Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of Visual Evoked Potentials in Patients Affected by Optic Neuritis From Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder

Purpose: To compare the visual evoked potentials (VEPs) of optic neuritis (ON) patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and controls. To evaluate correlations between VEP and optical coherence tomography (OCT), contrast sensitivity (CS), and automated perimetry. Methods: Fifty-five eyes with ON from 29 patients (MS = 14 and NMOSD = 15) and 57 eyes from 29 controls were evaluated using VEP, automated perimetry, CS, and optical coherence tomography. Three groups were analyzed: 1) MS eyes with history of ON (ON-MS), 2) NMOSD eyes with ON (ON-NMOSD), and 3) healthy controls. Groups were compared and associations between the parameters were tested. Results: Compared to controls, ON-MS eyes showed significantly delayed N75 and P100 latencies when using a medium-sized stimulus (30′), and delayed P100 latency when using a large stimulus (1.5°), but similar amplitudes. Compared to controls, ON-NMOSD eyes showed significantly lower N75/P100 amplitudes (both stimulus sizes) and P100/N135 amplitudes (with the 30′ stimulus), but latencies did not differ, except for a delayed P100 latency with the 30′ stimulus. When comparing the 2 ON groups using the 1.5° stimulus, there was significant delay in P100 latency in ON-MS eyes and a reduction in N75/P100 amplitude in ON-NMOSD eyes. Peripapillary retinal nerve fiber layer, macular inner retinal layers, and CS measurements were significantly smaller in ON patients than in controls. A strong correlation was found between VEP parameters and inner retinal layer thickness in ON-NMOSD eyes. Conclusions: ON-MS eyes had normal amplitude and delayed VEP latency, whereas ON-NMOSD eyes displayed reduced amplitude and preserved latency when elicited by checkerboard stimulus with large 1.5° checks. Under such conditions, VEP may help distinguish resolved MS-related ON from resolved NMOSD-related ON.
Monoallelic IDH1 R132H Mutation Mediates Glioma Cell Response to Anticancer Therapies via Induction of Senescence

Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G2–M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non–cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies. Implications: The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant–mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas.
Dosimetric evaluation of ovaries and pelvic bones associated with clinical outcomes in patients receiving total body irradiation with ovarian shielding

Abstract Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients’ ovaries were shielded with cylinder-type lead blocks. The dose–volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose–volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.
A biodegradable, mechanically tunable micro‐arc oxidation AZ91D‐based composite implant with calcium phosphate/chitosan coating promotes long‐term bone tissue regeneration

To reduce the biodegradable rate and develop the long‐term osteogenic ability of magnesium (Mg) alloy, we prepared a new biodegradable micro arc oxidation AZ91D‐based composite implant with calcium phosphate/chitosan coating (CaP‐CS/MAO/AZ91D) and investigated its mechanical property and long‐term bone tissue regeneration ability.
Treatment and Outcomes of Metastatic Pancreatic Cancer in Elderly Patients

Background and Aims: Although pancreatic cancers are common in older age-groups, the prognosis remains poor due to limited studies on treatment approaches and outcomes in a given population. We aimed to examine treatment patterns and their outcomes in older patients with metastatic pancreatic cancer in a real-world context. Materials and Methods: We conducted a retrospective study including 167 patients with metastatic pancreatic cancer (aged ≥70 years and male/female: 78/89) between January 2010 and July 2015. Patients’ retrieved data from medical records were analyzed according to treatment types, followed by a review of clinicopathologic variables and treatment outcomes. Results: Of the 167 eligible patients for the study, only 21.6% (n = 36) received palliative chemotherapy. The median age of the chemotherapy group was 74.0 years and 78.6 years for the supportive care group. The median survival of the chemotherapy group was 9.2 months (range: 1.0–24.9 months), compared with that of the supportive care group, which was 2.3 months (range: 0.1–31.8 months). Among the patients in the chemotherapy group, 50% (n = 18) received gemcitabine-based double therapy, and 30% patients (n = 9) received second-line chemotherapy. Conclusions: Our results showed that older patients with metastatic pancreatic cancer were less likely to receive chemotherapy. However, the survival benefit from chemotherapy was comparable to that of younger patients’ counterpart. Thus, further study involving identification of older patients who would benefit from cytotoxic chemotherapy is needed.
Perioperative Complications in Patients over 70 Years of Age following Simultaneous Bilateral Total Knee Arthroplasty

Abstract Single-stage bilateral total knee arthroplasty (ssBTKA) can be used for patients presenting with bilateral arthritis and may result in fewer systemic and wound complications compared with two, independent procedures. However, the safety of ssBTKA in the elderly remains controversial. Therefore, the purpose of this study was to compare early complications and transfusion rates following ssBTKA in patients ≤ 70 years old or > 70 years old. This retrospective chart review of 313 consecutive patients undergoing ssBTKA included 174 patients ≤ 70 years old and 139 patients > 70 years old. Perioperative variables and postoperative complications were compared with univariate analyses between age groups. Multivariate analyses were performed to determine risk factors for developing perioperative complications and transfusions. Compared with patients ≤ 70, patients > 70 had significantly lower body mass index (p < 0.001) and were more commonly female (p = 0.024). Although wound (p > 0.12) and systemic complications (p > 0.54) were similar, 23% of patients > 70 required transfusion compared with only 8% of patients ≤ 70 (p < 0.001). Patients with preoperative anemia (p < 0.001), age > 70 (p = 0.002), or diabetes mellitus (p = 0.007) were at 5.7, 3.3, and 2.9 times greater risk for requiring a transfusion, respectively. Patients > 70 undergoing ssBTKA have a similar complication profile to patients ≤ 70 years old, suggesting age should not be an absolute exclusion criterion for ssBTKA. However, the risk of transfusion was significantly higher in those > 70, despite lower tourniquet times. Treatment of preoperative anemia may decrease the risk of transfusion and could provide adequate safety for patients > 70 to undergo ssBTKA by an experienced surgeon.
Incidence and relevance of clinically indeterminate nonregional lymph nodes in the treatment of oesophageal cancer

Objectives Metastatic involvement of nonregional supraclavicular or superior mediastinal lymph nodes in distal oesophageal cancer is rare but has important implications for prognosis and management. The management of nonregional lymph nodes which appear indeterminate on CT and FDG PET-CT (subcentimeter nodes or those with preserved normal morphology, but increased FDG avidity) can present a diagnostic dilemma. This study investigates the incidence, work-up and clinical significance of nonregional clinically indeterminate FDG avid lymph nodes. Methods A single-centre retrospective review of all FDG PET-CT scans conducted over 5 years was conducted. Patients with mid- or distal oesophageal cancer with nonregional FDG avid nodes were identified. Subsequent work-up, management and outcomes were retrieved from electronic health records. Results Reports for 1189 PET-CT scans were reviewed. A total of 79 patients met the inclusion criteria. Of these, 18 (23%) were deemed to have disease and performance status potentially amenable to radical surgery and underwent further assessment. The indeterminate lymph nodes were successfully sampled via endobronchial ultrasound (EBUS) or ultrasound-guided fine-needle aspiration (US-FNA) in 100% of cases. 15/18 (83.3%) of samples were benign and proceeded to surgery. Outcomes for patients who proceeded to surgery were similar to other cohorts. None had pathology suggesting false-negative lymph node sampling. Conclusions EBUS and US-FNA are effective means of sampling clinically indeterminate nonregional lymph nodes, and can significantly impact prognosis, and management. Further investigations in this context are of value in this cohort and should be pursued. Nonregional clinically indeterminate lymph nodes represent a diagnostic dilemma in oesophageal cancer staging. Additional investigations in the form of endobronchial ultrasound are effective at providing additional staging information, and can substantially influence patient care.
The effect of vitamin B12 on synaptic plasticity of hippocampus in Alzheimer’s disease model rats

Abstract Background Hippocampus cells, responsible for learning and memory, are disturbed in Alzheimer’s disease (AD), resulting in production of several inflammatory markers, such as neurexin 1 –neuroligin, cyclooxygenase–2 (COX–2), and caspase–3 proteins, used in measurement of AD’s severity and development. Vitamin B12, which plays a role in brain functioning, has anti–inflammatory properties and its impairment is associated with apoptosis in Alzheimer’s disease. This study aimed to investigate the effect of vitamin B12 on restoration of Synaptic Plasticity on scopolamine–induced AD in rats. Methods To simulate AD, Rats, except the control group were i.p. injected with 3 mg/kg scopolamine. Before scopolamine the pretreatment group vitamin B12 (0.5, 2, and 4 mg/kg) was injected every day for the next 14 days. After 24 h, sectioning the rats’ brains, the concentration of postsynaptic density protein 95 (PSD–95), neurexin 1–neurolgin, COX–2, and caspase–3 proteins in hippocampus were measured using immunoblotting. Results B12 significantly enhanced molecular balance. PSD–95 and neurexin 1 and neuroligin concentrations were significantly reduced, whereas COX–2 and activated caspase–3 were enhanced in the hippocampus of scopolamine–injected subjects. Their alterations were decreased after B12 administration. Conclusions Vitamin B12 protected scopolamine–injected rats and inhibited hippocampal inflammation and apoptosis and preserved pre– and post–synaptic proteins and possibly synaptic integrity in hippocampus route.
Solving Two-Person Zero-Sum Stochastic Games With Incomplete Information Using Learning Automata With Artificial Barriers

Learning automata (LA) with artificially absorbing barriers was a completely new horizon of research in the 1980s (Oommen, 1986). These new machines yielded properties that were previously unknown. More recently, absorbing barriers have been introduced in continuous estimator algorithms so that the proofs could follow a martingale property, as opposed to monotonicity (Zhang et al., 2014), (Zhang et al., 2015). However, the applications of LA with artificial barriers are almost nonexistent. In that regard, this article is pioneering in that it provides effective and accurate solutions to an extremely complex application domain, namely that of solving two-person zero-sum stochastic games that are provided with incomplete information. LA have been previously used (Sastry et al., 1994) to design algorithms capable of converging to the game’s Nash equilibrium under limited information. Those algorithms have focused on the case where the saddle point of the game exists in a pure strategy. However, the majority of the LA algorithms used for games are absorbing in the probability simplex space, and thus, they converge to an exclusive choice of a single action. These LA are thus unable to converge to other mixed Nash equilibria when the game possesses no saddle point for a pure strategy. The pioneering contribution of this article is that we propose an LA solution that is able to converge to an optimal mixed Nash equilibrium even though there may be no saddle point when a pure strategy is invoked. The scheme, being of the linear reward-inaction ( $L_{R-I}$ ) paradigm, is in and of itself, absorbing. However, by incorporating artificial barriers, we prevent it from being “stuck” or getting absorbed in pure strategies. Unlike the linear reward- $\epsilon $ penalty ( $L_{R-\epsilon P}$ ) scheme proposed by Lakshmivarahan and Narendra almost four decades ago, our new scheme achieves the same goal with much less parameter tuning and in a more elegant manner. This article includes the nontrial proofs of the theoretical results characterizing our scheme and also contains experimental verification that confirms our theoretical findings.
The impact of amino acid dialysate on anthropometric measures in adult patients on peritoneal dialysis: A systematic review and meta-analysis

Background: Glucose-containing dialysate underpins peritoneal dialysis (PD) therapy. However, its use is associated with amino acid loss in the dialysis effluent, a risk factor for protein-energy wasting (PEW) in PD patients. Amino acid-based dialysis solutions (AAD) may ameliorate this loss. However, the evidence of clinical benefit in preventing PEW is unclear. The aim of this review was to assess the effect of AAD versus standard dialysis solutions (STD) on anthropometric measures and serum albumin. Methods: Studies up until 30 September 2020 were identified from databases including MEDLINE and Embase, using a prespecified protocol (PROSPERO – CRD42020209581). Studies evaluating adults on PD were included. Data pertaining to muscle mass (primary outcome), other anthropometric measures and serum albumin were extracted. A meta-analysis of the eligible studies was conducted. Results: A total of 6945 abstracts were reviewed, from which 14 studies (9 randomised and 5 non-randomised) were included. There was no significant difference in any of the anthropometric measures, between AAD and STD during follow-up. Serum albumin at 6 months was statistically lower with AAD compared to STD [mean difference = −0.89 (95%CI −1.77 to −0.01, p = 0.046)]. The quality of evidence was graded low for each outcome. Conclusions: AAD may not alter anthropometric measures when compared to STD. The impact on serum albumin is uncertain, with an estimated difference that is unlikely to be of clinical value. These findings should be cautiously interpreted due to low quality of the evidence. Robust studies are needed to address the limitations in evidence.
CPL207280, a Novel G Protein–Coupled Receptor 40/Free Fatty Acid Receptor 1–Specific Agonist, Shows a Favorable Safety Profile and Exerts Antidiabetic Effects in Type 2 Diabetic Animals

G protein–coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic β-cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca2+]i). Activation of GPR40 in pancreatic β-cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist—TAK-875 (fasiglifam)—was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca2+ influx assay with a human GPR40 protein (EC50 = 80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of glucose-stimulated insulin secretion in mouse MIN6 pancreatic β-cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5 times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47) and selectivity of CPL207280 (at 10 μM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment. SIGNIFICANCE STATEMENT GPR40 is a well-known and promising target for diabetes. This study is the first to show the safety and effects of CPL207280, a novel GPR40/free fatty acid receptor 1 agonist, on glucose homeostasis both in vitro and in vivo in different diabetic animal models. Therefore, we propose the CPL207280 compound as a novel, glucose-lowering agent, overcoming the unmet medical needs of patients with type 2 diabetes.
Eight weeks of mineralocorticoid blockade does not improve insulin sensitivity in type 2 diabetes

Individuals with type 2 diabetes have an increased risk of cardiovascular disease. A correlation between plasma aldosterone and hyperinsulinemia has been demonstrated in vivo, and hyperinsulinemia and insulin resistance are independently associated with the development of cardiovascular complications. We investigated if mineralocorticoid blockade (Eplerenone) improves insulin sensitivity in individuals with type 2 diabetes compared to healthy controls. We included 13 participants with type 2 diabetes (<5 years; male/female, Caucasians) and 10 healthy control participants (male/female, Caucasians). On 2 experimental days, before and at the end of the 8 weeks of treatment with mineralocorticoid blockade, a two‐stage hyperinsulinemic‐isoglycemic clamp (20 and 50 mU∙m−2min−1) was performed for the determination of insulin sensitivity. No change in insulin sensitivity was detected at the end of the mineralocorticoid blockade in the individuals with type 2 diabetes or the healthy controls. Both before and at the end of the treatment with mineralocorticoid blockade, the individuals with type 2 diabetes had a lower insulin sensitivity compared to healthy controls. In conclusion, mineralocorticoid receptor blockade does not appear to improve insulin sensitivity in individuals with type 2 diabetes.
Variations in oxidative stress and antioxidant defense level during different phases of hibernation in common Asian toad, Duttaphrynus melanostictus

ABSTRACT To assess redox status during hibernation with metabolic depression, oxidative stress parameters and antioxidant defense were assessed during different phases of hibernation including active period, hibernation, arousal, and post-arousal period, in the liver and brain tissues of Duttaphrynus melanostictus. We hypothesized low levels of oxidative stress and antioxidant defense during the hibernation period in comparison to the summer active period, due to hypometabolism and their subsequent increase during the arousal period following an increase in body temperature and metabolism. Contrary to our hypothesis, increased oxidative stress with significantly higher lipid peroxidation, protein carbonylation, oxidized glutathione (GSSG): glutathione (GSH) ratio, and elevated antioxidants defense consisting of higher catalase activity and high ascorbic acid content to control oxidative stress were found during hibernation. However, GSH and uric acid levels were found low with super oxide dismutase (SOD) activities at a steady level during hibernation. Supporting our hypothesis, increased oxidative stress with high lipid peroxidation and GSSG:GSH ratio were found during arousal from hibernation owing to increased oxygen consumption and rewarming. Augmented catalase and SOD activities and nonenzymatic antioxidants (GSH, ascorbic acid, and uric acid) level were found to counteract oxidative stress during arousal periods as it was expected. A steady level of protein carbonylation, indicating no oxidative damage during arousal from hibernation due to elevated antioxidant defense, shows the significance of hibernation to overcome food and water scarcity and cold climatic condition. Decrease in antioxidants levels accompanying coming down of lipid peroxidation, protein carbonylation, and GSSG:GSH ratio to their lower levels during the post-arousal period showing normalcy in redox status as it was during active period indicates controllability of oxidative stress in hibernating toads.