Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors ...Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following injury.At the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to regenerate.Recent works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of regeneration.The role of glia in neuron regeneration has long been studied.展开更多
The environment can impose strong limitations on the efficacy of signal transmission. In particular, for vibratory communication, the signaling environment is often extremely heterogeneous at small scales. Nevertheles...The environment can impose strong limitations on the efficacy of signal transmission. In particular, for vibratory communication, the signaling environment is often extremely heterogeneous at small scales. Nevertheless, natural selection is expected to select for signals well-suited for effective transmission. Here, we test for substrate-dependent signal efficacy in the wolf spider Schizocosa stridulans Strattou 1991. We first explore the transmission characteristics of this important signaling mo- dality by playing recorded substrate-bome signals through three different substrates （leaf litter, pine litter, and red clay） and measuring the propagated signal. We found that the substrate-bome signal of S. stridulans attenuates the least on leaf litter, the substrate upon which the species is naturally found. Next, by assessing mating success with artificially muted and non-muted males across different signaling substrates （leaf litter, pine litter, and sand）, we explored the relationship between substrate-bome signaling and signaling substrate for mating success. We found that muted males were unsuccessful in obtaining copulations re- gardless of substrate, while mating success was dependent on the signaling substrate for non-muted males. For non-muted males, more males copulated on leaf litter than any other substrate. Taken together, these results confLrm the importance of sub- strate-bome signaling in S. stridulans and suggest a match between signal properties and signal efficacy - leaf litter transmits the signal most effectively and males are most successful in obtaining copulations on leaf litter [Current Zoology 56 （3）： 370-378, 2010].展开更多
BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into...BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis,a potential life-threatening condition.Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections.AIM To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease.METHODS A systematic review and meta-analysis was done by searching PubMed,EMBASE and the Cochrane Library,using entry terms related to:(1)Hirschsprung disease;and(2)Botulinum toxin injections.14 studies representing 278 patients met eligibility criteria.Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection,proportion of patients with adverse effects and data on type botulinum toxin,mean dose,average age at first injection and patients with associated syndromes.Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors.RESULTS Botulinum toxin injections are effective in treating obstructive symptoms in on average 66%of patients[event rate(ER)=0.66,P=0.004,I2=49.5,n=278 patients].Type of botulinum toxin,average dose,average age at first injections and proportion of patients with associated syndromes were not predictive for this effect.Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures.There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections(ER=0.79,vs ER=0.46,Q=19.37,P<0.001).Botulinum toxin injections were not effective in treating enterocolitis(ER 0.58,P=0.65,I2=71.0,n=52 patients).There were adverse effects in on average 17%of patients(ER=0.17,P<0.001,I2=52.1,n=187 patients),varying from temporary incontinence to mild anal pain.CONCLUSION Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present,but mild and temporary.展开更多
Type 2 diabetes is a risk factor for Alzheimer’s disease and Parkinson’s disease. Insulin signaling in the brains of people with Alzheimer’s disease or Parkinson’s disease is impaired. Preclinical studies of growt...Type 2 diabetes is a risk factor for Alzheimer’s disease and Parkinson’s disease. Insulin signaling in the brains of people with Alzheimer’s disease or Parkinson’s disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alz-heimer’s disease and Parkinson’s disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer’s disease and Parkinson’s disease. On the basis of these promising ifndings, several clinical trials are ongoing with the ifrst encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer’s disease and Parkinson’s disease that are currently unavailable.展开更多
Parkinson’s disease(PD)is a common movement disorder of the elderly caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain.Both environmental and genetic factors pointed...Parkinson’s disease(PD)is a common movement disorder of the elderly caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain.Both environmental and genetic factors pointed out mitochondrial dysfunction as a major cause of neurodegeneration in PD.Pioneering studies using mitochondrial toxins revealed their ability to trigger dopaminergic cell death and irreversible parkinsonism in different animal models(Poewe et al.,2017).Typical features of mitochondrial dysfunction have been also observed in the human brain of idiopathic PD cases,showing alterations of respiratory chain complex I and IV activity,accumulation of mtDNA deletions and increased oxidative stress(Bender et al.,2006).Moreover,a number of genes found mutated in familial PD forms encode for proteins involved in the maintenance of mitochondrial homeostasis and quality control.Among these,the PINK1 gene encodes a mitochondrial serine/threonine kinase implicated in key neuroprotective functions,including mitophagy,regulation of mitochondrial transport,control of the mitochondria/endoplasmic reticulum crosstalk and calcium homeostasis(Brunelli et al.,2020).展开更多
BACKGROUND Patients with Hirschsprung disease(HD)are at risk of persistent constipation,fecal incontinence or recurrent enterocolitis after surgical treatment,which in turn may impact physical and psychosocial functio...BACKGROUND Patients with Hirschsprung disease(HD)are at risk of persistent constipation,fecal incontinence or recurrent enterocolitis after surgical treatment,which in turn may impact physical and psychosocial functioning.Generic health-related quality of life(HRQoL)and disease-specific health-related quality of life are relevant outcome measures to assess the impact of HD on the QoL of these patients.AIM To summarize all available evidence on HRQoL of patients with HD after surgery and the impact of possible moderating factors.METHODS Pubmed,Web of Sciences,Psyc Info and Embase were searched with search terms related to’Hirschsprung disease’,’Pediatrics’and’Quality of life’.Mean and standard deviation of generic HRQoL overall and domain scores were extracted from each study,as well as data describing potential factors associated with QoL.Random effect models were used for meta-analytic aggregation of generic HRQoL scores.Meta-regression was used to assess the relationship between patient and clinical characteristics and generic HRQoL.Disease-specific HRQoL outcomes of patients with HD were systematically reviewed.RESULTS Seventeen articles were included in the systematic review(n=1137 patients)and 15 in the quantitative meta-analysis(n=1024 patients).Four studies reported disease-specific HRQoL.Patient’s age ranged between 0 and 21 years.Meta-analytic aggregation showed a nonsignificantly impaired generic HRQoL(d=-0.168[95%CI:-0.481;0.145],P=0.293,I^(2)=94.9)in patients with HD compared to healthy controls.Physical(d=-0.042[95%CI:-0.419;0.335],P=0.829,I^(2)=95.1),psychosocial(d=-0.159[95%CI:-0.458;0.141],P=0.299,I^(2)=93.6)and social HRQoL(d=-0.092[95%CI:-0.642;0.457],P=0.742,I^(2)=92.3)were also not significantly lower compared to healthy controls.There was no relation between health-related outcomes and the sex of the patients and whether generic HRQoL was measured by parental proxy or self-report.Disease-specific complaints of patients with HD impaired physical HRQoL,but not psychosocial and social HRQoL.CONCLUSION In this systematic review and meta-analysis,no evidence was found for impaired generic HRQoL in patients with HD compared to healthy controls,neither for moderating effects of sex,parental proxy or self-report.展开更多
OBJECTIVE： To investigate the neuroprotective mechanism of combination extract of Renshen （Ponax Ginseng）, Yinyanghuo （Herba Epimedii Brevi-comus）, Yuanzhi （Radix Palygalae） and Jianghuang （Rhizoma Curcumae Lo...OBJECTIVE： To investigate the neuroprotective mechanism of combination extract of Renshen （Ponax Ginseng）, Yinyanghuo （Herba Epimedii Brevi-comus）, Yuanzhi （Radix Palygalae） and Jianghuang （Rhizoma Curcumae Longae） （GEPT） in treating AI- zheimer＇s disease on the target of glycogen syn- thase kinase 3β（GSK-3β）. METHODS： Three-month-old APPV7171 transgenic mice were randomly divided into ten groups （n=12 per group） and intragastrically administrated vehi- cle or medicines： APP group was given 0.5% CMC, donepezil group was given donepezil （APP ＋ D group） （0.92 mg/kg-1. day-1）, and GEPT groups were given small dose of GEPT （APP＋Gs group） （0.075 g/ kg-1. day-1）, medium dose （APP＋Gm group） （0.15 g/ kg-1. day-1）, and large dose （APP＋GI group） （0.30 g/ kg-1. day-1） for 4 or 8 months, respectively. Three-month-old C57BL/6J mice as vehicle controls （n=12） were given 0.5% CMC for 4 or 8 months as well. The GSK-3β expression in the cortex of 7- and 11-month-old APPV7171 transgenic mice with and without GEPT or donepezil treatment and normal C57BL/6J mice were measured via Western blotting and Immunohistochemistry. RESULTS： Immunohistochemistry analysis showed significant increase of GSK-3β in the cerebral cortex of 7-month-old APP group （compare to control group P=0.003）, while the GSK-313 expression of donepezil or OEPT group were all significantly de-creased （Donepezil vs APP： P=0.041; GI vs APP： P=0.049, Gm vs APP： P=0.029, Gh vs APP： P=0.036）. Western blot analysis showed similar results. The densitometric measures of GSK-3β in APP mice in- creased significantly as compared with the control group （P=0.008）. And the GSK-3β expression indonepezil and GEPT groups were all decreased. There was significant difference between Gh group or donepezil group and the control group （P=0.05）. Similar findings were shown in the 11-month-old mice in each group, except for greater decrease of GSK-3β in the GEPT group. CONCLUSION： GEPT can effectively decrease the level of GSK-3β expression in the brain cortex of AP- PV7171 transgenic mice, and such effect is more sig- nificant in 11-month-old mice. This partially ex- plains the neuroprotecting mechanism of GEPT in preventing and treating of AD.展开更多
Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain inclu...Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.展开更多
The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activati...The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.展开更多
A nonlinear autoregressive approach with exogenous input is used as a novel method for statistical forecasting of the disturbance storm time index, a measure of space weather related to the ring current which surround...A nonlinear autoregressive approach with exogenous input is used as a novel method for statistical forecasting of the disturbance storm time index, a measure of space weather related to the ring current which surrounds the Earth, and fluctuations in disturbance storm time field strength as a result of incoming solar particles. This ring current produces a magnetic field which opposes the planetary geomagnetic field. Given the occurrence of solar activity hours or days before subsequent geomagnetic fluctuations and the potential effects that geomagnetic storms have on terrestrial systems, it would be useful to be able to predict geophysical parameters in advance using both historical disturbance storm time indices and external input of solar winds and the interplanetary magnetic field. By assessing various statistical techniques it is determined that artificial neural networks may be ideal for the prediction of disturbance storm time index values which may in turn be used to forecast geomagnetic storms. Furthermore, it is found that a Bayesian regularization neural network algorithm may be the most accurate model compared to both other forms of artificial neural network used and the linear models employing regression analyses.展开更多
We have previously found that unilateral labyrinthectomy is accompanied by modification of hyaluronan and chondroitin sulfate proteoglycan staining in the lateral vestibular nucleus of rats and the time course of subs...We have previously found that unilateral labyrinthectomy is accompanied by modification of hyaluronan and chondroitin sulfate proteoglycan staining in the lateral vestibular nucleus of rats and the time course of subsequent reorganization of extracellular matrix assembly correlates to the restoration of impaired vestibular function. The tenascin-R has repelling effect on pathfinding during axonal growth/regrowth, and thus inhibits neural circuit repair. By using immunohistochemical method, we studied the modification of tenascin-R expression in the superior, medial, lateral, and descending vestibular nuclei of the rat following unilateral labyrin- thectomy. On postoperative day 1, tenascin-R reaction in the perineuronal nets disappeared on the side of labyrinthectomy in the superior, lateral, medial, and rostral part of the descending vestibular nuclei. On survival day 3, the staining intensity of tenascin-R reaction in perineuronal nets recovered on the operated side of the medial vestibular nucleus, whereas it was restored by the time of postoperative day 7 in the superior, lateral and rostral part of the descending vestib- ular nuclei. The staining intensity of tenascin-R reaction remained unchanged in the caudal part of the descending vestibular nucleus bilaterally. Regional differences in the modification of tena- scin-R expression presented here may be associated with different roles of individual vestibular nuclei in the compensatory processes. The decreased expression of the tenascin-R may suggest the extracellular facilitation of plastic modifications in the vestibular neural circuit after lesion of the labyrinthine receptors.展开更多
AIM: To determine real life clinical outcomes in poorly responsive and treatment-nave neovascular age-related macular degeneration(nv AMD) patients using bimonthly fixed dosing aflibercept regimen.METHODS: This was a ...AIM: To determine real life clinical outcomes in poorly responsive and treatment-nave neovascular age-related macular degeneration(nv AMD) patients using bimonthly fixed dosing aflibercept regimen.METHODS: This was a retrospective study of 165 eyes with nv AMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata(PRN) ranibizumab/bevacizumab due to poor response(107 eyes), or treatment- nave( 58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity(BCVA) and central retinal thickness(CRT)from baseline were assessed using the Wilcoxon signedrank test. The proportion of patients maintaining BCVA(<15 letters loss) at 12 mo was also evaluated.RESULTS: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and nave aflibercept groups respectively(P <0.01). BCVA was maintained in 95.3% of switched and 96.6% of nave patients. CRT at month 12 showed a decrease of -6.16 μm in the switched group and -35.36 μm in the nave group(P <0.01).Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6 mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections(nave group), 7.5 injections(switched group) and 4 clinic visits per year.CONCLUSION: Fixed bimonthly aflibercept is effective in both treatment-nave and poorly responsive nv AMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.展开更多
Damage to the vestibular sense organs evokes static and dynamic deficits in the eye movements,posture and vegetative functions.After a shorter or longer period of time,the vestibular function is partially or completel...Damage to the vestibular sense organs evokes static and dynamic deficits in the eye movements,posture and vegetative functions.After a shorter or longer period of time,the vestibular function is partially or completely restored via a series of processes such as modification in the efficacy of synaptic inputs.As the plasticity of adult central nervous system is associated with the alteration of extracellular matrix,including its condensed form,the perineuronal net,we studied the changes of brevican expression in the perineuronal nets of the superior vestibular nucleus after unilateral labyrinth lesion.Our results demonstrated that the unilateral labyrinth lesion and subsequent compensation are accompanied by the changing of brevican staining pattern in the perineuronal nets of superior vestibular nucleus of the rat.The reduction of brevican in the perineuronal nets of superior vestibular nucleus may contribute to the vestibular plasticity by suspending the non-permissive role of brevican in the restoration of perineuronal net assembly.After a transitory decrease,the brevican expression restored to the control level parallel to the partial restoration of impaired vestibular function.The bilateral changing in the brevican expression supports the involvement of commissural vestibular fibers in the vestibular compensation.All experimental procedures were approved by the 'University of Debrecen–Committee of Animal Welfare'(approval No.6/2017/DEMAB) and the 'Scientific Ethics Committee of Animal Experimentation'(approval No.HB/06/éLB/2270-10/2017;approved on June 6,2017).展开更多
Spinal cord injury(SCI),second only to stroke,is the leading cause of paralysis.The ability to walk is often lost after SCI,reducing independence and quality of life.Restoration of walking is cited as a priority among...Spinal cord injury(SCI),second only to stroke,is the leading cause of paralysis.The ability to walk is often lost after SCI,reducing independence and quality of life.Restoration of walking is cited as a priority among persons with SCI of all degrees of severity,chronicity,or age at injury.As 70%of SCIs are anatomically incomplete,some neural connections relaying information to and from the brain are spared.展开更多
文摘Neural damage or degeneration is at the crux of many diseases,and treatment of these diseases will require the development of therapeutics to enhance and guide neural regeneration.Both intrinsic and extrinsic factors dictate a neuron’s ability to regenerate,and the combination of these factors results in the great regenerative capacity of the peripheral nervous system(PNS)and the poor regenerative capacity of the central nervous system(CNS)following injury.At the core of a neuron’s function is its ability to relay electrochemical signals,and a neuron’s excitability is a key factor in its ability to regenerate.Recent works have focused on the changes in neuronal electrophysiological properties,firing patterns,and ion flux after injury,which differentially activate signaling pathways at the core of regeneration.The role of glia in neuron regeneration has long been studied.
基金National Science Foundation International Research Fellowship (0502239)NSERC Discovery Grant (238882 241419)National Science Foundation CAREER award (IOS-0934990)
文摘The environment can impose strong limitations on the efficacy of signal transmission. In particular, for vibratory communication, the signaling environment is often extremely heterogeneous at small scales. Nevertheless, natural selection is expected to select for signals well-suited for effective transmission. Here, we test for substrate-dependent signal efficacy in the wolf spider Schizocosa stridulans Strattou 1991. We first explore the transmission characteristics of this important signaling mo- dality by playing recorded substrate-bome signals through three different substrates （leaf litter, pine litter, and red clay） and measuring the propagated signal. We found that the substrate-bome signal of S. stridulans attenuates the least on leaf litter, the substrate upon which the species is naturally found. Next, by assessing mating success with artificially muted and non-muted males across different signaling substrates （leaf litter, pine litter, and sand）, we explored the relationship between substrate-bome signaling and signaling substrate for mating success. We found that muted males were unsuccessful in obtaining copulations re- gardless of substrate, while mating success was dependent on the signaling substrate for non-muted males. For non-muted males, more males copulated on leaf litter than any other substrate. Taken together, these results confLrm the importance of sub- strate-bome signaling in S. stridulans and suggest a match between signal properties and signal efficacy - leaf litter transmits the signal most effectively and males are most successful in obtaining copulations on leaf litter [Current Zoology 56 （3）： 370-378, 2010].
文摘BACKGROUND A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery.Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis,a potential life-threatening condition.Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections.AIM To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease.METHODS A systematic review and meta-analysis was done by searching PubMed,EMBASE and the Cochrane Library,using entry terms related to:(1)Hirschsprung disease;and(2)Botulinum toxin injections.14 studies representing 278 patients met eligibility criteria.Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection,proportion of patients with adverse effects and data on type botulinum toxin,mean dose,average age at first injection and patients with associated syndromes.Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors.RESULTS Botulinum toxin injections are effective in treating obstructive symptoms in on average 66%of patients[event rate(ER)=0.66,P=0.004,I2=49.5,n=278 patients].Type of botulinum toxin,average dose,average age at first injections and proportion of patients with associated syndromes were not predictive for this effect.Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures.There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections(ER=0.79,vs ER=0.46,Q=19.37,P<0.001).Botulinum toxin injections were not effective in treating enterocolitis(ER 0.58,P=0.65,I2=71.0,n=52 patients).There were adverse effects in on average 17%of patients(ER=0.17,P<0.001,I2=52.1,n=187 patients),varying from temporary incontinence to mild anal pain.CONCLUSION Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present,but mild and temporary.
文摘Type 2 diabetes is a risk factor for Alzheimer’s disease and Parkinson’s disease. Insulin signaling in the brains of people with Alzheimer’s disease or Parkinson’s disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alz-heimer’s disease and Parkinson’s disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer’s disease and Parkinson’s disease. On the basis of these promising ifndings, several clinical trials are ongoing with the ifrst encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer’s disease and Parkinson’s disease that are currently unavailable.
基金supported by grants from the Luxembourg National Research Fund(FNR)for the National Centre for Excellence in Research on Parkinson’s disease(NCERPD to RK),the PEARL program(FNR/P13/6682797 to RK)and MiRisk‐PD(C17/BM/11676395 to RK and GA).RK has also received research grants from the Michael J Fox Foundation,the European Union’s Joint Program-Neurodegenerative Diseases(JPNDCOURAGE-PD)+2 种基金e European Union’s Horizon2020 research and innovation program(No.692320)the Federal Ministry for Education and Research(BMBF,Mito-PD 031 A 430 A).NM was supported by the French National Cancer Institute(INCA2017-1-PLBIO-08)by Fondation pour la recherche contre le cancer(ARC).
文摘Parkinson’s disease(PD)is a common movement disorder of the elderly caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain.Both environmental and genetic factors pointed out mitochondrial dysfunction as a major cause of neurodegeneration in PD.Pioneering studies using mitochondrial toxins revealed their ability to trigger dopaminergic cell death and irreversible parkinsonism in different animal models(Poewe et al.,2017).Typical features of mitochondrial dysfunction have been also observed in the human brain of idiopathic PD cases,showing alterations of respiratory chain complex I and IV activity,accumulation of mtDNA deletions and increased oxidative stress(Bender et al.,2006).Moreover,a number of genes found mutated in familial PD forms encode for proteins involved in the maintenance of mitochondrial homeostasis and quality control.Among these,the PINK1 gene encodes a mitochondrial serine/threonine kinase implicated in key neuroprotective functions,including mitophagy,regulation of mitochondrial transport,control of the mitochondria/endoplasmic reticulum crosstalk and calcium homeostasis(Brunelli et al.,2020).
文摘BACKGROUND Patients with Hirschsprung disease(HD)are at risk of persistent constipation,fecal incontinence or recurrent enterocolitis after surgical treatment,which in turn may impact physical and psychosocial functioning.Generic health-related quality of life(HRQoL)and disease-specific health-related quality of life are relevant outcome measures to assess the impact of HD on the QoL of these patients.AIM To summarize all available evidence on HRQoL of patients with HD after surgery and the impact of possible moderating factors.METHODS Pubmed,Web of Sciences,Psyc Info and Embase were searched with search terms related to’Hirschsprung disease’,’Pediatrics’and’Quality of life’.Mean and standard deviation of generic HRQoL overall and domain scores were extracted from each study,as well as data describing potential factors associated with QoL.Random effect models were used for meta-analytic aggregation of generic HRQoL scores.Meta-regression was used to assess the relationship between patient and clinical characteristics and generic HRQoL.Disease-specific HRQoL outcomes of patients with HD were systematically reviewed.RESULTS Seventeen articles were included in the systematic review(n=1137 patients)and 15 in the quantitative meta-analysis(n=1024 patients).Four studies reported disease-specific HRQoL.Patient’s age ranged between 0 and 21 years.Meta-analytic aggregation showed a nonsignificantly impaired generic HRQoL(d=-0.168[95%CI:-0.481;0.145],P=0.293,I^(2)=94.9)in patients with HD compared to healthy controls.Physical(d=-0.042[95%CI:-0.419;0.335],P=0.829,I^(2)=95.1),psychosocial(d=-0.159[95%CI:-0.458;0.141],P=0.299,I^(2)=93.6)and social HRQoL(d=-0.092[95%CI:-0.642;0.457],P=0.742,I^(2)=92.3)were also not significantly lower compared to healthy controls.There was no relation between health-related outcomes and the sex of the patients and whether generic HRQoL was measured by parental proxy or self-report.Disease-specific complaints of patients with HD impaired physical HRQoL,but not psychosocial and social HRQoL.CONCLUSION In this systematic review and meta-analysis,no evidence was found for impaired generic HRQoL in patients with HD compared to healthy controls,neither for moderating effects of sex,parental proxy or self-report.
基金Supported by Grant from the Innovative Research Team for Alzheimer's Disease's Prevention and Treatment of Ministry of Education of China (No. IRT-08-010)the Project on Absorption of Intellects by Institutions of Higher Education for Academic Disciplinary Innovations (the "111 Project") (No.B08006)+5 种基金the National Natural Science Foundation of China(No. 30973738)the National Key Technology R & D Program(No. 2009BA177B09)the Technological Platform of Clinical Evaluation and Research for New Herbal Medicinal Products(No. 2011ZX09302-006-01)the Innovative Research Team in Beijing University of Chinese Medicine (No. 2011-CXTD-21)Research Fund of Capital Medical Development (No.SF-2009-Ⅲ-11)the Study of Secondary Prevention with Chinese Herbal Medicine for Chronic Diseases (No.Z111107056811043)
文摘OBJECTIVE： To investigate the neuroprotective mechanism of combination extract of Renshen （Ponax Ginseng）, Yinyanghuo （Herba Epimedii Brevi-comus）, Yuanzhi （Radix Palygalae） and Jianghuang （Rhizoma Curcumae Longae） （GEPT） in treating AI- zheimer＇s disease on the target of glycogen syn- thase kinase 3β（GSK-3β）. METHODS： Three-month-old APPV7171 transgenic mice were randomly divided into ten groups （n=12 per group） and intragastrically administrated vehi- cle or medicines： APP group was given 0.5% CMC, donepezil group was given donepezil （APP ＋ D group） （0.92 mg/kg-1. day-1）, and GEPT groups were given small dose of GEPT （APP＋Gs group） （0.075 g/ kg-1. day-1）, medium dose （APP＋Gm group） （0.15 g/ kg-1. day-1）, and large dose （APP＋GI group） （0.30 g/ kg-1. day-1） for 4 or 8 months, respectively. Three-month-old C57BL/6J mice as vehicle controls （n=12） were given 0.5% CMC for 4 or 8 months as well. The GSK-3β expression in the cortex of 7- and 11-month-old APPV7171 transgenic mice with and without GEPT or donepezil treatment and normal C57BL/6J mice were measured via Western blotting and Immunohistochemistry. RESULTS： Immunohistochemistry analysis showed significant increase of GSK-3β in the cerebral cortex of 7-month-old APP group （compare to control group P=0.003）, while the GSK-313 expression of donepezil or OEPT group were all significantly de-creased （Donepezil vs APP： P=0.041; GI vs APP： P=0.049, Gm vs APP： P=0.029, Gh vs APP： P=0.036）. Western blot analysis showed similar results. The densitometric measures of GSK-3β in APP mice in- creased significantly as compared with the control group （P=0.008）. And the GSK-3β expression indonepezil and GEPT groups were all decreased. There was significant difference between Gh group or donepezil group and the control group （P=0.05）. Similar findings were shown in the 11-month-old mice in each group, except for greater decrease of GSK-3β in the GEPT group. CONCLUSION： GEPT can effectively decrease the level of GSK-3β expression in the brain cortex of AP- PV7171 transgenic mice, and such effect is more sig- nificant in 11-month-old mice. This partially ex- plains the neuroprotecting mechanism of GEPT in preventing and treating of AD.
文摘Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.
基金supported by the European Union Grant Alehoop(H2020-BBIJTI-2019-887259)And from the Xunta de Galicia(Centro singular de Investigación de Galicia accreditation 2016-2019),ED431 G/02(to FM)。
文摘The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.
文摘A nonlinear autoregressive approach with exogenous input is used as a novel method for statistical forecasting of the disturbance storm time index, a measure of space weather related to the ring current which surrounds the Earth, and fluctuations in disturbance storm time field strength as a result of incoming solar particles. This ring current produces a magnetic field which opposes the planetary geomagnetic field. Given the occurrence of solar activity hours or days before subsequent geomagnetic fluctuations and the potential effects that geomagnetic storms have on terrestrial systems, it would be useful to be able to predict geophysical parameters in advance using both historical disturbance storm time indices and external input of solar winds and the interplanetary magnetic field. By assessing various statistical techniques it is determined that artificial neural networks may be ideal for the prediction of disturbance storm time index values which may in turn be used to forecast geomagnetic storms. Furthermore, it is found that a Bayesian regularization neural network algorithm may be the most accurate model compared to both other forms of artificial neural network used and the linear models employing regression analyses.
基金supported by a grant from the Hungarian Academy of Sciences(MTA-TKI 11008)a grant from the European Union and the State of Hungarythe European Social Fund in the framework of TáMOP-4.2.4.A/2-11/1-2012-0001‘National Excellence Program’
文摘We have previously found that unilateral labyrinthectomy is accompanied by modification of hyaluronan and chondroitin sulfate proteoglycan staining in the lateral vestibular nucleus of rats and the time course of subsequent reorganization of extracellular matrix assembly correlates to the restoration of impaired vestibular function. The tenascin-R has repelling effect on pathfinding during axonal growth/regrowth, and thus inhibits neural circuit repair. By using immunohistochemical method, we studied the modification of tenascin-R expression in the superior, medial, lateral, and descending vestibular nuclei of the rat following unilateral labyrin- thectomy. On postoperative day 1, tenascin-R reaction in the perineuronal nets disappeared on the side of labyrinthectomy in the superior, lateral, medial, and rostral part of the descending vestibular nuclei. On survival day 3, the staining intensity of tenascin-R reaction in perineuronal nets recovered on the operated side of the medial vestibular nucleus, whereas it was restored by the time of postoperative day 7 in the superior, lateral and rostral part of the descending vestib- ular nuclei. The staining intensity of tenascin-R reaction remained unchanged in the caudal part of the descending vestibular nucleus bilaterally. Regional differences in the modification of tena- scin-R expression presented here may be associated with different roles of individual vestibular nuclei in the compensatory processes. The decreased expression of the tenascin-R may suggest the extracellular facilitation of plastic modifications in the vestibular neural circuit after lesion of the labyrinthine receptors.
文摘AIM: To determine real life clinical outcomes in poorly responsive and treatment-nave neovascular age-related macular degeneration(nv AMD) patients using bimonthly fixed dosing aflibercept regimen.METHODS: This was a retrospective study of 165 eyes with nv AMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata(PRN) ranibizumab/bevacizumab due to poor response(107 eyes), or treatment- nave( 58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity(BCVA) and central retinal thickness(CRT)from baseline were assessed using the Wilcoxon signedrank test. The proportion of patients maintaining BCVA(<15 letters loss) at 12 mo was also evaluated.RESULTS: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and nave aflibercept groups respectively(P <0.01). BCVA was maintained in 95.3% of switched and 96.6% of nave patients. CRT at month 12 showed a decrease of -6.16 μm in the switched group and -35.36 μm in the nave group(P <0.01).Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6 mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections(nave group), 7.5 injections(switched group) and 4 clinic visits per year.CONCLUSION: Fixed bimonthly aflibercept is effective in both treatment-nave and poorly responsive nv AMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.
基金supported by the Hungarian Academy of Sciences–Office for Supported Research Groups:MTA-TKI 355University of Debrecen–Medical and Health Sciences Center Bridging FundHungarian Scientific Research Fund K115471.Obtained by Clara Matesz and colleagues。
文摘Damage to the vestibular sense organs evokes static and dynamic deficits in the eye movements,posture and vegetative functions.After a shorter or longer period of time,the vestibular function is partially or completely restored via a series of processes such as modification in the efficacy of synaptic inputs.As the plasticity of adult central nervous system is associated with the alteration of extracellular matrix,including its condensed form,the perineuronal net,we studied the changes of brevican expression in the perineuronal nets of the superior vestibular nucleus after unilateral labyrinth lesion.Our results demonstrated that the unilateral labyrinth lesion and subsequent compensation are accompanied by the changing of brevican staining pattern in the perineuronal nets of superior vestibular nucleus of the rat.The reduction of brevican in the perineuronal nets of superior vestibular nucleus may contribute to the vestibular plasticity by suspending the non-permissive role of brevican in the restoration of perineuronal net assembly.After a transitory decrease,the brevican expression restored to the control level parallel to the partial restoration of impaired vestibular function.The bilateral changing in the brevican expression supports the involvement of commissural vestibular fibers in the vestibular compensation.All experimental procedures were approved by the 'University of Debrecen–Committee of Animal Welfare'(approval No.6/2017/DEMAB) and the 'Scientific Ethics Committee of Animal Experimentation'(approval No.HB/06/éLB/2270-10/2017;approved on June 6,2017).
基金supported by the Craig H.Neilsen Foundationthe Natural Sciences and Engineering Research Council of Canada+1 种基金the Canadian Institutes of Health Research(to MM)supported by a salary award from Fonds de Recherche Québec-Santé。
文摘Spinal cord injury(SCI),second only to stroke,is the leading cause of paralysis.The ability to walk is often lost after SCI,reducing independence and quality of life.Restoration of walking is cited as a priority among persons with SCI of all degrees of severity,chronicity,or age at injury.As 70%of SCIs are anatomically incomplete,some neural connections relaying information to and from the brain are spared.
