Misoprostol decreases oxidative stress and liver injury in bacterial lipopolysaccharide-induced endotoxemia in mice

The effect of misoprostol, a synthetic prostaglandin E1 analog, on the development of oxidative stress induced in mice with lipopolysaccharide (LPS) endotoxin was investigated. Misoprostol was administered by intraperitoneal route (i.p.) at doses of 10, 100, or 1,000 μg/kg at the time of LPS injection (200 μg/kg, i.p.). Mice were euthanized 4 h later. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH), nitric oxide (nitrite/nitrate) levels as well as paraoxonase activity were measured in brain and liver. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as DNA fragmentation were determined in the liver. The administration of LPS increased oxidative stress both in the brain and liver tissue. There were significantly increased MDA and nitrite and decreased GSH and PON1 activity in the brain and liver, respectively. In addition, LPS was associated with markedly elevated plasma ALT and AST level as well as increased liver DNA fragmentation. The administration of misoprostol at 100 or 1,000 μg/kg decreased brain MDA by 17.6 and 30 %, increased GSH by 29.8 and 33.3 %, and decreased nitric oxide by 21.74 and 42.5 %, respectively, compared with the lipopolysaccharide control group. Liver MDA decreased by 27 %, GSH increased by 47.7 %, and nitric oxide decreased by 37.2 % with misoprostol at 1,000 μg/kg. Paraoxonase activity increased in both the brain and liver by misoprostol administration. The increase in liver AST and ALT and DNA fragmentation after endotoxin administration was normalized by misoprostol. These results indicate that misoprostol can alleviate oxidative stress in the presence of a mild systemic inflammatory illness, indicating a new and potentially important therapeutic application for the drug.     

Subclinical Vascular Endothelial Dysfunctions and Myocardial Changes With Type 1 Diabetes Mellitus in Children and Adolescents

Vascular endothelial dysfunction, accelerated thickening of arterial intima, and changes in ventricular functions contribute to increased cardiovascular morbidity in type 1 diabetes mellitus (T1DM). This study aimed to investigate the functional-structural changes in the arteries and myocardium together with affection of highly sensitive C-reactive protein (hsCRP), circulating endothelial cells (CECs), and vitamin C levels in children with T1DM. Also, to test the association with early atherosclerotic changes. The study included 30 children with a diagnosis of T1DM and 30 healthy subjects matched by sex, age, and body mass index. Serum lipids, HbA1c, hsCRP, vitamin C, and CECs were detected. Corrected QT interval (QTc), cardiac dimensions, and left ventricular (LV) functions were assessed using conventional echocardiography. Noninvasive ultrasound was used to measure brachial artery flow-mediated dilation (FMD) responses and carotid intima-media thickness (IMT). The QTc interval was significantly higher in the diabetic patients than in the control subjects (P < 0.001). The findings showed LV diastolic dysfunction as reflected by significantly lower early peak flow velocity, decreased E/A ratio, increased early filling deceleration time (DcT), and prolonged isovolumic relaxation time (IVRT) (P < 0.001 for each). The children with diabetes had a significantly lower FMD response, increased IMT, lower vitamin C level, higher hsCRP, and higher CEC compared with the control subjects (P < 0.001 for each). A positive correlation between CEC and HbA1c was found (P = 0.004). An alteration in myocardial function and endothelial dysfunction may begin early with the association of early atherosclerotic changes. These changes are accelerated when glycemic control is poor. The authors recommend early and close observation of children with diabetes for any alterations in cardiac and vascular endothelial function. Vitamin C supplementation may reduce the risk of complications.     

An experimental study on ulcerative colitis as a potential target for probiotic therapy by Lactobacillus acidophilus with or without “olsalazine”

Traditional medical treatments for ulcerative colitis (UC) are still compromised by its adverse effects and not potent enough to keep in remission for long-term periods. So, new therapies that are targeted at specific disease mechanisms have the potential to provide more effective and safe treatments for ulcerative colitis. Probiotics is recently introduced as a therapy for ulcerative colitis. In the present study, Lactobacillus acidophilus was selected as a probiotic therapy to investigate its effects in oxazolone-induced colitis model in rats that mimics the picture in human. The rats were grouped (8 rats each) as normal control group (Group I), Group II served as untreated oxazolone-induced colitis, Group III oxazolone-induced colitis treated with probiotic L. acidophilus (1 × 10⁷ colony-forming units (CFU)/mL/day oral for 14 days), Group IV oxazolone-induced colitis treated with olsalazine (60 mg/kg/day oral for 14 days), Group V oxazolone-induced colitis treated with probiotic L. acidophilus and olsalazine in the same doses and duration. Disease activity index (DAI) was recorded, serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and intrleukin-6 (IL-6) was assessed as inflammatory markers and the histopathological picture of the colon of each rat was studied. Disease activity index (DAI) showed significant positive correlation with the elevated serum levels of CRP (r = 0.741, p < 0.05), TNF-α (r = 0.802, p < 0.05) and IL-6 (r = 0.801, p < 0.05). Treatment with either L. acidophilus (group III) or olsalazine (group IV) resulted in significant reduction in serum levels of CRP, TNF-α and IL-6, as well as disease activity index (DAI). Treatment with combination of L. acidophilus and olsalazine (group V) offered more significant reduction in serum levels of CRP, TNF-α, IL-6 and disease activity index (DAI) when compared to either group II (untreated group), group III (treated with L. acidophilus) or group IV (treated with olsalazine). So, it was concluded that L. acidophilus probiotic could be recommended as adjuvant therapy in combination with olsalazine to achieve more effective treatment for ulcerative colitis. For application in human, this needs to be verified in further clinical studies.     

Evaluation of the effect of neoadjuvant chemotherapy on tumor and axillary lymph nodes in locally advanced breast cancer： a study of 50 patients

Objective： The purpose of the study was to correlate between effect of pre-neoadjuvant chemotherapy （NACT） and post-NACT clinical, sonographic and pathologic features of the tumor and axillary lymph nodes （ALNs） and to raise the possibility of applying the concept of sentinel lymph node biopsy （SLNB） in patients with initially positive ALNs before NACT. Methods： A prospective study of 50 female patients with locally advanced breast cancer （LABC） with clinically palpable.and cytologically （under ultrasonographic guidance） positive ALNs. All patients received NACT and then referred for ultrasono- graphic assessment of the axilla regarding any detectable sonographic criteria of metastatic deposits in ALNs as well as the tumor size in relation to its prechemotherapy size, All patients were then subjected either to modified radical mastectomy or breast conserving surgery. The clinical, sonographic and pathological response of the tumor and the ALNs were documented, classified and correlated with each other. Results： Patients＇ mean age was 47.7±9.1 years. The mean clinical tumor size was 6.7 ± 1.4 cm; stage IliA that was presented in 32 patients （64%） and IIIB was presented in 18 patients （36%）. Chemotherapy was given for a median of 4 cycles, there was reduction of the mean clinical tumor size from 6.7 ± 1.4 cm to 4.3 ± 2.7 cm （P 〈 0.001）. Clinical response was complete in 5 （10%） tumors, complete pathological tumor response （post-neoadjuvant） was detected in 6 （16%） of patients. Complete clinical nodal response （post-neoadjuvant） in 23 （46%） axillae, on sonographic assessment of the axilla, response was complete in 17 （34%） axillae. Complete pathological nodal response occurred in 16 （32%） axillae. Out of 17 axillae that showed complete sonographic response 11 axillae showed complete pathological nodal response （P 〈 0.001）. Conclusion： Formal axillary lymph node dissection can be avoided and replaced by SLNB post NACT in patients with L     

Contribution of different mechanisms to the resistance to fluoroquinolones in clinical isolates of Salmonella enterica

ObjectivesTo study the potential factors include gene mutation, efflux pump and alteration of permeability associated with quinolone-resistance of Salmonella enterica strains isolated from patients with acute gastroenteritis and to evaluate the degree of synergistic activity of efflux pump inhibitors when combined with ciprofloxacin against resistant isolates.MethodsAntimicrobial resistance patterns of fifty-eight Salmonella isolates were tested. Five isolates were selected to study the mechanism of resistance associated with quinolone group, including mutation in topoisomerase-encoding gene, altered cell permeability, and expression of an active efflux system. In addition, the combination between antibiotics and efflux pump inhibitors to overcome the microbial resistance was evaluated.ResultsFive Salmonella isolates totally resistant to all quinolones were studied. All isolates showed alterations in outer membrane proteins including disappearance of some or all of these proteins (Omp-A, Omp-C, Omp-D and Omp-F). Minimum inhibitory concentration values of ciprofloxacin were determined in the presence/absence of the efflux pump inhibitors: carbonyl cyanide m-chlorophenylhydrazone, norepinephrin and trimethoprim. Minimum inhibitory concentration values for two of the isolates were 2–4 fold lower with the addition of efflux pump inhibitors. All five Salmonella isolates were amplified for gyrA and parC genes and only two isolates were sequenced. S. Enteritidis 22 had double mutations at codon 83 and 87 in addition to three mutations at parC at codons 67, 76 and 80 whereas S. Typhimurium 57 had three mutations at codons 83, 87 and 119, but no mutations at parC.ConclusionsEfflux pump inhibitors may inhibit the major AcrAB-TolC in Salmonella efflux systems which are the major efflux pumps responsible for multidrug resistance in Gram-negative clinical isolates.     

Physiological impairment in mild COPD

Chronic obstructive pulmonary disease (COPD) is a common and often progressive inflammatory disease of the airways, alveoli and microvasculature that is both preventable and treatable. It is well established that smokers with mild airway obstruction, as spirometrically defined, represent the vast majority of patients with COPD, yet this population has not been extensively studied. An insidious preclinical course means that mild COPD is both underdiagnosed and undertreated. In this context, recent studies have confirmed that even patients with mild COPD can have extensive physiological impairment, which contributes to poor perceived health status compared with non‐smoking healthy controls. This review describes the heterogeneous pathophysiology that can exist in COPD patients with only mild airway obstruction on spirometry. It exposes the compensatory adaptations that develop in such patients to ensure that the respiratory system fulfils its primary task of maintaining adequate pulmonary gas exchange for the prevailing metabolic demand. It demonstrates that adaptations such as increased inspiratory neural drive to the diaphragm due to combined effects of increased mechanical loading and chemostimulation underscore the increased dyspnoea and exercise intolerance in this population. Finally, based on available evidence, we present what we believe is a sound physiological rationale for earlier diagnosis in this population.     

Serum cystatin C as an early predictor of acute kidney injury in preterm neonates with respiratory distress syndrome

Abstract

Preterm neonates with respiratory distress syndrome (RDS) are at increased risk of acute kidney injury (AKI). Our study aimed at determining whether serum cystatin C (sCysC) on day 3 of life (D3) can early predict AKI in preterm neonates with RDS. This prospective study was conducted on 75 preterm neonates; 50 with RDS and 25 without RDS. On D3, sCysC, serum creatinine (sCr) and blood urea nitrogen (BUN) were measured and estimated glomerular filtration rate (eGFR) was calculated. sCr and BUN levels were measured again on days 5 and 7. Neonates were evaluated for development of AKI during first week of life according to the modified pediatric RIFLE (pRIFLE) criteria. Thirteen neonates with RDS developed AKI (26%).There was no significant difference between RDS and control groups with respect to sCysC. RDS neonates with AKI had significantly higher sCysC than those without AKI (1.62?±?0.12 versus 1.16?±?0.09?mg/l; p?<?.001). RDS grade III–IV neonates had significantly higher sCysC than RDS grade I–II. There was a significant positive correlation between D3 sCysC and (D5 and D7 sCr and BUN). Receiver operating characteristic (ROC) curve showed that D3 sCysC can predict AKI in preterm neonates with RDS at a cutoff point of >1.3?mg/l with sensitivity of 92.30% and specificity of 96%. We conclude that neonates with RDS are at increased risk of AKI. sCysC on day 3 of life can predict AKI earlier than Cr and eGFR.     

Factors influencing the participation of gastroenterologists and hepatologists in clinical research

Background  

Although clinical research is integral to the advancement of medical knowledge, physicians face a variety of obstacles to their participation as investigators in clinical trials. We examined factors that influence the participation of gastroenterologists and hepatologists in clinical research.