Rebamipide Does Not Protect Against Naproxen-induced Gastric Damage: A Randomized Double-blind Controlled Trial

Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. Methods: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. Results: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95% CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 +/- 129 pg/mL before treatment and 241 +/- 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 +/- 109 pg/mL before treatment, and 168 +/- 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95% CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Conclusion: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers.1658Biolab Industria Farmaceutica Ltd

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The Role of [18F]F-Choline PET/CT in the Initial Management and Outcome Prediction of Prostate Cancer: A Real-World Experience from a Multidisciplinary Approach

Initial staging of prostate cancer (PCa) is usually performed with conventional imaging (CI), involving computed tomography (CT) and bone scanning (BS). The aim of this study was to analyze the role of [18F]F-choline positron emission tomography (PET)/CT in the initial management and outcome prediction of PCa patients by analyzing data from a multidisciplinary approach. We retrospectively analyzed 82 patients who were discussed by the uro-oncology board of the University Hospital of Ferrara for primary staging newly diagnosed PCa (median age 72 (56&ndash;86) years; median baseline prostate specific antigen (PSA) equal to 8.73 ng/mL). Patients were divided into three groups based on the imaging performed: group A = only CI; group B = CI + [18F]F-choline PET/CT; group C = only [18F]F-choline PET/CT. All data on imaging findings, therapy decisions and patient outcomes were retrieved from hospital information systems. Moreover, we performed a sub-analysis of semiquantitative parameters extracted from [18F]F-choline PET/CT to search any correlation with patient outcomes. The number of patients included in each group was 35, 35 and 12, respectively. Patients with higher values of initial PSA were subjected to CI + PET/CT (p = 0.005). Moreover, the use of [18F]F-choline PET/CT was more frequent in patients with higher Gleason score (GS) or ISUP grade (p = 0.013). The type of treatment performed (surgery n = 33; radiation therapy n = 22; surveillance n = 6; multimodality therapy n = 6; systemic therapy n = 13; not available n = 2) did not show any relationship with the modality adopted to stage the disease. [18F]F-choline PET/CT induced a change of planned therapy in 5/35 patients in group B (14.3%). Moreover, patients investigated with [18F]F-choline PET/CT alone demonstrated longer biochemical recurrence (BCR)-free survival (30.8 months) in comparison to patients of groups A and B (15.5 and 23.5 months, respectively, p = 0.006), probably due to a more accurate selection of primary treatment. Finally, total lesion choline kinase activity (TLCKA) of the primary lesion, calculated by multiplying metabolic tumor volume and mean standardized uptake value (SUVmean), was able to more effectively discriminate patients who had recurrence after therapy compared to those without (p = 0.03). In our real-world experience [18F]F-choline PET/CT as a tool for the initial management of PCa had a relevant impact in terms of therapy selection and was associated with longer BCR-free survival. Moreover, TLCKA of the primary lesion looks a promising parameter for predicting recurrence after curative therapy

Prenatal exposure to diazepam and alprazolam, but not to zolpidem, affects behavioural stress reactivity in handling-na\uefve and handling-habituated adult male rat progeny.

A gentle long-lasting handling produces persistent neurochemical and behavioural changes and attenuates the impairment in the behavioural reactivity to novelty induced by the prenatal exposure to diazepam (DZ) in adult male rat progeny. This study investigated the consequences of a late prenatal treatment with three GABA/BDZ R agonists (DZ) alprazolam (ALP) and zolpidem (ZOLP)), on different stress-related behavioural patterns, in non-handled (NH), short-lasting handled (SLH) and long-lasting handled (LLH) adult male rats exposed to forced swim test (FST), acoustic startle reflex (ASR) and Vogel test (VT). The effects on motor activity were evaluated in the open field and in the Skinner box. The seizure sensitivity to picrotoxin (PTX) was investigated as an index of the functional state of GABA/BDZ Rs. A single daily s.c. injection of DZ (1.25–2.50 mg/kg) and ALP (0.125–0.250 mg/kg) over gestational days 14–20 induced a decrease in immobility time in the FST in NH rats, no change in SLH rats and an increase in LLH rats; DZ induced an increase in the peak amplitude of the ASR in NH rats, no change in SLH rats and a reduction in LLH rats; ALP was ineffective in all groups. DZ and ALP reduced the number of punished licks in the VT in NH, SLH and LLH rats while the unpunished licks were not modified. DZ decreased locomotion and the lever pressing responses while ALP increased them. DZ and ALP increased the seizure sensitivity to PTX (2.5–4.0 mg/kg i.p.). These findings indicate a convergence on anxiety-related behaviours in the effects of prenatal exposure to DZ and ALP and a differentiation on motor activity. Long-lasting handling was able to overcompensate the increased behavioural stress reactivity induced by the prenatal exposure to DZ and ALP

Functional characterization of a new deletion in CDKN1B 5'-UTR region

Introduction: CDKN1B gene, which encodes a cyclin-dependent kinase (Cdk) inhibitor, regulates the progression throughout G1 to S cell cycle progression. CDKN1B loss-of-function germinal mutations cause the multiple endocrine neoplasia type 4 syndrome (MEN4). Objective: The aim of the study is the functional characterization of a new 4 bp deletion in CDKN1B 5′-UTR region, identified in an acromegalic patient. Materials and methods: We assessed a functional in vitro study, based on firefly luciferase reporter gene, on the deleted promoter of human (MCF-7), murine (AtT20/D16V-F2) and rat (GH3) cell lines. Total mRNA and proteins were extracted from peripheral blood of the patient and control subjects to analyze CDKN1B/p27Kip1 expression. In addition, we evaluated p27Kip1 expression in tissue sections of the patient’s GH-secreting pituitary adenoma by immunohistochemistry. Results: A novel heterozygous deletion in CDKN1B 5′-UTR region was identified in an acromegalic patient. The deletion extends from nucleotide −29 to −26 from the translation start site. Transcriptional activity of the deleted promoter is significantly decreased (~30–60% P<0.01). CDKN1B/p27Kip1 expression analysis of patient’s circulating leukocytes showed a significant reduction (~72%) in mRNA levels, while p27Kip1 protein levels are similar to WT controls. Immunohistochemistry shows a reduced p27Kip1 expression in the patient’s pituitary adenoma compared to the control. Conclusions: Our data show that the identified deletion causes a significant reduction in promoter transcriptional activity and in CDKN1B mRNA expression, indicating a putative role of the deletion in the patient’s disease. Further studies are needed order to understand whether the deletion could impact protein function

Long-lasting handling affects behavioural reactivity in adult rats of both sexes prenatally exposed to diazepam.

Environmental stressors can substantially affect the adaptive response of rats to novelty in a sexually dimorphic manner. Gender-related differences are also observed in neurochemical and behavioural patterns of adult rats following prenatal exposure to diazepam (DZ). In the present study the behavioural reactivity to novelty is investigated in open field (OF) and in acoustic startle reflex (ASR) tests, in non handled (NH), short-lasting handled (SLH) and long-lasting handled (LLH) adult male and female rats prenatally exposed to DZ. A single daily s.c. injection of DZ (1.5 mg/kg) over gestation days 14\u201320 decreases GABA/BDZ receptor function in both sexes, as shown by the decreased electrographic hippocampal response to DZ and the increased response to picrotoxin, after intra-locus coeruleus injection of the two compounds. In OF NH DZ-exposed males display a lower total distance travelled (TDT), a higher rearing frequency (RF) and a greater number of transitions in the centre of the arena (CNT) compared to NH rats prenatally exposed to vehicle. Conversely, NH DZ-exposed females show slight changes in TDT and RF and a greater reduction in CNT and in the amount of time spent in the centre of the arena (CAT). These effects are associated with an increase in the peak amplitude of the ASR in both sexes. Short-lasting handling slightly influences DZ-evoked effects in animals of both sexes. In DZ-exposed males long-lasting handling attenuates the reduction in TDT and the enhancement in RF, prevents the increase in CNT and reduces the peak amplitude of ASR. In DZ-exposed females, long-lasting handling increases TDT and RF, induces a lower avoidance of the centre of the arena, and does not modify the peak amplitude of ASR, when compared to controls. These findings indicate that prenatal exposure to DZ differently affects behavioural reactivity in adult male and female rats, and suggest that a long-lasting handling is able to attenuate some behavioural deficits induced by prenatal DZ exposure

Additional file 3: Table S3. of Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial

Individual histopathological scores and H. pylori status before and after treatment for each volunteer. (DOCX 15 kb

Additional file 3: Table S3. of Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial

Individual histopathological scores and H. pylori status before and after treatment for each volunteer. (DOCX 15 kb

Additional file 1: Table S1. of Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial

Gastrointestinal symptoms occurrence in the previous 7 days as reported by each volunteer before the initiation and at the end of treatments. (DOCX 17 kb

Hydrochlorothiazide Potentiates Contractile Activity of Mouse Cavernosal Smooth Muscle

Introduction: Hydrochlorothiazide has a negative influence on penile erection but little is known about the mechanism(s) involved. Aims: To characterize the effects of this diuretic on mouse corpus cavernosum (CC) smooth muscle in vitro and ex vivo. Methods: CC strips of C57BL/6 mice (12–16 weeks old) were mounted in organ baths containing Krebs-Henseleit solution and tissue reactivity was evaluated. Expression of genes encoding diuretic targets and enzymes involved in penile erection were evaluated by polymerase chain reaction. Main Outcome Measures: Stimulation-response curves to phenylephrine (10 nmol/L–100 μmol/L) or to electrical field stimulation (1–32 Hz) were constructed, with or without hydrochlorothiazide. Strips of CC from mice after long-term hydrochlorothiazide treatment (6 mg/kg/day for 4 weeks) with or without amiloride (0.6 mg/kg/day for 4 weeks) in vivo also were studied. Nitric oxide and Rho-kinase pathways were evaluated. Results: Hydrochlorothiazide (100 μmol/L) increased the maximum response to phenylephrine by 64% in vitro. This effect was unaffected by the addition of indomethacin (5 μmol/L) but was abolished by N(ω)-nitro-L-arginine methyl ester (100 μmol/L). Hydrochlorothiazide (100 μmol/L) potentiated electrical field stimulation-induced contraction in vitro, but not ex vivo. Long-term treatment with hydrochlorothiazide increased the maximum response to phenylephrine by 60% and resulted in a plasma concentration of 500 ± 180 nmol/L. Amiloride (100μmol/L) caused rightward shifts in concentration-response curves to phenylephrine in vitro. Long-term treatment with hydrochlorothiazide plus amiloride did not significantly increase the maximum response to phenylephrine (+13%). Reverse transcriptase polymerase chain reaction did not detect the NaCl cotransporter in mouse CC. Hydrochlorothiazide did not change Rho-kinase activity, whereas amiloride decreased it in vitro and ex vivo (approximately 18% and 24% respectively). A 40% decrease in Rock1 expression also was observed after long-term treatment with hydrochlorothiazide plus amiloride. Conclusion: Hydrochlorothiazide potentiates contraction of smooth muscle from mouse CC. These findings could explain why diuretics such as hydrochlorothiazide are associated with erectile dysfunction