Hany M. Abo-Haded

Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats

There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo- and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factor-alpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicin-induced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis.

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Cardiac functions assessment in children with celiac disease and its correlation with the degree of mucosal injury: Doppler tissue imaging study.

Background/Aims: Celiac disease (CD)-associated cardiologic disorders is a growing concern. However, data regarding cardiac affection in children with CD are few. This study aimed at assessing the subclinical impact of CD on the global myocardial performance in Saudi children with CD using Doppler tissue imaging (DTI). Patients and Methods: Conventional two-dimensional echocardiography was performed among 20 Saudi children with CDas well as 20 age and sex-matched healthy controls. DTI were used to determine right ventricular (RV) and left ventricular (LV) Tei indexes. These findings were correlated with the Modified Marsh Classification of the histologic findings in CD. Results: LV and RV Tei indexes were significantly higher in children with CD than the control group (mean ± standard deviation: 0.47 ± 0.05 vs. 0.31 ± 0.18; P < 0.0005 and 0.51 ± 0.04 vs. 0.32 ± 0.05; P < 0.0001, respectively). RV Tei index was found to be positively correlated with the Modified Marsh Classification of CD (r = 0.7753, P < 0.0001). LV Tei index tended to be more affected in patients with more severe histologic findings, however, such relation did not reach statistical significance (r = 0.2479, P = 0.292). Fractional shortening did not correlate with the Modified Marsh Classification of histologic findings in CD patients (r= −0.11, P = 0.641). Conclusions: Subclinical myocardial dysfunction of both ventricles occurs in children with CD. The DTI method appears to be more sensitive than conventional two-dimensional echocardiography in the early detection of myocardial dysfunction in children with CD.

The spectrum of congenital heart diseases in down syndrome. A retrospective study from Northwest Saudi Arabia

Objectives: To to define the frequency and patterns of congenital heart disease (CHD) among children with Down syndrome (DS) in Northwest Saudi Arabia. Methods: We included children with confirmed DS referred to the regional pediatric cardiology unit in Madinah Maternity and Children Hospital between January 2008 and December 2013. Children were identified from the unit’s data-base and the charts were reviewed retrospectively. We excluded term and preterm children with patent ducts arteriosus (PDA) and persistent foramen oval spontaneously resolved during the first 4 weeks of life. Results: A total of 302 children with DS were identified (50.3% male). Of these, 177 (58.6%) had CHD. Atrioventricular septal defect (AVSD) was the most frequent lesion identified in 72/177 (40.7%) followed by mixed left to right shunt defects (14.7%) and secundum atrial septal defect (ASD) (11.8%). Ventricular septal defect was detected in 10.7% and 8.5% had PDA beyond the neonatal period. There was no gender difference in the frequency of CHD (p=0.9) and the presence of CHD was not related to the genetic cause of DS (p=0.9). Conclusion: The frequency of CHD in our DS cohort is comparable with Europe, Asia, and other KSA regions. However its pattern appears to be different from some areas in KSA.

Oral Propranolol: A Corner Stonein the Therapeutic Strategy ofInfantile Haemangiomas

Oral Propranolol: A Corner Stone in the Therapeutic Strategy of Infantile Haemangiomas Infantile hemangiomas are the most common tumors of childhood. Despite their benign and self-limited nature, some hemangiomas can cause complications such as ulceration or life-altering disfigurement. In addition, they may compromise vital organ function, or herald underlying developmental anomalies of the central nervous system or spine [1]. Until recently, high-dose steroid therapy was the mainstay treatment for problematic proliferating infantile hemangioma [2]. Whilst corticosteroids are effective, they are associated with significant adverse effects as cushing syndrome, growth retardation, hirsutism, hypertension, and immunosuppression [3]. Interferon alpha is a potent inhibitor of angiogenesis that can be used in the treatment of infantile hemangiomas [4]. However, its reported severe neurotoxicity, including spastic diplegia, limits its use to cases with life-threatening hemangiomas that have not responded to other forms of treatment [5]. Vincristine was initially used in the treatment of the Kasabach-Merritt phenomenon [6]. Moreover,it is used as an alternative therapy for glucocorticoid-unresponsive, lifethreatening, or severely life-altering hemangiomas[7]. Pulsed dye laser therapyis another treatment option that was found to be beneficial for select infantile hemangiomas including those with small superficial, ulcerated, or involuting lesions [8,9]. In 2008, a French group accidently observed accelerated involution of large facial hemangiomas in two infants following treatment with propranolol for heart failure [10]. These favorable results led to the initiation of some case reports and observational studies to evaluate the efficacy of propranolol in the treatment of proliferating infantile hemangioma [11-14]. To date, the mechanism of action of propranolol on infantile hemangioma is not clear [15]. Moreover, there are some concerns about the potential complications with propranolol usage. The most frequently reported serious side effects were asymptomatic hypotension, asymptomatic bradycardia[16], pulmonary symptoms related to blockade of adrenergic bronchodilation [17], hypoglycemia [17], and hyperkalemia [18]. The most commonly reported non potentially life-threatening side effects were sleep disturbances including nightmares, somnolence, cool or mottled extremities, diarrhea, and gastroesophageal reflux/upset [19]. .

Does type of cardioplegia affect myocardial and cerebral outcome in pediatric open cardiac surgeries

Background A single-dose strategy for cardioplegia is desired in pediatric congenital cardiac surgery, especially in repair of complex congenital defects. The hypothesis of this study is that a single infusion of Bretschneider HTK solution may offer myocardial and cerebral protection superior to repeated doses of a cold oxygenated blood cardioplegic solution in pediatric congenital cardiac surgery. Patients and methods Sixty patients who underwent congenital cardiac repair using cardiopulmonary bypass were grouped randomly to receive either a single dose of Custodiol (group A) or repeated oxygenated blood cardioplegia (group B). Echocardiography, ECG, and microscopic examination were used to evaluate left-ventricular function and structure. Myocardial injury was assessed with creatine kinase MB and serum troponin T, whereas cerebral outcome was assessed by jugular venous oxygen saturation. Patients were also neurologically examined and studied by brain computed tomography for gross neurological manifestation of cerebral ischemia or infarction preoperative and 2 days postoperatively. Results Myocardial enzymes and oxygen extraction were significantly high in group B compared with group A. Ultrastructure evaluation and cerebral outcome were significantly better in group A than in group B. Conclusion A single dose of an HTK cardioplegic solution provides better myocardial and cerebral protection than repeated doses of oxygenated blood cardioplegia during pediatric congenital cardiac surgery.