Therapeutic enhancing potential of piracetam with diethylstilbestrol in prevention of grand-mal seizures in rats: inhibition of PI3K/Akt/mTOR signaling pathway and IL-1ß, IL-6, TNF-α cytokines levels.

OBJECTIVE: Epilepsy, a neurodegenerative disorder, continues to throw challenges in the therapeutic management. The current study sought to ascertain if the therapeutic interactions between piracetam and diethylstilbestrol may prevent grand-mal seizures in rats. MATERIALS AND METHODS: Piracetam (PIR; 10 and 20 mg/kg) and diethylstilbestrol (DES; 10 and 20 mg/kg) alone as a low-dose combination were administered to rats for 14 days. The electroshock (MES; 180 mA, 220 V for 0.20 s) was delivered via auricular electrodes on the last day of treatment and rats were monitored for convulsive behavior. To elucidate the mechanism, hippocampal mechanistic target of rapamycin (mTOR) and interleukin (IL)-1ß, IL-6 and tumor necrotic factor-alpha (TNF-α) levels were quantified. Hippocampal histopathology was conducted to study the neuroprotective effect of drug/s. In vitro studies and in silico studies were conducted in parallel. RESULTS: To our surprise, the low dose of the combination regimen of PIR (10 mg/kg) and DES (10 mg/kg) unfolded synergistic anti-seizure potential, with brimming neuroprotective properties. The mechanism could be related to a significant reduction in the levels of hippocampal mTOR and proinflammatory cytokines. The docking scores revealed higher affinities for phosphatidylinositol 3-kinase (PI3K) in co-bound complex, and when docking DES first, while better affinities for protein kinase B (Akt) were revealed when docking PIR first (both drugs bind cooperatively as well). This indicated that the entire PI3K/Akt/mTOR signaling pathway is intercepted by the said combination. In addition, the % of cell viability of HEK-293 cells [pre-exposed to pentylenetetrazol (PTZ)] was increased by 327.29% compared to PTZ-treated cells (toxic control; 85.16%). CONCLUSIONS: We are the first to report the promising efficacy of the combination (PIR 10 mg/kg + DES 10 mg/kg) to restrain seizures and epileptogenic changes induced by electroshock by a novel mechanism involving inhibiting the PI3K/Akt/mTOR signaling.

Laboratory evaluation of a novel anaesthesia delivery device.

Here, we describe proof of concept of a novel method for delivering volatile anaesthetics, where the liquid anaesthetic (sevoflurane or isoflurane) is formulated into an emulsion that is contained in a compact, lightweight device through which carrier gas flows. Release of anaesthetic is achieved by stirring of the formulation, allowing controlled and responsive release of anaesthetic at a variety of fixed flow rates between 0.5 l.min-1 and 5 l.min-1 , with ventilated, non-ventilated and draw-over breathing systems. Anaesthetic release was evaluated using target anaesthetic concentrations ranging from 0.5% v/v to 8% v/v to mimic those typically required for induction and maintenance of anaesthesia, and lower concentrations suitable for sedation. Under all conditions, output could be maintained within 0.1% v/v of the intended setting, and the device could deliver a controlled level of anaesthetic for at least 60 min, with compensation for different ambient temperatures (10-30 °C) and carrier gas flow rates. This device offers a simple, inexpensive method of delivering safe concentrations of volatile anaesthetics for a wide range of applications.

Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small-platelet thrombocytopenia.

BACKGROUND: The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds. PATIENTS AND METHODS: We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy. RESULTS: We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy. CONCLUSIONS: This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.

A review of the S100 proteins in cancer.

AIM: In the quest to reduce mortality and morbidity from cancer, there is continued effort to identify novel biomarkers to aid in the early detection and the accurate prediction of tumour behaviour. One group of proteins that is emerging as a potentially important group of markers in multiple tumour types is the S100 family. This review summarises the biological and clinical relevance of these proteins in relation to different tumour types. METHODS: A literature search was performed using the PubMed database and the reference lists of relevant articles. Single case studies were excluded and only reports with a clinical relevance from 1961 to 2007 were included. RESULTS: The search yielded over 1000 published articles and reports. Important reports and studies were reviewed, screened and tracked for further relevant publications. Only the most relevant publications are discussed with relation to individual members of the S100 family. CONCLUSION: There is increasing evidence that altered expression of S100 family members is seen in many cancers including breast, lung, bladder, kidney, thyroid, gastric, prostate and oral cancers. S100 proteins are commonly up-regulated in tumours and this is often associated with tumour progression. In contrast S100A2, S100A11 and S100A9 have been documented as tumour suppressors in some cancers but as tumour promoters in others. This demonstrates the complexity of the family and variability of their functions. Although the precise roles of these proteins in cancer is still to be discovered many of the family are associated with promoting metastases through interactions with matrix metalloproteinases or by acting as chemoattractants. There is also evidence that some members can regulate transcription factors such as p53. S100B already has a role in a clinical setting in the diagnosis and therapeutic monitoring of malignant melanoma. As our understanding of this family develops it is likely that many more members will aid the diagnosis, monitoring and potential treatment of cancers in the future.

Seroprevalence of hepatitis A among children of different socioeconomic status in Cairo.

To determine seroprevalence of anti-hepatitis A virus (HAV) antibodies and potential risk factors for and age of contracting symptomatic hepatitis A infection among children of different socioeconomic status (SES) in Cairo, we carried out a cross-sectional study on 426 children aged 3-18 years from low SES areas and 142 from high SES areas. Seroprevalence was significantly higher with age. Seropositivity to anti-HAV antibodies was significantly higher among children of low and very low SES, 90%, compared to children of high SES, 50%. Water supply and sewage disposal were the most significant risk factors for HAV seropositivity in children of low SES. Children of high SES were more likely to be vulnerable to infection in adolescence than those of low SES.

Seroprevalence of hepatitis A among children of different socioeconomic status in Cairo

To determine seroprevalence of anti-hepatitis A virus [HAV] antibodies and potential risk factors for and age of contracting symptomatic hepatitis A infection among children of different socioeconomic status [SES] in Cairo, we carried out a cross-sectional study on 426 children aged 3-18 years from low SES areas and 142 from high SES areas. Seroprevalence was significantly higher with age. Seropositivity to anti-HAV antibodies was significantly higher among children of low and very low SES, 90%, compared to children of high SES, 50%. Water supply and sewage disposal were the most significant risk factors for HAV seropositivity in children of low SES. Children of high SES were more likely to be vulnerable to infection in adolescence than those of low SES

Laparoscopic esophagogastric devascularization in bleeding varices.

BACKGROUND: Bleeding from esophageal varices is the major cause of death in patients with portal hypertension. The ideal surgical procedure should effectively control bleeding and maintain liver function with low rates of encephalopathy. Based on this objective, laparoscopic devascularization of the lower esophagus and upper stomach was studied. METHODS: Eighteen patients were studied prospectively who underwent a laparoscopic esophagogastric devascularization procedure for variceal hemorrhage. The diaphragmatic hiatus and esophagus are dissected. The lower 7 or 8 cm of esophagus is devascularized. Devascularization of the gastric fundus is then accomplished by meticulous dissection and ligation of the short gastric vessels. The hepatogastric ligament is opened, permitting identification and isolation/ligation of the left gastric vessels. The dissection and ligation of the vessels at lesser curvature proceeded up to the diaphragmatic hiatus with devascularization of the external varices from the retroperitoneum or mediastinum at the esophagogastric junction. RESULTS: Mean operating room time was 111 min (range, 80-140 min) (6 emergent/12 elective). Mean blood loss 388 ml (range, 150-650 ml). Intensive care unit stay averaged 48 h, with a mean hospitalization of 11 days. Liver function and coagulation parameters remained stable postoperatively. Duplex sonography on the portal and splenic veins revealed patency in all patients. The flow velocity in the portal vein decreased from 15.5 +/- 4.1 to 13.4 +/- 3.5 cm/s postoperatively ( p = 0.021). Splenic vein velocity was unchanged. Bleeding recurred in 6 patients, and grade 1 encephalopathy developed in 1 patient. Follow-up endoscopy (8-24 months) demonstrated substantial reduction in variceal grade. CONCLUSION: Laparoscopic devascularization of the lower esophagus and the upper stomach is technically feasible and promising. Rapid recovery and control of variceal hemorrhage are accomplished in most patients without exposing them to the risk of open surgery.

HIV/AIDS knowledge and attitudes among alcohol and drug abusers in Egypt.

The aim of this study was to assess knowledge, attitudes and practice towards HIV/AIDS among alcohol and drug abusers and the effect of health education (HE) on their knowledge and attitudes. Participants were 265 substance abusers, recruited from 8 addiction rehabilitation centers. A base line study preceding HE was done using a questionnaire composed of five sections. Three scores were developed to assess HIV/AIDS related knowledge. The base line study indicates that addicts with good knowledge scores > or =75%) regarding modes of transmission were significantly higher among males than females. About 70% of the addicts had negative attitudes towards dealing with HIV/AIDS patients, while 55.5% felt sympathy for them. Eleven percent of the injection drug abusers were sharing needle with others, while 38% of the participating females were previously convicted of prostitution. Logistic analysis showed that high level of education was the best predictive variable for good knowledge scores (> or =75%). Evaluation of the health education program revealed a highly significant increase in the knowledge scores among both males and females compared to the pretest scores. An increase in the percentages of male and female addicts with improved attitudes towards HIV/AIDS patients was also noted after HE. So, HE was found to be a successful tool in improving the knowledge and attitudes of substance abusers towards HIV/AIDS.

Hirsutism in the United Arab Emirates: a hospital study.

In a study of 102 women (Arabs and Asians) with hirsutism, polycystic ovary syndrome was diagnosed in 93 patients (91%) including 26 cases with hirsutism and regular menstrual periods. In more than half of the cases the diagnosis was made on the basis of transabdominal ultrasonography, which was the single test with the highest yield. Luteinising hormone hyperresponsiveness to gonadotropin-releasing hormone was positive in only seven of 50 patients tested. Late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency was identified in two cases, thus forming a prevalence of 8% in those who underwent adrenocorticotropin stimulation. In one case, polycystic ovary syndrome was an associated condition. In this study of a population of women with hirsutism and regular menses, the majority had polycystic ovaries. It is suggested that the term 'idiopathic or racial' hirsutism should not be applied unless a thorough evaluation has failed to reveal a diagnosable underlying disorder.