Elevated Basal Levels Research Articles

A human exposure based mixture of persistent organic pollutants affects the stress response in female mice and their offspring

Persistent organic pollutants (POPs) are found in the food chain of both humans and animals and exert a wide spectrum of potentially adverse effects. The present experiment aimed to investigate whether a defined mixture of 29 POPs, based on the dietary intake of Scandinavians, could affect the stress response in female mice exposed through ingestion, and in their offspring. Female mice 129:C57BL/6F0 hybrids were exposed from weaning, throughout pregnancy, and up until necropsy, to either 5000 × or 100 000 × the estimated daily intake for Scandinavians. The offspring were fed a reference diet containing no POPs. Both the mothers and their offspring were tested for basal and stress responsive corticosterone levels, and in an open field test to measure locomotor activity and anxiety-like behaviours. We found mothers to have elevated basal corticosterone levels, as well as a prolonged stress response following POP exposure. In the offspring, there was no effect of POPs on the stress response in females, but the exposed males had an over-sensitised stress response. There was no effect on behaviour in either the mothers or the offspring. In conclusion, we found a human relevant POP mixture can lead to subtle dysregulation of the hypothalamus-pituitary-adrenal axis in mice. As HPA axis dysregulation is commonly associated with neurological disorders, further studies should explore the relevance of this outcome for humans.

View Insulin Resistance from an Interaction Between Pancreatic Islets and Peripheral Tissues

Curl rent hypotheses of insulin resistance mostly emphasize cellular mechanisms in peripheral tissues. Although received broad recognition, these opinions may have overlooked the interaction between pancreatic endocrine cells and the peripheral tissues in the process of establishment and maintenance of insulin resistance in the whole body. It has been suggested that basal hyperinsulinemia is the root cause of insulin resistance. Basal insulin release does not share the same intracellular mechanism of high glucose stimulated insulin release; instead, it is regulated by local Ca2+ fluctuation and activation of the cAMP-Epac2/Rap1 signaling pathway. Basal insulin release is controlled by the interaction between pancreatic head β-cells and pancreatic tail α-cells, which release insulin and glucagon, respectively. In diabetes, an elevated basal insulin level would mitigate the sensitivity of peripheral tissues to insulin; the decreased insulin sensitivity and elevated plasma glucose concentration could further stimulate more basal insulin release partially by increasing T-type Ca2+ channel expression and activity in β-cells. This interaction forms a positive feedback loop. Therefore, T-type Ca2+ channel antagonists can potentially be employed to break this positive feedback loop, thus reversing insulin resistance.

Influence of Male to Female Ratio on Hormone Profiles and Reproductive Performance of Anestrus Postpartum Ewes Subjected to the Male Effect

Background: Complete isolation of genders allows intense estrous induction and synchronization once rams are introduced in ewe flocks at the onset of the breeding season (BS). This management practice, defined as the male effect, results from a neuroendocrine process mediated by pheromones. The male effect is a straightforward procedure to induce estrous in noncycling ewes, but conditions for its use have not been fully explored. Thus, this study aimed to evaluate hormone levels and ovarian activity of postpartum ewes in anestrus which are subjected to the male effect under different male to female ratios.Material, Methods & Results: Pospartum females were selected according to body condition score and cyclicity status. Females were kept apart from males during 30 days at a distance of 10 m. Anestrus and ovulation were determined by P4 measures on days 10, 20 and 30 after isolation from males. After P4 concentration diagnosis, anestrus ewe (n = 99) were subjected to male to ewe ratios (MFR) of 1:20 (MFR20), 1:30 (MFR30) and 1:40 (MFR40). Santa Inês rams (n = 3) of proven fertility were used. Three females of each group were randomly subjected to blood collection for LH concentration analysis. Ovarian activity was performed by ultrasonography after estrus manifestation in six ewe of each group. Estrus events were observed twice a day during the BS of 35 days, and estrus were considered synchronized when it occured within the initial five days of the BS. Pregnancy diagnosis was performed by ultrasonography on days 35 and 60 after the last mating. All ewe were in a non-cycling condition before BS onset, based upon P4 analysis. After initiation of the BS, P4 concentrations increased for all groups. Irrespectively of male to female ratio, male effect induced LH pre-ovulatory peaks within the initial 26 to 86 h of the BS. Synchronization of estrus reached 50% for MFR20, 40% for MFR30 and 20% for MFR40 for all ewe. Moreover, overall estrus incidence was 100% (MFR20), 90% (MFR30) and 65% (MFR40) within the initial 15 days of the BS. However, incidence of ewe that had repeated estrus events was lower for MFR20 than for MFR30. Follicular growth and number of ovulations was similar between groups. Conception rates on first service was higher than that of second service for MFR20 and MFR30, although there was no difference between services for MFR40. In contrast, overall conception rates, delivery type and prolificacy were similar between groups.Discussion: P4 increased to cyclicity levels after contact between genders, demonstrating the potential of the male effect to induce estrus in non-cycling ewes. Most ewe ovulated within three days after the male effect, possibly due to elevated basal LH levels. Moreover, the LH preovulatory peak varied within groups, possibly due to greater interactions between genders, which ultimately may have led to earlier ovulation anticipation under lower MFR. Estrus parameters were similar between groups, suggesting low or negligible effects of MFR. Ovulatory follicle size and growth and the number of ovulations were similar between all groups; previous reports have suggested that this may be due to a strong effect of their genetic background. Conception rates were higher at first than second services, demonstrating the potential of male effect. In conclusion, male to female ratio affects the efficiency of the male effect to induce and synchronize estrus in ewes under postpartum anestrus, but it does not affect conception rates and prolificacy.

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab

BackgroundNivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients.MethodsIn this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel’s C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival.ResultsOur results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression–free survival was 2.6 months [95% confidence interval (CI) 1.9–3.3] in patients with high sCD73 enzyme activity (> 27.8 pmol/min/mg protein), and 14.2 months (95% CI 4.6–23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24 months range. The median overall survival was not reached in patients with low sCD73 activity (< 27.8 pmol/min/mg protein) compared with 6.1 months (95% CI 0–14.8) in patients with higher sCD73 activity. In multivariate analyses, the sCD73 enzyme activity emerged as the strongest prognostic factor for overall survival and progression-free survival. Elevated basal levels of sCD73 enzyme activity, before starting nivolumab treatment, were associated with lower response rates to therapy.ConclusionsWe observed a significant association between the activity of sCD73 in the blood and clinical outcomes in patients with metastatic melanoma stage IV, receiving nivolumab. Although our results need to be confirmed and validated, we suggest that sCD73 might be used as serologic prognostic biomarker. Potentially evaluating sCD73 enzyme activity in the peripheral blood before treatment could help to estimate the response to nivolumab.

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance.

The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and moesin. Mutations in the moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging moesin-deficient mice develop a systemic lupus erythematosus-like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8+CD44+CD122+Ly49+ regulatory T (CD8+ Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8+ Treg cells from moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that moesin plays a key role in IL-15-mediated signaling. These findings underscore the importance of moesin in IL-15-dependent CD8+ Treg cell homeostasis and, thus, the control of self-tolerance.

Patients with papillary thyroid carcinoma associated with high stimulated serum calcitonin levels.

Among various substances produced by C-cells, the most important one is calcitonin (CT) that is used for detection, post-operative follow-up and evaluation of individuals at risk of developing medullary thyroid carcinoma (MTC). However, the role of serum CT measurement in the evaluation of thyroid nodules has been widely discussed, and there is still no consensus about the role of CT in the initial evaluation of all thyroid nodules. Two patients with thyroid nodules whose fine-needle aspiration results were compatible with benign cytology besides having mildly elevated basal serum calcitonin levels were reported. Calcitonin responses (peak levels were 313 and 229 pg/mL, respectively) to calcium stimulation test were compatible with the possible diagnosis of MTC. However, the final diagnosis was papillary thyroid carcinoma of the thyroid gland. There are limited numbers of case reports showing such an increased serum calcitonin responses to calcium stimulation test associated with papillary or follicular thyroid carcinoma of the thyroid. We suggest to measure serum CT level once and in case of normal levels, no further CT measurement is necessary. Physicians should keep in mind that thyroid carcinomas other than MTCs may also be associated with high serum CT levels.Learning points:Although serum calcitonin is a valuable tumor marker for MTC, it is well known that mild elevations may be seen in some other diseases such as Hashimoto thyroiditis, neuroendocrine tumors or due to medications such as proton pump inhibitors, calcium salts, beta blockers and glucocorticoids.Those two cases indicate that high calcitonin responses to calcium stimulation test, mimicking MTC, may also be seen in patients with papillary thyroid carcinoma although the mechanism is not clear.

All bonds are not alike: A psychoendocrine evaluation of infant attachment.

Characteristics of attachment were assessed in peer- and object-reared lambs, and compared to mothered subjects by taking into consideration distress, proximity seeking, and exploration during two separation-reunion tests in both the familiar and a novel environment. Plasma cortisol and oxytocin were assayed as physiological indicators of stress and being comforted during the separation-reunion test. Rewarding properties of the familiar figures were also determined in a conditioned place preference-like paradigm. Between-group analysis revealed the existence of secure attachment with the mother, alteration of secure attachment with the peer and weaker attachment with the object. Weaker attachment was expressed by a lack of distress during separation in the home pen and no preference for the place conditioned with the familiar object. Elevated basal plasma oxytocin levels, but not cortisol, observed in maternally deprived lambs were more likely linked to the absence of a maternal figure rather than social comfort during reunion.

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress

Major depression is hypothesized to be associated with dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis.

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.

Hormonal dynamics during salt stress responses of salt-sensitive Arabidopsis thaliana and salt-tolerant Thellungiella salsuginea

Salt stress responses in salt-sensitive Arabidopsis thaliana (2–150mM NaCl) and the closely related salt-tolerant Thellungiella salsuginea (Eutrema halophila, 150–350mM NaCl) were compared to identify hormonal and transcriptomic changes associated with enhanced stress tolerance. Phytohormone levels, expression of selected genes, membrane stability, and Na+ and K+ concentrations were measured in shoot apices, leaves, and roots. Thellungiella exhibited higher salt stress tolerance associated with elevated basal levels of abscisic acid and jasmonic acid, and lower levels of active cytokinins (excluding cis-zeatin) in shoot apices. Analysis of the dynamics of the early salt stress response (15min to 24h) revealed that the halophyte response was faster and stronger. Very mild stress, in our hydropony arrangement 2–25mM NaCl, affected the transcription of genes involved in cytokinin metabolism (AtIPTs, AtCKXs). Mild stress induced in Arabidopsis (50mM) stress responses only in shoot apices, while in Thellungiella (150mM) across the whole plant. Arabidopsis exhibited in hydropony evidence of severe stress above 75mM NaCl and died in 150mM, whereas the halophyte only became severely stressed above 225mM. The responses of individual phytohormones (cytokinins, auxin, abscisic acid, jasmonic acid, salicylic acid and their metabolites) to salinity are discussed.

Abstract 6: Restoration of Impaired Diastolic Function in Hypertrophic Cardiomyopathy Induced Pluripotent Stem Cell-derived Cardiomyocytes by Re-balancing the Calcium Homeostasis

Background: Diastolic dysfunction is commonly seen in hypertrophic cardiomyopathy (HCM). However, the cellular mechanism is not fully understood, and no effective treatment so far has been developed. We hypothesize here that HCM patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can recapitulate the cellular mechanism, and provide us a platform for mechanistic study and for drug screening of diastolic dysfunctions in HCM. Methods and Results: We generated beating iPSC-CMs from healthy individuals and HCM patients carrying familial mutations (MYH7 R663H (n=2 lines) and MYBPC3 R943ter (n=2 lines)). Sarcomere shortening measurement in patterned iPSC-CMs with live cell confocal imaging showed significantly prolonged diastolic phase and slower relaxation velocity in HCM iPSC-CMs compared to WT cells. To elucidate the cellular mechanism, Fura-2 AM ratiometric calcium imaging showed marked elevation of resting calcium level and increased abnormal calcium handlings in HCM iPSC-CMs, which were exaggerated by β-adrenergic activation with isoproterenol. By applying calcium transient and contractile force simultaneous recording, we defined a “risk index of diastolic dysfunction” (measured as transient-contraction gain factor), which was significantly increased in HCM iPSC-CMs. Thus, both elevated basal calcium level and increased calcium sensitivity of myofilament contribute to the abnormal diastolic function in HCM iPSC-CMs. Gene expression profiling of HCM and WT iPSC-CMs indicated that increased calcium channels may underlie the increased basal calcium concentration in HCM cells. Indeed, partially blocking the calcium influx by calcium blockers reset the basal calcium level, attenuated calcium mishandling, and restored the diastolic function in HCM iPSC-CMs. Moreover, re-balancing calcium homeostasis significantly improved long-term survival rate of HCM iPSC-CMs at both basal level and under β-adrenergic stress. Conclusion: The iPSC-CM models carrying patient-specific HCM mutations recapitulated diastolic dysfunction on single cell level. Future studies using these platform may reveal additional novel cellular mechanisms and therapeutic targets of diastolic dysfunction in HCM disease.

Adrenal crisis in metastatic breast cancer

A female patient with oestrogen receptor-positive and human epidermal growth factor receptor 2 (HER2)-positive invasive lobular breast cancer presented with progressive disease on CT scan. Some days after initiation of...

Elevated basal progesterone levels are associated with increased preovulatory progesterone rise but not with higher pregnancy rates in ICSI cycles with GnRH antagonists

ObjectiveTo ascertain the association between basal progesterone (P) levels and the occurrence of preovulatory progesterone rise (PPR) and clinical pregnancy rates (CPRs) in ICSI cycles with GnRH antagonists. Study designSerum P levels of 464 patients were measured on day 2 and day of hCG of cycles. Cycles with basal P levels>1.6ng/mL were cancelled. All embryos were cryopreserved in cycles with P levels≥2ng/mL on the day of hCG. The primary outcome measures were the incidence of PPR (P>1.5ng/mL) and CPR with regard to basal P. ResultsBasal P levels were significantly higher in cycles with PPR than in those without PPR (0.63±0.31 vs. 0.48±0.28ng/mL). Area under the curve for basal P according to ROC analysis to discriminate between elevated and normal P levels on the day of hCG was 0.65 (0.58–0.71 95% CI, p<0.01). The cut-off value for basal P levels that best discriminates between cycles with and without PPR was 0.65ng/mL. Cycles with basal P levels above 0.65ng/mL had a significantly higher incidence of PPR (30.9% vs. 13.5%) but similar clinical and cumulative pregnancy rates (38.8% vs. 31.1% and 41.7% vs. 32.6%, respectively) in comparison to cycles with basal P levels below 0.65ng/mL. In multivariate regression analysis, basal P levels, LH level on the first day of antagonist administration, and estradiol levels on the day of hCG trigger were the variables that predicted PPR. ConclusionBasal P levels were associated with increased incidence of PPR but not with CPR.

Correlation of alpha- and beta-specific tryptase gene expression with TPSAB1 and TPSB2 genotypes in humans

Abstract Germline duplications or triplications of alpha-tryptase encoding sequence at TPSAB1 have been linked to elevated basal serum tryptase and are estimated to effect approximately 5% of the general population. However, no assay currently exists to quantify specific alpha- or beta-tryptase gene expression. Using a similar bioinformatic approach to what we used when designing the alpha- and beta-tryptase sequence-specific TPSAB1 genotyping assay, we developed a novel ddPCR assay able to specifically quantify alpha- and beta-tryptase gene expression. Using this assay, we then interrogated cultured primary human mast cells and isolated basophils from individuals with hereditary alpha tryptasemia syndrome – caused by increased TPSAB1 copy number – and from healthy controls. By correlating these results with individual germline TPSAB1 and TPSB2 genotypes we found that, as would be predicted, increasing alpha-tryptase encoding copy number at the TPSAB1 locus correlated with higher alpha-tryptase gene expression in healthy volunteers. Similarly volunteers lacking alpha-trytpase sequence at TPSAB1 were not detected to have alpha-tryptase gene expression, confirming the specificity of the assay. However, among individuals harboring extra TPSAB1 copies, alpha-tryptase gene expression levels were several orders of magnitude higher than beta tryptases, even when they were present in allelic balance (e.g. 3,3). These data suggest that elevated basal serum tryptase levels seen in hereditary alpha tryptasemia result predominantly from deregulated alpha-trypase gene expression, likely due to co-inheritance of as yet unidentified enhancer or promoter elements.

Regulation of Hyphal Growth and N-Acetylglucosamine Catabolism by Two Transcription Factors in Candida albicans.

The amino sugar N-acetylglucosamine (GlcNAc) is increasingly recognized as an important signaling molecule in addition to its well-known structural roles at the cell surface. In the human fungal pathogen Candida albicans, GlcNAc stimulates several responses including the induction of the genes needed for its catabolism and a switch from budding to filamentous hyphal growth. We identified two genes needed for growth on GlcNAc (RON1 and NGS1) and found that mutants lacking these genes fail to induce the genes needed for GlcNAc catabolism. NGS1 was also important for growth on other sugars, such as maltose, but RON1 appeared to be specific for GlcNAc. Both mutants could grow on nonfermentable carbon sources indicating that they do not affect mitochondrial function, which we show is important for growth on GlcNAc but not for GlcNAc induction of hyphal morphogenesis. Interestingly, both the ron1Δ and ngs1Δ mutants were defective in forming hyphae in response to GlcNAc, even though GlcNAc catabolism is not required for induction of hyphal morphogenesis. The ron1Δ mutant showed a partial defect in forming hyphae, which was surprising since it displayed an elevated level of filamentous cells under noninducing conditions. The ron1Δ mutant also displayed an elevated basal level of expression of genes that are normally upregulated during hyphal growth. Consistent with this, Ron1 contains an Ndt80-like DNA-binding domain, indicating that it regulates gene expression. Thus, Ron1 is a key new component of the GlcNAc response pathway that acts as both an activator and a repressor of hyphal morphogenesis.

563. Vasopressin (AVP) Gene Modulates Risk of Alcohol Dependence via Effects on Stress and Anxiety

Evidence suggests a role for AVP in addictive disorders given its ability to modulate stress responses and social interaction. In rats, elevated basal AVP levels are associated with increased alcohol consumption, while pharmacological antagonism of AVP receptors reduces alcohol consumption. AVP single nucleotide polymorphism (SNP) rs2282018 (A G) is associated with decreased AVP levels. We studied the relationship of rs2282018 to AD, and anxiety and stress responses that may mediate AD vulnerability.

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

AbstractKinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR–induced signaling. This contrasted MCL tumors, where α-BCR–induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR–induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.

Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system.

Secretin (SCT) and its receptor (SCTR) are important in fluid regulation at multiple levels via the modulation of expression and translocation of renal aquaporin 2 and functions of central angiotensin II (ANGII). The functional interaction of SCT with peripheral ANGII, however, remains unknown. As the ANGII-aldosterone axis dominates the regulation of renal epithelial sodium channel (ENaC) function, we therefore tested whether SCT/SCTR can regulate sodium homeostasis via the renin-angiotensin-aldosterone system. SCTR-knockout (SCTR-/-) mice showed impaired aldosterone synthase (CYP11B2) expression and, consequently, aldosterone release upon intraperitoneal injection of ANGII. Endogenous ANGII production induced by dietary sodium restriction was higher in SCTR-/- than in C57BL/6N [wild-type (WT)] mice, but CYP11B2 and aldosterone synthesis were not elevated. Reduced accumulation of cholesteryl ester-the precursor of aldosterone-was observed in adrenal glands of SCTR-/- mice that were fed a low-sodium diet. Absence of SCTR resulted in elevated basal transcript levels of adrenal CYP11B2 and renal ENaCs. Although transcript and protein levels of ENaCs were similar in WT and SCTR-/- mice under sodium restriction, ENaCs in SCTR-/- mice were less sensitive to amiloride hydrochloride. In summary, the SCT/SCTR axis is involved in aldosterone precursor uptake, and the knockout of SCTR results in defective aldosterone biosynthesis/release and altered sensitivity of ENaCs to amiloride.-Bai, J., Chow, B. K. C. Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system.

High Progesterone levels in the beginning of ICSI antagonist cycles and clinical pregnancy: still a concern?

ObjectiveIn controlled ovarian hyperstimulation (COH) using antagonist cycles, an incomplete luteolysis could happen after an inefficient previous luteolysis. Since antagonist cycles are frequent today, this study aims to access the impact of serum progesterone in the beginning and at the end of stimulation, and pregnancy outcomes.Methodssingle-center cohort study, 461 fresh embryo transfers in ICSI antagonist cycles. Serum progesterone levels was measured in the beginning of COH (P4i) and on hCG day (P4f) using threshold values of 1.5ng/mL. Four groups were created: Group 1, P4i and P4f ≤ 1.5; Group 2, P4i ≤ 1.5 and P4f > 1.5; Group 3, P4i > 1.5 and P4f ≤ 1.5 and Group 4, P4i and P4f > 1.5. The clinical pregnancy rate (CPR) and live birth rates (LBR) were the primary outcomes.ResultsThe number of cycles per group was: 393, 51, 6 and 11, respectively. Group 1 was considered the expected normal, while group 4 represented the persistence of higher levels. There was no difference in age, basal FSH and Estradiol, days of stimulation endometrium thickness and total amount of gonadotropins between group 1 versus group 4. However, significant differences occurred in embryological and clinical outcomes between these 2 groups.ConclusionThe impact of serum progesterone in the beginning of stimulation and pregnancy outcomes is a matter of concern. Basal elevated levels could help identify patients that will repeat it on hCG day, being probably a marker to define a freeze-all strategy to these cycles.

Protein tolerance to standard and high protein meals in patients with liver cirrhosis.

AIMTo investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis.METHODSThe plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the “number connection test” (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage.RESULTSThe changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients.CONCLUSIONPatients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.