Neuroprotective effects of pramipexole against tunicamycin‐induced cell death in PC12 cells

• 1 Pramipexole (PPX), a dopamine D2 and D3 receptor agonist, exerts neuroprotective effects via both dopamine receptor‐mediated and non‐dopaminergic mechanisms. In the present study, we demonstrate that PPX reduces the toxicity of tunicamycin, a typical endoplasmic reticulum (ER) stressor, in PC12h cells, a subline of PC12 cells.
• 2 The PC12h cells were treated with 300 μmol / L PPX in the presence of 0.5 μmol / L tunicamycin for 24 h. The neuroprotective effects of PPX against tunicamycin‐induced cell death were evaluated using 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, Hoechst 33258 staining and western blot analysis.
• 3 Tunicamycin (0.2, 0.3 and 0.5 μg / mL) dose‐dependently decreased MTT activity and increased LDH release from PC12h cells. Treatment with 300 μmol / L PPX rescued the tunicamycin‐induced decrease in cell viability.
• 4 Spiperone (10 μmol / L), a dopamine D2 and D4 receptor antagonist, had no effect on PPX neuroprotection against tunicamycin in these cells. Marker proteins of ER stress and apoptosis are known to be upregulated by tunicamycin, but we detected no significant effects of PPX on these factors.
• 5 In conclusion, we speculate that a combination of several mechanisms may be involved in PPX‐induced neuroprotection.

     

Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I,dose-finding study

Aim

To investigate whether mesna—sodium-2-mercaptoethane sulfonate) can reduce diet-induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%.

Methods

C3H/HeH mice were shifted to a high-fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24-hour urine.

Results

Compared with controls, mesna-treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; P_overall = .002), but similar lean mass gain. In men with overweight, mesna doses of 400-1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post-dosing). With increasing mesna dose, tCys AUC_0-12h decreased (P_trend < .001), and urine tCys excretion increased (P_trend = .004).

Conclusions

Mesna reduces diet-induced fat gain in mice. In men with overweight, single oral doses of mesna (800-1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys-lowering by repeated mesna administration on weight loss in humans deserves investigation.     

Comparative study of two versatile multi-analyte chromatographic methods for determination of diacerein together with four non-steroidal anti-inflammatory drugs: Greenness appraisal using Analytical Eco-Scale and AGREE metrics

According to green analytical chemistry (GAC) principles, multi-analyte methods are usually more preferred than methods determining one analyte at a time (principle 8) as they allow saving resources (time, reagents and money) (principle 9) and permit the reduction of generated waste (principle 7) as well as reduction of needed samples (principle 2). The present work herein, describes for the first time the development, validation and comparison of novel green versatile multi-analyte HPLC-DAD and HPTLC methods for the quantitative estimation of five drugs (diacerein, aceclofenac, diclofenac sodium, celecoxib and meloxicam) within a single run in a short analysis time. For HPLC-DAD, separation was performed through using Zorbax SB C18 (4.6 × 250 mm, 5 μm particle size) with the mobile phase composed of 0.05 M phosphate buffer pH 3.0 and acetonitrile (42:58, v/v) at a flow rate of 1 mL/min. The chromatograms were extracted at 258, 276 and 355 nm. In HPTLC procedure, precoated TLC silica gel aluminum plates 60 F₂₅₄ were used with a mobile phase consisting of mixture of (chloroform: methanol: acetic acid, 92:8:0.25, v/v/v). The developed plates were scanned densitometrically at 258, 280 and 360 nm. Validation of the proposed methods was performed following the ICH guidelines for linearity, ranges, precision, accuracy, robustness, detection and quantification limits. Good linearities were confirmed by the high values of correlation coefficients (r > 0.9992). Appraisal of the greenness of the developed methods and comparison with different reported chromatographic methods was performed using the analytical Eco-scale (AES) approach and the novel Analytical GREEnness (AGREE) metric.     

Does the patient's position influence the detection of detrusor overactivity?

AIMS: The demonstration of preoperative detrusor overactivity (DO) with associated overactive bladder symptoms (OAB) is known to have an adverse effect on surgery performed for stress incontinence or for prostatic obstruction. The purpose of this review is to examine the best position, when filling the bladder during urodynamics, to demonstrate detrusor overactivity and reproduce the OAB symptoms, when the demonstration of DO might be important. MATERIALS AND METHODS: MEDLINE and PUBMED literature searches were performed, spanning the period from 1956 to August 2005 using the keywords "detrusor overactivity" or "detrusor instability" combined with "posture or position or standing or sitting" and "urodynamics." Other studies were identified by reviewing secondary references in the original citations. RESULTS: Sixteen studies looked at the effect of position on the detection rate of DO. There is good consistency between the studies analyzed. All but two [Ramsden et al., Br J Urol 49:633-9, 1977; Choe et al., J Urol 161:1541-4, 1999] showed a clear effect, with an increase in DO when the patient is filled in the vertical position or is asked to sit or stand, with a full bladder, after being filled supine. Performing the urodynamics (UDS) in the supine position would have missed a large proportion of DO diagnoses ranging from 33% to 100%. CONCLUSIONS: This review confirms that the patient's position is a significant variable during urodynamics and that supine cystometry will fail to detect a significant percentage of patients with DO. We suggest that all patients should be filled sitting or standing, unless physically disabled. It seems desirable for the International Continence Society (ICS) to extend its "Good urodynamic practice guideline" [Schafer et al., Neurourol Urodyn 21:261-74, 2002] to cover this important issue.     

The potential therapeutic effect of melatonin in gastro-esophageal reflux disease

Background  

Gastro-Esophageal Reflux Disease (GERD) defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Many drugs are used for the treatment of GERD such as omeprazole (a proton pump inhibitor) which is a widely used antiulcer drug demonstrated to protect against esophageal mucosal injury. Melatonin has been found to protect the gastrointestinal mucosa from oxidative damage caused by reactive oxygen species in different experimental ulcer models. The aim of this study is to evaluate the role of exogenous melatonin in the treatment of reflux disease in humans either alone or in combination with omeprazole therapy.     

Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity

Objective: To study the relation between CD226 rs763361 gene polymorphism and CD226 serum level and to evaluate their role in susceptibility and disease activity of RA in a cohort of Egyptian individuals.

Methods: The serum level of CD226 was measured using a suitable ELISA kit and the CD226 rs763361 gene polymorphism was typed by PCR-RFLP for 112 RA patients and 100 healthy controls.

Results: Significant association with RA was found with CD226 T allele (OR (95%CI) = 1.6 (1.04–2.4), P = 0.032), and higher CD226 serum level (P = 0.001). Higher CD226 levels were associated with higher ESR values (P = 0.035), positive CRP (0.048), increased number of tender joints (P = 0.045), and higher DAS score (P = 0.035). Serum CD226 is an independent risk factor for the prediction of RA (P = 0.001). No correlations were found between the serum level of CD226 and different CD226 genotypes and also between them and RA activity grades.

Conclusion: The CD226 T allele may be susceptibility risk factors for the development of RA and the higher serum level of CD226 may be involved in the pathogenesis of RA in Egyptian patients. The serum level of CD226 and not CD226 genotypes could be considered as an independent risk factor for the prediction of RA within healthy individuals and also for RA disease activity.     

How does esophagus look on barium esophagram in pediatric eosinophilic esophagitis?

Purpose

The clinical, endoscopic, and histologic findings of eosinophilic esophagitis (EoE) are well characterized; however, there have been very limited data regarding the radiologic findings of pediatric EoE. We report on the radiologic findings of pediatric EoE observed on barium esophagram and correlate them with the endoscopic findings.

Methods and materials

We identified children diagnosed with EoE in our center from 2004 to 2015. Two pediatric radiologists met after their independent evaluations of each fluoroscopic study to reach a consensus on each case. Clinical and endoscopic data were collected by retrospective chart review.

Results

Twenty-six pediatric EoE cases (age range 2–13 years; median 7.5 years) had barium esophagram done as part of the diagnostic approach for dysphagia. Thirteen children had abnormal radiologic findings of esophagus (50%): rings formation (n = 4), diffuse irregularity of mucosa (n = 8), fixed stricture formation (n = 3), and narrow-caliber esophagus (n = 10). Barium esophagram failed to show one of 10 cases of narrow-caliber esophagus and 10 of 14 cases of rings formation visualized endoscopically. The mean duration of symptoms prior to diagnosis of EoE was longer (3.7 vs. 1.7 year; p value 0.019), and the presentation with intermittent food impaction was commoner in the group with abnormal barium esophagram as compared to the group with normal barium esophagram (69% vs. 8%; p value 0.04).

Conclusion

Barium swallow study is frequently normal in pediatric EoE. With the exception of narrow-caliber esophagus, our data show poor correlation between radiologic and endoscopic findings.

     

Silent myocardial ischemia: Current perspectives and future directions

Silent myocardial ischemia (SMI) is increasingly being recognized as part of the spectrum of ischemic heart disease. The spectrum of SMI ranges from asymptomatic coronary artery disease to critical illness necessitating intensive care. Although many diagnostic tools have been used to identify low- and high-risk subgroups, their use is limited by modest sensitivities and specificities. The present review identifies current concepts in the management of SMI in various clinical settings, as well as emerging technologies that may simplify the diagnosis and treatment of this condition.