Modulation of NMDA Receptor Currents in Rat Substantia Nigra

Dopamine receptor signalling is essential for normal basal ganglia function but in Parkinson’s Disease (PD) substantia nigra (SNc) dopaminergic (DAergic) neurons degenerate with consequent loss of dopamine signalling. SNc DAergic neurons express D2 autoreceptors (D2Rs) that have been shown to mediate inhibition of NMDA responses in both hippocampus and striatum while Gascoupled adenosine A2A receptors (A2ARs) have the potential to counteract the action of Gai -coupled D2Rs. Here I tested whether D2R activation with ropinirole, a D2 receptor agonist currently used in PD therapy, modulates DAergic neuron NMDA responses in the SNc along with other proteins in the cell. Whole-cell patch clamp recordings were made from DAergic neurons in the SNc of acute midbrain slices from young (P7, P21 and P28) rats. DAergic neurons were identified by the presence of a prominent hyperpolarisation-activated inward current (in P7 rats, amplitude, 178 ± 5 pA; activation time constant, 797 ± 77 ms; mean ± SEM, N = 19) in response to a voltage step from -60 to -120 mV. In P7 and P28 rats, upon application of 200 nM ropinirole, the steady state NMDA current was not significantly changed suggesting D2-R activation may not modulate NMDARs in neonatal rat SNc. In addition, an A2AR agonist, CGS21680, and an A2AR antagonist, SCH 58621 were applied in the presence and absence of ropinirole to test for any A2AR – D2R interaction. Upon A2A-R activation, the NMDA-R current increased (P = 0.002, N = 16). Furthermore, to establish the effects of PKA on NMDA-R responses, 2.5µM Forskolin was introduced. It produced a statistically significant increase in NMDA-R current (NMDA: 419 ± 78pA; NMDA+ Forskolin: 515 ± 54pA, N=13). To determine whether the lack of effect of the D2-R agonist on NMDA-R response might be due to a low resting concentration of cAMP in the cell, forskolin was introduced to increase the levels of cAMP prior to introducing ropinirole. However, following addition of D2-R agonist after forskolin treatment, the NMDA-R current changed by only 11% (N=12). Intracellular tyrosine kinases, Src and Fyn have shown modulatory potential on NMDA-Receptors (NMDA-R) that is governed by the balance between kinase and phosphatase activity. Inhibiting Src kinase activity with PP2 and Src-I1 decreased the NMDA-R inward current however no such effect was seen in the presence of the interfering peptides suggesting a lack of direct interaction between Src/Fyn kinase and NMDA-Rs. Furthermore, ERK1/2 inhibitor, Ulixertinib, decreased the NMDA-R current suggesting an involvement in receptor modulation. Similar results were obtained in the presence of a CaMKII inhibitor CN21

A marginal structural model for normal tissue complication probability

The goal of radiation therapy for cancer is to deliver prescribed radiation dose to the tumor while minimizing dose to the surrounding healthy tissues. To evaluate treatment plans, the dose distribution to healthy organs is commonly summarized as dose-volume histograms (DVHs). Normal tissue complication probability (NTCP) modelling has centered around making patient-level risk predictions with features extracted from the DVHs, but few have considered adapting a causal framework to evaluate the comparative effectiveness of alternative treatment plans. We propose causal estimands for NTCP based on deterministic and stochastic interventions, as well as propose estimators based on marginal structural models that parametrize the biologically necessary bivariable monotonicity between dose, volume, and toxicity risk. The properties of these estimators are studied through simulations, along with an illustration of their use in the context of anal canal cancer patients treated with radiotherapy

Intrahepatic Expression of Interferon Alpha & Interferon Alpha Receptor m-RNA can be Used as Predictors to Interferon Response in HCV and HCC Patients

Chronic hepatitis C Virus (HCV) is the leading cause of liver cirrhosis worldwide and in Egypt. Patients with cirrhosis secondary to chronic HCV infection are at increased risk for developing Hepatocellular carcinoma (HCC) in which Interferon therapy is the only effective anti-viral therapy. The current study aimed to investigate the expression IFN-\u3b1and IFN-\u3b1Receptor genes in liver biopsies from patients with HCV and HCC. Correlation of their expression with the clinical, histopathological progress of the disease and the effectiveness of IFN therapy in HCV patients after a period of 6 months follow-up was done. Expression of IFN-\u3b1 and IFN\u3b1-Rc m-RNA was investigated by RT-PCR using liver biopsy specimens from 30 HCV patients including 7 patients complicated with HCC. Liver biopsies were also subjected to formalin fixation for complete histopathological examination. Ninety seven percent of patients expressed Interferon Alpha m-RNA while 30% only expressed Interferon Alpha Receptor m-RNA. Responders and non-responders to Interferon therapy were divided according to their HCV RNA after six-months follow up period of interferon therapy. Responders showed significantly lower mean age, better histopathological states and higher incidence of expression of IFN Alpha Receptor mRNA. Regardless of the response to interferon, histological activity index scores and the degree of fibrosis showed a significant inverse correlation to the presence of IFN\u3b1-R m-RNA. IFN\u3b1-R mRNA expression decreases with the histological progress of the disease, suggesting that lower expression of the IFN\u3b1-Rc may be partially responsible for the unfavorable response to interferon in these patients

MR-guided radiotherapy for liver malignancies

MR guided radiotherapy represents one of the most promising recent technological innovations in the field. The possibility to better visualize therapy volumes, coupled with the innovative online adaptive radiotherapy and motion management approaches, paves the way to more efficient treatment delivery and may be translated in better clinical outcomes both in terms of response and reduced toxicity. The aim of this review is to present the existing evidence about MRgRT applications for liver malignancies, discussing the potential clinical advantages and the current pitfalls of this new technology

ASSESSMENT OF WATER QUALITY IN CHLORINATED DRINKING WATER DISTRIBUTION NETWORKS REGARDING TO TRIHALOMETHANES FORMATION

Chlorine disinfection in conventional water treatment plants in Egypt is a popular and inexpensive technique for disinfecting raw surface water before distribution to consumers. Nevertheless, the chlorination process in the presence of natural organic matter and decreased water quality due to uncontrollable population results in formation of high concentrations of carcinogenic disinfection by-products, from which trihalomethanes (THMs). In this paper, the water quality of Assiut drinking water network (ADWN) was assessed in terms of THMs studying different water quality parameters. An extended period simulation based on a modelling software WaterGEMS was employed to obtain the critical locations to be examined according to key parameters namely: water age, residual chlorine concentration, water velocity, and type of storage. The study concluded that THMs concentrations from all critical locations in Assiut drinking water network would not exceed the Egyptian regulatory threshold and US Environmental Protection Agency (EPA) guidelines. Even more, an investigated domestic roof tank should be critically operated under a planned scheme of monitoring and maintenance due to its deteriorated water quality

Construction of a Scale for Emotions Management of the Educational Supervisors in the Sultanate of Oman

This study aimed to construct of a scale for emotions management of the educational supervisors in the Sultanate of Oman. It aimed to find out its psychometric properties in terms of validity, reliability, and performance norms. The sample size consisted of 335 supervisors from the Omani educational governorate. The scale was applied during the first semester of the academic year 2010-2011. The validity was verified by three methods: face validity, factorialvalidity and concurrentvalidity. Since there were no significant differences in the scale averages of males and females, the norms were derived for both males and females combined. Finally, a number of recommendations and suggestions have been introduced

Rare Mucinous Colorectal Adenocarcinoma: Analysis of the Epidemiological Factors in Relation to Survival in Egyptian Patients

Colorectal carcinoma (CRC) is one of the leading causes of cancer related deaths; in Egypt it constitutes 6.5% of all cancers. Previous studies have shown conflicting results on clinicohistopathological features and survival of patients with colorectal mucinous (MA) and non-mucinous adenocarcinoma (NMA). To the best of our knowledge, this study is the first to investigate these features in Egypt. In this work, we studied tumor tissue specimens from 150 patients with colorectal MA and NMA who underwent radical surgery from Jan 2007 to Jan 2012 at Gastroenterology Centre, Mansoura University, Egypt. Their clinicohistopathological parameters and survival were analyzed using established statistical methodologies. Incidence of MA and its subtypes was much higher in Egypt than worldwide incidence. MA was significantly associated with younger age, more depth of invasion, lymph node metastasis, less microscopic abscess formation and less peri-tumoral lymphocytic response (Crohn-like response) than NMA. Both groups were not significantly different "among others" in other clinicopathological parameters including lymphovascular and perineural invasion, association with adenoma and schistosomiasis. Multivariate analyses for disease free and overall survival revealed that mucinous histology is an independent prognostic factor. Among several factors, only distant metastasis and presentation with recurrent disease were independent prognostic factors within MA patients. In conclusion, MA represents a distinct clinicopathological entity with worse survival than NMA. Distant metastasis and presentation with recurrent disease are independent prognostic factors. Further molecular investigations considering genetic features of MA will lead to drug development and better management

Livestock as Sources of Greenhouse Gases and Its Significance to Climate Change

This chapter outlines the role of livestock in the production of greenhouse gases (GHGs) that contributes to climate change. Livestock contribute both directly and indirectly to climate change through the emissions of GHGs such as carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). As animal production systems are vulnerable to climate change and are large contributors to potential global warming, it is vital to understand in detail enteric CH4 emission and manure management in different livestock species. Methane emissions from livestock are estimated to be approximately 2.2 billion tonnes of CO2 equivalents, accounting for about 80% of agricultural CH4 and 35% of the total anthropogenic CH4 emissions. Furthermore, the global livestock sector contributes about 75% of the agricultural N2O emissions. Other sources of GHG emission from livestock and related activities are fossil fuels used for associated farm activities, N2O emissions from fertilizer use, CH4 release from the breakdown of fertilizers and from animal manure, and land-use changes for feed production. There are several techniques available to quantify CH4 emission, and simulation models offer a scope to predict accurately the GHG emission from a livestock enterprise as a whole. Quantifying GHG emission from livestock may pave the way for understanding the role of livestock to climate change and this will help in designing appropriate mitigation strategies to reduce livestock-related GHGs