7-day Washout Research Articles

RNA synthesis and turnover in the molluscan nervous system studied by Click-iT method

RNA synthesis can be detected by means of the in vivo incorporation of 5-ethynyluridine (EU) in newly-synthesized RNA with the relatively simple Click-iT method. We used this method to study the RNA synthesis in the CNS tissue of adult and juvenile terrestrial snails Helix lucorum L. Temporally, first labeled neurons were detected in the adult CNS after 4-h of isolated CNS incubation in EU solution, while 12-h of incubation led to extensive labeling of most CNS neurons. The EU labeling was present as the nuclear and nucleolar staining. The cytoplasm staining was observed after 2–3 days of CNS washout following the EU exposure for 16h. In juvenile CNS, the first staining reaction was apparent as the staining of apical region in the procerebral lobe of cerebral ganglia after 1h of CNS incubation in EU, while the maximum pattern of staining was obtained after 4h of CNS incubation. Thus, age-related differences in RNA synthesis are present. Activation of neurons elicited by serotonin and caffeine applications noticeably increased the intensity of staining. EU readily penetrates into the bodies of juvenile snails immersed in the EU solution. When the intact juvenile animals were immersed in the EU solution for 1h, the procerebrum staining, similar to the one detected in the incubated juvenile CNS, was observed.

Immediate changes in electroencephalography activity in individuals with nonspecific chronic low back pain after cranial osteopathic manipulative treatment: study protocol of a randomized, controlled crossover trial.

BackgroundOsteopathic medicine is based on a diagnostic and therapeutic system to treat tissue mobility/ motility dysfunctions in general, using different approaches (depending on the target tissue) known as osteopathic manipulative treatment. Among the available techniques those ones addressed to the cranial field are the most questioned because of the lack of scientific evidence; but the compression of the 4th ventricle technique has been largely studied in clinical trials. Studies have shown that the technique may affect both central and autonomous nervous system, modulating some reflexes (Traube-Hering baro signal), and modifying brain cortex electrical activity through central sensitization in subjects with chronic low back pain. Thus, investigators hypothesize that the compression of the 4th ventricle may modulate peak alpha frequency (eletroencephalographic assessment) and promote physical relaxation in subjects in vigil.Methods/DesignA randomized, controlled crossover trial with blinded assessor was designed to test the hypothesis. A total of 81 participants will be assigned to three treatment conditions, with seven days of washout: (I) compression of the 4th ventricle; (II) sham compression of the fourth ventricle; (III) control (no intervention). The (I) power amplitude and the (II) frequencies of the dominant peak in the alpha band will be the primary outcome measures of the study. All participants will be recruited at the Outpatient Rehabilitation Service of the University Hospital of Brasília – University of Brasília. All the electroencephalographic exams will be conducted by a blinded assessor.DiscussionThe investigators hypothesize that patients with chronic low back pain submitted to the technique would have the peak alpha frequency modulated and, thus, would experience physical relaxation.Trial registrationNCT02111382

L-Citrulline Supplementation Attenuates Cardiovascular Responses to Metaboreflex Activation with Cold Exposure in Young Overweight Men

Cold-induced increases in left ventricular afterload may increase the risk for cardiac events in individuals with high cardiovascular risk. Obese individuals have higher blood pressure (BP) and sympathetic responses to post-exercise muscle ischemia (PEMI) than lean counterparts. L-citrulline supplementation attenuates systolic BP (SBP) and pressure wave reflection (augmentation index, AIx) responses to the cold pressor test (CPT), but the capacity of L-citrulline to reduce aortic hemodynamics and arterial stiffness responses during PEMI with and without cold exposure is unknown. PURPOSE: To examine if L-citrulline supplementation would attenuate hemodynamic responses to PEMI with and without CPT (PEMI+CPT). METHODS: Fourteen healthy overweight/obese men (age 24 ± 6 y; BMI 29.3 ± 4.0 kg/m2) were randomly assigned to placebo (maltodextrin) or L-citrulline (6 g/day) supplementation for 14 days and cross-over after 14 days of wash-out. Brachial SBP, aortic SBP, aortic AIx, brachial-ankle pulse wave velocity (baPWV, a marker of arterial stiffness), and heart rate were evaluated at baseline, during PEMI, and during PEMI+CPT. RESULTS: During PEMI, L-citrulline significantly decreased aortic AIx (-8.6 ± 2.0%; P < 0.01) compared with placebo, but did not affect brachial SBP, aortic SBP, and baPWV. During PEMI+CPT, L-citrulline decreased brachial SBP (-11 ± 3 mmHg, P < 0.01), aortic SBP (-13 ± 3 mmHg, P < 0.01), aortic AIx (-13.8 ± 2.2%, P < 0.01), and baPWV (-0.9 ± 0.4 m/s, P < 0.05) compared with placebo. CONCLUSIONS: L-citrulline supplementation attenuated the increases in peripheral and central SBP, wave reflection, and arterial stiffness during metaboreflex activation in the cold, a condition with greater vascular responses than PEMI without CPT.

Confronting the Effects of 0.9% Saline Administration on Breathing

Saline (0.9%) is regularly used in hospitals and research settings as a resuscitation solution or as a conduit to administer compounds to patients or subjects. Preliminary data in our laboratory suggested dissimilar ventilation following short‐term i.p. saline administration (n=4) compared to non‐injected (n=6) mice (frequency: 111±15 vs. 126±4 breaths/min; tidal volume (TV): 0.31±0.02 vs. 0.35±0.01 mL/breath; minute ventilation (MV): 35.1±5.9 vs 43.9±1.4 mL/min). In addition, previous reports suggest that the addition of 0.9% saline could induce changes in pH, possibly altering breathing. We tested the hypothesis that ventilation would be higher in mice prior to saline administration compared to after saline administration. Utilizing unrestrained barometric plethysmography, we tested 18 week old CD‐1 male mice prior to intervention and following 7 days of 0.9% saline (i.p., 10mL/kg body mass) during exposure to room air. Values are reported as MEAN ± SEM; p&lt;0.05; n=4. There were no differences when comparing PRE vs. POST saline in frequency (137±9 vs. 142±10 breaths/min, TV (0.46±.01 vs. 0.52±.02 mL/breath), or MV (62.5±3.8 vs. 72.5±7.7 mL/min). Conscious blood gas sampling showed no differences between 7 days of saline administration (pH: 7.46±0.00; PaCO2: 29.3±2.3) and 1 day of washout (pH: 7.39±0.03; PaCO2: 39.1±4.6). Our preliminary findings indicate no impact of saline administration on the pattern of breathing during exposure to room air. Funding: Le Moyne College Student Research Committee and McDevitt Center Research Fellowship in Natural Science (TG).

Acute hyperhydration reduces athlete biological passport OFF-hr score.

Anecdotal evidence suggests that athletes hyperhydrate to mask prohibited substances in urine and potentially counteract suspicious fluctuations in blood parameters in the athlete biological passport (ABP). It is examined if acute hyperhydration changes parameters included in the ABP. Twenty subjects received recombinant human erythropoietin (rhEPO) for 3 weeks. After 10 days of rhEPO washout, 10 subjects ingested normal amount of water (∼ 270 mL), whereas the remaining 10 ingested a 1000 mL bolus of water. Blood variables were measured 20, 40, 60, and 80 min after ingestion. Three days later, the subjects were crossed-over with regard to water ingestion and the procedure was repeated. OFF-hr was reduced by ∼ 4%, ∼ 3%, and ∼ 2% at 40, 60, and 80 min, respectively, after drinking 1000 mL of water, compared with normal water ingestion (P < 0.05). Forty percent of the subjects were identified with atypical blood profiles (99% specificity level) before drinking 1000 mL of water, whereas 11% (n = 18), 10% and 11% (n = 18) were identified 40, 60, and 80 min, respectively, after ingestion. This was different (P < 0.05) compared with normal water intake, where 45% of the subjects were identified before ingestion, and 54% (n = 19), 45%, and 47% (n = 19) were identified 40, 60, and 80 min, respectively, after ingestion. In conclusion, acute hyperhydration reduces ABP OFF-hr and reduces ABP sensitivity.

A randomised, double- blind, cross-over study investigating the prebiotic effect of agave fructans in healthy human subjects.

This placebo-controlled, randomised, double-blind, cross-over human feeding study aimed to determine the prebiotic effect of agave fructans. A total of thirty-eight volunteers completed this trial. The treatment consisted of 3 weeks' supplementation with 5g/d of prebiotic agave fructan (Predilife) or equivalent placebo (maltodextrin), followed by a 2-week washout period following which subjects were crossed over to alternate the treatment arm for 3 weeks followed by a 2-week washout. Faecal samples were collected at baseline, on the last day of treatment (days 22 and 58) and washout (days 36 and 72), respectively. Changes in faecal bacterial populations, SCFA and secretory IgA were assessed using fluorescent in situ hybridisation, GC and ELISA, respectively. Bowel movements, stool consistencies, abdominal comfort and mood changes were evaluated by a recorded daily questionnaire. In parallel, the effect of agave fructans on different regions of the colon using a three-stage continuous culture simulator was studied. Predilife significantly increased faecal bifidobacteria (log10 9·6 (sd 0·4)) and lactobacilli (log10 7·7 (sd 0·8)) compared with placebo (log10 9·2 (sd 0·4); P=0·00) (log10 7·4 (sd 0·7); P =0·000), respectively. No change was observed for other bacterial groups tested, SCFA, secretory IgA, and PGE2 concentrations between the treatment and placebo. Denaturing gradient gel electrophoresis analysis indicated that bacterial communities were randomly dispersed and no significant differences were observed between Predilife and placebo treatments. The in vitro models showed similar increases in bifidobacterial and lactobacilli populations to that observed with the in vivo trial. To conclude, agave fructans are well tolerated in healthy human subjects and increased bifidobacteria and lactobacilli numbers in vitro and in vivo but did not influence other products of fermentation.

Genetic background influences the change from the discriminative stimulus to the rewarding effects of psychostimulants in rats

Aims: Antagonist therapy for opioid dependence with naltrexone, available in long-acting injectable form, represents an important but underutilized treatment option. The aims of this study are to develop procedures for outpatient detoxification and to compare induction rates onto injectable naltrexone (XR-NTX) between groups receiving naltrexone-assisted vs. buprenorphineassisted outpatient detoxification. Methods: Opioid-dependent participants seeking treatment were randomized into 2 groups for short-term outpatient opioid detoxification. One group received a 7-day buprenorphine taper, followed by a 7-day long washout and an injection of XR-NTX. A second group received a single day of buprenorphine, followed by a washout day and 4-day oral naltrexone taper and an injection of XR-NTX. Following induction, participants received behavioral therapy for 4 weeks Results: To date, 79 participants (65% white, 86% male, 34% prescription opioid users) have entered the study and were randomized to naltrexone (n=53) or buprenorphine (n=26) arm. 51% of participants in the naltrexone arm and 46% in the buprenorphine arm have been successfully inducted onto XR-NTX (p= .69). 50% of participants in the naltrexone arm and 36% in the buprenorphine arm completed Week 5 (p= .25) and received a second XR-NTX injection. Conclusions: The data from this study suggests that oral naltrexone is an important alternative medication useful in the opioid detoxification process. Participants treated with naltrexone during detoxification had comparable outcomes with those in the buprenorphine-assisted detoxification in becoming inducted onto XR-NTX. At least half of the patients undergoing oral naltrexone-assisted outpatient detoxification completed induction onto XR-NTX. These results suggest initiation of XR-NTX on an outpatient basis is a clinically viable treatment option that may be attractive to many patients and providers. Financial support: NIDA (DA 010746-09A1).

Abstract 16820: CaMKIIδc Transgenic Mice Develop Spontaneous Ventricular Arrhythmias Which Can Be Suppressed by Inhibition of Late Na+ Current

Introduction: It has been shown that activated CaMKII can phosphorylate cardiac Na+ channels that leads to an enhanced late Na current (INaL). We hypothesized that enhanced INaL plays an important role in arrhythmogenesis linked to increased CaMKII activity. To test this hypothesis we determined the effect of a selective INaL inhibitor GS-967 on spontaneously occurring ventricular arrhythmias in mice overexpressing CaMKIIδc (TG). Methods: TG (n=6) and wild type (WT, n=3) mice at age 8 week (wk) were instrumented with telemetry transmitters to record ECG. ECG were recorded continuously starting 1 wk post- surgery (age 9 wk) until age 19 wk. Incidence and burden of arrhythmias were evaluated at ages 9, 11, 13, 15, 17 and 19 wks using DSI ECG Pro software. At age 17 wk, when arrhythmia burden was relatively stable, mice were treated with a single dose of GS-967 (1 mg/kg, i.p.) or vehicle. After 4 days of washout, the treatment was repeated in a cross-over manner. Arrhythmia burden was quantified over a duration of 15-hours post-treatment. Using patch clamp technique, INaL was measured in ventricular myocytes isolated from both TG and WT mice at 17 wk age. Results: Incidence and burden of spontaneous ventricular arrhythmias increased progressively with age in TG mice. Between age 9 and 11 wks, 50% of TG mice had an arrhythmia burden ≥ 5 minutes/24 hours. The incidence increased to 83% at wk 13, 15, 17 and to 100% at 19 wks and the burden increased to 71 ± 35 min/24 hr at 17 wk. A single dose of GS-967 significantly decreased arrhythmia burden from 42.5 ± 9.6 min (treated with vehicle) to 9.4 ± 4.3 min (p&lt;0.05) during a 15-hr period. No arrhythmias were observed in WT mice during the course of the study. INaL was enhanced by more than 2-fold in myocytes isolated from TG mice compared to WT (0.2±0.03 vs. 0.08±0.02 pA/pF, n=16 each, p&lt;0.05). GS-967 caused a concentration-dependent reduction of INaL (50.5±3.4% at 0.3 μM, n=7; and 91±5.2% at 1 μM, n=4). Conclusions: This is the first report to show a reduction of spontaneously occurring ventricular arrhythmias by inhibition of INaL indicating a key role for INaL in CaMKII associated arrhythmogenesis.

Macitentan, a dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension, does not affect cardiac repolarization in healthy subjects

Macitentan is an orally active dual endothelin receptor antagonist, which demonstrated a reduction of the risk of morbidity/mortality events in pulmonary arterial hypertension patients. This double-blind, randomized, placebo- and positive-controlled, four-way crossover thorough QTc study was designed to investigate the effects of therapeutic and supratherapeutic doses of macitentan on cardiac repolarization in healthy male and female subjects. Each subject received the following treatments: moxifloxacin 400 mg, macitentan 10 mg, macitentan 30 mg, and placebo. Each treatment period lasted 9 days and was followed by at least 10 days of washout. The primary endpoint of this study was the baseline-adjusted, placebo-corrected QT interval corrected using the Fridericia method (ΔΔQTcF). Pharmacokinetic (PK), safety, and tolerability assessments were performed during each treatment.A total of 64 subjects were randomized. The upper bound of the 2-sided 90% confidence interval for ΔΔQTcF following macitentan was <10 ms at all time points and no correlation was observed between ΔΔQTcF and PK parameters. Findings in the analysis of the morphological patterns of the ECGs were randomly distributed across all treatments and did not indicate an association with macitentan. Macitentan was well tolerated in this study. Headache and nasopharyngitis were the most frequently reported adverse events. No effects on clinical laboratory and vital signs parameters were observed.In summary, repeated doses of macitentan 10 mg and 30 mg did not indicate any pro-arrhythmic potential.

The Effects of Venlafaxine on Cortical Motor Area Activity in Healthy Subjects

In the study, we used functional magnetic resonance imaging associated with behavioral assessment to observe the effects of venlafaxine on the modulation of human motor cortex activation and to provide preliminary data for further assessing its influence on motor functional reorganization after stroke injury. In a randomized, double-blind, crossover study, 8 right-handed subjects received 75 mg of either venlafaxine or a placebo daily over a period of 7 days separated by 3 washout days. The volunteers were asked to execute motor tasks, which included the dynamometer and finger-tapping test. In addition, laboratory tests and functional magnetic resonance imaging examination, before the start of the experiment and after administration of placebo and venlafaxine, were performed. It was shown that the finger-tapping rate of each hand in the venlafaxine stage was significantly improved compared with that observed in the placebo stage (n = 8, F left hand = 57.69, F right hand = 184.48, P < 0.001). The changes in the recorded grip strengths of both hands were not significant between the stages (n = 8, F = 2.63, P > 0.05). In the venlafaxine stage, the activations of the contralateral primary sensorimotor cortex, contralateral premotor cortex, and contralateral supplementary motor area were enhanced significantly, whereas the activation of the bilateral parietal cortices was decreased when compared with the placebo stage. Meanwhile, the enhancement of contralateral primary sensorimotor cortex activation had a positive correlation with the improvement of the finger-tapping rate. It was concluded that venlafaxine could modulate the cortical excitability and improve finger dexterity and reaction speed, which greatly related to the increase of contralateral motor cortical excitability.

A preliminary study of the neuroprotective role of citicoline eye drops in glaucomatous optic neuropathy.

Purpose:To study the neuroprotective effect of topical citicoline.Materials and Methods:Experimental phase to evaluate the ability of citicoline eye drops to reach the vitreous and the retina: The right eyes of 5 mice CD1 were treated with two drops per day for three days of citicoline 1% and 2% (OMK1, Omikron Italia s.r.l.), and then the vitreous was analyzed with the liquid chromatography and spectrometry mass (LC-MS/MS). Clinical phase to determine if topical citicoline is able to delay glaucoma progression, considering perimetric parameters and electro functional tests. Patients were randomized in two groups, OMK1 and OAG. The first group was treated with OMK1 three times per day, plus hypotensive therapy for two months and one month of wash out. The second group was treated only with hypotensive treatment for three months.Results:LC-MS/MS detected the molecule very well, and only OMK1 showed systemic absorption. Thirty-four patients were enrolled, 16 in the OMK1 and 18 in the OAG group. Perimetric parameters showed a positive trend in individual eyes of patients in OMK1 group, but these values were not statistically significant in the whole group. Retinal ganglion cells function improved as shown by reduced P50 latency (P = 0.04) and increased P50-N95 amplitude (P < 0.0001) of pattern electroretinogram, up to 30 days after the washout (P = 0.01; P = 0.002). Visual evoked potential and retino-cortical time improvement regressed after 30 days of washout. In OAG group, there was any change during the follow-up. No adverse reactions were reported in both groups.Conclusions:Topical citicoline seems to have a neuroprotective action.

Evaluation Of The Effect Of Idelalisib On The QT/QTc Interval In Healthy Subjects

AbstractAbstract 5573 BackgroundIdelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA displayed no significant inhibition of hERG channel activity for in vitro studies (IC50 ≥ 50 μM). ECG assessments in clinical studies indicated no evidence of QT interval prolongation or relationships between IDELA concentrations and QT or PR interval parameters over a dose range of 17 mg to 400 mg. A Phase 1, thorough QT study was performed in accordance with ICH E14 requirements for clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential of non-antiarrhythmic drugs. This study evaluated the effect of therapeutic and supratherapeutic doses of IDELA on QTc interval in healthy subjects, relative to matched placebo and active control. MethodsA total of 48 subjects were enrolled in the study and randomized to one of two cohorts, each with a 4 x 4 Williams square design, to receive IDELA single dose at 150 (therapeutic dose) or 400 mg (supratherapeutic dose), placebo, or moxifloxacin at 400 mg (positive control) with 10 days of washout between each treatment. Multiple 12-lead time-matched ECGs were collected in triplicate at various time points over 24hours after each treatment and ECGs collected were obtained digitally using a Mortara H12+ Holter monitor. Time matched blood samples were collected and levels of IDELA and GS-563117 were measured using LC/MS/MS. Parametric analyses of covariance (ANCOVA) using a mixed-effects model were used to assess the change of QTc from predose baseline and proportionality of IDELA PK. A linear mixed effects model was used to quantify the relationship between IDELA plasma concentration and the DDQTc (time-matched, baseline-adjusted, placebo corrected QTc). Safety assessments were performed throughout the study. ResultsA total of 48 subjects were enrolled into this study. The majority of subjects were Black or African-American (58.3%) or White (33.3%), with even distribution of female (47.9%) and male (52.1%), and with a mean age of 33 years (range, 20 to 45 years). Study treatments were generally well tolerated. The majority of AEs were reported as Grade 1 (mild) in severity. There were no clinically relevant changes in any hematology or chemistry parameter for any treatment (including IDELA 150 and 400 mg, placebo, and moxifloxacin). The majority of treatment-emergent laboratory abnormalities were Grade 1. Idelalisib was generally well-tolerated at therapeutic (150 mg) and supratherapeutic (400 mg) doses.Plasma exposures IDELA and its major circulating metabolite GS-563117 were slightly less than dose-proportional between the 400 mg vs 150 mg (over a 2.7-fold dose range, IDELA and GS-563117 Cmax increased ∼1.7- and ∼1.8-fold respectively; corresponding values for AUCinfincreased ∼2.3 and 2.4-fold, respectively). Following moxifloxacin treatment, the lower bound of the 2-sided 90% CI for the mean difference in QTcF between moxifloxacin and placebo was greater than 5 msec at 2 time points (3 and 4 hours) after dosing, thereby establishing assay sensitivity. Following IDELA treatment, the upper bounds of the 2-sided 90% CIs for the mean difference in QTcF between therapeutic or supratherapeutic doses of IDELA and placebo were below 10 msec at all time points after dosing, meeting the definition of a “negative” thorough QT study. Results from the analyses of secondary endpoints QTcB, QTcN, and QTcI were consistent with those from the primary QTcF analysis. There were no relevant relationships between time-matched, baseline-adjusted, placebo-corrected QTcF and IDELA or GS-563117 plasma concentrations. ConclusionIn a study with demonstrated assay sensitivity, IDELA 150 mg and 400 mg administration did not affect QTc interval in healthy adults, and met the definition of a negative thorough QT study as defined by ICH guidance. There were no relevant relationships between time-matched, baseline-adjusted, placebocorrected QTcF and IDELA or GS-563117 plasma concentrations. Single oral doses of IDELA 150 mg and 400 mg were well tolerated. Disclosures:Jin:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Nichols:Gilead Sciences: Employment. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats

Concomitant behavioral and dorsal raphe (DR) neuronal activity were recorded following acute and chronic dose response of methylphenidate (MPD) in freely moving rats previously implanted with permanent semi-microelectrodes using telemetric (wireless) technology. On experimental day (ED) 1, the neuronal and locomotor activity were recorded after saline (baseline) and MPD (0.6, 2.5 or 10.0mg/kg) injection (i.p.). Animals were injected daily with a single dose of MPD for five consecutive days (ED 2-6) to elicit behavioral sensitization or tolerance. After three washout days, the neuronal and locomotor activity recording was resumed on ED 10 followed by saline and MPD rechallenge injection. The main findings were: (1) the same dose of chronic MPD administration elicited behavioral sensitization in some animals and behavioral tolerance in others. (2) 46%, 56% and 73% of DR units responded to acute 0.6, 2.5 and 10.0mg/kg MPD respectively. (3) 89%, 70% and 86% of DR units changed their baseline activity on ED 10 compared to that on ED 1 in the 0.6, 2.5 and 10.0mg/kg MPD groups respectively. (4) A significant difference in ED 10 baseline activity was observed in the DR neuronal population recording from animals expressing behavioral sensitization compared to that of animals expressing behavioral tolerance. (5) 89%, 78% and 88% of DR units responded to chronic 0.6, 2.5 and 10.0mg/kg MPD respectively. (6) The DR neuronal population recording following acute MPD on ED 1 and rechallenge MPD on ED 10 from animals expressing behavioral sensitization was significantly different from the neuronal population recorded from animals exhibited behavioral tolerance. The correlation between the DR neuronal activity and animal's behavior following chronic MPD exposure suggested that the DR neuronal activity may play an important role in the expression of behavioral sensitization and tolerance induced by chronic MPD administration.

Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus

The cellular morphology of the collecting duct is altered by chronic lithium treatment. We have previously shown that lithium increases the fraction of type-A intercalated cells and lowers the fraction of principal cells along the collecting duct. Moreover, type-A intercalated cells acquire a long-row distribution pattern along the tubules. In the present study, we show that these morphological changes reverse progressively after discontinuation of lithium and finally disappear after 19 days from lithium suspension. In this time frame we have identified for the first time, in vivo, a novel cellular type positive for both intercalated and principal cells functional markers, as recognized by colabeling with H(+)-ATPase/aquaporin-4 (AQP4) and anion exchanger-1 (AE-1)/AQP2 and Foxi1/AQP4. This cell type is mainly present after 6 days of lithium washout, and it disappears in parallel with the long-row pattern of the type-A intercalated cells. It usually localizes either in the middle or at the edge of the long-row pattern. Its ultrastructure resembles the intercalated cells as shown both by differential interference contrast and by electron microscopy. The time course of appearance, the localization along the collecting duct, and the ultrastructure suggest that the cells double labeled for principal and intercalated cells markers could represent a transition element driving the conversion of intercalated cells into principal cells.

Food intake modulation by hop phytoestrogen (PE) in overweight neutered cats

Estrogen inhibition of food intake diminishes with neutering, often resulting in unhealthy weight gain. A potent hop PE, 8‐prenylnaringinen (8PN), may be a suitable source of estrogen‐replacement to stem excessive post‐neutering food intake. Ad libitum‐fed, adult (3.9–4.3 y), neutered males (n=6) of 105–148% of pre‐neuter weight (4.7–7.0 kg) received daily for 5 d subcutaneous (SQ) injections (20 μL/kg) of 8PN at 10, 50, 100, &amp; 200 μg/kg, 17β‐estradiol (E2) at 0.1 μg/kg, and vehicle of sesame oil:ethanol (9:1). Using a Latin‐square design with 2‐week blocks and 9 washout days between injection treatments, food intake was found decreased (P&lt;0.05) with injections of E2 (−41±7%) and 8PN at 100 (−17±3%) and 200 (−29±5%) μg/kg. Effectiveness of oral daily dosage for 5 d was subsequently evaluated. Vehicle (ethanol) and 8PN at 10‐fold the minimally effective SQ dose (1 mg/kg) were air‐dried on voluntarily ingested kibbles. Food intakes during 8PN and vehicle ingestions were not significantly different, indicating low oral 8PN bioavailability relative to E2. Potency for food intake modulation by 8PN appears much greater than that reported for genistein, a soybean PE, but much less than that found for E2.

Discomfort Symptoms Reduction and Ocular Surface Parameters Recovery with Artelac Rebalance Treatment in Mild–moderate Dry Eye

To evaluate Artelac Rebalance® eyedrops' efficacy in symptoms reduction, ocular surface parameters recovery, and tolerability in the treatment of mild to moderate dry eye. Fifteen patients were enrolled. Inclusion criteria were Ocular Surface Disease Index (OSDI) score >16, tear film break-up time (TFBUT) <10 seconds, Schirmer test I >10 mm/5 min, and mild ocular surface damage (Oxford grading) ≤3. Artelac Rebalance® eyedrops were administered 3 times daily for 2 months. Patients were evaluated at enrollment, after 2 days of washout (baseline), and after 1 and 2 months of treatment. Parameters for ocular discomfort (OSDI score), tear film quality (Schirmer test I, TFBUT, tear osmolarity), ocular surface damage (fluorescein staining, conjunctival imprint cytology), and inflammation (scraping cytology and exuded serum albumin) were measured. Tolerability and satisfaction were assessed by validated questionnaires. At endpoint versus baseline, all variables showed a statistically significant improvement (paired Student t test, p<0.01 for all parameters) as follows: OSDI score (21.9 ± 10.6 vs 35.8 ± 12.2), TFBUT (6.5 ± 1.1 s vs 5.2 ± 2.3 s), Oxford grading of corneal and conjunctival damage (0.56 ± 0.50 vs 1.16 ± 0.37), tear osmolarity (294.6 ± 2.1 mOsm/L vs 303.1 ± 4.6 mOsm/L), conjunctival goblet cell density/mm2 (140.8 ± 43.3 cells/mm2 vs 115.1 ± 15.8 cells/mm2), scraping cytology score (2.9 ± 1.0 vs 4.2 ± 1.3), and percentage of serum albumin in tears (9.2% ± 4.8% vs 24.1% ± 10.8%). Tolerability and satisfaction were scored high, with no adverse events reported. Application of Artelac Rebalance® eyedrops for 2 months in mild to moderate dry eye resulted in a reduction of ocular inflammation parameters, ocular surface damage, and subjective discomfort symptoms, with a parallel improvement in tear film quality (measured by TFBUT and osmolarity).

1041 THE EFFECTS OF REGULAR AND DECAFFEINATED COFFEE ON VOIDING SYMPTOMS IN YOUNG HEALTHY VOLUNTEERS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Incontinence, Evaluation & Therapy (II)1 Apr 20131041 THE EFFECTS OF REGULAR AND DECAFFEINATED COFFEE ON VOIDING SYMPTOMS IN YOUNG HEALTHY VOLUNTEERS Andrea Staack, Brian Distelberg, Christopher Chung, Kirk Baker, Amy Schlaifer, Kirk Anderson, and Herbert Ruckle Andrea StaackAndrea Staack Loma Linda, CA More articles by this author , Brian DistelbergBrian Distelberg Loma Linda, CA More articles by this author , Christopher ChungChristopher Chung Loma Linda, CA More articles by this author , Kirk BakerKirk Baker Loma Linda, CA More articles by this author , Amy SchlaiferAmy Schlaifer Loma Linda, CA More articles by this author , Kirk AndersonKirk Anderson Loma Linda, CA More articles by this author , and Herbert RuckleHerbert Ruckle Loma Linda, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.627AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Objective: About 15% of the U.S. general population report having stopped drinking coffee altogether, citing concerns about side effects of caffeine. To our knowledge, no studies have been conducted that explore the effects of higher dosage coffee and decaffeinated coffee on lower urinary symptoms in a younger population. Therefore, the main purpose of this study is to compare decaffeinated with regular coffee and their effects on LUTS in young volunteers, who are not regularly exposed to caffeine, using water consumption as the internal control. METHODS Methods: In this randomized prospective longitudinal study all subjects underwent a 5-day washout phase, were they were restricted from consuming any caffeinated products, followed by the 5-day coffee phase. During the treatment phase the subjects were randomly assigned to drink 24 oz. of either decaffeinated coffee (12 mg caffeine) or regular coffee (450 mg caffeine). The coffee was brewed blindly in a standardized fashion. The study concluded with a 5-day washout phase. Throughout the three phases of the study subjects filled out voiding logs, health surveys, UDI-6, interstitial cystitis problem and symptom indices (ICSI, ICPI) at eight different time points. Continuous variables were compared using the ANOVA and post hoc t-test comparison test. RESULTS Results: Between April and June 2012, 49 healthy individuals between the ages of 18 and 45 years (mean age: 27) were enrolled and completed the study. 25 subjects were randomized into the regular coffee and 24 into the decaffeinated coffee arm and underwent a pre and post treatment washout phases. Consumption of 450mg caffeine produced significant increase in urine output at the first day of treatment (p<0.01), which normalized after three days of washout. The ICSI was elevated in the coffee arm (p<0.03). There was no difference between the decaffeinated treatment and the water phase (wash out) on any of the outcome measures. CONCLUSIONS Conclusion: This is the first randomized prospective study, which showed a significant increase in LUTS and voided volume during consumption of high dosage coffee, when compared to decaffeinated coffee or water intake. Symptoms were normalizing three days after termination of coffee. Findings suggest consuming decaffeinated coffee instead of regular coffee to avoid LUTS and increase of urine out put. Further studies are warranted to assess effects of caffeine in patients presenting with overactive bladder symptoms to improve counseling. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e427 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Staack Loma Linda, CA More articles by this author Brian Distelberg Loma Linda, CA More articles by this author Christopher Chung Loma Linda, CA More articles by this author Kirk Baker Loma Linda, CA More articles by this author Amy Schlaifer Loma Linda, CA More articles by this author Kirk Anderson Loma Linda, CA More articles by this author Herbert Ruckle Loma Linda, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Chronic phencyclidine increases synapsin-1 and synaptic adaptation proteins in the medial prefrontal cortex.

Phencyclidine (PCP) mimics many aspects of schizophrenia, yet the underlying mechanism of neurochemical adaptation for PCP is unknown. We therefore used proteomics to study changes in the medial prefrontal cortex in animals with PCP-induced behavioural deficits. Male Wistar rats were injected with saline or 5 mg/kg phencyclidine for 5 days followed by two days of washout. Spontaneous alternation behaviour was tested in a Y-maze and then proteins were extracted from the medial prefrontal cortex. 2D-DIGE analysis followed by spot picking and protein identification with mass spectrometry then provided a list of differentially expressed proteins. Treatment with 5 mg/kg phencyclidine decreased the percentage of correct alternations in the Y-maze compared to saline-treated controls. Proteomics analysis of the medial prefrontal cortex found upregulation of 6 proteins (synapsin-1, Dpysl3, Aco2, Fscn1, Tuba1c, and Mapk1) and downregulation of 11 (Bin1, Dpysl2, Sugt1, ApoE, Psme1, ERp29, Pgam1, Uchl1, Ndufv2, Pcmt1, and Vdac1). A trend to upregulation was observed for Gnb4 and Capza2, while downregulation trends were noted for alpha-enolase and Fh. Many of the hits in this study concur with recent postmortem data from schizophrenic patients and this further validates the use of phencyclidine in preclinical translational research.

Behavioral daily rhythmic activity pattern of adolescent female rat is modulated by acute and chronic cocaine

Cocaine is one of well-known drugs of abuse, and many children experience early exposure to cocaine. Because of an immature neuronal system in adolescents, they may react differently to repeated cocaine administration compared to adults. Most of the published papers report the effect of cocaine on adult male rats and this paper focused on the effects of cocaine on the 24h locomotor activity rhythm patterns activity of adolescent Sprague Dawley (SD) female rats. Changes in the locomotor activity rhythm patterns could indicate that cocaine elicits long-term changes in the clock genes of the body that regulate different physiological processes. The objective of this study was to investigate whether cocaine in adolescent female rats modulated their daily activity pattern. Animals were divided into control (saline), 3.0, 7.5, 15.0mg/kg cocaine groups. On experimental day 1 (ED 1), all groups were given saline injection. From ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0mg/kg) was given daily. ED 8 to ED 10 were the washout days, where no injection was given. On ED 11, the animals were injected with saline or with the same dose of cocaine as they were treated on ED 2 to ED 7. Each animal's locomotor activities was recorded nonstop following saline or cocaine injection for 11 consecutive days using the open field assay. In conclusion, it was observed that all three groups receiving repeated cocaine administration (3.0, 7.5, and 15.0mg/kg) displayed significantly altered locomotor activity rhythm patterns.

대기질 예측을 위한 기후·대기환경 통합모델링시스템 (ICAMS)의 기온 및 강수량 예측 능력 평가

This study provides an evaluation for capability of Integrated Climate and Air quality Modeling System (ICAMS) on future regional scale climate projection. Temperature and precipitation are compared between ground-level observation data and results of regional models (MM5) for the past 30 years over the Korean peninsula. The ICAMS successfully simulates the local-scale spatial/seasonal variation of the temperature and precipitation. The probability distribution of simulated daily mean and minimum temperature agree well with the observed patterns and trends, although mean temperature shows a little cold bias about compared to observations. It seems that a systematic cold bias is mostly due to an underestimation of maximum temperature. In the case of precipitation, the rainfall in winter and light rainfall are remarkably simulated well, but summer precipitation is underestimated in the heavy rainfall phenomena of exceeding 20 mm/day. The ICAMS shows a tendency to overestimate the number of washout days about 7%. Those results of this study indicate that the performance of ICAMS is reasonable regarding to air quality predication over the Korean peninsula.