The neuroprotective effects of oxygen therapy in Alzheimer’s disease:a narrative review

Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Beneficial effects of protocatechuic acid on diabetic retinopathy in streptozocin-induced diabetic rats

·AIM:To determine the effects of protocatechuic acid(PCA)on streptozocin-induced diabetic retinopathy(DR)in rats.·METHODS:Wistar rats were given a 50 mg/kg intraperitoneal injection of streptozocin to induce diabetes.Animals were assigned randomly one of four groups(8 rats per group):control,diabetic,diabetic plus PCA(25 mg/kg·d),and diabetic plus PCA(50 mg/kg·d).After inducing diabetes,treatments were started one week later and continued for eight weeks.After the experiment,the rats were sacrificed,and their retinas were taken for biochemical and molecular analysis.·RESULTS:PCA administration diminished the blood glucose and glycated haemoglobin levels relative to the diabetic group.In diabetic rats,PCA lowered elevated levels of advanced glycosylated end products(AGEs)and receptor for AGEs(RAGE).In the retina of diabetic rats,PCA effectively decreased inflammatory cytokine,nuclear factor-κB,tumour necrosis factor-α,interleukin-1β,and vascular endothelial growth factor,and increased antioxidant markers glutathione,superoxide dismutase,and catalase.·CONCLUSION:The protective benefits of PCA against DR may be attributable to its suppression of the AGEs and RAGE and its antioxidant and anti-inflammatory properties.

Analysis of the personalized treatment and the relevant prognostic factors in children with medulloblastoma

Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.

What we know about axons in Parkinson’s disease

Tremendous research efforts have been made regarding the pathogenesis of Parkinson’s disease(PD).However,there are still no effective strategies to restore midbrain dopaminergic(mDA)innervation and prevent disease progression.One possibility is that we may have been neglecting the role of axons in mDA neuronal degeneration.This review first summarizes mDA axon development during the early stage of PD and discusses how axon guidance defects contribute to PD vulnerability.Furthermore,we review axonal transport dysregulation in the numerous PD-related genetic mutations,including Parkin,PINK1,DJ1,LRRK2 and SNCA.The evidence suggests that proper axonal transport is crucial for neuronal function and survival.Finally,advanced tools for axonal studies were evaluated,including light-sheet and super-resolution microscopy.These adapted microscopes have been used to help solve questions unanswered before.Overall,the role of axon terminals in the initiation of the degeneration cascade remains undeciphered,and more research in the related area may be conducted further to restore dopamine levels in the striatum to alleviate the motor complications of PD.

Association between Helicobacter pylori infection and food-specific immunoglobulin G in Southwest China

BACKGROUND Helicobacter pylori(H.pylori)has been found to be associated with extragastrointestinal diseases,possibly including adverse food reactions(such as food allergy or intolerance).However,there are few studies on H.pylori and food allergy or intolerance,and the results are inconsistent.Food-specific immunoglobulin(Ig)G has been revealed to be associated with food allergy or intolerance and can be used as a marker to explore the correlation between H.pylori infection and food allergy or intolerance.AIM To explore the relationship between H.pylori infection and food-specific IgG METHODS We retrospectively analyzed the physical examination data of 21822 subjects from February 2014 to December 2018 in this study.H.pylori infection was detected using the 13C urea breath test.Food-specific IgG of eggs,milk and wheat in serum was assessed.Subjects were grouped according to H.pylori positivity,and the positive rates of three kinds of food-specific IgG were compared between the two groups.Multivariable logistic regression analysis was performed to elucidate the association between H.pylori infection and food-specific IgG.RESULTS The total infection rate of H.pylori was 39.3%,and the total food-specific IgGpositive rates of eggs,milk and wheat were 25.2%,9.0%and 4.9%,respectively.The infection rate of H.pylori was higher in males than in females,while the positive rates of food-specific IgG were lower in males than in females.The positive rates of food-specific IgG decreased with age in both males and females.In the H.pylori-positive groups,the positive rates of food-specific IgG of eggs,milk and wheat were all lower than those in the H.pylori-negative groups.Multivariate logistic regression analysis revealed that H.pylori infection was negatively correlated with the food-specific IgG-positive rates of eggs,milk and wheat(odds ratio value of eggs 0.844-0.873,milk 0.741-0.751 and wheat 0.755-0.788,in different models).CONCLUSION H.pylori infection was found to be negatively associated with the food-specific IgG of eggs,milk and wheat in Southwest China.

Parabiosis modeling:protocol,application and perspectives

Parabiosis is a surgical method of animal modeling with a long history.It has been widely used in medical research,particularly in the fields of aging,stem cells,neuroscience,and immunity in the past two decades.The protocols for parabiosis have been improved many times and are now widely accepted.However,researchers need to consider many details,from surgical operation to perioperative management,to reduce mortality and maintain the parabiosis union.Although parabiosis has certain inevitable limitations,it still has broad application prospects as an irreplaceable animal model in the medical research field.

A selective inhibitor of OMA1 and targeted delivery system for the treatment of acute myocardial infarction

The rescue of dying cardiomyocytes in penumbra within 4 hours is the best way to preserve cardiac function in acute myocardial infarction(AMI).Mitochondrial fission contributes to mitochondrial energy supply deficiency and cardiomyocytes death,and OMA1 promotes mitochondrial fission.Accurate targeting of OMA1 inhibition is important for the treatment of myocardial infarction.Here,a selective inhibitor of OMA1,UNC-R,was firstly described,which could protect the cardiomyocytes through mitochondrial fission inhibition.Moreover,the accurately targeted microsphere was designed,and loaded the UNC-R to form the POMU,which could avoid the phagocytosis of phagocytes in blood,precisely accumulated in the ischemic area,further target the dying cardiomyocytes.

Recent research progress on small molecule compounds and its derivatives of antiparasitic drugs

Neglected tropical diseases(NTDs)refer to infectious diseases caused by multiple pathogens that are prevalent in hot,humid climates in tropical areas.With the global economic growth and the improvement of public health status,eliminating neglected tropical diseases will be of great significance to the healthy development of human beings.However,the number of drugs and vaccines for NTDs treatment is extremely limited,so it is urgent to develop new drugs.Since most NTDs are caused by parasites,this paper selected parasitic diseases with high morbidity and mortality,and focused on new effective therapeutic targets and excellent lead compounds for these diseases.Schistosomiasis,human African trypanosomiasis(HAT),Chagas disease,leishmaniasis,filariasis and toxoplasmosis correspond to a series targets such as smHDAC8,thioredoxin glutathione reductase(TGR),T.cruzi glucokinase(TcGlcK),phosphofructokinase(PFK),type IB topoisomerase,cell division cycle-2-related Kinase,sterolmethyl transferase,calumenin,dihydrofolate reductase(DHFR)and Toxoplasma gondii farnesyl-diphosphate synthase(TgFPPs).In this paper,the pharmacological effects of typical lead compounds corresponding to each disease,the structural characteristics of the mother nucleus and the pharmacological activities of the substituent.In addition,the binding patterns of some involved targets(such as smHDAC8)with corresponding lead compounds(such as compound 13)and the signaling pathways associated with gluconeogenesis,glycolysis,and pentose phosphate pathways are analyzed in detail.In this paper,the interaction mechanism between the lead compounds and the target were thoroughly discussed,in order to provide the research ideas of potential anti-parasite compounds,and further improve the understanding and prevention ability of such diseases of NTDs.

Progress on early diagnosing Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder that affects both cognition and non-cognition functions.The disease follows a continuum,starting with preclinical stages,progressing to mild cognitive and behavioral impairment,ultimately leading to dementia.Early detection of AD is crucial for better diagnosis and more effective treatment.However,the current AD diagnostic tests of biomarkers using cerebrospinal fluid and/or brain imaging are invasive or expensive,and mostly are still not able to detect early disease state.Consequently,there is an urgent need to develop new diagnostic techniques with higher sensitivity and specificity during the preclinical stages of AD.Various non-cognitive manifestations,including behavioral abnormalities,sleep disturbances,sensory dysfunctions,and physical changes,have been observed in the preclinical AD stage before occurrence of notable cognitive decline.Recent research advances have identified several biofluid biomarkers as early indicators of AD.This review focuses on these non-cognitive changes and newly discovered biomarkers in AD,specifically addressing the preclinical stages of the disease.Furthermore,it is of importance to explore the potential for developing a predictive system or network to forecast disease onset and progression at the early stage of AD.

Current Alzheimer disease research highlights: evidence for novel risk factors

Alzheimer disease(AD)is the most common type of dementia characterized by the progressive cognitive and social decline.Clinical drug targets have heavily focused on the amyloid hypothesis,with amyloid beta(Aβ),and tau proteins as key pathophysiologic markers of AD.However,no effective treatment has been developed so far,which prompts researchers to focus on other aspects of AD beyond Aβ,and tau proteins.Additionally,there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous.In the past decades,new risk factors or potential etiologies have been widely studied.Here,we review several novel epidemiologic and clinical research developments that focus on sleep,hypoxia,diet,gut microbiota,and hearing impairment and their links to AD published in recent years.At the frontiers of AD research,these findings and updates could be worthy of further attention.

Imaging Findings of Hepatic Ewing’s Sarcoma on Computed Tomography and Gadobenate Dimeglumine-enhanced Magnetic Resonance Imaging: A Case Report and Literature Review

Ewing’s sarcoma(ES)is a tumor that often occurs in the long bones and rarely arises from visceral organs primarily.Here,we report a case of primary hepatic ES,discuss its computed tomography(CT)and gadobenate dimeglumineenhanced magnetic resonance(MRI)features.This is the first Chinese and fifth primary hepatic ES case reported,based on a literature review.Imaging examinations showed that the tumor was solid,with necrosis and hemorrhage.Contrast-enhanced images showed that the tumor was hypervascular and especially had heterogeneous signal intensity on hepatobiliary phase MRI images.Intratumoral vessels and vascular invasion were also present.

Evaluation of FGF10 as a candidate gene for high myopia in a Han Chinese population

Background:Fibroblast growth factor 10(FGF10)is implicated in the growth and development of the eye.Four singles nucleotide polymorphisms(SNPs)in the FGF10 gene(including rs1384449,rs339501,rs12517396 and rs10462070)were found to be associated with extreme myopia(EM,refractive error≤−10.0 diopters)in Japanese and Chinese Taiwan population.This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population.Methods:A total of 869 high myopia patients(HM,including 485 EM patients)and 899 healthy controls were recruited.These four SNPs were genotyped using the ABI SNaPshot method.Five genetic models(allelic,homozygous,heterozygous,dominant,and recessive)were applied to further evaluate the possible correlation between the SNPs and high myopia.The linkage-disequilibrium block(LD)structure was tested by Haploview Software.Results:In our study,no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction(P>0.05)in the allele frequencies of these four SNPs in the FGF10 gene.We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC+CC and rs10462070GA+AA carriers(P=0.045,OR=0.366;P=0.021,OR=0.131;P=0.03,OR=0.341;P=0.015,OR=0.122;respectively).Additionally,rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers(P=0.048,OR=0.370;P=0.023,OR=0.133;P=0.032,OR=0.346;P=0.017,OR=0.126).However,these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction(P>0.05).Conclusion:Our findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM.The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population.Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

A structure-supporting,self-healing,and high permeating hydrogel bioink for establishment of diverse homogeneous tissue-like constructs

The ready-to-use,structure-supporting hydrogel bioink can shorten the time for ink preparation,ensure cell dispersion,and maintain the preset shape/microstructure without additional assistance during printing.Meanwhile,ink with high permeability might facilitate uniform cell growth in biological constructs,which is beneficial to homogeneous tissue repair.Unfortunately,current bioinks are hard to meet these requirements simultaneously in a simple way.Here,based on the fast dynamic crosslinking of aldehyde hyaluronic acid(AHA)/N-carboxymethyl chitosan(CMC)and the slow stable crosslinking of gelatin(GEL)/4-arm poly(ethylene glycol)succinimidyl glutarate(PEG-SG),we present a time-sharing structure-supporting(TSHSP)hydrogel bioink with high permeability,containing 1%AHA,0.75%CMC,1%GEL and 0.5%PEG-SG.The TSHSP hydrogel can facilitate printing with proper viscoelastic property and self-healing behavior.By crosslinking with 4%PEG-SG for only 3 min,the integrity of the cell-laden construct can last for 21 days due to the stable internal and external GEL/PEG-SG networks,and cells manifested long-term viability and spreading morphology.Nerve-like,muscle-like,and cartilage-like in vitro constructs exhibited homogeneous cell growth and remarkable biological specificities.This work provides not only a convenient and practical bioink for tissue engineering,targeted cell therapy,but also a new direction for hydrogel bioink development.

A facile,versatile hydrogel bioink for 3D bioprinting benefits long-term subaqueous fidelity,cell viability and proliferation

Both of the long-term fidelity and cell viability of three-dimensional(3D)-bioprinted constructs are essential to precise soft tissue repair.However,the shrinking/swelling behavior of hydrogels brings about inadequate long-term fidelity of constructs,and bioinks containing excessive polymer are detrimental to cell viability.Here,we obtained a facile hydrogel by introducing 1%aldehyde hyaluronic acid(AHA)and 0.375%N-carboxymethyl chitosan(CMC),two polysaccharides with strong water absorption and water retention capacity,into classic gelatin(GEL,5%)–alginate(ALG,1%)ink.This GEL–ALG/CMC/AHA bioink possesses weak temperature dependence due to the Schiff base linkage of CMC/AHA and electrostatic interaction of CMC/ALG.We fabricated integrated constructs through traditional printing at room temperature and in vivo simulation printing at 37C.The printed cell-laden constructs can maintain subaqueous fidelity for 30 days after being reinforced by 3%calcium chloride for only 20 s.Flow cytometry results showed that the cell viability was 91.3861.55%on day 29,and the cells in the proliferation plateau at this time still maintained their dynamic renewal with a DNA replication rate of 6.0661.24%.This work provides a convenient and practical bioink option for 3D bioprinting in precise soft tissue repair.

Analysis of COVID-19 Guideline Quality and Change of Recommendations:A Systematic Review

Background.Hundreds of coronavirus disease 2019(COVID-19)clinical practice guidelines(CPGs)and expert consensus statements have been developed and published since the outbreak of the epidemic.However,these CPGs are of widely variable quality.So,this review is aimed at systematically evaluating the methodological and reporting qualities of COVID-19 CPGs,exploring factors that may influence their quality,and analyzing the change of recommendations in CPGs with evidence published.Methods.We searched five electronic databases and five websites from 1 January to 31 December 2020 to retrieve all COVID-19 CPGs.The assessment of the methodological and reporting qualities of CPGs was performed using the AGREE II instrument and RIGHT checklist.Recommendations and evidence used to make recommendations in the CPGs regarding some treatments for COVID-19(remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavir-ritonavir)were also systematically assessed.And the statistical inference was performed to identify factors associated with the quality of CPGs.Results.We included a total of 92 COVID-19 CPGs developed by 19 countries.Overall,the RIGHT checklist reporting rate of COVID-19 CPGs was 33.0%,and the AGREE II domain score was 30.4%.The overall methodological and reporting qualities of COVID-19 CPGs gradually improved during the year 2020.Factors associated with high methodological and reporting qualities included the evidence-based development process,management of conflicts of interest,and use of established rating systems to assess the quality of evidence and strength of recommendations.The recommendations of only seven(7.6%)CPGs were informed by a systematic review of evidence,and these seven CPGs have relatively high methodological and reporting qualities,in which six of them fully meet the Institute of Medicine(IOM)criteria of guidelines.Besides,a rapid advice CPG developed by the World Health Organization(WHO)of the seven CPGs got the highest overall scores in methodological(72.8%)and reporting qualities(83.8%).Many CPGs covered the same clinical questions(it refers to the clinical questions on the effectiveness of treatments of remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavirritonavir in COVID-19 patients)and were published by different countries or organizations.Although randomized controlled trials and systematic reviews on the effectiveness of treatments of remdesivir,glucocorticoids,hydroxychloroquine/chloroquine,interferon,and lopinavir-ritonavir for patients with COVID-19 have been published,the recommendations on those treatments still varied greatly across COVID-19 CPGs published in different countries or regions,which may suggest that the CPGs do not make sufficient use of the latest evidence.Conclusions.Both the methodological and reporting qualities of COVID-19 CPGs increased over time,but there is still room for further improvement.The lack of effective use of available evidence and management of conflicts of interest were the main reasons for the low quality of the CPGs.The use of formal rating systems for the quality of evidence and strength of recommendations may help to improve the quality of CPGs in the context of the COVID-19 pandemic.During the pandemic,we suggest developing a living guideline of which recommendations are supported by a systematic review for it can facilitate the timely translation of the latest research findings to clinical practice.We also suggest that CPG developers should register the guidelines in a registration platform at the beginning for it can reduce duplication development of guidelines on the same clinical question,increase the transparency of the development process,and promote cooperation among guideline developers all over the world.Since the International Practice Guideline Registry Platform has been created,developers could register guidelines prospectively and internationally on this platform.

Whole exome sequencing identifies mutations of multiple genes in a Chinese cohort of 95 sporadic probands with presumptive retinitis pigmentosa

Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.

Sleep deprivation reorganizes the dynamic configurations of default mode network activity during recovery sleep

Sleep deprivation causes disturbances of the neural activity, leading to the impairment of brain functions. However, the exact mechanism of sleep deprivation and how it affects the dynamics of brain activity during the recovery sleep remains unclear. In the current study, we performed sleep deprivation experiments on ten adult rats, and recorded the local field potentials from default mode network(DMN) regions during sleep before and after sleep deprivation. The DMN dynamics was assessed with the configurations of coactive micropatterns(CAMPs) using our previously proposed CAMP method. Our analysis revealed that the effects of sleep deprivation on DMN dynamics in the slow-wave sleep(SWS) state and the rapid eye-movement sleep(REM)state were disparate. Dynamic configurations of DMN activity in the SWS state were significantly impaired after sleep deprivation, with increased occurrence of low-activity CAMP and reorganized transition structure across three CAMPs. Moreover,enhanced functional connectivity and improved efficiencies in all CAMP networks were observed during the SWS state in the recovery sleep. However, there were no significant alterations in either DMN dynamics or CAMP network structures in the REM sleep state after sleep deprivation. Our results described the alterations of DMN dynamics in different sleep states after sleep deprivation, and illustrated the differential effects of sleep deprivation on two sleep states. These findings demonstrated the underlying neural mechanisms of the effects of sleep deprivation on DMN activity during sleep and increased our understanding of the physiological roles of the DMN in maintain sleep homeostasis after sleep deprivation.