Heat-related illness and dementia: a study integrating epidemiological and experimental evidence.

BACKGROUND: Heat-related illness (HRI) is commonly considered an acute condition, and its potential long-term consequences are not well understood. We conducted a population-based cohort study and an animal experiment to evaluate whether HRI is associated with dementia later in life. METHODS: The Taiwan National Health Insurance Research Database was used in the epidemiological study. We identified newly diagnosed HRI patients between 2001 and 2015, but excluded those with any pre-existing dementia, as the study cohort. Through matching by age, sex, and the index date with the study cohort, we selected individuals without HRI and without any pre-existing dementia as a comparison cohort at a 1:4 ratio. We followed each cohort member until the end of 2018 and compared the risk between the two cohorts using Cox proportional hazards regression models. In the animal experiment, we used a rat model to assess cognitive functions and the histopathological changes in the hippocampus after a heat stroke event. RESULTS: In the epidemiological study, the study cohort consisted of 70,721 HRI patients and the comparison cohort consisted of 282,884 individuals without HRI. After adjusting for potential confounders, the HRI patients had a higher risk of dementia (adjusted hazard ratio [AHR] = 1.24; 95% confidence interval [CI]: 1.19-1.29). Patients with heat stroke had a higher risk of dementia compared with individuals without HRI (AHR = 1.26; 95% CI: 1.18-1.34). In the animal experiment, we found cognitive dysfunction evidenced by animal behavioral tests and observed remarkable neuronal damage, degeneration, apoptosis, and amyloid plaque deposition in the hippocampus after a heat stroke event. CONCLUSIONS: Our epidemiological study indicated that HRI elevated the risk of dementia. This finding was substantiated by the histopathological features observed in the hippocampus, along with the cognitive impairments detected, in the experimental heat stroke rat model.

Hypothyroidism following carbon monoxide poisoning: An epidemiological study supported by animal experiments.

Previous studies have suggested a possible association between carbon monoxide poisoning (COP) and hypothyroidism, but the evidence is limited. Therefore, the aim of this study was to further investigate this relationship. Using data from the Taiwan National Health Research Database, we identified 32,162 COP patients and matched with 96,486 non-COP patients by age and index date for an epidemiological study. The risk of hypothyroidism was compared between the two cohorts until 2018. Independent predictors of hypothyroidism were analyzed using competing risk analysis. An animal study was also conducted to support the findings. COP patients had an increased risk of hypothyroidism compared to non-COP patients in the overall analysis (adjusted hazard ratio [AHR]= 3.88; 95 % confidence interval [CI]: 3.27-4.60) and in stratified analyses by age, sex, and comorbidities. The increase in the overall risk persisted even after more than six years of follow-up (AHR= 4.19; 95 % CI: 3.18-5.53). Independent predictors of hypothyroidism, in addition to COP, included age ≥65 years, female sex, hyperlipidemia, and mental disorder. The animal study showed damages in the hypothalamus, pituitary gland, and thyroid, as well as altered hormone levels 28 days after COP exposure. The epidemiological results showed an increased risk of hypothyroidism in COP patients, which was further supported by the animal study. These findings suggest the need for close monitoring of thyroid function in COP patients, especially in those who are age ≥65 years, female, and have hyperlipidemia or mental disorder.

Neuroserpin normalization by mesenchymal stem cell therapy after encephalopathy of prematurity in neonatal rats.

BACKGROUND: Hypoxic-ischemia (HI), infection/inflammation and reperfusion injury are pathogenic factors of encephalopathy of prematurity, which involves maturational/neurotrophic disturbances in oligodendrocyte progenitor cells (OPC) and neurons/axons. Mesenchymal stem cells (MSCs) might facilitate neuroserpin production, which is neurotrophic for OPC/neurons. This study investigated MSC effects on developmental disturbances after lipopolysaccharide (LPS)-sensitized HI/reperfusion (LHIR) injury and the relation to neuroserpin expression. METHODS: Postnatal day 2 (P2) rat pups received intraperitoneal LPS (5 µg/kg) injection followed by HI (unilateral common-carotid-artery ligation and 6.5% oxygen exposure for 90 min) and post-HI reperfusion (release of ligation). MSCs (5 × 104 cells) were injected into the left lateral ventricle at 24 h post-LHIR. Neurological tests and brain tissue examinations were performed between P5 and P56. RESULTS: After LHIR injury, MSC therapy significantly reduced cell death in subplate neurons, attenuated axonal damage, and facilitated synaptophysin synthesis in the cortex. It also alleviated OPC maturation arrest and preserved the complexity of myelinated axons in the white matter, leading to cognitive, motor and behavioral functional improvements. These beneficial effects were linked to restored neuroserpin expression in subplate neurons. CONCLUSIONS: MSC therapy ameliorated developmental disturbances after LHIR injury through protection of neuroserpin expression, serving as a promising approach for treating encephalopathy of prematurity. IMPACT: Neuroserpin is secreted by subplate neurons and may regulate the development of neurons and oligodendrocyte-axon contact for myelination in the premature brain. LPS-sensitized hypoxic-ischemia/reperfusion (LHIR) injury caused the developmental disturbances of neurons/axons and oligodendrocytes, and lowered neuroserpin levels in a neonatal rat model simulating encephalopathy of prematurity. Mesenchymal stem cell therapy alleviated the developmental disturbances after LHIR injury through protection of neuroserpin expression in subplate neurons, offering a new perspective on potential treatment for encephalopathy of prematurity.

Thrombomodulin Improves Cognitive Deficits in Heat-Stressed Mice.

BACKGROUND: Thrombomodulin (TM) exerts anticoagulant and anti-inflammatory effects to improve the survival of patients with septic shock. Heat stroke resembles septic shock in many aspects. We tested whether TM would improve cognitive deficits and related causative factors in heat-stressed (HS) mice. METHODS: Adult male mice were exposed to HS (33°C for 2 hours daily for 7 consecutive days) to induce cognitive deficits. Recombinant human soluble TM (1 mg/kg, i.p.) was administered immediately after the first HS trial and then once daily for 7 consecutive days. We performed the Y-maze, novel objective recognition, and passive avoidance tests to evaluate cognitive function. Plasma levels of lipopolysaccharide (LPS), high-mobility group box 1 (HMGB1), coagulation parameters, and both plasma and tissue levels of inflammatory and oxidative stress markers were biochemically measured. The duodenum and hippocampus sections were immunohistochemically stained. The intestinal and blood-brain barrier permeability were determined. RESULTS: Compared with controls, HS mice treated with TM had lesser extents of cognitive deficits, exacerbated stress reactions, gut barrier disruption, endotoxemia, blood-brain barrier disruption, and inflammatory, oxidative, and coagulatory injury to heart, duodenum, and hippocampal tissues, and increased plasma HMGB1. In addition to reducing cognitive deficits, TM therapy alleviated all the abovementioned complications in heat-stressed mice. CONCLUSIONS: The findings suggest that HS can lead to exacerbated stress reactions, endotoxemia, gut barrier disruption, blood-brain barrier disruption, hippocampal inflammation, coagulopathy, and oxidative stress, which may act as causative factors for cognitive deficits. TM, an anti-inflammatory, antioxidant, and anti-coagulatory agent, inhibited heat stress-induced cognitive deficits in mice.

Mesenchymal stem cells reduce long-term cognitive deficits and attenuate myelin disintegration and microglia activation following repetitive traumatic brain injury.

The underlying mechanisms for the beneficial effects exerted by bone marrow-mesenchymal stem cells (BM-MSCs) in treating repetitive traumatic brain injury (rTBI)-induced long-term sensorimotor/cognitive impairments are not fully elucidated. Herein, we aimed to explore whether BM-MSCs therapy protects against rTBI-induced long-term neurobehavioral disorders in rats via normalizing white matter integrity and gray matter microglial response. Rats were subjected to repeated mild lateral fluid percussion on day 0 and day 3. On the fourth day post-surgery, MSCs groups received MSCs (4 × 106 cells/ml/kg, intravenously) and were assessed by the radial maze, Y maze, passive avoidance tests, and modified neurological severity scores. Hematoxylin & eosin, and Luxol fast blue stainings were used to examine the histopathology and white matter thickness. At the same time, immunofluorescence staining was used to investigate the numbers of tumor necrosis factor-alpha (TNF-α)-containing microglia in gray matter. Three to nine months after neurotrauma, rats displayed sensorimotor and cognitive impairments, reduced thickness in white matter, and over-accumulation of TNF-α-containing microglia and cellular damage in gray matter. Therapy with BM-MSCs significantly attenuated the rTBI-induced sensorimotor and cognitive impairments and all their complications. Mesenchymal stem cell therapy might accelerate the recovery of sensorimotor and cognitive impairments in rats with rTBI via normalizing myelin integrity and microglia response.

White and gray matter integrity evaluated by MRI-DTI can serve as noninvasive and reliable indicators of structural and functional alterations in chronic neurotrauma.

We aimed to evaluate whether white and gray matter microstructure changes observed with magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) can be used to reflect the progression of chronic brain trauma. The MRI-DTI parameters, neuropathologic changes, and behavioral performance of adult male Wistar rats that underwent moderate (2.1 atm on day "0") or repeated mild (1.5 atm on days "0" and "2") traumatic brain injury (TBI or rmTBI) or sham operation were evaluated at 7 days, 14 days, and 1-9 months after surgery. Neurobehavioral tests showed that TBI causes long-term motor, cognitive and neurological deficits, whereas rmTBI results in more significant deficits in these paradigms. Both histology and MRI show that rmTBI causes more significant changes in brain lesion volumes than TBI. In vivo DTI further reveals that TBI and rmTBI cause persistent microstructural changes in white matter tracts (such as the body of the corpus callosum, splenium of corpus callus, internal capsule and/or angular bundle) of both two hemispheres. Luxol fast blue measurements reveal similar myelin loss (as well as reduction in white matter thickness) in ipsilateral and contralateral hemispheres as observed by DTI analysis in injured rats. These data indicate that the disintegration of microstructural changes in white and gray matter parameters analyzed by MRI-DTI can serve as noninvasive and reliable markers of structural and functional level alterations in chronic TBI.

Hyperbaric oxygen preconditioning normalizes scrotal temperature, sperm quality, testicular structure, and erectile function in adult male rats subjected to exertional heat injury.

Testicular hyperthermia has been noted in men who work in high ambient temperatures. Scrotal temperatures above the normal range caused germ cell loss in the testes and resulted in male subfertility. In adult male rats, exercising at a higher environmental temperature (36 °C with relative humidity of 50%, 52 min) caused exertional heat stroke (EHS) characterized by scrotal hyperthermia, impaired sperm quality, dysmorphology in testes, prostates and bladders, and erectile dysfunction. Here, we aim to ascertain whether hyperbaric oxygen preconditioning (HBOP: 100% O2 at 2.0 atm absolute [ATA] for 2 h daily for 14 days consequently before the onset of EHS) is able to prevent the problem of EHS-induced sterility, testes, prostates, and bladders dysmorphology and erectile dysfunction. At the end of exertional heat stress compared to normobaric air (NBA or non-HBOP) rats, the HBOP rats exhibited lower body core temperature (40 °C vs. 43 °C), lower scrotal temperature (34 °C vs. 36 °C), lower neurological severity scores (2.8 vs. 5.8), higher erectile ability, (5984 mmHg-sec vs. 3788 mmHg-sec), higher plasma testosterone (6.8 ng/mL vs. 3.5 ng/mL), lower plasma follicle stimulating hormone (196.3 mIU/mL vs. 513.8 mIU/mL), lower plasma luteinizing hormone (131 IU/L vs. 189 IU/L), lower plasma adrenocorticotropic hormone (5136 pg/mL vs. 6129 pg/mL), lower plasma corticosterone (0.56 ng/mL vs. 1.18 ng/mL), lower sperm loss and lower values of histopathological scores for epididymis, testis, seminal vesicle, prostate, and bladder. Our data suggest that HBOP reduces body core and scrotal hyperthermia and improves sperm loss, testis/prostate/bladder dysmorphology, and erectile dysfunction after EHS in rats.

Effect of stress on the rehabilitation performance of rats with repetitive mild fluid percussion-induced traumatic brain injuries.

Animal models of traumatic brain injury (TBI) have shown that impaired motor and cognitive function can be improved by physical exercise. However, not each animal with TBI can be well rehabilitated at the same training intensity due to a high inter-subject variability. Hence, this paper presents a two-stage wheel-based mixed-mode rehabilitation mechanism by which the effect of stress on the rehabilitation performance was investigated. The mixed-mode rehabilitation mechanism consists of a two-week adaptive and a one-week voluntary rehabilitation program as Stages 1 and 2, respectively. In Stage 1, the common over and undertraining problem were completely resolved due to the adaptive design, and rats ran voluntarily over a 30-min duration in Stage 2. The training intensity adapted to the physical condition of all the TBI rats at all times in Stage 1, and then the self-motivated running rats were further rehabilitated under the lowest level of stress in Stage 2. For comparison purposes, another group of rats took a 3-week adaptive rehabilitation program. During the 3-week program, the rehabilitation performance of the rats were assessed using modified neurologic severity score (mNSS) and an 8-arm radial maze. Surprisingly, the group taking the mixed mode program turned out to outperform its counterpart in terms of mNSS. The mixed-mode rehabilitation mechanism was validated as an effective and efficient way to help rats restore motor, neurological and cognitive function after TBI. It was validated that the rehabilitation performance can be optimized under the lowest level of stress.

Hyperbaric oxygen therapy suppresses hypoxia and reoxygenation injury to retinal pigment epithelial cells through activating peroxisome proliferator activator receptor-alpha signalling.

Retinal ischemia followed by reperfusion (IR) is a common cause of many ocular disorders, such as age-related macular degeneration (AMD), which leads to blindness in the elderly population, and proper therapies remain unavailable. Retinal pigment epithelial (RPE) cell death is a hallmark of AMD. Hyperbaric oxygen (HBO) therapy can improve IR tissue survival by inducing ischemic preconditioning responses. We conducted an in vitro study to examine the effects of HBO preconditioning on oxygen-glucose deprivation (OGD)-induced IR-injured RPE cells. RPE cells were treated with HBO (100% O2 at 3 atmospheres absolute for 90 min) once a day for three consecutive days before retinal IR onset. Compared with normal cells, the IR-injured RPE cells had lower cell viability, lower peroxisome proliferator activator receptor-alpha (PPAR-α) expression, more severe oxidation status, higher blood-retinal barrier disruption and more elevated apoptosis and autophagy rates. HBO preconditioning increased PPAR-α expression, improved cell viability, decreased oxidative stress, blood-retinal barrier disruption and cellular apoptosis and autophagy. A specific PPAR-α antagonist, GW6471, antagonized all the protective effects of HBO preconditioning in IR-injured RPE cells. Combining these observations, HBO therapy can reverse OGD-induced RPE cell injury by activating PPAR-α signalling.

Myocardial structure and functional alterations in a preclinical model of exertional heat stroke.

AIM: Relatively little information is available about the effect of an acute exertional heat stroke (EHS) on myocardium structure and function. Herein, we used a survival male rat model of EHS to answer the question. MAIN METHODS: Adult male Wistar rats underwent forced treadmill running at a 36 °C room temperature and 50 % relative humidity until EHS onset, characterized by hyperthermia and collapse. All rats that were followed for 14 days survived. Injury severity scores of both gastrocnemius and myocardium were determined histologically. Following an EHS event, pathological echocardiography, skeletal muscle and myocardial damage scores and indicators, myocardial fibrosis, hypertrophy, and autophagy were elucidated. KEY FINDINGS: Rats with EHS onset displayed skeletal muscle damage, elevated serum levels of skeletal muscle damage indicators (e.g., creatinine kinase, myoglobin, and potassium), and myocardial injury indicators (e.g., cardiac troponin I, creatinine kinase, and lactate dehydrogenase) returning to homeostasis within 3 days post-EHS. However, EHS-induced myocardial damage, pathological echocardiography, myocardial fibrosis, hypertrophy, and deposited misfolded proteins lasted up to 14 days post-EHS at least. SIGNIFICANCE: First, we provide evidence to confirm that despite the apparent return to homeostasis, underlying processes may still be ongoing after EHS onset. Second, we provide several key findings emphasizing the pathophysiology and risk factors of EHS, highlighting gaps in knowledge with the aim of stimulating future studies.

Rat Hair Metabolomics Analysis Reveals Perturbations of Unsaturated Fatty Acid Biosynthesis, Phenylalanine, and Arachidonic Acid Metabolism Pathways Are Associated with Amyloid-ß-Induced Cognitive Deficits.

Hair is a noninvasive valuable biospecimen for the long-term assessment of endogenous metabolic disturbance. Whether the hair is suitable for identifying biomarkers of the Alzheimer's disease (AD) process remains unknown. We aim to investigate the metabolism changes in hair after ß-amyloid (Aß1-42) exposure in rats using ultra-high-performance liquid chromatography-high-resolution mass spectrometry-based untargeted and targeted methods. Thirty-five days after Aß1-42 induction, rats displayed significant cognitive deficits, and forty metabolites were changed, of which twenty belonged to three perturbed pathways: (1) phenylalanine metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis-L-phenylalanine, phenylpyruvate, ortho-hydroxyphenylacetic acid, and phenyllactic acid are up-regulated; (2) arachidonic acid (ARA) metabolism-leukotriene B4 (LTB4), arachidonyl carnitine, and 5(S)-HPETE are upregulation, but ARA, 14,15-DiHETrE, 5(S)-HETE, and PGB2 are opposite; and (3) unsaturated fatty acid biosynthesis- eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), FA 18:3 + 1O, and FA 18:3 + 2O are downregulated. Linoleic acid metabolism belonging to the biosynthesis of unsaturated fatty acid includes the upregulation of 8-hydroxy-9,10-epoxystearic acid, 13-oxoODE, and FA 18:2 + 4O, and downregulation of 9(S)-HPODE and dihomo-γ-linolenic acid. In addition, cortisone and dehydroepiandrosterone belonging to steroid hormone biosynthesis are upregulated. These three perturbed metabolic pathways also correlate with cognitive impairment after Aß1-42 stimulation. Furthermore, ARA, DHA, EPA, L-phenylalanine, and cortisone have been previously implicated in the cerebrospinal fluid of AD patients and show a similar changing trend in Aß1-42 rats' hair. These data suggest hair can be a useful biospecimen that well reflects the expression of non-polar molecules under Aß1-42 stimulation, and the five metabolites have the potential to serve as novel AD biomarkers.

CDCP1 (CUB domain containing protein 1) is a potential urine-based biomarker in the diagnosis of low-grade urothelial carcinoma.

Urine-based cytology is non-invasive and widely used for clinical diagnosis of urothelial carcinoma (UC), but its sensitivity is less than 40% for low-grade UC detection. As such, there is a need for new diagnostic and prognostic biomarkers of UC. CUB domain containing protein 1 (CDCP1) is a type I transmembrane glycoprotein highly expressed in various cancers. Using tissue array analysis, we demonstrated that CDCP1 expression in UC patients (n = 133), especially in those with low-grade UC, was significantly higher than in 16 normal persons. In addition, CDCP1 expression in urinary UC cells could also be detected by using immunocytochemistry method (n = 11). Furthermore, in 5637-CD cells, overexpression of CDCP1 affected the expression of epithelial mesenchymal transition-related markers and increased matrix metalloproteinase 2 expression and migration ability. Conversely, the knockdown of CDCP1 in T24 cells had the opposite effects. Using specific inhibitors, we demonstrated the involvement of c-Src/PKCδ signaling in the CDCP1-regulated migration of UC. In conclusion, our data suggest that CDCP1 contributes to the malignant progression of UC and may have the potential as a urine-based biomarker for detecting low-grade UC. However, a cohort study needs to be conducted.

Recovery of neurosurgical high-frequency electroporation injury in the canine brain can be accelerated by 7,8-dihydroxyflavone.

BACKGROUND: Although traumatic brain injury (TBI) occurs in a very short time, the biological consequence of a TBI, such as Alzheimer's disease, may last a lifetime. To date, effective interventions are not available to improve recovery from a TBI. Herein we aimed to ascertain whether recovery of neurosurgical high-frequency irreversible electroporation (HFIRE) injury in brain tissues can be accelerated by 7,8-dihydroxyflavone (7,8-DHF). METHODS: The HFIRE injury was induced in the right parietal cortex of 8 adult healthy and neurologically intact male dogs. Two weeks before HFIRE injury, each dog was administered orally with or without 7,8-DHF (30 mg/kg) once daily for consecutive 2 weeks (n = 4 for each group). The values of blood-brain barrier (BBB) disruption, brain edema, and cerebral infarction volumes were measured. The concentrations of beta-amyloid, interleukin-1ß, interleukin-6 and tumor necrosis factor-α in the cerebrospinal fluid were measured biochemically. RESULTS: The BBB disruption, brain edema, infarction volumes, and maximal cross-section area caused by HFIRE injury in canine brain were significantly attenuated by 7,8-DHF therapy (P < 0.0001). Additionally, 7,8-DHF significantly reduced the HFIRE-induced cerebral overproduction of beta-amyloid and proinflammatory cytokines in the cerebrospinal fluid (P < 0.0001) in dogs with HFIRE. CONCLUSIONS: Recovery of neurosurgical HFIRE injury in canine brain tissues can be accelerated by 7,8-DHT via ameliorating BBB disruption as well as cerebral overproduction of both beta-amyloid and proinflammatory cytokines.

The interrelationships between neuronal viability, synaptic integrity, microglial responses, and amyloid-beta formation in an in vitro neurotrauma model.

The interrelationships between neuronal viability, synaptic integrity, and microglial responses remain in infancy. In dealing with the question, we induced a stretch injury to evaluate the mechanical effects of trauma on rat primary cortical neurons and BV2 microglial cells in a transwell culture system. The viability of primary neurons and BV2 cells was determined by MTT. Synaptic integrity was evaluated by determining the expression of beta-secretase 1 (BACE1), amyloid-beta (Aß), microtubule-associated protein 2 (MAP2), and synaptophysin (vehicle protein). Both CD16/32-positive (CD16/32+) and CD206-positive (CD206+) microglia cells were detected by immunofluorescence staining. The phagocytic ability of the BV2 cells was determined using pHrodo E. coli BioParticles conjugates and flow cytometry. We found that stretch injury BV2 cells caused reduced viability and synaptic abnormalities characterized by Aß accumulation and reductions of BACE1, MAP2, and synaptophysin in primary neurons. Intact BV2 cells exhibited normal phagocytic ability and were predominantly CD206+ microglia cells, whereas the injured BV2 cells exhibited reduced phagocytic ability and were predominantly CD16/32+ microglial cells. Like a stretch injury, the injured BV2 cells can cause both reduced viability and synaptic abnormalities in primary neurons; intact BV2 cells, when cocultured with primary neurons, can protect against the stretch-injured-induced reduced viability and synaptic abnormalities in primary neurons. We conclude that CD206+ and CD16/32+ BV-2 cells can produce neuroprotective and cytotoxic effects on primary cortical neurons.

Uncovering the Inhibitory Molecular Mechanism of Pomegranate Peel to Urinary Bladder Urothelial Carcinoma Using Proteomics Techniques.

Pomegranate (Punica granatum L.) fruit demonstrates the repressive effectiveness of many tumors. Our previous studies showed that the PEP (pomegranate peel extract) E2 fraction obtained from the ethyl acetate layer of the pomegranate peel's ethanol extract exhibited the highest inhibitory activities to induce Urinary bladder urothelial carcinoma (UBUC) cell apoptosis. The ethyl acetate layer could lower the volume and weight of T24 tumors and initiate apoptosis in nude mice xenografted bladder tumors. In this study, we intended to clarify the inhibitory molecular process of Taiwanese local pomegranate peel to urinary bladder urothelial carcinoma using a proteomics strategy. Gel-based proteomics (two-dimensional gel electrophoresis coupled with tandem mass spectrometry) was used to get an insight into the molecular mechanisms initiated by PEPE2 to evoke bladder cancer cell apoptosis. We found eleven down-regulated and eight up-regulated proteins in PEPE2-treated T24 cells. Our results implied that these PEPE2-dysregulated proteins belong to cell apoptosis, cell proliferation, death receptor signaling, JAK/STAT signaling, the PPAR pathway, the PPARα/RXR α pathway, Rho family GTPase signaling, and RhoGDI signaling. In addition, HSP90 and PTP1B proteins, associated with apoptosis, were de-regulated in xenografted bladder tumors in nude mice fed with an ethyl acetate layer of ethanol extract. The findings above implied that pomegranate might be a potential chemopreventive resource for UBUC carcinogenesis.

Risks of Developing Diabetes and Hyperglycemic Crisis Following Carbon Monoxide Poisoning: A Study Incorporating Epidemiologic Analysis and Animal Experiment.

Purpose: Carbon monoxide (CO) poisoning may damage the pancreas, but the effects of CO poisoning on the development of diabetes and on existing diabetes remain unclear. We conducted a study incorporating data from epidemiologic analyses and animal experiments to clarify these issues. Methods: Using the National Health Insurance Database of Taiwan, we identified CO poisoning patients diagnosed between 2002 and 2016 (CO poisoning cohort) together with references without CO poisoning who were matched by age, sex, and index date at a 1:3 ratio. We followed participants until 2017 and compared the risks of diabetes and hyperglycemic crisis between two cohorts using Cox proportional hazards regressions. In addition, a rat model was used to assess glucose and insulin levels in blood as well as pathological changes in the pancreas and hypothalamus following CO poisoning. Results: Among participants without diabetes history, 29,141 in the CO poisoning cohort had a higher risk for developing diabetes than the 87,423 in the comparison cohort after adjusting for potential confounders (adjusted hazard ratio [AHR]=1.23; 95% confidence interval [CI]: 1.18-1.28). Among participants with diabetes history, 2302 in the CO poisoning cohort had a higher risk for developing hyperglycemic crisis than the 6906 in participants without CO poisoning (AHR = 2.12; 95% CI: 1.52-2.96). In the rat model, CO poisoning led to increased glucose and decreased insulin in blood and damages to pancreas and hypothalamus. Conclusion: Our epidemiological study revealed that CO poisoning increased the risks of diabetes and hyperglycemic crisis, which might be attributable to damages in the pancreas and hypothalamus as shown in the animal experiments.

Exercise Rehabilitation and/or Astragaloside Attenuate Amyloid-beta Pathology by Reversing BDNF/TrkB Signaling Deficits and Mitochondrial Dysfunction.

We aim to investigate the mechanisms underlying the beneficial effects of exercise rehabilitation (ER) and/or astragaloside (AST) in counteracting amyloid-beta (Aß) pathology. Aß oligomers were microinjected into the bilateral ventricles to induce Aß neuropathology in rats. Neurobehavioral functions were evaluated. Cortical and hippocampal expressions of both BDNF/TrkB and cathepsin D were determined by the western blotting method. The rat primary cultured cortical neurons were incubated with BDNF and/or AST and ANA12 followed by exposure to aggregated Aß for 24 h. In vivo results showed that ER and/or AST reversed neurobehavioral disorders, downregulation of cortical and hippocampal expression of both BDNF/TrkB and cathepsin D, neural pathology, Aß accumulation, and altered microglial polarization caused by Aß. In vitro studies also confirmed that topical application of BDNF and/or AST reversed the Aß-induced cytotoxicity, apoptosis, mitochondrial distress, and synaptotoxicity and decreased expression of p-TrkB, p-Akt, p-GSK3ß, and ß-catenin in rat cortical neurons. The beneficial effects of combined ER (or BDNF) and AST therapy in vivo and in vitro were superior to ER (or BDNF) or AST alone. Furthermore, we observed that any gains from ER (or BDNF) and/or AST could be significantly eliminated by ANA-12, a potent BDNF/TrkB antagonist. These results indicate that whereas ER (or BDNF) and/or AST attenuate Aß pathology by reversing BDNF/TrkB signaling deficits and mitochondrial dysfunction, combining these two potentiates each other's therapeutic effects. In particular, AST can be an alternative therapy to replace ER.

Effects of Micro-Arc Oxidation Discharge Parameters on Formation and Biomedical Properties of Hydroxyapatite-Containing Flower-like Structure Coatings.

The micro-arc oxidation (MAO) process was used to prepare hydroxyapatite-containing flower-like structure coatings on commercially pure titanium substrates with various values of the applied voltage (330, 390, 450 V), applied current (0.4, 0.5, 0.6 A), and duration time (1, 3, 5 min). It was found that the surface morphology of the coatings was determined primarily by the applied voltage. A voltage of 330 V yielded a flower-like/plate-like structure, while voltages of 390 V and 450 V produced a flower-like structure and a porous morphology, respectively. The applied current and duration time mainly affected the coating formation speed and petal size of the flower-like structures, respectively. The coatings prepared using voltages of 330 V and 390 V (0.6 A, 5 min) both contained Ti, TiO2-A (anatase), TiO2-R (rutile), DCPD (CaHPO4·2H2O, calcium hydrogen phosphate), and hydroxyapatite (HA). However, the latter coating contained less DCPD and had a higher HA/DCPD ratio and a Ca/P ratio closer to the ideal value of HA. The coating prepared with a voltage of 450 V consisted mainly of Ti, TiO2-A, TiO2-R, and CaTiO3. For the coatings prepared with a voltage of 390 V, the flower-like structures consisted mainly of HA-containing compounds. DCPD plate-like structures were observed either between the HA-containing flower-like structures (330 V samples) or within the flower-like structures themselves (390 V samples). The coating surfaces with flower-like/plate-like or flower-like structures had a greater roughness, which increased their hydrophilicity and resulted in superior bioactivity (SBF immersion) and biocompatibility (MG-63 cell culture). The optimal biomedical performance was found in the 390 V coating due to its flower-like structure and high HA/DCPD ratio.

A robust bitmap-based real-time position tracking algorithm for rats in radial arm maze tests.

This paper aims to develop a position tracking algorithm by which a rat in a radial arm maze can be accurately located in real time. An infrared (IR) night-vision camera was hung above the maze to capture IR images of the rat. The IR images were binarized and then duplicated for subsequent intersection and opening operations. Due to simple operations and a high robustness against the noise spots formed by the droppings of the rat, it took just minutes to process more than 9000 frames, and an accuracy above 99% was reached as well. The maze was intruded by an experimenter to further test the robustness, and the accuracy slightly fell to 98%. For comparison purposes, the same experiments were carried out using a pre-trained YOLO v2 model. The YOLO counterpart gave an accuracy beyond 97% in the absence and in the presence of the intruder. In other words, this work slightly outperformed the YOLO counterpart in terms of the accuracy in both cases, which indicates the robustness of this work. However, it took the YOLO counterpart an hour or so to locate a rat contained in the frames, which highlights the contribution of this work.