UNASSIGNED: Biphasic insulin secretion is an intrinsic characteristic of the pancreatic islet and has clinical relevance due to the loss of first-phase in patients with Type 2 diabetes. As it has long been shown that first-phase insulin secretion only occurs in response to rapid changes in glucose, we tested the hypothesis that islet response to an increase in glucose is a combination of metabolism plus an osmotic effect where hypertonicity is driving first-phase insulin secretion.
UNASSIGNED: Experiments were performed using perifusion analysis of rat, mouse, and human islets. Insulin secretion rate (ISR) and other parameters associated with its regulation were measured in response to combinations of D-glucose and membrane-impermeable carbohydrates (L-glucose or mannitol) designed to dissect the effect of hypertonicity from that of glucose metabolism.
UNASSIGNED: Remarkably, the appearance of first-phase responses was wholly dependent on changes in tonicity: no first-phase in NAD(P)H, cytosolic calcium, cAMP secretion rate (cAMP SR), or ISR was observed when increased D-glucose concentration was counterbalanced by decreases in membrane-impermeable carbohydrates. When D-glucose was greater than 8 mM, rapid increases in L-glucose without any change in D-glucose resulted in first-phase responses in all measured parameters that were kinetically similar to D-glucose. First-phase ISR was completely abolished by H89 (a non-specific inhibitor of protein kinases) without affecting first-phase calcium response. Defining first-phase ISR as the difference between glucose-stimulated ISR with and without a change in hypertonicity, the peak of first-phase ISR occurred after second-phase ISR had reached steady state, consistent with the well-established glucose-dependency of mechanisms that potentiate glucose-stimulated ISR.
UNASSIGNED: The data collected in this study suggests a new model of glucose-stimulated biphasic ISR where first-phase ISR derives from (and after) a transitory amplification of second-phase ISR and driven by hypertonicity-induced rise in H89-inhibitable kinases likely driven by first-phase responses in cAMP, calcium, or a combination of both.

Pelvic floor disorders can result in laxity, hypertonicity or spasm, all of which can impact sexual function. It is important for clinicians to understand this impact in order to appropriately counsel and treat their patients.

Farnesoid X receptor (FXR), a ligand-activated transcription factor, plays an important role in maintaining water homeostasis by up-regulating aquaporin 2 (AQP2) expression in renal medullary collecting ducts; however, its role in the survival of renal medullary interstitial cells (RMICs) under hypertonic conditions remains unclear. We cultured primary mouse RMICs and found that the FXR was expressed constitutively in RMICs, and that its expression was significantly up-regulated at both mRNA and protein levels by hypertonic stress. Using luciferase and ChIP assays, we found a potential binding site of nuclear factor kappa-B (NF-κB) located in the FXR gene promoter which can be bound and activated by NF-κB. Moreover, hypertonic stress-induced cell death in RMICs was significantly attenuated by FXR activation but worsened by FXR inhibition. Furthermore, FXR increased the expression and nuclear translocation of hypertonicity-induced tonicity-responsive enhance-binding protein (TonEBP), the expressions of its downstream target gene sodium myo-inositol transporter (SMIT), and heat shock protein 70 (HSP70). The present study demonstrates that the NF-κB/FXR/TonEBP pathway protects RMICs against hypertonic stress.

BACKGROUND: Sepsis is a recognized global health challenge that places a considerable disease burden on countries. Although there has been some progress in the study of sepsis, the mortality rate of sepsis remains high. The relationship between serum osmolality and the prognosis of patients with sepsis is unclear.
METHODS: Patients with sepsis who met the criteria in the Medical Information Mart for Intensive Care IV database were included in the study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using multivariable Cox regression. The relationship between serum osmolality and the 28-day mortality risk in patients with sepsis was investigated using curve fitting, and inflection points were calculated.
RESULTS: A total of 13,219 patients with sepsis were enrolled in the study; the mean age was 65.1 years, 56.9 % were male, and the 28-day mortality rate was 18.8 %. After adjusting for covariates, the risk of 28-day mortality was elevated by 99% (HR 1.99, 95%CI 1.74-2.28) in the highest quintile of serum osmolality (Q5 >303.21) and by 59% (HR 1.59, 95%CI 1.39-1.83) in the lowest quintile (Q1 ≤285.80), as compared to the reference quintile (Q3 291.38-296.29). The results of the curve fitting showed a U-shaped relationship between serum osmolality and the risk of 28-day mortality, with an inflection point of 286.9 mmol/L.
CONCLUSIONS: There is a U-shaped relationship between serum osmolality and the 28-day mortality risk in patients with sepsis. Higher or lower serum osmolality is associated with an increased risk of mortality in patients with sepsis. Patients with sepsis have a lower risk of mortality when their osmolality is 285.80-296.29 mmol/L.

BACKGROUND: Functional bladder outlet obstruction (BOO) in women is postulated to be caused by pelvic floor muscle (PFM) dyssynergia or increased tone. The aim of the present review was to investigate the effect of PFM relaxation training on PFM tone and female BOO symptoms.
METHODS: This was a narrative review using an open search strategy on PubMed with the search terms \"Bladder outlet obstruction\" AND \"female\" AND (\"pelvic floor muscles\" OR \"Kegel\"). The risk of bias of the randomized controlled trials (RCTs) was scored with the Physiotherapy Evidence Database (PEDro) scale (0-10).
RESULTS: Only three RCTs were found. All three RCTs compared different types of exercise, and no trial compared relaxation training with no or sham treatment. None of the trials reported the effect between groups on the reduction of PFM tone. There was a tendency toward positive effect of PFM relaxation training to improve BOO symptoms in women. PEDro score varied between 4 and 7. Few studies yielded information on the immediate effect of any type of PFM relaxation technique on PFM tone.
CONCLUSIONS: Few RCTs have been conducted on the effect of PFM relaxation training on PFM tone and functional female BOO symptoms. There is an urgent need for RCTs with high methodological and interventional quality in addition to basic research on mechanisms of different relaxation techniques on PFM activity.

Inflamed and infected tissues can display increased local sodium (Na+) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a Na+/Ca2+-exchanger 1 (NCX1)-dependent increase in intracellular Na+ levels. This results in augmented osmoprotective signaling and enhanced proinflammatory activation, such as enhanced expression of type 2 nitric oxide synthase and antimicrobial function. In this study, the role of elevated intracellular Na+ levels in macrophages was investigated. Therefore, the Na+/K+-ATPase (NKA) was pharmacologically inhibited with two cardiac glycosides (CGs), ouabain (OUA) and digoxin (DIG), to raise intracellular Na+ without increasing extracellular Na+ levels. Exposure to HS conditions and treatment with both inhibitors resulted in intracellular Na+ accumulation and subsequent phosphorylation of p38/MAPK. The CGs had different effects on intracellular Ca2+ and K+ compared to HS stimulation. Moreover, the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) was not upregulated on RNA and protein levels upon OUA and DIG treatment. Accordingly, OUA and DIG did not boost nitric oxide (NO) production and showed heterogeneous effects toward eliminating intracellular bacteria. While HS environments cause hypertonic stress and ionic perturbations, cardiac glycosides only induce the latter. Cotreatment of macrophages with OUA and non-ionic osmolyte mannitol (MAN) partially mimicked the HS-boosted antimicrobial macrophage activity. These findings suggest that intracellular Na+ accumulation and hypertonic stress are required but not sufficient to mimic boosted macrophage function induced by increased extracellular sodium availability.

OBJECTIVE: Was to assess the impact of masticatory muscles hypertonicity on the bite formation.
METHODS: The study comprised 60 patients aged 7-14 years. Group 1 consisted of 20 individuals with Angle class 1 occlusion without masticatory muscle hypertonicity. Group 2 comprised 20 patients with class II malocclusion with hypertonicity of the masticatory muscles, group 3 - 20 patients class II malocclusion and no hypertonic masticatory muscles. All patients were examined according to common diagnostic protocol that included electromyography of the temporal and masticatory muscles at rest and in dynamics).
RESULTS: In group 1 the mean IMPACT at rest was 242.8±133.6 µV, IMPACT during contraction was 880.50±201.5 µV; in group 2 - 797.9±413.0 and 1561.23±568.0 μV; in group 3 - 236.7±93.5 and 955.60±295.5 μV, correspondingly. The ratio of the activity of the temporal muscles to the masticatory muscles with neutral occlusion at rest correlates as 1:09, with compression 1:1. In patients with distal occlusion and the presence of hypertonicity at rest, the temporal muscles correspond to the chewing proper as 1:0.8, and with compression 1:09.
CONCLUSIONS: The estimated ratio can contribute to the retroposition of the mandible, as well as inhibition of the growth of the mandible in the sagittal direction.
UNASSIGNED: Определение влияние гипертонуса жевательных мышц на формирование аномалии окклюзии.
UNASSIGNED: Было обследовано 60 пациентов в возрасте от 7 до 14 лет. 1-я группа 1 состояла из 20 пациентов со смыканием зубов по I классу Энгля и без гипертонуса жевательной мускулатуры. 2-ю группу составили 20 человек с патологией прикуса по II классу Энгля и с гипертонусом жевательной мускулатуры, 3-ю группу — 20 человек со смыканием зубов по II классу Энгля, не имеющих гипертонуса жевательных мышц. Все пациенты были обследованы по единому диагностическому протоколу, включающему электромиографию височных и жевательных мышц в покое и в динамике.
UNASSIGNED: В 1-й группе среднее значение IMPACT в покое было 242,8±133,6 мкВ, IMPACT при сжатии — 880,50±201,5 мкВ; во 2-й группе — 797,9±413,0 и 1561,23±568,0 мкВ; в 3-й группе — 236,7±93,5 и 955,60±295,5 мкВ, соответственно. Соотношение активности височных мышц к жевательным при нейтральной окклюзии в покое соотносится как 1:0,9, при сжатии 1:1. У пациентов при дистальной окклюзии и наличии гипертонуса в покое височные мышцы соотносятся к собственно жевательным как 1:0,8, а при сжатии 1:0,9.
UNASSIGNED: Выявленное соотношение активности мышц может способствовать ретроположению нижней челюсти, а также торможению роста нижней челюсти в сагиттальном направлении.

Pelvic floor muscle tone, which includes active and passive components, is argued to be increased in many pelvic health conditions, including those involving pain. This study systematically reviewed evidence for increased pelvic floor muscle tone in pelvic health conditions.
Electronic databases (PubMed, CINAHL, and Embase) were searched up to May 31, 2021. The search strategy included variants of pelvic and/or floor, muscle, and tone using keywords and Medical Subject Headings (MeSH) terms.
Studies were included if they investigated increased tone of the pelvic floor muscle and reported measures of active or mechanical properties of the pelvic floor muscle in humans with any pelvic health condition, including pain, bowel, urogenital, or sexual dysfunctions. Studies of any design were included, except systematic and narrative reviews. Reference lists of studies, reviews, and book chapters were searched for additional studies.
Data were extracted using a standardized form, including measurement tool and outcome measure. Risk of bias was analyzed using a modified ROBINS-I (Risk of Bias In Non-randomized Studies - of Interventions) tool, and a score was allocated to determine whether the study provided \"convincing\" interpretation (comparison with condition-free control group, valid measure, no application issues).
In total, 151 studies were included, reporting 8 different tools (electromyography, dynamometry, manometry, digital palpation, defecography, ultrasound, magnetic resonance imaging, other). The most common pelvic health condition was pelvic pain (n=16 conditions), followed by bowel and urogenital conditions. Most studies (57%) were cross-sectional. A healthy control group was infrequently included for comparison (27%). Unvalidated methods or methods applied in a manner that precluded convincing interpretation were common (94%). Of the 15 measurement tools that provided convincing evidence, 10 demonstrated greater tone in a pelvic health condition (all pain) compared with controls, and 5 showed no difference.
Despite the large literature, few studies provide convincing evidence for increased tone/overactivity of pelvic floor muscles in pelvic health conditions. Interpretation is hampered by design and measurement issues. Terminology was often inaccurate. Few studies investigate male, transgender, and pediatric groups.

Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of extracellular tonicity. Herein, we highlight a novel regulatory mechanism involving the recruitment of microRNAs (miRNAs) under hypertonicity. RT-qPCR validated miRNAs candidates identified by high throughput screening approaches and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Overexpression strategies using Mimics or lentivirus revealed the impact on MR expression and signaling in renal KC3AC1 cells. miR-324-5p and miR-30c-2-3p expression are increased under hypertonicity in KC3AC1 cells. These miRNAs directly affect Nr3c2 (MR) transcript stability, act with Tis11b to destabilize MR transcript but also repress Elavl1 (HuR) transcript, which enhances MR expression and signaling. Overexpression of miR-324-5p and miR-30c-2-3p alter MR expression and signaling in KC3AC1 cells with blunted responses in terms of aldosterone-regulated genes expression. We also confirm that their expression is increased by hypertonicity in vivo in the kidneys of mice treated with furosemide. These findings may have major implications for the pathogenesis of renal dysfunctions, sodium retention, and mineralocorticoid resistance.