function score (F = 3.99; p = 0.01), SF-36 mental health score (F = 7.69; p < 0.001), and PASE score (F = 14.95; p < 0.001) were best described by a quadratic equation, with worse scores for [Na+]G in either the lowest or the highest ends of the range. After dividing the sample into [Na+]G < 136 mmol/L (n = 81), 136-147 mmol/L (n = 3223) and > 147 mmol/L (n = 36), linear regression analyses with linear spline functions adjusted for confounders did not confirm these relationships. Similarly, erectile dysfunction and [Na+]G, were in a quadratic relationship (F = 9.00; p < 0.001). After adjusting for confounders, the linear regression with spline functions denoted a significantly worsened erectile function for increases in serum [Na+]G > 147 mmol/L (B = 0.15 [0.04;0.26], p < 0.01) but no relationship with [Na+]G < 136 mmol/L. Likewise, the relationship of [Na+]G with concerns about sexual dysfunction was confirmed only for men with serum [Na+]G > 147 mmol/L. CONCLUSIONS: This is the first study supporting an association between [Na+]G and sexual function. A worsening of erection and concerns about sexual function were observed for the highest values of [Na+]G, independently of other relevant factors.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Hyponatremia-related liver steatofibrosis and impaired spermatogenesis: evidence from a mouse model of the syndrome of inappropriate antidiuresis.

PURPOSE: Hyponatremia is the most frequent electrolytic disorder in clinical practice. In addition to neurological symptoms, hyponatremia, even when mild/moderate and chronic, has been related to other manifestations, such as bone demineralization and increased risk of fractures. To better elucidate tissue alterations associated with reduced serum sodium concentration [Na+], we developed an in vivo model of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. METHODS AND RESULTS: Hyponatremia was induced in Foxn1nu/nu mice by subcutaneous infusion of the vasopressin analog 1-deamino [8-D-arginine] vasopressin (dDAVP) for 14 days via osmotic mini-pumps. Mice in the control group were infused with isotonic saline solution. Serum [Na+] progressively decreased, with a nadir of 123.4 ± 2.3 mEq/L (mean ± SD, dDAVP 0.3 ng/h) and 111.6 ± 4.7 mEq/L (mean ± SD, dDAVP 0.5 ng/h). Evident signs of liver steatofibrosis were observed at histology in hyponatremic mice. Accordingly, the expression of proteins involved in lipid metabolism (SREBP-1, PPARα and PPARγ) and in myofibroblast formation (αSMA and CTGF) significantly increased. Furthermore, heme oxygenase 1 expression was up-regulated in Kupffer and hepatic stellate cells in the liver of hyponatremic mice. Testis alterations were also observed. In particular, the thickness of the seminiferous epithelium appeared reduced. The expression levels of PCNA and PTMA, which are involved in DNA replication and germ cells maturation, were markedly reduced in the testis of hyponatremic mice. CONCLUSION: Overall, these findings shed new light on the possible consequences of chronic hyponatremia and prompt a more thorough evaluation of hyponatremic patients.

Relationship between hyponatremia at hospital admission and cardiopulmonary profile at follow-up in patients with SARS-CoV-2 (COVID-19) infection.

PURPOSE: Hyponatremia occurs in about 30% of patients with pneumonia, including those with SARS-CoV-2 (COVID-19) infection. Hyponatremia predicts a worse outcome in several pathologic conditions and in COVID-19 has been associated with a higher risk of non-invasive ventilation, ICU transfer and death. The main objective of this study was to determine whether early hyponatremia is also a predictor of long-term sequelae at follow-up. METHODS: In this observational study, we collected 6-month follow-up data from 189 laboratory-confirmed COVID-19 patients previously admitted to a University Hospital. About 25% of the patients (n = 47) had hyponatremia at the time of hospital admission. RESULTS: Serum [Na+] was significantly increased in the whole group of 189 patients at 6 months, compared to the value at hospital admission (141.4 ± 2.2 vs 137 ± 3.5 mEq/L, p < 0.001). In addition, IL-6 levels decreased and the PaO2/FiO2 increased. Accordingly, pulmonary involvement, evaluated at the chest X-ray by the RALE score, decreased. However, in patients with hyponatremia at hospital admission, higher levels of LDH, fibrinogen, troponin T and NT-ProBNP were detected at follow-up, compared to patients with normonatremia at admission. In addition, hyponatremia at admission was associated with worse echocardiography parameters related to right ventricular function, together with a higher RALE score. CONCLUSION: These results suggest that early hyponatremia in COVID-19 patients is associated with the presence of laboratory and imaging parameters indicating a greater pulmonary and right-sided heart involvement at follow-up.

Austropuccinia psidii uses tetrapolar mating and produces meiotic spores in older infections on Eucalyptus grandis.

Austropuccinia psidii is the causal agent of myrtle rust, a fungal disease that infects over 480 species in the Myrtaceae. A. psidii is a biotrophic pathogen that reproduces sexually and asexually. Sexual reproduction has been previously shown on Syzygium jambos and little is known about its reproductive biology on other hosts or whether populations that were formerly structured by host range can outcross on universally susceptible hosts. We investigated if mating genes in three genomes of A. psidii were under selection as a proxy for whether different strains can reproduce sexually on a shared host. We examined three homologs of the STE3.2 gene, sequences of which were near-identical in the three genomes, and the homeodomain locus, which contained two alleles of two homeodomain genes in each genome. A. psidii likely uses tetrapolar mating. Pheromone/receptor loci were distal to homeodomain loci, and based on haplotypes of a phased assembly, mate compatibility is regulated by multiallelic HD genes and biallelic STE3.2 genes; the third homolog of STE3.2 (STE3.2-1) was present in both haplotypes, and our study supports hypotheses this gene does not regulate mate recognition. Populations of A. psidii formerly structured by host range could potentially outcross on universal hosts based on their related mating genes, however this hypothesis should remain theoretical given the implications for biosecurity. Additionally, we searched for core meiotic genes in genomes of A. psidii, four species of Puccinia, and Sphaerophragmium acaciae through comparative genomics based on 136 meiosis-related orthologous genes modeled from Mycosarcoma maydis. Meiotic genes are conserved in rust fungi at family rank. We analyzed the expression of two meiotic and four mitotic genes of A. psidii on E. grandis over a 28-day time course to validate that identified meiotic genes were upregulated in teliospores. Three mitotic genes were significantly downregulated in samples collected 28 days after inoculation (DAI) compared to 14 DAI. Expression of meiotic genes was significantly up-regulated in samples collected 28 DAI compared to 14 DAI, indicating a temporal switch from production of uredinia (mitotic stage) to telia in the life cycle, which we hypothesize may be in response to leaf ageing.

Technical details for a robot-assisted hand-sewn esophago-gastric anastomosis during minimally invasive Ivor Lewis esophagectomy.

BACKGROUND: Minimally invasive Ivor Lewis esophagectomy (MIILE) provides better outcomes than open techniques, particularly in terms of post-operative recovery and pulmonary complications. However, in addition to requiring advanced technical skills, thoracoscopic access makes it hard to perform esophagogastric anastomosis safely, and the reported rates of anastomotic leak vary from 5 to 16%. Several minimally invasive esophago-gastric anastomotic techniques have been described, but to date strong evidence to support one technique over the others is still lacking. We herein report the technical details and preliminary results of a new robot-assisted hand-sewn esophago-gastric anastomosis technique. METHODS: From January 2018 to December 2020, 12 cases of laparoscopic/thoracoscopic Ivor Lewis esophagectomy with robot-assisted hand-sewn esophago-gastric anastomosis were performed. The gastric conduit was prepared and tailored taking care of vascularization with a complete resection of the gastric fundus. The anastomosis consisted of a robot-assisted, hand-sewn four layers of absorbable monofilament running barbed suture (V-lock). The posterior outer layer incorporated the gastric and esophageal staple lines. RESULTS: The post-operative course was uneventful in nine cases. Two patients developed chyloperitoneum, one patient a Sars-Cov-2 infection, and one patient a late anastomotic stricture. In all cases, there were no anastomotic leaks or delayed gastric conduit emptying. The median post-operative stay was 13 days (min 7, max 37 days); the longest in-hospital stay was recorded in patients who developed chyloperitoneum. CONCLUSION: Despite the small series, we believe that our technique looks to be promising, safe, and reproducible. Some key points may be useful to guarantee a low complications rate after MIILE, particularly regarding anastomotic leaks and delayed emptying: the resection of the gastric fundus, the use of robot assistance, the incorporation of the staple lines in the posterior aspect of the anastomosis, and the use of barbed suture. Further cases are needed to validate the preliminary, but very encouraging, results.

The V2 receptor antagonist tolvaptan counteracts proliferation and invasivity in human cancer cells.

PURPOSE: Hyponatremia, the most frequent electrolyte alteration in clinical practice, has been associated with a worse prognosis in cancer patients. On the other hand, a better outcome has been related to serum sodium normalization. In vitro studies have shown that low extracellular sodium promotes cancer cells proliferation and invasiveness. Tolvaptan, a selective vasopressin receptor type 2 (V2) antagonist, has been effectively used in the last decade for the treatment of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. A few in vitro data suggested a direct role of tolvaptan in counteracting cancer progression, so far. The aim of this study was to evaluate the effect and the mechanism of action of tolvaptan in cell lines from different tumours [i.e. colon cancer (HCT-8), hepatocarcinoma (HepG2), neuroblastoma (SK-N-AS)]. METHODS AND RESULTS: First, we showed that these cell lines express the V2 receptor. Tolvaptan significantly reduced cell proliferation with an IC50 in the micromolar range. Accordingly, reduced levels of cAMP, of the catalytic α subunit of PKA, and a reduced pAKT/AKT ratio were observed. Tolvaptan effectively inhibited cell cycle progression, whereas it induced apoptotis. Furthermore, it reduced cell invasiveness. In particular, anchorage-independent growth and the activity of collagenases type IV were blunted in the three cell lines. Accordingly, tolvaptan counteracted the RhoA/ROCK1-2 pathway, which has a pivotal role in regulating cell movement. CONCLUSIONS: Overall, these findings indicate that tolvaptan effectively inhibits tumour progression in vitro. Further studies should clarify whether the V2 receptor might be considered a possible target in anti-cancer strategies in the future.

Quality of life and psychopathology in candidates to bariatric surgery: relationship with BMI class.

PURPOSE: This cross-sectional study aimed at comparing the quality of life (Qol), the prevalence of psychiatric diagnosis and pharmacological treatment in 104 candidates to bariatric surgery according to the degree of obesity (class 2 vs. class ≥ 3 obesity). METHODS: All surgical candidates underwent a detailed psychiatric interview based on DSM-5 criteria, including sociodemographic, clinical, psychological and psychiatric data. Participants completed the Binge Eating Scale (BES) and the 12-Item Short Form Health Survey (SF-12). RESULTS: Overall, bariatric candidates reported a significant impairment in the physical (PCS 38.8 [95% CI 36.2-41.5]) and mental (MCS 42.2 [95% CI 40.4-43.9]) components of Qol compared to population norms (p < 0.001 for both). Subjects with class 2 obesity scored significantly lower in the MCS compared to those with class 3 (38.7 (8.1) vs. 43.6 (8.4), p = 0.008). No other statistically significant differences were found between the two groups in terms of sociodemographic and clinical variables. CONCLUSION: These data support the usefulness of Qol assessment in bariatric candidates as a sensible screening parameter, especially in patients with lower BMI, in whom MCS could identify the need for early psychosocial intervention. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Fatal respiratory infection due to ST308 VIM-1-producing Pseudomonas aeruginosa in a lung transplant recipient: case report and review of the literature.

BACKGROUND: Data regarding the prevalence of metallo-ß-lactamases (MBLs) among Pseudomonas aeruginosa isolates in cystic fibrosis patients are scarce. Furthermore, there is limited knowledge on the effect of MBL production on patient outcomes. Here we describe a fatal respiratory infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient and the results of the subsequent epidemiological investigation. CASE PRESENTATION: P. aeruginosa isolates collected in the index patient and among patients temporally or spatially linked with the index patient were analyzed in terms of antibiotic susceptibility profile and MBL production. Whole-genome sequencing and phylogenetic reconstruction were also performed for all P. aeruginosa isolates producing VIM-type MBLs. A VIM-producing P. aeruginosa strain was identified in a lung biopsy of a lung transplant recipient with cystic fibrosis. The strain was VIM-1-producer and belonged to the ST308. Despite aggressive treatment, the transplant patient succumbed to the pulmonary infection due to the ST308 strain. A VIM-producing P. aeruginosa strain was also collected from the respiratory samples of a different cystic fibrosis patient attending the same cystic fibrosis center. This isolate harbored the blaVIM-2 gene and belonged to the clone ST175. This patient did not experience an adverse outcome. CONCLUSIONS: This is the first description of a fatal infection due to P. aeruginosa producing VIM-type MBLs in a lung transplant recipient. The circulation of P. aeruginosa isolates harboring MBLs pose a substantial risk to the cystic fibrosis population due to the limited therapeutic options available and their spreading potential.

Oral microbiome and mucosal trauma as risk factors for oral cancer: beyond alcohol and tobacco. A literature review.

Oral and oropharyngeal cancer represents the sixth more common type of cancer affecting the worldwide population. It has been estimated the number of 650,000 new cases per year globally and a greater prevalence has been registered among men. The main risk factors for oral cancer such as tobacco smoking and alcohol are uncontroversial and have been deeply investigated and evidenced in the scientific literature. Recently, viral infections related to Human Papilloma Virus (HPV), with the genotype 16 and 32, have shown a correlation mainly with oropharyngeal cancer (OPC) especially in the non-smoking and non-drinkers young adults. Its transmission is mainly related to sexually transmitted diseases (STDs) although its involvement in oral squamous cell carcinoma (OSCC) is still unclear. This review aims to explore the hypotheses of the OSCC etiology and other possible risk factors, such as chronic traumatisms, chronic periodontitis, and poor oral hygiene that affect directly the oral mucosa and might trigger the carcinogenesis process that should not be underestimated. Furthermore, in the last 10 years, the role of oral microbiome gained attention as a predicting biomarker, for a possible bacterial, viral, and fungal involvement in tumorigenesis.

A unique neuroendocrine cell model derived from the human foetal neural crest.

PURPOSE: Nowadays, no human neuroendocrine cell models derived from the neural crest are available. In this study, we present non-transformed long-term primary Neural Crest Cells (NCCs) isolated from the trunk region of the neural crest at VIII-XII gestational weeks of human foetuses obtained from voluntary legal abortion. METHODS AND RESULTS: In NCC, quantitative real-time RT PCR demonstrated the expression of neural crest specifier genes, such as Snail1, Snail2/SLUG, Sox10, FoxD3, c-Myc, and p75NTR. Moreover, these cell populations expressed stemness markers (such as Nanog and nestin), as well as markers of motility and invasion (TAGLN, MMP9, CXCR4, and CXCR7), and of neuronal/glial differentiation (MAP2, GFAP, SYP, and TAU). Functional analysis demonstrated that these cells not only possessed high migration properties, but most importantly, they expressed markers of sympatho-adrenal lineage, such as ASCL1 and tyrosine hydroxylase (TH). Moreover, the expression of TH increased after the induction with two different protocols of differentiation towards neuronal and sympatho-adrenal phenotypes. Finally, exposure to conditioned culture media from NCC induced a mature phenotype in a neuronal cell model (namely SH-SY5Y), suggesting that NCC may also act like Schwann precursors. CONCLUSION: This unique human cell model provides a solid tool for future studies addressing the bases of human neural crest-derived neuroendocrine tumours.

Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: results of a large multicentre study.

INTRODUCTION: The immune checkpoint inhibitors (ICPIs) agents anti-T lymphocytes-associated antigen 4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) and its ligands (PD-L1/PD-L2) have opened a new scenario in the treatment of cancer. These agents can induce immuno-related adverse events (irAEs), which may affect the endocrine system. PURPOSE: The aim of this study was to analyze the occurrence and the course of endocrine irAEs in cancer patients treated with anti-PD-1 immunotherapy. METHODS: This was a retrospective, multicentre study, involving cancer patients treated with the PD-1 inhibitors nivolumab or pembrolizumab at reference Oncology Centres. One hundred and seventy-nine consecutive patients with different types of cancer (mostly non-small cell lung cancer, melanoma, kidney cancer) were included in the study. Patients had received nivolumab (70.9%) or pembrolizumab (29.1%) for 2-33 months. The study evaluated clinical data records until the established date of July 15, 2018. The primary end point was the assessment of endocrine toxicity and possible predictive factors. RESULTS: Endocrine toxicity occurred in 54 out of 179 patients (30.2%) and was related to thyroid dysfunction, with the exception of one case of diabetes mellitus. Thyroid toxicity occurred mostly within 2 months from the initiation of immunotherapy (83% of cases). A pre-existing thyroid dysfunction was a significant predictor of disease flare. CONCLUSIONS: Thyroid alterations are frequently associated with anti PD-1 treatment in cancer patients. Regular thyroid assessment should be performed, particularly in the first months of treatment and in patients with a pre-existing thyroid disease.

Salt-Treated Roots of Oryza australiensis Seedlings are Enriched with Proteins Involved in Energetics and Transport.

Salinity is a major constraint on rice productivity worldwide. However, mechanisms of salt tolerance in wild rice relatives are unknown. Root microsomal proteins are extracted from two Oryza australiensis accessions contrasting in salt tolerance. Whole roots of 2-week-old seedlings are treated with 80 mM NaCl for 30 days to induce salt stress. Proteins are quantified by tandem mass tags (TMT) and triple-stage Mass Spectrometry. More than 200 differentially expressed proteins between the salt-treated and control samples in the two accessions (p-value <0.05) are found. Gene Ontology (GO) analysis shows that proteins categorized as "metabolic process," "transport," and "transmembrane transporter" are highly responsive to salt treatment. In particular, mitochondrial ATPases and SNARE proteins are more abundant in roots of the salt-tolerant accession and responded strongly when roots are exposed to salinity. mRNA quantification validated the elevated protein abundances of a monosaccharide transporter and an antiporter observed in the salt-tolerant genotype. The importance of the upregulated monosaccharide transporter and a VAMP-like protein by measuring salinity responses of two yeast knockout mutants for genes homologous to those encoding these proteins in rice are confirmed. Potential new mechanisms of salt tolerance in rice, with implications for breeding of elite cultivars are also discussed.

De Novo Transcriptome Study Identifies Candidate Genes Involved in Resistance to Austropuccinia psidii (Myrtle Rust) in Syzygium luehmannii (Riberry).

Austropuccinia psidii, causal agent of myrtle rust, was discovered in Australia in 2010 and has since become established on a wide range of species within the family Myrtaceae. Syzygium luehmannii, endemic to Australia, is an increasingly valuable berry crop. Plants were screened for responses to A. psidii inoculation, and specific resistance, in the form of localized necrosis, was determined in 29% of individuals. To understand the molecular basis underlying this response, mRNA was sequenced from leaf samples taken preinoculation, and at 24 and 48 h postinoculation, from four resistant and four susceptible plants. Analyses, based on de novo transcriptome assemblies for all plants, identified significant expression changes in resistant plants (438 transcripts) 48 h after pathogen exposure compared with susceptible plants (three transcripts). Most significantly up-regulated in resistant plants were gene homologs for transcription factors, receptor-like kinases, and enzymes involved in secondary metabolite pathways. A putative G-type lectin receptor-like kinase was exclusively expressed in resistant individuals and two transcripts incorporating toll/interleukin-1, nucleotide binding site, and leucine-rich repeat domains were up-regulated in resistant plants. The results of this study provide the first early gene expression profiles for a plant of the family Myrtaceae in response to the myrtle rust pathogen.

Localization of Defensive Chemicals in Two Congeneric Butterflies (Euphydryas, Nymphalidae).

Many insect species sequester compounds acquired from their host plants for defense against natural enemies. The distribution of these compounds is likely to affect both their efficacy as defenses, and their costs. In this study we examined the distribution of sequestered iridoid glycosides (IGs) in two congeneric species of nymphalid butterfly, Euphydryas anicia and E. phaeton, and found that the pattern of localization of IGs differed between the two species. Although IG concentrations were quite high in the heads of both species, the relative concentrations in wings and abdomens differed substantially. Euphydryas anicia had relatively high IG concentrations in their abdomens and low IG concentrations in their wings, whereas the reverse was true in E. phaeton. We interpret these results in light of two current hypotheses regarding where sequestered chemicals should be localized: that they should be found in wings, which would allow non-lethal sampling by predators; and that their distribution is constrained by the distribution of tissue types to which sequestered compounds bind. We also offer the third hypothesis, that costs of storage may differ among body parts, and that the localization of compounds may reflect a cost-reduction strategy. Results from E. phaeton were consistent with all three of these non-mutually exclusive hypotheses, whereas results from E. anicia were only consistent with the notion that tissue bias among body parts plays a role in IG distribution. The finding that these two congeneric butterflies exhibit different patterns of IG localization suggests that they have been shaped by different selection regimes.

Hypothyroidism and hyponatremia: data from a series of patients with iatrogenic acute hypothyroidism undergoing radioactive iodine therapy after total thyroidectomy for thyroid cancer.

PURPOSE: The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. METHODS: The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). RESULTS: The frequency of hypothyroidism-associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 ± 1.6 vs 138.7 ± 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. CONCLUSIONS: Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+].

Neuroprotective effects of estrogens: the role of cholesterol.

INTRODUCTION: Experimental and clinical evidence suggests that estrogens have protective effects in the brain. Nevertheless, their potential role against neurodegenerative diseases, in particular Alzheimer's disease (AD), is still a matter of debate. The identification of the seladin-1 gene (for SELective Alzheimer's Disease INdicator-1), which appeared to be significantly less expressed in brain region affected in AD, opened a new scenario in the field of neuroprotective mechanisms. Seladin-1 was found to have neuroprotective properties through its anti-apoptotic activity. In addition, it was subsequently demonstrated that seladin-1 also has enzymatic activity, because it catalyzes the conversion of desmosterol into cholesterol. Several studies have shown that an appropriate amount of membrane cholesterol plays a pivotal role to protect nerve cells against ß-amyloid toxicity in AD and to counteract the synthesis of ß-amyloid. METHODS AND RESULTS: We demonstrated that the expression of seladin-1, as well as the synthesis of cell cholesterol, is stimulated by estrogens in human neuronal precursor cells. Cholesterol enriched cells became more resistant against oxidative stress and ß-amyloid toxicity. We thus hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. Indeed, in cells in which seladin-1 gene expression had been silenced by siRNA the protective effects of estrogens were lost. This finding indicates that seladin-1 is a crucial mediator of the neuroprotective effects of these hormones, at least in our cell model. CONCLUSIONS: In summary, these results establish a new link between estrogens and cholesterol, which is represented by the neuroprotective factor seladin-1.

Neuronal distress induced by low extracellular sodium in vitro is partially reverted by the return to normal sodium.

BACKGROUND: Hyponatremia is associated with negative clinical outcomes even when chronic and mild. It is also known that hyponatremia treatment should be appropriately performed, to avoid dramatic consequences possibly leading to death. We have previously demonstrated that chronically low extracellular [Na(+)], independently of reduced osmolality, is associated with signs of neuronal cell distress, possibly involving oxidative stress. AIM: The aim of the present study was to assess whether the return to normal extracellular [Na(+)] is able to revert neuronal cell damage. METHODS: After exposing SH-SY5Y and SK-N-AS cells to low [Na(+)] and returning to normal [Na(+)], we analyzed cell viability by MTS assay, ROS accumulation by FASCan and expression of anti-apoptotic genes. RESULTS: We found that the viability of cells was restored upon return to normal [Na(+)]. However, when more subtle signs of cell distress were assessed, such as the expression level of the anti-apoptotic genes Bcl-2 and DHCR24 or of the heme oxygenase 1 gene, a complete return to basal values was not observed, in particular in SK-N-AS, even when [Na(+)] was gradually increased. We also demonstrated that the amount of ROS significantly increased in low [Na(+)], thus confirming that oxidative stress appears to contribute to the effects of low [Na(+)] on cell homeostasis. CONCLUSIONS: Overall, this study provided the first demonstration that the correction of chronically low extracellular [Na(+)] may not be able to revert all the cell alterations associated with reduced [Na(+)]. These results suggest that prompt hyponatremia treatment might prevent possible residual abnormalities.