Mechanisms into the development of fatty liver disease: role of bile acids, Betaine and MHY908

Background: Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic worldwide. It is a metabolic condition that etiologically parallels with obesity, type 2 diabetes, and the metabolic syndrome. However, the pathogenesis of NAFLD remains elusive, though it is known free fatty acids such as palmitate promote liver injury. Therefore, there is a pressing need to find a potent therapeutic approach for NAFLD. Firstly, this study aimed to investigate the lipotoxicity and mitochondrial dysfunction attributable to palmitic acid. Subsequent investigations focused on investigating possible alternative therapies for NAFLD such as bile acids, betaine and a PPARα/γ dual agonist MHY908. Method: Human hepatoma cell line, VL17A cells were treated with saturated fatty acid palmitic acid (PA) with a range of concentrations between 10 μM - 300 μM for 24 h, 48 h and 72 h after which lipid accumulation, cell toxicity, oxidative stress and mitochondrial function were assessed. Further investigations were employed with bile acids chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), betaine and MHY908 to determine whether lipotoxicity induced by PA would be attenuated and therefore could be a potential therapy for NAFLD. Results: PA treatment showed a detrimental effect on cell viability in a time and dose dependant manner, where longer incubation time and higher concentrations of PA exhibited the greatest cytotoxicity. At 72 h, 300 μM PA led to a 90% decrease in cell viability (p < 0.001). Lipid accumulation also increased with higher doses, 250 μM PA treatment led to a 21% increase in lipid accumulation (p < 0.001). PA induced oxidative stress and mitochondrial dysfunction at higher concentration. At 300 μM PA treatment led to increases in ROS at 30 minutes (+46%, p <0.001) and 1 h (+61%, p <0.001). Lower PA doses 50 μM and 100 μM PA were employed in subsequent studies. UDCA exhibited hepatoprotective effects when co-incubated with PA predominantly at 24 h with 30 μM treatment; cell viability (UDCA +13%, p < 0.05), lipid accumulation (UDCA -47%, p < 0.001), ROS levels and mitochondrial function improved in all parameters investigated. CDCA showed less hepatoprotective effects in comparison to UDCA. Betaine 20μM displayed anti-oxidative properties and attenuated PA induced lipotoxicity as cell viability increased +41%, p < 0.001 but there was no significant effect on lipid accumulation. PPARα/γ dual agonist MHY908 also showed beneficial effect with 1 μM treatment where cell viability increased by 26% (P < 0.001), lipid accumulation decreased by 13% (p < 0.001), ROS generation had a less significant effect as levels decreased by 3% though mitochondrial function improved. Conclusion: This study determined the saturated fatty acid PA induced cytotoxicity and lipid accumulation in hepatocytes. This may be due to the increased activity of the lipogenic pathway which consequently promotes oxidative stress and mitochondrial dysfunction. Alternative therapies such as UDCA, betaine and MHY908 attenuated PA induced lipotoxicity and improved mitochondrial function. However, further work aims to elucidate the protein expression and gene expression of transcriptional factors involved in the molecular pathways to gain a better understanding of fatty liver disease progression and development of novel therapies to treat NAFLD

Coannihilation Scenarios and Particle Spectroscopy in SU(4)_c x SU(2)_L x SU(2)_R

We identify a variety of coannihilation scenarios in a supersymmetric SU(4)_c x SU(2)_L x SU(2)_R model with discrete left-right symmetry. Non-universal gaugino masses, compatible with the gauge symmetry, play an essential role in realizing gluino and bino-wino coannihilation regions that are consistent with the WMAP dark matter constraints. We also explore regions of the parameter space in which the little hierarchy problem is partially resolved. We present several phenomenologically interesting benchmark points and the associated sparticle and Higgs mass spectra.Comment: 16 pages, 5 figures and 1 tabl

Experimental Characterization of Electrical Discharge Machining of Aluminum 6061 T6 Alloy using Different Dielectrics

Electrical discharge machining is a non-traditional machining method broadly employed in industries for machining of parts that have typical profiles and require great accuracy. This paper investigates the effects of electrical parameters: pulse-on-time and current on three performance measures (material removal rate, microstructures and electrode wear rate), using distilled water and kerosene as dielectrics. A comparison between dielectrics for the machining of aluminum 6061 T6 alloy material in terms of performance measures was performed. Aluminum 6061 T6 alloy material was selected, because of its growing use in the automotive and aerospace industrial sectors. The experimental sequence was designed using Taguchi technique of L9 orthogonal array by changing three levels of pulse-on-time and current, and test runs were performed separately for each dielectric. The results obtained show that greater electrode wear rate (EWR) and higher material removal rate (MRR) were achieved with distilled water when compared with kerosene. These greater EWR and MRR responses can be attributed to the early breakage of the weak oxide and carbide layers formed on the tool and alloy material surfaces, respectively. The innovative contributions of this study include, but are not limited to, the possibility of machining of aluminum 6061 T6 alloy with graphite electrode to enhance machinability and fast cutting rate employing two different dielectrics.Peer reviewe

Evaluation of combined disc method for the detection of metallo-β-lactamase producing Gram negative bacilli

Aims: Infections due to metallo-β-lactamase (MBL) producing Gram negative rods are a cause of high mortality and morbidity. Early detection by an economical and accurate method may improve patient outcome. This study was aimed to evaluate the diagnostic accuracy of combined disc method for MBL detection by comparing it with MBL-Etest.Methodology and Results: This cross-sectional, validation study was carried out in the Department of Microbiology, Army Medical College, National University of Sciences and Technology, Rawalpindi, over a period of six months. A total of 52 non-duplicate Gram-negative rods isolated from the routine clinical specimens and found resistant to meropenem/imipenem on Kirby Bauer Disc Diffusion method were subjected to two tests for metallo-β-lactamase detection. One was combined Disc test using imipenem with Ethylene Diamine Tetraacetic Acid (EDTA), where a strain showing an increase in zone of inhibition of combined disc of ≥ 7 mm as compared to imipenem alone, was considered as MBL producer and the other one was MBL-Etest for which results were interpreted as per manufacturer’s guidelines. Combined disc method for MBL detection was found to have a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 97.5%, 100%, 100%, 92% and 98%.Conclusion, Significance and Impact of study: Combined disc method is an economical and reliable method for metallo-β-lactamase detection which can be used routinely in any laboratory

Neonatal Birth Traumas: Risk factors and types

Background: Birth trauma is defined as injury to neonates resulting from mechanical forces (such as compression or traction) during the process of birth. Birth injury is used to denote avoidable and unavoidable mechanical and hypoxic- ischemic injury incurred by neonates during labor and delivery. Maternal, labor and infant factors can predispose to birth traumas. Many types of birth traumas can be found including intra and extra cranial, spinal, peripheral nerves, fractures and visceral. Patients and methods: A cross sectional study was done on 200 babies (100 babies for the study group and 100 babies for the control group), admitted to special care baby unit of Baghdad Teaching Hospital, during the period between 1st of October 2007 to the 30th of March 2008. Results: There was an increased percentage of birth trauma in preterm babies, large birth weight, mothers who were primigravida, had history of contracted pelvis, diabetes mellitus, prolong second stage of labor, abnormal fetal presentation, and shoulder dystocia. Trauma of cranium was the most common type of birth trauma, of which caput succedaneum (68%) was the most common one. Conclusions: Birth trauma is still a significant problem in this maternity ward causing some morbidity. The significant risk factors were macrosomia, prematurity and multiple pregnancies, primigravida, chronic maternal illness like diabetes mellitus, history of pelvic anomalies or contracted pelvis, prolonged labor especially the second stage, abnormal fetal presentation and shoulder dystocia. So we recommend assessment of the fetal weight, mother pelvis capacity and presentation before delivery, so that macrosomic fetus might be delivered by cesarean section, and prevent premature delivery, and better use of investigations like ultrasound,x-ray,CT scan for early diagnosis and further management of birth trauma

Recycled Concrete Aggregated for the use in Roller Compacted Concrete: A Literature Review

The using of recycled aggregates from construction and demolition waste (CDW) can preserve natural aggregate resources, reduce the demand for landfill, and contribute to a sustainable built environment. Concrete demolition waste has been proven to be an excellent source of aggregates for new concrete production. At a technical, economic, and environmental level, roller compacted concrete (RCC) applications benefit various civil construction projects. Roller Compacted Concrete (RCC) is a homogenous mixture that is best described as a zero-slump concrete placed with compacting equipment, uses in storage areas, dams, and most often as a basis for rigid pavements. The mix must be sufficiently dry to support the weight of vibratory machinery while still being sufficiently moist to enough paste binder dispersion throughout the mass for efficient compaction. Limited studies into the use of RCC with fine recycled aggregate not from pavements are figured. This study aims to see how well-recycled concrete aggregates (RCA) perform in RCC mixtures. Also how well waste concrete could be used as a fine and coarse aggregate substitute in roller-compacted concrete pavement mixes, to create a good concrete mix in both wet and firm phases. The test results of mechanical properties showed 10% RCA is similar to those in the reference mix in the compressive strength, a 100% RCA ratio reduces compressive strength by almost 30%. Comparing Reference mix and Recycled concrete by 30% replacement, the compressive strength drops by just 6% when the RCA ratio is 30%