Histone-Specific CD4+ T Cell Plasticity in Active and Quiescent Systemic Lupus Erythematosus.

OBJECTIVE: The aim of this study was to assess whether circulating histone-specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). METHODS: Seroprevalence of autoantibodies and HLA-DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA-peptide autoepitope couples for ex vivo detection of antigen-specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA-DRB1*03:01 and/or HLA-DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. RESULTS: Histone-specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti-DNA antibodies, 77% had detectable histone-specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone-specific regulatory and effector T helper (Th) 1-, Th2-, and atypical Th1/Th17 (Th1*)-polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1-, Th2-, and Th1*-polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone-specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone-specific naive T (TN) and terminally differentiated T cells. CONCLUSION: Histone-specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy.

Association between Perceived Health-Related Quality of Life and Depression with Frailty in the FRASNET Study.

Frailty is a major challenge facing the aging world. The phenotype of the frail subject is still far from being satisfactorily defined. We report data on mood, cognition, and quality of life (QoL) in relation to anamnestic factors, health, and socio-economic status in the FRASNET geriatric population (1204 subjects in stable health conditions), which is an observational cohort study that includes fairly balanced groups of Italian frail (421, 35%), pre-frail (449, 37.3%) and robust (334, 27.7%) subjects. A conditional inference tree analysis revealed a substantial influence of psychological variables on frailty. The physical indicator of QoL (Short Form Survey-36-Physical Component Summary, SF-36-PCS) was the predominant variable in the full model (threshold at 39.9, p < 0.001): higher frailty was found in subjects with a caregiver and lower SF-36-PCS. Frailty was also associated with the mental indicator of QoL (Short Form Survey-36-Mental Component Summary, SF-36-MCS), depression (Geriatric Depression Scale, GDS-15), leisure activities, and level of education. In support of the prominent role of inflammation in aging and mental illness, the SF-36-PCS score was correlated with the blood concentration of C-X-C motif chemokine ligand 10 (CXCL10) (r Pearson -0.355, p = 0.015), a critical signal in cell senescence and inflammaging, while the rs7567647 variant in FN1 gene encoding a glycoprotein in the extracellular matrix was significantly associated with frailty in a multivariable model (p = 0.0006). The perception of health-related QoL and subclinical depression contribute to frailty. Their assessment could improve the identification of older patients at increased risk of adverse outcomes.

[The FRASNET study: identification of clinical and social factors of renal failure in an elderly population].

Background. Chronic renal failure is an epidemic in elderly patients. Older population have an increased prevalence of frailty and sarcopenia, associated with a wide range of adverse health outcomes such as falls, hospitalization, disability. Aim. Describe the sociodemographic and clinical variables of an elderly Lombard population and identify predictors of renal insufficiency. Materials and methods. Cross-sectional observational study conducted in hospitals, in recreational centers for the elderly, in the Universities of the Third Age of the provinces of Milan and Monza-Brianza conducted through a convenience sampling of 1250 subjects over the age of 65. Results. The study identified living alone, annual individual income < € 10,000, polypharmacy, sarcopenia and frailty as predictors of chronic kidney failure. The sample has a mean eGFR of 71.74 mL/min/1.73m2 (SD ± 16.56). Older people living alone are more likely to develop CRI (P = 0.031, confidence interval, CI [1.031-1.905]) as well as having an income < € 10,000 (P = 0.002, CI [0.392-0.923]). Taking more than 11 drugs a day increases the probability of having chronic renal failure by 16 times (P = 0.012, CI [1.155-3.16]). Sarcopenia and frailty increase the likelihood of having chronic renal failure (CRI) (P = 0.001, CI [1.198-2.095]). Conclusions. Identifying predictors of chronic kidney failure is a key step in introducing preventive measures and providing better care to the elderly population.

Inverse salt sensitivity: an independent risk factor for cardiovascular damage in essential hypertension.

OBJECTIVE: Salt sensitivity is a powerful risk factor for cardiovascular (CV) disease and mortality in both normotensive and hypertensive patients. We investigated the predictive value of the salt sensitivity phenotype in the development of CV events and hypertensive target organ damage (TOD) among essential hypertensive patients. METHODS: Eight hundred forty-four naive hypertensive patients were recruited and underwent an acute saline test during which blood pressure (BP) displayed either no substantial variation (salt-resistant, SR individuals), an increase (salt-sensitive, SS), or a paradoxical decrease (inverse salt-sensitive, ISS). Sixty-one patients with the longest monitored follow-up (median 16 years) for blood pressure and organ damage were selected for the present study. A clinical score for TOD development based on the severity and the age of onset was set up by considering hypertensive heart disease, cerebrovascular damage, microalbuminuria, and vascular events. RESULTS: CV events were significantly higher among SS and ISS than in SR patients. The relative risk of developing CV events was 12.67 times higher in SS than SR and 5.94 times higher in ISS than SR patients. The development of moderate to severe TOD was 10-fold higher in SS and over 15-fold higher in ISS than in SR patients. Among the three phenotypes, changes in plasma endogenous ouabain were linked with the blood pressure effects of saline. CONCLUSIONS: Salt sensitivity and inverse salt sensitivity appear to be equivalent risk factors for CV events. The response to an acute saline test is predictive of CV damage for newly identified ISS individuals.

[New year, new variant: drawing lessons from frail elderly people].

A recent study called FRASNET enrolled on a voluntary basis a cohort on 1240 elderly people. They were either patients of the Nephrology and Dialysis unit at San Raffaele hospital in Milan, guests of care homes, or members of cultural, social and recreational centers for the elderly in the wider Milan area. Demographic, anthropometric and biochemical data were collected, together with information on comorbidities and pharmacological therapies, psychophysical test results and biological samples. After the first wave of the SARS-Cov-2 pandemic, we have interviewed the members of this same cohort to gather information on possible coronavirus infections and evaluate the impact of the pandemic on frail patients. It emerged that the prevalence of SARS-Cov-2 infections was 0.7% within this cohort. This encouraging result seems to confirm the effectiveness of the measures taken at the start of the pandemic, especially social distancing and personal protective equipment.

Acute Kidney Injury at Hospital Admission for SARS-CoV-2 Infection as a Marker of Poor Prognosis: Clinical Implications for Triage Risk Stratification.

BACKGROUND/AIMS: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. METHODS: We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). RESULTS: Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; p = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; p = 0.9). CONCLUSIONS: These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

Could ionic regulation disorders explain the overlap between meniere's disease and migraine?

Ménière's disease (MD) is an inner ear disorder characterized by a burden of symptoms and comorbidities, including migraine. In both disorders, ionic dysregulation may play a role as a predisposing factor. In recent years. aquaporins have been widely investigated, but the results are far from conclusive. We recently studied the genetics of ionic transporters and the hormone endogenous ouabain as predisposing factors for development of MD. In particular, we found two genetic polymorphisms associated with MD: 1) rs3746951, a missense variant (Gly180Ser) in the salt-inducible kinase-1 (SIK1) gene encoding a Na+, K+ ATPase; 2) rs487119, an intronic variant of gene SLC8A1 coding for a Na+, Ca++ exchanger (NCX-1). Ionic concentration in the brain also plays a role in the pathophysiology of migraine. In this brief review we summarize what has been published on MD and migraine.

Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion.

BACKGROUND: Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. METHODS: Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. RESULTS: Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. CONCLUSIONS: Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule.

Klotho Gene in Human Salt-Sensitive Hypertension.

BACKGROUND AND OBJECTIVES: Hypertension is a common aging-related disorder. Salt intake is one of the main environmental factors contributing to the development of hypertension. Transgenic mice with one-half Klotho deficiency displayed a spontaneous BP increase and salt-sensitive hypertension in response to high sodium intake. Usually circulating levels of α-Klotho decrease with age, and this reduction may be stronger in patients with several aging-related diseases. This study aimed at exploring the association of Klotho with salt sensitivity in humans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The role of Klotho polymorphisms and α-Klotho serum levels was evaluated in patients with hypertension who were treatment naive and underwent an acute salt-sensitivity test (discovery n=673, intravenous 2 L of 0.9% saline in 2 hours). Salt sensitivity was defined as a mean BP increase of >4 mm Hg at the end of the infusion. A total of 32 single nucleotide polymorphisms in the Klotho gene (KL), previously identified with a genome-wide association study, were used in the genetic analysis and studied for a pressure-natriuresis relationship. RESULTS: Of the patients with hypertension, 35% were classified as salt sensitive. The most relevant polymorphism associated with pressure natriuresis was the common missense single nucleotide polymorphism rs9536314, and the GG and GT genotypes were more represented among patients who were salt sensitive (P=0.001). Those carrying the G allele showed a less steep pressure-natriuresis relationship, meaning that a significant increase in mean BP was needed to excrete the same quantity of salt compared with patients who were salt resistant. KL rs9536314 also replicated the pressure-natriuresis association in an independent replication cohort (n=193) and in the combined analysis (n=866). There was an inverse relationship between circulating Klotho and mean BP changes after the saline infusion (r=-0.14, P=0.03). Moreover, circulating α-Klotho was directly related to kidney function at baseline eGFR (r=0.22, P<0.001). CONCLUSIONS: KL rs9536314 is associated with salt-sensitive hypertension in patients with hypertension who are treatment naive. Moreover, circulating α-Klotho levels were mainly related to diastolic BP changes at the end of a salt load and to eGFR as an expression of kidney aging.

Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

Endolymphatic hydrops and ionic transporters: genetic and biohumoral aspects.

Ménière's disease (MD) is an inner ear disorder, characterized by a burden of symptoms, probably arising from the interplay of genetic and environmental factors. In this brief review, we consider the role of ion channels and transporters in the pathophysiology of MD, focusing on genetic and biohumoral aspects. Pathophysiological mechanisms related to altered concentrations of ions in the endolymph include altered osmotic pressure leading to hydrops and/or immunomodulatory effects of K+ and Endogenous Ouabain (EO) concentrations in the inner ear. Aquaporins 1-5 (AQPs) have been found in the inner ear; AQP2 is the only isoform controlled by a hormone, namely, vasopressin (antidiuretic hormone, ADH). Genetic studies on AQPs have provided inconclusive results. Recently, two genetic polymorphisms have been associated with MD: rs3746951, a missense variant (Gly180Ser) in the Salt-Inducible Kinase-1 (SIK1) gene and rs487119, an intronic variant of gene SLC8A1 coding for a Na+,Ca++ exchanger (NCX-1). EO is a hormone released by the midbrain and adrenal glands. It controls the constitutive capacity of modulating Na+,K+-ATPase activity. Higher plasma levels of EO have been found in MD subjects compared to a control group.

Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury.

RATIONALE & OBJECTIVE: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. STUDY DESIGN: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. SETTING & PARTICIPANTS: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. EXPOSURE: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. OUTCOMES: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. ANALYTICAL APPROACH: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. RESULTS: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P=0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14±0.29 vs 1.25±0.08ng/g; P<0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (-4.39±1.18mL/min/1.73m2 per year) than in the AC or CC genotype groups (-1.07±0.55 and -2.00±0.45mL/min/1.73m2 per year respectively; P = 0.03). LIMITATIONS: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. CONCLUSIONS: These findings support the potential value of LSS rs2254524 genotype-based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.

The TRPC6 intronic polymorphism, associated with the risk of neurological disorders in systemic lupus erythematous, influences immune cell function.

Patients with systemic lupus erythematosus (SLE) carrying a TT genotype for the rs7925662 single nucleotide polymorphism (SNP) in the transient receptor potential canonical channel 6 (TRPC6) gene are more likely to develop neuropsychiatric manifestations (NPSLE). We functionally characterised the effects of TRPC6 on peripheral blood mononuclear cells from 18 patients with SLE and 8 healthy controls with a known genotype. TRPC6 influenced calcium currents, apoptosis rates and cytokine secretion in a disease- and genotype-dependent manner. Cells from TT patients with NPSLE were more dependent on TRPC6 for the generation of calcium currents.

Genetics of ion homeostasis in Ménière's Disease.

Aim of this work was to assess the role of polymorphisms belonging to genes involved in the regulation of ionic homeostasis in Caucasian patients with Ménière Disease (MD). We recruited 155 patients with definite Ménière Disease and 186 controls (Control Group 1) without a lifetime history of vertigo, overlapping with patients for age and rate of hypertension. We validated the positive results on 413 Caucasian subjects selected from a European general population (Control Group 2). The clinical history for migraine and hypertension was collected; genomic DNA was characterized for a panel of 33 SNPs encoding proteins involved in ionic transport. We found a higher rate of migraineurs in MD subjects compared to Group 1 (46.8 vs 15.5%, p = 0.00005). Four SNPs displayed differences in MD patients compared to Group 1 controls: rs3746951 and rs2838301 in SIK1 gene, rs434082 and rs487119 in SLC8A1; the p values of Chi-squared test for genotype frequencies are 0.009, 0.023, 0.009 and 0.048, respectively. SLC8A1 gene encodes for Na+-Ca++ exchanger, while SIK1 gene encodes for Salt Inducible Kinase 1, an enzyme associated with Na+-K+ ATPase function. The validation with Control Group 2 displayed that only rs3746951 and rs487119 are strongly associated to MD (p = 0.001 and p = 0.0004, respectively). These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

BACKGROUND: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

Salt Sensitivity: Challenging and Controversial Phenotype of Primary Hypertension.

Increases in life expectancy and cardiovascular adverse events in patients with hypertension highlight the need for new risk-reduction strategies to reduce the burden of degenerative diseases. Among the environmental factors, high salt consumption is currently considered the most important risk factor of hypertension. However, while high salt intake significantly raises blood pressure in some individuals, others do not show variation or even decrease their blood pressure. This heterogeneity is respectively classified as salt sensitivity and salt resistance. In this review, we propose salt sensitivity as a useful phenotype to unravel the mechanistic complexity of primary hypertension. The individual variability in blood pressure modification in response to salt intake changes derives from the combination of genetic and environmental determinants. This combination of random and non random determinants leads to the development of a personal index of sensitivity to salt. However, those genes involved in susceptibility to salt are still not completely identified, and the triggering mechanisms underlying the following development of hypertension still remain uncovered. One reason might be represented by the absence of a specific protocol, universally followed, for a standard definition of salt sensitivity. Another reason may be linked to the absence of common criteria for patient recruitment during clinical studies. Thus, the generation of a reliable approach for a proper recognition of this personal index of sensitivity to salt, and through it the identification of novel therapeutic targets for primary hypertension, should be one of the aspirations for the scientific community.

Endogenous ouabain and aldosterone are coelevated in the circulation of patients with essential hypertension.

OBJECTIVE: In the setting of normal sodium (Na) intake, many patients with hypertension have inappropriately elevated plasma aldosterone (Aldo) levels and may be at increased risk for tissue damage. Moreover, other adrenocortical steroids, including endogenous ouabain can stimulate tissue damage. As endogenous ouabain is often elevated in chronically Na-loaded states, is a vasoconstrictor, raises blood pressure (BP), and also promotes tissue fibrosis, we investigated the extent to which plasma Aldo and endogenous ouabain were coelevated among naïve hypertensive patients (NHP). We also investigated the impact of an acute salt load on these steroids, BP, and renal function. METHODS: NHP (590) were grouped in tertiles based on their baseline plasma Aldo (mean ±â€ŠSEM first 7.59 ±â€Š0.18, versus third 24.15 ±â€Š0.31 ng/dl). Baseline plasma renin activity (2.4 ±â€Š0.1 versus 1.2 ±â€Š0.1 ng/ml per h, P < 0.001), endogenous ouabain (268 ±â€Š14.9 pmol/l versus 239.0 ±â€Š13.6 pmol, P < 0.01) and DBP (91.9 ±â€Š0.76 versus 89.6 ±â€Š0.71 mmHg, P = 0.017) were higher in NHP in the third versus the first Aldo tertile, respectively. RESULTS: Acute Na loading showed that the BP of the third Aldo tertile NHP was especially salt-sensitive (slope of pressure-natriuresis relationship 0.015 ±â€Š0.002 versus 0.003 ±â€Š0.001 µEq/mmHg per min, P = 0.00024 after adjustment for sex, BMI, and age). Regression analyses showed that plasma Aldo and endogenous ouabain were linearly related (ß = 0.181, P = 0.0003). CONCLUSION: Among patients with essential hypertension, circulating endogenous ouabain and Aldo are typically coelevated and their BP is salt-sensitive. In conditions where Aldo is inappropriately elevated, both Aldo and endogenous ouabain may contribute to adverse cardiovascular and renal outcomes.

ADDing a piece to the puzzle of cognition in schizophrenia.

The biological bases of cognitive impairment in schizophrenia are poorly understood and may lie in insults in neurodevelopment, leading to alterations in critical structures. Synapses proteins are claimed to have etiopathogenic roles and more direct effects on core cognitive functions. Adducins family proteins seem of great interest, as they are fundamental constituents of synapses, involved in actin cytoskeleton assembly-disassembly, responsible of synaptic plasticity. ADD2 is more prominently expressed in brain tissues and influences memory and learning, commonly impaired in schizophrenia. In the present study we tested 342 patients with schizophrenia for three common adducins genetic variants, ADD1 rs4961, ADD2 rs4984 and ADD3 rs3731566, reported to have significant effects on circulatory system in humans. Neuropsychological measures were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS), a broad battery evaluating core cognitive domains. The analysis showed significant effects of ADD2 genotype on almost every cognitive domain. Moreover, significant interactions between ADD1 and ADD3 were also observed on some BACS subtests, namely Symbol Coding and Verbal Memory. Our findings suggest that adducins are involved in cognitive impairment in schizophrenia. This effect may result both from a direct mechanism affecting synaptic building and plasticity and indirectly as a consequence of vascular insults.

Lanosterol Synthase Gene Polymorphisms and Changes in Endogenous Ouabain in the Response to Low Sodium Intake.

Circulating levels of endogenous ouabain (EO), a vasopressor hormone of adrenocortical origin, are increased by sodium depletion. Furthermore, lanosterol synthase, an enzyme involved in cholesterol biosynthesis, has a missense polymorphism (rs2254524 V642L) that affects EO biosynthesis in adrenocortical cells. Here, we investigated the hypothesis that lanosterol synthase rs2254524 alleles in vivo impact the blood pressure (BP) and EO responses evoked by a low dietary Na intake (<100 mEq/d, 2 weeks) among patients with mild essential hypertension. During the low salt diet, the declines in both systolic BP (SBP: -8.7±1.7 versus -3.0±1.5; P=0.013) and diastolic BP (DBP: -5.1±0.98 versus -1.4±0.94 mm Hg; P<0.05), and the slope of the long-term pressure-natriuresis relationship affected significantly the presence of the lanosterol synthase rs2254524 A variant (AA: 0.71±0.22, AC 0.09±0.13, and CC 0.04±0.11 mEq/mm Hg/24 h; P=0.028). In addition, BP rose in ≈25% of the patients in response to the low salt diet and this was associated with increased circulating EO. Lanosterol synthase gene polymorphisms influence both the salt sensitivity of BP and changes in circulating EO in response to a low salt diet. The response of BP and EO to the low salt diet is markedly heterogeneous. Approximately 25% of patients experienced adverse effects, that is, increased BP and EO when salt intake was reduced and may be at increased long-term risk. The augmented response of EO to the low salt diet further supports the view that adrenocortical function is abnormal in some essential hypertensives.

TRPC6 gene variants and neuropsychiatric lupus.

Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) influence patients' quality of life and their survival. Little is known about the pathophysiological bases of NPSLE and accordingly there are no specific therapeutic agents to be employed in this setting. Genetic research in systemic lupus erythematosus (SLE) is rapidly evolving as a tool to find clues about the pathogenic determinants of the disease and of its manifestations. Here, we describe the association of a single nucleotide polymorphic variant of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene with protection from the development of NPSLE in a cohort of 106 patients with SLE. TRPC6 is involved in the regulation of N-methyl-d-aspartate (NMDA) receptor signalling, a major player in post-ischemic neuronal injury and in the pathogenesis of NPSLE. TRPC6 genetic variants are promising candidate predictors of nervous system involvement in SLE, whereas the TRPC6 pathway might constitute a potential novel therapeutic target.