The adenosine A2B receptor is involved in anion secretion in human pancreatic duct Capan-1 epithelial cells

Adenosine modulates a wide variety of biological processes via adenosine receptors. In the exocrine pancreas, adenosine regulates transepithelial anion secretion in duct cells and is considered to play a role in acini-to-duct signaling. To identify the functional adenosine receptors and Cl− channels important for anion secretion, we herein performed experiments on Capan-1, a human pancreatic duct cell line, using open-circuit Ussing chamber and gramicidin-perforated patch-clamp techniques. The luminal addition of adenosine increased the negative transepithelial potential difference (V te) in Capan-1 monolayers with a half-maximal effective concentration value of approximately 10 μM, which corresponded to the value obtained on whole-cell Cl− currents in Capan-1 single cells. The effects of adenosine on V te, an equivalent short-circuit current (I sc), and whole-cell Cl− currents were inhibited by CFTRinh-172, a cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel inhibitor. The adenosine A2B receptor agonist, BAY 60-6583, increased I sc and whole-cell Cl− currents through CFTR Cl− channels, whereas the A2A receptor agonist, CGS 21680, had negligible effects. The A2B receptor antagonist, PSB 603, inhibited the response of I sc to adenosine. Immunohistochemical analysis showed that the A2A and A2B receptors colocalized with Ezrin in the luminal membranes of Capan-1 monolayers and in rat pancreatic ducts. Adenosine elicited the whole-cell Cl− currents in guinea pig duct cells. These results demonstrate that luminal adenosine regulates anion secretion by activating CFTR Cl− channels via adenosine A2B receptors on the luminal membranes of Capan-1 cells. The present study endorses that purinergic signaling is important in the regulation of pancreatic secretion

Involvement of butyrate in electrogenic K+ secretion in rat rectal colon

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are synthesized from dietary carbohydrates by colonic bacterial fermentation. These SCFAs supply energy, suppress cancer, and affect ion transport. However, their roles in ion transport and regulation in the intracellular environment remain unknown. In order to elucidate the roles of SCFAs, we measured short-circuit currents (ISC) and performed RT-PCR and immunohistochemical analyses of ion transporters in rat rectal colon. The application of 30 mM butyrate shifted ISC in a negative direction, but did not attenuate the activity of epithelial Na+ channels (ENaC). The application of bumetanide, a Na+-K+-2Cl− cotransporter inhibitor, to the basolateral side reduced the negative ISC shift induced by butyrate. The application of XE991, a KCNQ-type K+ channel inhibitor, to the apical side decreased the ISC shift induced by butyrate in a dose-dependent manner. The ISC shift was independent of HCO3− and insensitive to ibuprofen, an SMCT1 inhibitor. The mucosa from rat rectal colon expressed mRNAs of H+-coupled monocarboxylate transporters (MCT1, MCT4, and MCT5, also referred to as SLC16A1, SLC16A3, and SLC16A4, respectively). RT-PCR and immunofluorescence analyses demonstrated that KCNQ2 and KCNQ4 localized to the apical membrane of surface cells in rat rectal colon. These results indicate that butyrate, which may be transported by H+-coupled monocarboxylate transporters, activates K+ secretion through KCNQ-type K+ channels on the apical membrane in rat rectal colon. KCNQ-type K+ channels may play a role in intestinal secretion and defense mechanisms in the gastrointestinal tract

Prone Position Impairs Oxygen Supply-Demand Balance During Systemic Hypoxia in Rabbits

Ventilation in the prone position improves the prognosis of patients with severe acute respiratory distress syndrome (ARDS). Contraindications to ventilation in this position include unstable systemic circulation. Only a few reports exist on the effects of prone ventilation in respiratory failure on systemic circulation. This animal study compared systemic hemodynamic changes between supine and prone positions in anesthetized rabbits under acute systemic hypoxia (breathing 15% O2). Cardiac output and the systemic O2 extraction ratio increased under the hypoxia, but only in the supine group. Besides, the rate pressure product was higher in the prone group than in the supine group. This study showed that prone ventilation increases myocardial O2 consumption and suppresses compensatory mechanisms to maintain aerobic metabolism during systemic hypoxia. First of all, it will be necessary to examine the effect of prone ventilation on the O2 supply-demand balance in the ARDS model

Clinical Practice Changes After Post-Market Safety Reports on Desmopressin Orally Disintegrating Tablet in Japan: A Single-Center Retrospective Study

Background: Desmopressin orally disintegrating tablet (ODT) was approved in March 2012 in Japan; the post-market safety reports, which warned about adequate initial dose of desmopressin ODT, were published in 2014. However, it is unclear how the warning affected physician and patient behavior. Methods: We performed a retrospective single-center study to compare the clinical situation of Japanese central diabetes insipidus patients before and after the report. Results: Thirty-four patients before October 2014 and 16 patients after November 2014 switched from intranasal desmopressin to desmopressin ODT. The mean follow-up period after the switch to desmopressin ODT was 38 ± 3 months. Patients switching after November 2014 tended to have lower ratios of oral to nasal desmopressin dose at switching and 3 months after the switch (at switching; P = 0.20, 3 months; P = 0.42, respectively), and higher ratios from 6 to 12 months than before October 2014 (6 months; P = 0.93, 9 months; P = 0.52, 12 months; P = 0.80, respectively). Relative doses per initial desmopressin ODT at 9 and 12 months were significantly higher in patients switching after November 2014 than in patients switching before October 2014 (9 months; P = 0.02, 12 months; P = 0.04, respectively). Moreover, logistic regression analysis revealed that the incidence of hyponatremia was dependent on the ratio of nasal to oral desmopressin dose (P = 0.02). In addition, in four out of six patients who had serum sodium level reduced below 130 mEq/L, hyponatremia occurred within 1 month after the switch. Conclusions: A more gradual dose titration after the safety reports was performed, which involved the long-term safety of desmopressin ODT use. Vigilance of hyponatremia in early phase of desmopressin ODT use should be noted

Marathoners’ Breathing Pattern Protects Against Lung Injury by Mechanical Ventilation: An Ex Vivo Study Using Rabbit Lungs

[Background] Breathing during a marathon is often empirically conducted in a so-called “2:2 breathing rhythm,” which is based on a four-phase cycle, consisting of the 1st and 2nd inspiratory and the 1st and 2nd expiratory phases. We developed a prototype ventilator that can perform intermittent positive pressure ventilation, mimicking the breathing cycle of the 2:2 breathing rhythm. This mode of ventilation was named the marathoners’ breathing rhythm ventilation (MBV). We hypothesized that MBV may have a lung protective effect. [Methods] We examined the effects of the MBV on the pulmonary pre-edema model in isolated perfused rabbit lungs. The pulmonary pre-edema state was induced using bloodless perfusate with low colloid osmotic pressure. The 14 isolated rabbit lung preparations were randomly divided into the conventional mechanical ventilation (CMV) group and MBV group, (both had an inspiratory/expiratory ratio of 1/1). In the CMV group, seven rabbit lungs were ventilated using the Harvard Ventilator 683 with a tidal volume (TV) of 8 mL/kg, a respiratory rate (RR) of 30 cycles/min, and a positive end-expiratory pressure (PEEP) of 2 cmH2O for 60 min. In the MBV group, seven rabbit lungs were ventilated using the prototype ventilator with a TV of 6 mL/kg, an RR of 30 cycles/min, and a PEEP of 4 cmH2O (first step) and 2 cmH2O (second step) for 60 min. The time allocation of the MBV for one cycle was 0.3 s for each of the 1st and 2nd inspiratory and expiratory phases with 0.2 s of intermittent resting between each phase. [Results] Peak airway pressure and lung wet-to-dry ratio after 60 min of ventilation were lower in the MBV group than in the CMV group. [Conclusion] MBV was considered to have a lung-protective effect compared to CMV

Chemical effect on muonic atom formation through muon transfer reaction in benzene and cyclohexane samples

To investigate the chemical effect on the muon capture process through a muon transfer reaction from a muonic hydrogen atom, the formation rate of muonic carbon atoms is measured for benzene and cyclohexane molecules in liquid samples. The muon transfer rate to carbon atoms of the benzene molecule is higher than that to the carbon atoms of the cyclohexane molecule. Such a deviation has never been observed among those molecules for gas samples. This may be because the transfers occur from the excited states of muonic hydrogen atoms in the liquid system, whereas in the gas system, all the transfers occur from the 1s (ground) state of muon hydrogen atoms. The muonic hydrogen atoms in the excited states have a larger radius than those in the 1s state and are therefore considered to be affected by the steric hindrance of the molecular structure. This indicates that the excited states of muonic hydrogen atoms contribute significantly to the chemical effects on the muon transfer reaction

A new equation to estimate basal energy expenditure of patients with diabetes

[Background & aims]Predictive equations for basal energy expenditure (BEE) derived from Caucasians tend to overestimate BEE in non-Caucasians. The aim of this study was to develop a more suitable method to estimate BEE in Japanese patients with diabetes using indices readily measured in clinical practice. [Methods]BEE was measured by indirect calorimetry under a strict basal condition in 68 Japanese patients with type 1 or type 2 diabetes. The best fitting equation was investigated by multiple regression analysis using of age, sex, and anthropometric indices. The resultant new equation was tested in a separate group of 60 Japanese patients with type 1 or type 2 diabetes, and the accuracy compared with existing equations. [Results]The best-fit equation was BEE [kcal/day] = 10 × (body weight)[kg] – 3 × (age)[y] + 125 (if male) + 750. Adjusted coefficient of determination was 81.0%. Root mean squared errors and accurate prediction in the validation set were 103 kcal/day and 78% for the new equation; 184 and 50 for Harris-Benedict; 209 and 38 for Oxford; 205 and 42 for Liu; and 140 and 63 for Ganpule. [Conclusions]This new equation is simpler and estimates BEE more accurately in Japanese patients with diabetes than the presently used equations do

Effects of 3 Years of Treatment with a Selective Estrogen Receptor Modulator for Postmenopausal Osteoporosis on Markers of Bone Turnover and Bone Mineral Density

Aim: The aim of the present study was to assess the changes in bone mineral density and bone turnover markers in long-term SERM. Methods: The study was performed on 25 female outpatients with primary osteoporosis treated at the Osteoporosis Department of Showa University School of Medicine. All patients had been on raloxifene (60mg/day) for ≥ 3 years. The mean patient age was 67.1 years and the women were, on average, 18.4 years postmenopausal. Levels of bone turnover markers (urinary naltrexone [NTX] and bone-specific alkaline phosphatase [BAP]) and bone mineral density (BMD; front lumbar vertebrae, three proximal femur sites, and two distal radius sites) were determined before and then annually after starting raloxifene for a period of 3 years. Results: Over the 3-year treatment period, significant decreases were seen in both urinary NTX and BAP levels. Although BMD of the lumbar vertebrae and distal radius was increased over the 3 years after initiation of raloxifene treatment, the difference failed to reach statistical significance. The BMD of the femoral neck decreased, whereas that of the femoral trochanter and femoral intertrochanter area increased. Conclusions: The selective estrogen receptor modulator raloxifene is suitable for the treatment of osteoporosis in postmenopausal patients because it reduces bone turnover while maintaining adequate bone density

Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1–induced Rho-kinase activation and the enhancement of stress fibers were inhibited by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements

Nonlinear Excitation of Subcritical Instabilities in a Toroidal Plasma

In a collisionless plasma, it is known that linearly stable modes can be destabilized (subcritically) by the presence of structures in phase space. However, nonlinear growth requires the presence of a seed structure with a relatively large threshold in amplitude. We demonstrate that, in the presence of another, linearly unstable (supercritical) mode, wave-wave coupling can provide a seed, which is significantly below the threshold, but can still grow by (and only by) the collaboration of fluid and kinetic nonlinearities. By modeling the subcritical mode kinetically, and the impact of the supercritical mode by simple wave-wave coupling equations, it is shown that this new kind of subcritical instability can be triggered, even when the frequency of the supercritical mode is rapidly sweeping. The model is applied to the bursty onset of geodesic acoustic modes in a LHD experiment. The model recovers several key features such as relative amplitude, time scales, and phase relations. It suggests that the strongest bursts are subcritical instabilities, driven by this mechanism of combined fluid and kinetic nonlinearities