Function Of Na Research Articles

Диабетическая кардиальная автономная нейропатия: каковы перспективы в лечении?

Кардиальная автономная нейропатия (КАН) является серьезным и частым осложнением сахарного диабета. Несмотря на ее связь с повышенным риском сердечно-сосудистой смертности и различными симптомами и нарушениями, значимость КАН сложно переоценить. Изменение образа жизни, интенсивный гликемический контроль позволяют предотвратить развитие или прогрессирование КАН. Патогенетическое лечение КАН включает: сбалансированную диету и физическую активность; оптимизацию гликемического контроля; лечение дислипопротеинемии; коррекцию метаболических нарушений в миокарде; профилактику и лечение тромбоза; применение ингибиторов альдозоредуктазы; применение дигомо-гамма-линоленовой кислоты (ДГЛК); применение ацетил-L-карнитина, антиоксидантов, в первую очередь α-липоевой кислоты (α-ЛК), применение ω-3 и ω-6 полиненасыщенных жирных кислот (ω-3 и ω-6 ПНЖК), вазодилататоров, жирорастворимого витамина B1, аминогуанидина; заместительную терапию ростовыми факторами, в тяжелых случаях — лечение ортостатической гипотензии. Многообещающим является применение средств, которые повышают кровоток в vasa vasorum, в том числе аналогов простациклина, блокаторов тромбоксана А2, а также препаратов, которые способствуют усилению и/или нормализации функции Na+-,К+-АТФазы (ингибиторы фосфодиэстеразы), α-ЛК, ДГЛК, ω-3 ПНЖК, а также одновременное назначение α-ЛК, ω-3 ПНЖК и ДГЛК.

Regulatory effect of insulin on the structure, function and metabolism of Na+/K+-ATPase (Review).

Na+/K+-ATPase is an ancient enzyme, the role of which is to maintain Na+ and K+ gradients across cell membranes, thus preserving intracellular ion homeostasis. The regulation of Na+/K+-ATPase is affected by several regulatory factors through a number of pathways, with hormones serving important short-term and long-term regulatory functions. Na+/K+-ATPase can also be degraded through activation of the ubiquitin proteasome and autophagy-lysosomal pathways, thereby affecting its abundance and enzymatic activity. As regards the regulatory effect of insulin, it has been found to upregulate the relative abundance of Na+/K+-ATPase and restore the transport efficiency in multiple in vitro and in vivo experiments. Therefore, elucidating the role of insulin in the regulation Na+/K+-ATPase may help uncover new drug targets for the treatment of related diseases. The aim of the present study was to review the structure and function of Na+/K+-ATPase and to discuss the possible mechanisms through which it may be regulated by insulin, in order to investigate the possibility of designing new therapies for related diseases.

Survival Benefit of Primary Tumor Resection Among Elderly Patients with Pancreatic Neuroendocrine Tumors.

Pancreatectomy is the main curative therapeutic option for pancreatic neuroendocrine tumors (pNETs). Given the indolent behavior of pNETs and the relatively limited lifetime of elderly patients, the impact of primary site surgery (PSS) of pNETs on long-term outcomes among older patients has been a topic of debate. Patients aged 70 or older with pNETs were identified in the Surveillance, Epidemiology and the End Results (SEER) database from 1998 to 2016. Propensity score matching was used to compare overall (OS) and cancer-specific survival (CSS) of patients who did versus did not undergo PSS. Among 2,319 elderly patients with pNETs, 942 patients (40.6%) underwent PSS, while 1,377 (59.4%) did not undergo PSS (non-PSS: NPSS). After propensity score matching (n = 433 in each group), PSS group had improved survival compared with the NPSS group (5-year OS: 53.4% vs. 37.3%; 5-year CSS: 77.2% vs. 58.1%, both p < 0.001). In contrast, subgroup analysis of individuals aged ≥ 80 revealed no difference in 5-year CSS (PSS: 69.2% vs. NPSS: 67.4%, p = 0.27). A subgroup analysis among patients who had small (≤ 2cm) non-functional (NF) pNETs noted comparable long-term outcomes among patients who underwent PSS versus NPSS patients (5-year OS: 73.1% vs. 66.5%, p = 0.19; 5-year CSS: 98.5% vs. 95.2%, p = 0.14). Approximately 2 in 5 elderly patients with pNETs underwent PSS. While PSS was generally associated with prolonged OS and CSS among older patients, PSS was not associated with improved CSS among a subset of patients aged 80 or older, as well as among patients age ≥ 70years with NF-pNET less than 2cm.

The utility of dynamic MRI in differentiating the hormone-producing ability of pituitary adenomas

PurposeTo investigate the relationship between dynamic magnetic resonance imaging (MRI) findings and hormonal activity in pituitary adenomas.MethodsWe retrospectively evaluated the dynamic MRI findings in 244 patients with pathologically confirmed pituitary adenomas and a diagnosis of clinically active prolactin (PRL)-producing adenomas. Among the 244 pituitary adenomas, 55, 16, 6, and 4 produced growth hormone (GH), PRL, adrenocorticotropic hormone, and thyroid-stimulating hormone, respectively, while 163 were non-functioning (NF) adenomas. For each adenoma, we calculated the washout rate (WR) and early (EER) and delayed (DER) tumour-to-normal-tissue enhancement ratios.ResultsThe respective mean values of the WR, EER, and DER were 9.4%, 75.2%, and 64.5% for GH-producing adenomas; 6.2%, 117.1%, and 106.2% for PRL-producing adenomas; and 5.4%, 116.7%, and 108.7% for NF adenomas. GH-producing adenomas had significantly lower EER and DER values than PRL-producing (P < 0.001) and NF adenomas (P < 0.001). In ROC analysis of GH-producing and non-GH-producing adenomas, the areas under the curves of WR, EER, and DER were 0.593, 0.825, and 0.857, respectively.ConclusionThere are differences in dynamic MRI features between GH-producing and non-GH-producing adenomas, which suggests that EER and DER may be useful for diagnosing GH-producing adenomas.

TGF-β1/Smad2/3 signaling pathway modulates octreotide antisecretory and antiproliferative effects in pituitary somatotroph tumor cells.

Octreotide (OCT) is used to inhibit hormone secretion and growth in somatotroph tumors, although a significant percentage of patients are resistant. It has also been tested in nonfunctioning (NF) tumors but with poor results, with these outcomes having been associated with SSTR2 levels and impaired signaling. We investigated whether OCT inhibitory effects can be improved by TGF-β1 in functioning and nonfunctioning somatotroph tumor cells. OCT effects on hormone secretion and proliferation were analyzed in the presence of TGF-β1 in WT and SSTR2-overexpressing secreting GH3 and silent somatotroph tumor cells. The mechanism underlying these effects was assessed by studying SSTR and TGFβR signaling pathways mediators. In addition, we analyzed the effects of OCT/TGF-β1 treatment on tumor growth and cell proliferation in vivo. The inhibitory effects of OCT on GH- and PRL-secretion and proliferation were improved in the presence of TGF-β1, as well as by SSTR2 overexpression. The OCT/TGF-β1 treatment induced downregulation of pERK1/2 and pAkt, upregulation of pSmad3, and inhibition of cyclin D1. In vivo experiments showed that OCT in the presence of TGF-β1 blocked tumor volume growth, decreased cell proliferation, and increased tumor necrosis. These results indicate that SSTR2 levels and the stimulation of TGF-β1/TGFβR/Smad2/3 pathway are important for strengthening the antiproliferative and antisecretory effects of OCT.

The impact of Dapagliflozin, and Empagliflozin on Na+/Li+ countertransport in erythrocyte membranes of healthy volunteers in acute drug tests

Abstract Background The formation of the effect of SGLT 2 inhibitors on the cardiovascular system implies inhibition of the Na+/H+exchanger (NHE) that leads to a decrease in the concentration of Na+, which in turn contributes to a decrease in the concentration of Ca2+ in the cardiomyocyte (S. Verma, J. McMurray, 2018). However, this effect may be different against the background of exposure to empagliflozin and dapagliflozin. A study of A. Baartscheer (2017) demonstrated the reduction of [Na+], systolic and diastolic [Ca+] in cardiomyocyte is affected by Empagliflozin. N.N. Hamouda's research shows that Dapagliflozin reduce [Na+], systolic, but not diastolic [Ca2+] in cardiomyocytes. In this regard, studying the Na+/Na+ exchanger (which is the mode of the NHE operation) activity estimated by the Na+/Li+countertransport (SLC) in the erythrocyte membrane (K. Morgan, M. Canessa, 1990; M. Canessa, 1989) is of great interest. Purpose A study of the impact of Dapagliflozin, and Empagliflozin on SLC in erythrocyte membranes of healthy volunteers in acute drug tests. Materials and methods 10 healthy volunteers (7 men and 3 women) were included in the study. The mean age of the study group was 24±0,6 years. The volunteers took singly Dapagliflozin, and Empagliflozin separately in one-month intervals. The activity of SLC was determined before drug consumption, as well as 2, 12, and 24 hours after consumption by the method of M.Canessa (1980). All data were tested for normality using the Kolmogorov–Smirnov test and statistically tested by paired Student t-test. Results Mean speeds of SLC before the drugs were administered was 289.1±33.1 mmol/L cell*h in the Dapagliflozin group and 287.8±37.3 mmol/L cell*h in the Empagliflozin group (p=0.979). Two hours after Dapagliflozin was administered, the speed of SLC increased to 76.3±17.0 mmol/L cell*h (95% CI: 37.9–114.7) and was maximum 365±41.6 mmol/L cell*h (p=0.002) for observation period. Then after 12 and 24 hours decreasing SLC activity was observed. However, the values were higher than the initial level and amounted to 335.5±39.18 mmol/L cell*h (p=0.024) after 12 hours and 331±31.8 mmol/L cell*h (p=0.001) after 24 hours. Two hours after Empagliflozin was administered, the speed of SLC not significantly changed and amounted to 287.8±37.3mmol/L cell*h (p=0.7). After 12 hours, the speed not significantly increased to 23.4±11.9 (95% CI: 4.6–51.4) mmol/L cell*h and amounted to 311.1±39.2 (p=0.08), with the subsequent decrease of speed within 24 hours to 277.6±40.5 mmol/L cell*h (p=0.5). Thus Dapagliflozin and Empagliflozin have different effects on the function of Na+/Na+ exchanger which may differently affect the changing of the [Na+] and [Ca2+] in the cardiomyocyte. Conclusions 1. When Dapagliflozin was administered the SLC speed reached its maximum level after 2h and maintained higher than initial level after 12h and 24h. 2. When Empagliflozin was administered no significant change in SLC speed was observed. Funding Acknowledgement Type of funding source: None

The Functioning of Na+-ATPases from Protozoan Parasites: Are These Pumps Targets for Antiparasitic Drugs?

The ENA ATPases (from exitus natru: the exit of sodium) belonging to the P-type ATPases are structurally very similar to the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA); they exchange Na+ for H+ and, therefore, are also known as Na+-ATPases. ENA ATPases are required in alkaline milieu, as in the case for Aspergillus, where other transporters cannot mediate an uphill Na+ efflux. They are also important for salt tolerance, as described for Arabidopsis. During their life cycles, protozoan parasites might encounter a high pH environment, thus allowing consideration of ENA ATPases as possible targets for controlling certain severe parasitic diseases, such as Chagas’ Disease. Phylogenetic analysis has now shown that, besides the types IIA, IIB, IIC, and IID P-type ATPases, there exists a 5th subgroup of ATPases classified as ATP4-type ATPases, found in Plasmodium falciparum and Toxoplasma gondii. In malaria, for example, some drugs targeting PfATP4 destroy Na+ homeostasis; these drugs, which include spiroindolones, are now in clinical trials. The ENA P-type (IID P-type ATPase) and ATP4-type ATPases have no structural homologue in mammalian cells, appearing only in fungi, plants, and protozoan parasites, e.g., Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium falciparum. This exclusivity makes Na+-ATPase a potential candidate for the biologically-based design of new therapeutic interventions; for this reason, Na+-ATPases deserves more attention.

Fatigue-induced change in T-system excitability and its major cause in rat fast-twitch skeletal muscle in vivo.

Using mechanically skinned rat muscle fibres, we investigated (i) transverse tubular-system (T-system) excitability after high-intensity contractions, and (ii) the mechanisms underlying the fatigue-induced alteration of the T-system excitability. T-system excitability estimated by using skinned fibres, which is highly regulated by T-system Na+ -K+ -ATPase, was decreased after muscle contractions, but was fully restored by treatment with dithiothreitol. The S-glutathionylation of Na+ -K+ -ATPase in whole muscle was increased after muscle contractions and also occurred under very low ATP conditions in rested but not stimulated fibres. In conclusion, T-system excitability was decreased after high-intensity exercise due at least in part to the S-glutathionylation of Na+ -K+ -ATPase, which may be enhanced by contraction-induced ATP depression. The purpose of this study was to investigate transverse tubular system (T-system) excitability after skeletal muscle contractions in vivo, and the contribution of S-glutathionylation of Na+ -K+ -ATPase. T-system excitability was estimated by measuring the repriming period (RP) required for double action potentials in mechanically skinned fibres where the sarcolemma was removed but the T-system still functioned. The RP under partially depolarized conditions was highly dependent on the function of Na+ -K+ -ATPase. Rat gastrocnemius (GAS) muscles were subjected to repetitive contractions until the force was decreased to ∼50% of initial force, and then the muscles were very quickly excised and used for skinned fibre and biochemical experiments. The RP under partially depolarized conditions was increased in stimulated fibres (5.9±1.0ms in rested vs. 8.0±1.5ms in stimulated); however, this increase in RP was reversed by sequential treatment with dithiothreitol. The skinned fibres from rested muscles exhibited slower repriming only when treated with oxidized glutathione (GSSG) under very low ATP (≤1mm) conditions, whereas the RP in stimulated fibres was not altered after GSSG treatment without ATP. In line with this, the α2- and β-subunits of Na+ -K+ -ATPase were more S-glutathionylated in stimulated than in rested muscles. These results suggest that (i) T-system excitability is decreased during contractions, in part due to a downregulation of T-system Na+ -K+ -ATPase, (ii) S-glutathionylation contributes to the fatigue-induced decline of the T-system Na+ -K+ -ATPase function, and (iii) ATP depression throughout contractions may enhance S-glutathionylation of T-system Na+ -K+ -ATPase.

The prevalence and characteristics of non-functioning and autonomous cortisol secreting adrenal incidentaloma after patients\u2019 stratification by body mass index and age

BackgroundThe escalating prevalence of adrenal incidentaloma (AI) has been associated with the improvement of radiologic techniques and widespread imaging in aging population. It is currently unclear whether patients with obesity more likely develop AI and the current rise in the prevalence of AI could be at least partly associated with the respective rise in obesity. We compared the prevalence and characteristics of non-functional (NF) and autonomous cortisol secreting (ACS) adrenal incidentalomas (AIs) after the study population was stratified by different body mass indexes (BMI) and age groups.MethodsRetrospective cross-sectional study comprising of 432 patients (40.6% male, 59.4% female) with NFAI (N = 290) and ACS (N = 142), of median age 63.4 (54.0–71.6) years and median BMI 28.6 (25.5–31.7) kg/m2. The data collection contained 11.132 points including demographic, anthropometric, radiologic, hormonal and metabolic parameters.ResultsWe observed 68–87% higher prevalence of AI across different age groups in NFAI and ACS in obese/overweight compared to normal weight subjects. Patients with ACS were older (P = 0.008), with higher basal cortisol (P < 0.001), lower basal DHEAS (P = 0.001), lower suppression DHEAS (P = 0.027) and higher aldosterone (P = 0.039). AIs with ACS were larger than NFAI (P < 0.001). Interestingly, ACS group had lower body mass (P = 0.023) and did not differ in BMI, blood pressure, heart rate, lipid profile, fasting glucose and presence of diabetes mellitus type 2 when compared to NFAI., By contrast to the similarity of metabolic profiles in ACS and NFAI, some components of adverse metabolic traits were rather associated with higher BMI and older age, in particular in NFAI.ConclusionThe prevalence of NFAI and ACS were significantly higher in overweight/obese subgroup across the age distribution. Stratification by age and BMI displayed significant differences in some metabolic traits, in particular in NFAI.

The cyclic lipopeptides suppress the motility of Vibrio alginolyticus via targeting the Na+ -driven flagellar motor component MotX.

In our previous study, we found that pumilacidin-like cyclic lipopeptides (CLPs) derived from marine bacterium Bacillus sp. strain 176 significantly suppressed the mobile capability and virulence of Vibrio alginolyticus. Here, to further disclose the mechanism of CLPs inhibiting the motility of V. alginolyticus, we first applied transcriptomic analysis to V. alginolyticus treated with or without CLPs. The transcriptomic results showed that the expression of several important components of the Na+ -driven flagellar motor closely related to bacterial motility were markedly suppressed, suggesting that the structure and function of Na+ -driven flagellar motor might be disabled by CLPs. The transcriptomic data were further analysed by the protein-protein interaction network, and the results supported that MotX, one of the essential components of Na+ -driven flagellar motor was most likely the action target of CLPs. In combination of gene knockout, electrophoretic mobility shift assay and immunoblotting techniques, CLPs were demonstrated to affect the rotation of flagella of Vibrio alginolyticus via direct interacting with the Na+ -driven flagellar motor component MotX, which eventually inhibited the bacterial motility. Interestingly, homologues of MotX were found broadly distributed and highly conserved in different pathogenic species, which extends the application range of CLPs as an antibacterial drug targeting bacterial motility in many pathogens.

Geochemical process of groundwater fluoride evolution along global coastal plains: Evidence from the comparison in seawater intrusion area and soil salinization area

High-fluoride groundwater along coastal plains is frequently documented. The typical geological processes of seawater intrusion and soil salinization both result in conditions of high Na+, HCO3−, Cl−, TDS (Total Dissolved Solid), and the previous related researches argue high-fluoride groundwater is favored in such conditions, together with low Ca2+. But the fluorosis in soil salinization area contrarily does not occur although more seawater mixes, and the region is characterized by higher Na+, Cl−, TDS. Thus, groundwater in Kenli District of soil salinization area and Buzhuang Town of seawater intrusion area was analyzed and compared, to reveal the potential groundwater fluoride evolution. Generally, the groundwater fluoride levels in Kenli District (0.19–1.27 mg/L) are within but those in Buzhuang Town (0.65–9.87 mg/L) are beyond the safe limit. Geochemical properties indicate a direct cation exchange in Kenli District but a reverse cation exchange in Buzhuang Town. The reverse cation exchange results in the decreasing of groundwater Ca2+(Mg2+) and under-saturation of CaF2, MgF2, CaCO3, MgCO3, CaSO4‧2H2O, MgSO4 minerals, which permits more fluoride dissolving and causes high-fluoride groundwater in seawater intrusion areas. However, the direct cation exchange increases groundwater Ca2+(Mg2+) levels to the saturation of CaF2, CaCO3 and MgCO3 minerals, and the high Ca2+ restricts the fluoride dissolution and causes low fluoride groundwater in soil salinization areas. Moreover, the calculated Ca2+, Mg2+ originating from cation exchange (△(Ca2++Mg2+)C) occupies a large proportion because of the high Na+ levels in Kenli District, and is positively correlated with the degree of mixed seawater. The difference of cation exchange processes and orientations in the two areas is confirmed to be the key to groundwater fluoride levels. Moreover, extraordinarily high levels of groundwater Na+ is found to contrarily decrease groundwater fluoride levels because of cation exchange, which is different from the previous observation that Na+ always enhances groundwater fluoride. A new insight into the function of Na+ on groundwater fluoride evolution was proposed. These findings provide some information about groundwater fluoride evolution along coastal plains.

FSH Levels Are Related to E-cadherin Expression and Subcellular Location in Nonfunctioning Pituitary Tumors.

ContextGonadotroph pituitary neuroendocrine tumors (PitNETs) can express follicle-stimulating hormone (FSH) and luteinizing hormone (LH) or be hormone negative, but they rarely secrete hormones. During tumor development, epithelial cells develop a mesenchymal phenotype. This process is characterized by decreased membranous E-cadherin and translocation of E-cadherin to the nucleus. Estrogen receptors (ERs) regulate both E-cadherin and FSH expression and secretion. Whether the hormone status of patients with gonadotroph PitNETs is regulated by epithelial-to-mesenchymal transition (EMT) and ERs is unknown.ObjectivesTo study the effect of EMT on hormone expression in gonadotroph nonfunctioning (NF)-PitNETs.DesignMolecular and clinical analyses of 105 gonadotroph PitNETs. Immunohistochemical studies and real-time quantitative polymerase chain reaction were performed for FSH, LH, E-cadherin, and ERα. Further analyses included blood samples, clinical data, and radiological images.SettingAll patients were operated on in the same tertiary referral center.ResultsNF-PitNET with high FSH expression had decreased immunohistochemical staining for membranous E-cadherin (P < .0001) and increased staining for nuclear E-cadherin (P < .0001). Furthermore, high FSH expression was associated with increased ERα staining (P = .0002) and ERα mRNA (P = .0039). Circulating levels of plasma-FSH (P-FSH) correlated with FSH staining in gonadotroph NF-PitNET (P = .0025). Tumor size and invasiveness was not related to FSH staining, E-cadherin, or ERα. LH expression was not associated with E-cadherin or ERα.ConclusionIn gonadotroph PitNETs, FSH staining is related to E-cadherin, ERα expression, and circulating levels of P-FSH. There was no association between FSH staining and invasiveness. The clinical significance of these findings will be investigated in ongoing prospective studies.

SAT-301 Relationship Between Clinicopathological Aspects and MSH6/MSH2 and PD-L1 Expressions in Clinically Nonfunctioning Pituitary Adenomas

Introduction: Mismatch repair (MMR) genes are associated with the MMR mechanism that corrects DNA polymerase misincorporation errors. We analyzed the aggressive pituitary adenomas (PAs) associated with Lynch syndrome due to germline mutation in the MMR gene. Reduced expression of MMR genes mutS homologs 6/2 (MSH6/2) directly promotes PA growth (1, 2). MMR gene expression and programmed cell death 1 ligand 1 (PD-L1) expression are involved in tumor immunity with immune checkpoint inhibitors, but the direct association in PAs is not fully understood. Hypothesis and Objectives: MSH6/2 and PD-L1 expression could affect PA proliferation and invasion by pathological classification of nonfunctioning (NF) PAs because the proliferation and invasiveness differ depending on the PA histological subtype. In this study, we therefore analyzed the correlation between MSH6/2 and PD-L1 mRNA expression levels and clinicopathological factors related to tumor proliferation using human NFPAs. Experimental Design: We performed immunohistochemistry to classify the NFPAs into gonadotroph adenomas (GAs), silent corticotroph adenomas (SCAs), null cell adenomas (NCAs) and pituitary transcription factor 1 (PIT1) lineage PAs according to 2017 WHO classifications. Quantitative analyses were by real-time PCR to detect MSH6/2 and PD-L1 mRNA expressions in NFPAs (n = 89). We also performed statistical analyses of the expressions and clinicopathological factors such as Knosp Grade and histological subtypes. We investigated the effect of MSH6 knockout on cell proliferation and PD-L1 expression in AtT-20ins cells. Major Results: MSH6/2 expression was positively associated with PD-L1 expression. MSH6/2 and PD-L1 expressions are significantly lower in invasive NFPAs with Knosp Grade 3–4 or recurrence than in non-invasive NFPAs with Knosp Grade 1–2. Their expression is significantly lower in SCAs and NCAs than in GAs. Although MSH6/2 expression also tends to be lower, the PD-L1 expression tends to be higher in PIT1 lineage PAs, which is unlike SCAs and NCAs. MSH6 knockout in AtT-20ins significantly decreased PD-L1 expression with cell proliferation promotion. Interpretation of results and Conclusion: MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1 lineage PAs compared to GAs were thought to contribute to their clinically aggressive behaviors. The molecular mechanism of the difference in clinical features of NFPAs was partially elucidated. In particular, reduced expressions of MSH6/2 were thought to be useful for predicting the proliferation and invasiveness of NFPAs.

MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes.

Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

Elevated levels of circulating betahydroxybutyrate in pituitary tumor patients may differentiate prolactinomas from other immunohistochemical subtypes

The diagnosis of various histological subtypes of pituitary tumors is made using serum based hormone panel test. However, certain subtypes secrete more than one hormone, making the diagnosis ambiguous. Here, we performed 1H-NMR based metabolomic analysis of serum and whole-blood from luteinizing/follicle-stimulating (LH/FSH)-secreting (n = 24), prolactinomas (n = 14), and non-functional (NF) (n = 9) tumors. We found elevated levels of betahydroxybutyrate (BHB) in serum and whole-blood (WB) of prolactinomas (0.481 ± 0.211/0.329 ± 0.228 mM in serum/WB), but it was statistically significant (p ≤ 0.0033, Bonferroni correction) only in serum when compared with LH/FSH-secreting tumor patients (0.269 ± 0.139/0.167 ± 0.113 mM in serum/WB). Phenylalanine in NF tumors was found to be elevated in both serum and WB when compared with prolactinomas but it met the statistical significance criteria (p ≤ 0.0028) only in the serum. Alanine (p ≤ 0.011), tyrosine (p ≤ 0.014) and formate (p ≤ 0.011) were also elevated in NF tumors but none showed statistically significance when compared with prolactinomas. Quantification of BHB and the above amino acids in the circulation may aid in the development of blood-based in vitro diagnostic methods which can supplement the currently used serum hormone panel in the diagnosis of various subtypes of pituitary tumors.

Lower 68 Ga-DOTATOC uptake in nonfunctioning pituitary neuroendocrine tumours compared to normal pituitary gland-A proof-of-concept study.

68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, ie non-functioning (NF)-PitNET. NF-PitNET patients (n=9) and controls (n=13) were examined preoperatively with 68 Ga-DOTATOC PET for 45min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROI) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression. Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P<.01]. In ROC analysis, the area under the curve was 0.87 (P<.01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n=7) and corticotroph (n=2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5. This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET.

What is the appropriate management of nonfunctioning pancreatic neuroendocrine tumours disclosed on screening in adult patients with multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterised by a predisposition to the development of endocrine tumours of the parathyroid glands, pituitary and pancreas: 30%-80% of patients with MEN1 develop pancreatic neuroendocrine tumours (pNETs), with metastatic tumours and/or their sequelae contributing to increased morbidity and early mortality. The optimal management of nonfunctioning (NF) pNETs in MEN1 remains controversial. Whilst pancreatic resection is widely recommended for tumours >2cm, for smaller tumours (≤2cm) a well-established consensus guiding the indications for surgical intervention does not exist. Although total pancreatectomy may be curative for some patients, both short- and long-term complications make this an unsatisfactory option for many patients. For small (<2cm) MEN1 NF-pNETs, some clinicians advocate surveillance based largely on retrospective data that suggest 50%-80% of these lesions are stable over time and infrequently exhibit accelerated growth rates. It is increasingly recognised, however, that NF-pNETs exhibit unpredictable malignant behaviour that is not determined by tumour size alone, thereby prompting other clinicians to advocate surgery for all MEN1 NF-pNETs, irrespective of size. Such uncertainty poses clinical management challenges with regards to the timing and extent of surgery, which is further hindered by the inability to stratify patients based on predicted tumour behaviour. It is therefore critical that future MEN1 research initiatives include: (a) the discovery of biomarkers that better predict tumour behaviour; (b) the evaluation of medical therapies that may delay, or even prevent, the need for pancreatic surgery; and, ultimately, (c) improvement in the quality of life for individuals with MEN1. Here, based on the published literature, we address the Clinical Question, 'What is the management of NF-pNETs disclosed on screening in adult patients with MEN1?'.

Viscosity of melts in the NaAlSiO4-KAlSiO4-SiO2 system: Configurational entropy modelling

We provide new viscosity data in the system SiO2-(Na,K)AlSiO4, for the nepheline-kalsilite and jadeite-leucite joins. We present a configurational entropy model for the viscosity of melts in the system as a function of Na/(Na + K) and Al/(Al + Si) ratios. Our modelling indicates that: i) Viscosity data are reproduced well by a non-ideal, symmetrical form of the parameters Sconf(Tg) and Be, ii) Na-K mixing is the main source of additional entropy in the system based on the limited dependence of Sconf(Tg) and Be parameters on Al/(Al + Si) ratio, iii) Ae likely varies as a function of Al/(Al + Si) ratio. Melt fragility in the system increases with increasing Al/(Al + Si) ratio and is greater for Na or K end-member melts than mixed melts. The viscosity of nominally fully-polymerized melts in the SiO2-(Na,K)AlSiO4 system can be modelled through chemical mixing, without explicit consideration of the important changes in structure related to changes in K/(Na + K) and Al/(Al + Si) ratios.

Evaluation of the thyroid characteristics of patients with growth hormone-secreting adenomas

BackgroundAcromegaly is highly associated with thyroid disorders. However, the clinical characteristics of thyroid nodules in individuals with acromegaly who present with thyroid diseases have not been completely elucidated.MethodsOverall, 134 consecutive participants with growth hormone (GH)-secreting adenoma (n = 67) and non-functioning (NF) pituitary adenoma (n = 67) were recruited from the outpatient and inpatient patient department of The First Affiliated Hospital, Jinan University from August 2015 to August 2017. Thyroid ultrasonography was performed using an ultrasound system. The cytopathological results of fine-needle aspiration biopsy were analyzed by a pathologist according to the Bethesda system. Twenty-one patients with GH-secreting adenoma and thyroid disease underwent transsphenoidal pituitary adenoma resection and were followed up for 1 year.ResultsThe prevalence of thyroid disease increased in the GH-secreting adenoma group compared with that in the NF pituitary adenoma group. The number of hypoechoic, isoechogenic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenoma plus thyroid disease compared with that in patients with NF pituitary adenoma plus thyroid disease. Finally, we found significant decreases in the morphology of solid nodules and significant increases in the morphology of cystic nodules after surgery compared with those before surgery in the cured group. Moreover, the numbers of heterogeneous and vascular thyroid nodules decreased significantly after surgery compared with those before surgery in the cured group. However, the characteristics of the thyroid nodules did not change after surgery compared with those before surgery in the non-cured group.ConclusionsThe numbers of hypoechoic, isoechoic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenomas. In these patients, surgery resulted in significant changes from solid to cystic nodules and also reduced the numbers of heterogeneous and vascular thyroid nodules.

Oestrogen receptor β mediates the actions of bisphenol-A on ion channel expression in mouse pancreatic beta cells.

Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 diabetes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα) and β (ERβ). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100μg/kg per day for 4days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the normalisation method based on the processing algorithm 'robust multi-array average'. Whole islets or dispersed islets from C57BL/6J or oestrogen receptor β (ERβ) knockout (Erβ-/-) mice were treated with vehicle or BPA (1nmol/l) for 48h. Whole-cell patch-clamp recordings were used to measure Na+ and K+ currents. mRNA expression was evaluated by quantitative real-time PCR. Microarray analysis showed that BPA modulated the expression of 1440 probe sets (1192 upregulated and 248 downregulated genes). Of these, more than 50 genes, including Scn9a, Kcnb2, Kcnma1 and Kcnip1, encoded important Na+ and K+ channel subunits. These findings were confirmed by quantitative RT-PCR in islets from C57BL/6J BPA-treated mice or whole islets treated ex vivo. Electrophysiological measurements showed a decrease in both Na+ and K+ currents in BPA-treated islets. The pharmacological profile indicated that BPA reduced currents mediated by voltage-activated K+ channels (Kv2.1/2.2 channels) and large-conductance Ca2+-activated K+ channels (KCa1.1 channels), which agrees with BPA's effects on gene expression. Beta cells from ERβ-/- mice did not present BPA-induced changes, suggesting that ERβ mediates BPA's effects in pancreatic islets. Finally, BPA increased burst duration, reduced the amplitude of the action potential and enlarged the action potential half-width, leading to alteration in beta cell electrical activity. Our data suggest that BPA modulates the expression and function of Na+ and K+ channels via ERβ in mouse pancreatic islets. Furthermore, BPA alters beta cell electrical activity. Altogether, these BPA-induced changes in beta cells might play a role in the diabetogenic action of BPA described in animal models.