Protective effect of prion protein via the N-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells

Transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (PrP(C)) into an infectious, disease-associated form (PrP(Sc)). Increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. We investigated the effect of oxidative stress mediated by paraquat exposure on SH-SY5Y neuroblastoma cells. A loss of mitochondrial membrane potential and subsequent reduction in ATP production were demonstrated in untransfected SH-SY5Y cells, an effect that was ameliorated by the expression of PrP(C). Cells expressing either PrP-DeltaOct, which lacks the octapeptide repeats, or PrP-DA, in which the N-terminus is tethered to the membrane, showed increased sensitivity to paraquat compared with cells expressing wild-type PrP(C) as shown by reduced viability, loss of their membrane integrity, and reduced mitochondrial bioenergetic measurements. Exposure of prion-infected mouse SMB15S cells to paraquat resulted in a reduction in viability to levels similar to those seen in the untransfected SH-SY5Y cells. However, "curing" the cells with pentosan sulfate restored the viability to the level observed in the SH-SY5Y cells expressing PrP(C). These data would indicate that the molecular mechanism promoting cellular resistance to oxidative stress had been compromised in the infected SMB15S cells, which could be reinstated upon curing. Our study supports the hypothesis that PrP(C) expression protects cells against paraquat-induced oxidative injury, demonstrates the significance of the N-terminal region of the protein in mediating this protective effect, and also shows that the biochemical consequences of prion infection may be reversed with therapeutic intervention.     

Early structural and functional neurovascular changes in the retina in the prediabetic stage

PurposeThis study was undertaken to investigate the neurovascular changes in the retina of prediabetic subjects.MethodsSubjects enroled in a prospective study were separated into prediabetic and normal control groups based on their glycosylated haemoglobin (HbA1C) levels, fasting and postprandial blood sugar levels and glucose tolerance test. All the subjects underwent detailed ophthalmic evaluation, which included fundus examination, fundus photography, optical coherence tomography angiography (OCTA), and multifocal electroretinogram (mfERG). Comparisons were done between the groups using the Wilcoxon signed rank test.ResultsThe median age was 48 years for the normal controls (n = 40), and 49.5 years for prediabetic subjects (n = 45) (p = 0.306). There was no difference in the vision, contrast sensitivity, thickness of the ganglion cell complex or the foveal avascular zone parameters between the groups. But the central foveal thickness and subfoveal choroidal thickness were significantly reduced in prediabetics (p < 0.01). The mfERG showed significant differences in the amplitude. The average amplitude was 35 ± 12 nv/deg² in the normals and 29 ± 11 nv/deg² in the prediabetics (p = 0.003). A weak positive correlation was noted between the mfERG and vascular parameters in the prediabetic group.ConclusionsThe prediabetic stage reveals earliest functional neuronal changes in the retina. The neuronal function seems to be affected much earlier than clinically appreciable structural changes in the ganglion cell complex and precedes vascular changes in the retina.Subject terms: Predictive markers, Blood flow     

Preliminary Impressions in Microstomia Patients: An Innovative Technique

Microstomia has been defined as an abnormally small oral orifice associated with various etiopathologic factors. Management of these patients poses extreme difficulties in every procedure during prosthesis fabrication. Restricted mouth opening of the patient makes the insertion and the removal of the tray extremely difficult. So sectioning of the existing stock tray is necessary, so that the trays can be inserted and removed in sections. The main problem encountered during this procedure is the reorientation of the tray back in position. This article presents an innovative technique for the easy handling of the sectioned stock impression trays.     

Changes in oxygen saturation during paediatric bronchoscopic procedures

Oximetric monitoring of paediatric pa-tients undergoing broncboscopy was done to determine the incidence and degree of bypoxaemia encountered at specific events occurring during the procedure. Heart rate and rhythm were also monitored to note concomitant changes. Twenty-six children were studied under general anaesthesia. The FiO₂ (0.5–1.0) and the pattern of ventilation were changed when bypoxaemia (SaO₂ < 85%) was detected. Despite this, severe hypoxaemia (SaO₂ < 75%) related to the actual process of instrumentation was noted in 50 per cent of cases. These episodes however did not produce any change in cardiac rate or rhythm. Though acute hypoxaemia appears to be a common event during broncboscopy in children, with continuous monitoring of SaO₂ it is possible to detect changes instantaneously. Episodes of hypoxaemia can then be rendered transient, thus minimising or preventing cardiac complications.     

Interaction between dendritic cells and nerve fibres in lymphoid organs after oral scrapie exposure

In transmissible spongiform encephalopathies (TSEs), the infectious agent, called PrPsc, an abnormal isoform of the cellular prion protein, accumulates and replicates in lymphoid organs before affecting the nervous system. To clarify the cellular requirements for the neuroinvasion of the scrapie agent from the lymphoid organs to the central nervous system, we have studied, by confocal microscopy, the innervations within Peyer’s patches, mesenteric lymph nodes and the spleen of mice in physiological conditions and after oral exposure to prion. Contacts between nerve fibres and PrPsc-associated cells, dendritic cells (DCs) and follicular dendritic cells (FDCs), were evaluated in preclinical prion-infected mice. Using a double immunolabelling strategy, we demonstrated the lack of innervation of PrPsc-accumulating cells (FDCs). Contacts between nerve fibers and PrPsc-propagating cells (DCs) were detected in T-cell zones and cell-trafficking areas. This supports, for the first time, the possible implication of dendritic cells in the prion neuroinvasion process.     

Can homeopathic arsenic remedy combat arsenic poisoning in humans exposed to groundwater arsenic contamination?: a preliminary report on first human trial

Groundwater arsenic (As) has affected millions of people globally distributed over 20 countries. In parts of West Bengal (India) and Bangladesh alone, over 100 million people are at risk, but supply of As-free water is grossly inadequate. Attempts to remove As by using orthodox medicines have mostly been unsuccessful. A potentized homeopathic remedy, Arsenicum Album-30, was administered to a group of As affected people and thereafter the As contents in their urine and blood were periodically determined. The activities of various toxicity marker enzymes and compounds in the blood, namely aspartate amino transferase, alanine amino transferase, acid phosphatase, alkaline phosphatase, lipid peroxidation and reduced glutathione, were also periodically monitored up to 3 months. The results are highly encouraging and suggest that the drug can alleviate As poisoning in humans.     

Validation of the European System for Cardiac Operative Risk Evaluation-II model in an urban Indian population and comparison with three other risk scoring systems

Aims and Objectives:

The aims were to compare the European System for Cardiac Operative Risk Evaluation (EuroSCORE)-II system against three established risk scoring systems for predictive accuracy in an urban Indian population and suggest improvements or amendments in the existing scoring system for adaptation in Indian population.

Materials and Methods:

EuroSCORE-II, Parsonnet score, System-97 score, and Cleveland score were obtained preoperatively for 1098 consecutive patients. EuroSCORE-II system was analyzed in comparison to each of the above three scoring systems in an urban Indian population. Calibrations of scoring systems were assessed using Hosmer–Lemeshow test. Areas under receiver operating characteristics (ROC) curves were compared according to the statistical approach suggested by Hanley and McNeil.

Results:

All EuroSCORE-II subgroups had highly significant P values stating good predictive mortality, except high-risk group (P = 0.175). The analysis of ROC curves of different scoring systems showed that the highest predictive value for mortality was calculated for the System-97 score followed by the Cleveland score. System-97 revealed extremely high predictive accuracies across all subgroups (curve area >80%). This difference in predictive accuracy was found to be statistically significant (P < 0.001).

Conclusions:

The present study suggests that the EuroSCORE-II model in its present form is not validated for use in the Indian population. An interesting observation was significantly accurate predictive abilities of the System-97 score.     

Theta‐ and alpha‐power enhancements in the electroencephalogram as an auditory delayed match‐to‐sample task becomes impossibly difficult

Recent studies have related enhancements of theta‐ (∼4–8 Hz) and alpha‐power (∼8–13 Hz) to listening effort based on parallels between enhancement and task difficulty. In contrast, nonauditory works demonstrate that, although increases in difficulty are initially accompanied by increases in effort, effort decreases when a task becomes so difficult as to exceed one's ability. Given the latter, we examined whether theta‐ and alpha‐power enhancements thought to reflect effortful listening show a quadratic trend across levels of listening difficulty from impossible to easy. Listeners (n = 14) performed an auditory delayed match‐to‐sample task with frequency‐modulated tonal sweeps under impossible, difficult (at ∼70.7% correct threshold), and easy (well above threshold) conditions. Frontal midline theta‐power and posterior alpha‐power enhancements were observed during the retention interval, with greatest enhancement in the difficult condition. Independent component‐based analyses of data suggest that theta‐power enhancements stemmed from medial frontal sources at or near the anterior cingulate cortex, whereas alpha‐power effects stemmed from occipital cortices. Results support the notion that theta‐ and alpha‐power enhancements reflect effortful cognitive processes during listening, related to auditory working memory and the inhibition of task‐irrelevant cortical processing regions, respectively. Theta‐ and alpha‐power dynamics can be used to characterize the cognitive processes that make up effortful listening, including qualitatively different types of listening effort.