Introduction In 2012, American Academy of Sleep Medicine (AASM) proposed a new rule for hypopnea in adults (Version 2), where hypopnea is scored when the flow signal excursions drop by ¡‘Ý30% of ...pre-event baseline accompanied by ¡‘Ý3% desaturation or arousal.The phase or the temporal shape of oxygen saturation of central hypopnea or mixed hypopnea is very different from those of obstructive hypopnea. Many patients with heart disease have more central apnea including Cheyne Stokes respiration (CSR) and mixed apnea and, therefore, application of the new rule may bring about a significant change in the judgment of sleep disordered breathing, especially in patients with heart disease.Thus, we analyzed and compared the respiratory events using both version 1 (AASM 2007, alternative rule) and version 2 rules. Materials and methods The subject comprised of 75 patients who underwent Full PSG at our sleep laboratory.Patients were classified into those without heart disease ( n = 20, age 52¡‘À15 years, male 85%), with heart disease ( n = 55, age, 62¡‘À15 years, male 76.2%).The patients with heart disease were further divided into those who mainly had CSA (CSA¡‘Ý50% and AHI¡‘Ý5/h, n = 13, age 63¡‘À18 years, male 85%) and those without CSA dominancy.Data were analyzed using both version 1 and 2 rules and compared between them. Results The mean apnea–hypopnea indices (AHI) of the group without heart disease by version 1 and 2 were 29¡‘À20/h vs 30¡‘À20/h respectively ( P = ns).Correlation coefficient between both analysis was y = 1.03x, R2 = 0.996.The mean AHI of the group with heart disease was 35¡‘À20/h and 36¡‘À20/h respectively ( P = ns).Correlation coefficient between both was y = 0.98 x + 2.29 and R2 = 0.995.The mean AHI of the group with CSA dominancy was 44¡‘À18/h vs 45¡‘À17/h respectively ( P = ns).Correlation coefficient between both was y = 1.02 x and R2 = 0.994. Conclusion Though there may be a substantial difference between the AHI results when analyzed using both versions of criteria in the cardiac or non-cardiac patients especially with low AHI, there was no significant difference among the groups as a whole.Thus, there may not be any serious problem by the analysis with the new version rule in these populations. Acknowledgement There is no COI in all authors.
Our goal was to provide comprehensive data on the effectiveness of ketamine in refractory status epilepticus (RSE) and to describe the potential consequences of long-term ketamine infusion. Ketamine, ...an N-methyl D-aspartate (NMDA) receptor antagonist, blocks excitatory pathways contributing to ongoing seizure. While ketamine use is standard in anaesthetic induction, no definitive protocol exists for its use in RSE, and little is known about its adverse effects in long-term, high-dose administration. We present two cases of RSE that responded rapidly to ketamine infusion, both with fatal outcomes secondary to metabolic acidosis and cardiovascular collapse. We performed a systematic review of the application and consequences of ketamine use in RSE. PubMed, Ovid, MEDLINE and PMC were searched for articles describing ketamine treatment for RSE according to a predetermined search strategy and inclusion criteria. The systematic review revealed wide discrepancies in ketamine dosing (infusion maintenance dose range 0.0075–10.5 mg/kg/hour), but good outcomes in medically managed RSE (75% of studies reported moderate or complete seizure control in adults, 62.5% in paediatrics). Additionally, literature review elucidated a potentially causal relationship between prolonged ketamine infusion and both cardiovascular and metabolic dysregulation. Ketamine is effective in RSE by antagonising excitotoxic NMDA receptors. However, there is high variability in ketamine dosing and scarce data on its safety in long-term infusion. Metabolic acidosis and haemodynamic instability associated with the use of long-term, high-dose ketamine infusions must be of concern to clinicians administering ketamine to critically ill patients.
Highlights • The overall expression of brain androgen receptor was stronger in the mouse than in the rat. • ‘OECI’ was identified as the putative SDN–MPN in the mouse. • AR expression in the ...suprachiasmatic nucleus was more prominent in the mouse than in the rat. • Male-dominant mouse-specific (TDN) & rat-specific (RNI/CNI) clusters were clarified. • Data on AR from one species should not always be directly applied to another one.
•First study to magnetically target stem cells to the inner ear using nanoparticles and a magnetized cochlear implant.•Structural and functional improvement in maintenance of spiral ganglion neuron ...survival is demonstrated.•Potential value in improving cochlea implant function and hearing recovery.
Severe sensorineural deafness is often accompanied by a loss of auditory neurons in addition to injury of the cochlear epithelium and hair cell loss. Cochlear implant function however depends on a healthy complement of neurons and their preservation is vital in achieving optimal results. We have developed a technique to target mesenchymal stem cells (MSCs) to a deafened rat cochlea. We then assessed the neuroprotective effect of systematically delivered MSCs on the survival and function of spiral ganglion neurons (SGNs). MSCs were labeled with superparamagnetic nanoparticles, injected via the systemic circulation, and targeted using a magnetized cochlea implant and external magnet. Neurotrophic factor concentrations, survival of SGNs, and auditory function were assessed at 1week and 4weeks after treatments and compared against multiple control groups. Significant numbers of magnetically targeted MSCs (>30MSCs/section) were present in the cochlea with accompanied elevation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels (p<0.001). In addition we saw improved survival of SGNs (approximately 80% survival at 4weeks). Hearing threshold levels in magnetically targeted rats were found to be significantly better than those of control rats (p<0.05). These results indicate that magnetic targeting of MSCs to the cochlea can be accomplished with a magnetized cochlear permalloy implant and an external magnet. The targeted stem cells release neurotrophic factors which results in improved SGN survival and hearing recovery. Combining magnetic cell-based therapy and cochlear implantation may improve cochlear implant function in treating deafness.
Aims/hypothesis
The
WFS1
gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in ...humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death.
Methods
We studied the effect of breeding
Wfs1
−/−
mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (
A
y
/a
). We also treated the mice with pioglitazone.
Results
Wfs1
−/−
mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However,
Wfs1
−/−
A
y
/a
mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In
Wfs1
+/+
A
y
/a
islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit α (eIF2α) apparently increased. Levels of both were further increased in
Wfs1
−/−
A
y
/a
murine islets. Electron micrography revealed markedly dilated ERs in
Wfs1
−/−
A
y
/a
murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development.
Conclusions/interpretation
Wfs1
-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common
WFS1
gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.
Prion diseases propagate by converting a normal glycoprotein of the host, PrPC, into a pathogenic ‘prion’ conformation. Several misfolding mutants of PrPC are degraded through the ER‐associated ...degradation (ERAD)–proteasome pathway. In their infectious form, prion diseases such as bovine spongiform encephalopathy involve PrPC of wild‐type sequence. In contrast to mutant PrP, wild‐type PrPC was hitherto thought to be stable in the ER and thus immune to ERAD. Using proteasome inhibitors, we now show that ∼10% of nascent PrPC molecules are diverted into the ERAD pathway. Cells incubated with N‐acetyl‐leucinal‐leucinal‐norleucinal (ALLN), lactacystin or MG132 accumulated both detergent‐soluble and insoluble PrP species. The insoluble fraction included an unglycosylated 26 kDa PrP species with a protease‐resistant core, and a Mr ‘ladder’ that contained ubiquitylated PrP. Our results show for the first time that wild‐type PrPC molecules are subjected to ERAD, in the course of which they are dislocated into the cytosol and ubiquitylated. The presence of wild‐type PrP molecules in the cytosol may have potential pathogenic implications.
Abstract
Interests on few-body hypernuclei have been increased by recent results of experiments employing relativistic heavy ion beams. Some of the experiments have revealed that the lifetime of the ...lightest hypernucleus, hypertriton, is significantly shorter than 263 ps which is expected by considering the hypertriton to be a weakly-bound system. The STAR collaboration has also measured the hypertriton binding energy, and the deduced value is contradicting to its formerly known small binding energy. These measurements have indicated that the fundamental physics quantities of the hypertriton such as its lifetime and binding energy have not been understood, therefore, they have to be measured very precisely. Furthermore, an unprecedented Λnn bound state observed by the HypHI collaboration has to be studied in order to draw a conclusion whether or not such a bound state exists. These three-body hypernuclear states are studied by the heavy-ion beam data in the WASA-FRS experiment and by analysing J-PARC E07 nuclear emulsion data with machine learning.
Subretinal transplantation of stem-cell-derived photoreceptor precursor cells (PPCs) is a promising and innovative approach to treating a range of blinding diseases. However, common barriers to ...efficient preclinical transplantation comes in the form of suboptimal graft architecture, limited graft survival, and immune-rejection, each of which cannot be assessed using conventional in vivo imaging (i.e., rodent ophthalmoscopy). With the majority of PPCs reported to die within the first few weeks after transplantation, understanding the mechanisms of graft failure, and ultimately devising preventative methods, currently relies on lengthy end point histology. To address these limitations, we hypothesized that combining two imaging modalities, optical coherence tomography (OCT) and fluorescence confocal scanning laser ophthalmoscopy (fcSLO), could provide a more rapid and comprehensive view of PPC engraftment.
Human ESC-derived PPCs were transplanted into 15 retinal dystrophic rats that underwent bimodal imaging at 0, 8, and 15 days posttransplant.
Bimodal imaging provided serial detection of graft: placement, architecture, and survival; each undetectable under ophthalmoscopy. Bimodal imaging determined graft placement to be either: subretinal (n=7), choroidal (n=4), or vitreal (n=4) indicating neural retinal perforation. Graft architecture was highly variable at the time of transplantation, with notable redistribution over time, while complete, or near complete, graft loss was observed in the majority of recipients after day 8. Of particular importance was detection of vitreal aggregates overlying the graft-possibly an indicator of host-site inflammation and rejection.
Early real-time feedback of engraftment has the potential to greatly increase efficiency of preclinical trials in cell-based retinal therapeutics.
Aim: Reporting the case of a patient with Edwards syndrome of above-average survival. Edwards syndrome is a chromosomal disorder with multiple and severe congenital malformations, a profound delay in ...neuropsychomotor development, and an average survival of around 2.5 to 14.5 days. Description: Patient age of seven years and six months, female, who presented at birth, congenital heart disease, microcephaly, micrognathia, cutis marmorata, pectus escavatum and other typical alterations of Edwards Syndrome. Intensive interventions were performed, and karyotype exam confirmed full trisomy of chromosome 18. The patient currently undergoes intensive occupational and speech-language therapy, physiotherapy, and is stable. Comments: Edwards syndrome has a reserved prognosis, and although it is proven that aggressive interventions improve the survival of these patients, there is still no consensus in neonatal resuscitation protocols, and there are differences in perception about prognosis and therapeutic recommendations. However, parental autonomy must always be considered, and it is known that patients who survive to childhood bring positive results in the family circle. The discussion of prognosis and therapy is necessary and should aim at the homogenization of medical conduct
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