Determination of quality gap for educational services in undergraduate medical education. A cross-sectional study in Saudi Specialized Health Sciences University.

OBJECTIVE: To assess the perception and expectation of students about the quality of educational services and identify the gap in educational services. METHODS: This cross-sectional study was conducted at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) colleges across all regions (Riyadh, Jeddah, and Al-Ahsa) within one academic year (September 2017- April 2018). The difference between the students' perceptions and expectations was calculated to identify the gap between these 2 opinions. RESULTS:   A total of 416 (83.2%) questionnaires were completed with an almost equal ratio of male to female (51% and 49%). There was a significant difference in mean (gap) between students' expectations and perceptions of educational service quality at KSAU-HS (p less than 0.05). The results showed negative values for most of the items. It revealed that there is a significant difference between male and female in responsiveness, empathy, and tangible. CONCLUSION: The findings of this study showed that all the dimensions were not up to the expectations of students. The results will help the higher management to initiate a protocol to address all weaknesses.

Ionic signalling and mitochondrial dynamics.

In age-related diseases, rise in intracellular reactive oxygen species (ROS) causes fragmentation of mitochondrial network. Our recent study demonstrated that ROS activation of TRPM2 (transient receptor potential melastatin-2) channels triggers lysosomal Zn2+ release that, in turn, triggers mitochondrial fragmentation. The findings provide new mechanistic insights that may have therapeutic implications.

High glucose-induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission.

Diabetic stress increases the production of reactive oxygen species (ROS), leading to mitochondrial fragmentation and dysfunction. We hypothesized that ROS-sensitive TRPM2 channels mediated diabetic stress-induced mitochondrial fragmentation. We found that chemical inhibitors, RNAi silencing, and genetic knockout of TRPM2 channels abolished the ability of high glucose to cause mitochondrial fission in endothelial cells, a cell type that is particularly vulnerable to diabetic stress. Similar to high glucose, increasing ROS in endothelial cells by applying H2O2 induced mitochondrial fission. Ca2+ that entered through TRPM2 induced lysosomal membrane permeabilization, which led to the release of lysosomal Zn2+ and a subsequent increase in mitochondrial Zn2+ Zn2+ promoted the recruitment of the fission factor Drp-1 to mitochondria to trigger their fission. This signaling pathway may operate in aging-associated illnesses in which excessive mitochondrial fragmentation plays a central role.

Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels.

Cell migration is a fundamental feature of tumour metastasis and angiogenesis. It is regulated by a variety of signalling molecules including H2O2 and Ca(2+) Here, we asked whether the H2O2-sensitive transient receptor potential melastatin 2 (TRPM2) Ca(2+) channel serves as a molecular link between H2O2 and Ca(2+) H2O2-mediated activation of TRPM2 channels induced filopodia formation, loss of actin stress fibres and disassembly of focal adhesions, leading to increased migration of HeLa and prostate cancer (PC)-3 cells. Activation of TRPM2 channels, however, caused intracellular release of not only Ca(2+) but also of Zn(2+) Intriguingly, elevation of intracellular Zn(2+) faithfully reproduced all of the effects of H2O2, whereas Ca(2+) showed opposite effects. Interestingly, H2O2 caused increased trafficking of Zn(2+)-enriched lysosomes to the leading edge of migrating cells, presumably to impart polarisation of Zn(2+) location. Thus, our results indicate that a reciprocal interplay between Ca(2+) and Zn(2+) regulates actin remodelling and cell migration; they call for a revision of the current notion that implicates an exclusive role for Ca(2+) in cell migration.

TRPM2-mediated intracellular Zn2+ release triggers pancreatic ß-cell death.

Reactive oxygen species (ROS) can cause pancreatic ß-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca2+. Recent studies however revealed that TRPM2 channels can also conduct Zn2+, but the physiological relevance of this property is enigmatic. Given that Zn2+ is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn2+ to affect cell viability. To address this, we used the insulin secreting (INS1) ß-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H2O2 activation of TRPM2 channels increases the cytosolic levels of both Ca2+ and Zn2+ and causes apoptotic cell death. Interestingly, chelation of Zn2+ alone was sufficient to prevent ß-cell death. The source of the cytotoxic Zn2+ is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn2+ release. Zn2+ release is potentiated by extracellular Ca2+ entry, indicating that Ca2+-induced Zn2+ release leads to apoptosis. Knockout of TRPM2 channels protects mice from ß-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca2+-potentiated Zn2+ release underlies ROS-induced ß-cell death and Zn2+, rather than Ca2+, plays a primary role in apoptosis.

Endocytosis of HERG is clathrin-independent and involves arf6.

The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression of hERG at the plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases the risk of ventricular arrhythmias. Thus, it is of fundamental importance to understand how the density of this channel at the plasma membrane is regulated. We used antibodies to an extracellular native or engineered epitope, in conjunction with immunofluorescence and ELISA, to investigate the mechanism of hERG endocytosis in recombinant cells and validated the findings in rat neonatal cardiac myocytes. The data reveal that this channel undergoes rapid internalisation, which is inhibited by neither dynasore, an inhibitor of dynamin, nor a dominant negative construct of Rab5a, into endosomes that are largely devoid of the transferrin receptor. These results support a clathrin-independent mechanism of endocytosis and exclude involvement of dynamin-dependent caveolin and RhoA mechanisms. In agreement, internalised hERG displayed marked overlap with glycosylphosphatidylinositol-anchored GFP, a clathrin-independent cargo. Endocytosis was significantly affected by cholesterol extraction with methyl-ß-cyclodextrin and inhibition of Arf6 function with dominant negative Arf6-T27N-eGFP. Taken together, we conclude that hERG undergoes clathrin-independent endocytosis via a mechanism involving Arf6.