Brain-penetrating neurotrophic factor mimetics: HER-096 as a disease-modifying therapy for Parkinson’s disease

Neurotrophic factors as a therapeutic approach in neurodegenerative diseases:A major unmet need in the field of central nervous system diseases is disease-modifying treatments.While for decades there have been various symptomatic treatments available to alleviate the symptoms of the disease,disease-modification,i.e.treatments that stop,significantly delay,or reverse the progression of the disease,has been turned out to a difficult goal to achieve.

Recent Advances for Global Perspectives on Etiology, Pathophysiology, Clinical Presentations, and Management of Moyamoya Disease

Moyamoya disease (MMD) is a condition characterized by the gradual narrowing and blockage of blood vessels in the brain, specifically those in the circle of Willis and the arteries that supply it. This results in reduced blood flow and oxygen to the brain, leading to progressive symptoms and potential complications. The underlying pathophysiological mechanism remains elucidated. However, recent studies have highlighted numerous etiologic factors: abnormal immune complex responses, susceptibility genes, branched-chain amino acids, antibodies, heritable diseases, and acquired diseases, which may be the great potential triggers for the development of moyamoya disease. Its clinical presentation has varying degrees from transient asymptomatic events to significant neurological deficits. Moyamoya disease (MMD) shows different patterns in children and adults. Children with MMD are more susceptible to ischemic events due to decreased blood flow to the brain. Conversely, adults with MMD are more prone to hemorrhagic events involving brain bleeding. Children with MMD may experience a range of symptoms including motor impairments, sensory issues, seizures, headaches, dizziness, cognitive delays, or ongoing neurological problems. Although adults may present with similar clinical symptoms as children, they are more prone to experiencing sudden onset intraventricular, subarachnoid, or intracerebral hemorrhages. One of the challenges in moyamoya disease is the potential for misdiagnosis or delayed diagnosis, particularly when physicians fail to consider MMD as a possible cause in stroke patients. This review aims to provide a comprehensive overview of recent global studies on the pathophysiology of MMD, along with advancements in its management. Additionally, the review will delve into various surgical treatment options for MMD, as well as its rare occurrence alongside atrioventricular malformations. Exciting prospects include the use of autologous bone marrow transplant and the potential role of Connexin 43 protein treatment in the development of moyamoya disease.

Is medical management useful in Moyamoya disease?

Moyamoya disease(MMD),characterized by progressive internal carotid artery stenosis and collateral vessel formation,prompts cerebral perfusion complications and is stratified into idiopathic and Moyamoya syndrome subtypes.A multifa-ceted approach toward MMD management addresses cerebral infarctions through revascularization surgery and adjunctive medical therapy,while also navigating risks such as intracranial hemorrhage and cerebral infarction resulting from arte-rial stenosis and fragile collateral vessels.Addressing antithrombotic management reveals a potential role for treatments like antiplatelet agents and anticoagulants,despite the ambiguous contribution of thrombosis to MMD-related infarctions and the critical balance between preventing ischemic events and averting hemo-rrhagic complications.Transcranial doppler has proven useful in thromboembolic detection,despite persisting challenges concerning the efficacy and safety of an-tithrombotic treatments.Furthermore,antihypertensive interventions aim to ma-nage blood pressure meticulously,especially during intracerebral hemorrhage,with recommendations and protocols varying based on the patient’s hypertension status.Additionally,lipid-lowering therapeutic strategies,particularly employing statins,are appraised for their possible beneficial role in MMD management,even as comprehensive data from disease-specific clinical trials remains elusive.Com-prehensive guidelines and protocols to navigate the multifaceted therapeutic ave-nues for MMD,while maintaining a delicate balance between efficacy and safety,warrant further meticulous research and development.This protocol manuscript seeks to elucidate the various aspects and challenges imbued in managing and navigating through the complex landscape of MMD treatment.

Managing Vogt–Koyanagi–Harada disease during pregnancy with steroid pulse therapy:A case report

BACKGROUND High-dose steroid administration is a common initial therapeutic approach for Vogt–Koyanagi–Harada disease(VKH).Nonetheless,administering substantial doses of steroids to pregnant women necessitates meticulous consideration due to the potential impacts on the mother and fetus.We present a case wherein steroid pulse therapy was administered to a patient who developed VKH during the late stages of pregnancy.CASE SUMMARY The patient was a 26-year-old nulliparous woman.At 33 weeks and 1 day of her pregnancy,she experienced a decline in visual acuity and noticed metamorphopsia in her left eye.Examination revealed bilateral serous retinal detachment,leading to VKH diagnosis.A collaborative effort involving the departments of ophthalmology,internal medicine,and neonatology was initiated.Steroid pulse therapy was administered at 34 weeks and 1 day of pregnancy under hospital supervision.Complications,such as threatened preterm labor and gestational diabetes,emerged,necessitating the initiation of oral ritodrine hydrochloride and insulin therapy.Then,serous retinal detachment was resolved,and visual acuity was restored.Labor pains initiated 32 days post-initiation of steroid pulse therapy(at 38 weeks and 4 days of gestation),culminating in a normal delivery.Mother and newborn experienced an uneventful puerperal course and were discharged from the hospital on the 5th day following delivery.CONCLUSION VKH management in pregnancy requires multidisciplinary coordination,emphasizing collaboration with ophthalmologists and specialists in internal medicine and neonatology.

Analysis of the Effect of the Comprehensive Nursing Model on Patients with Moyamoya Disease Undergoing Intracranial and Extracranial Revascularization Surgery

Objective:To explore the effect of a comprehensive nursing model on patients with Moyamoya disease who underwent intracranial and extracranial revascularization surgery.Methods:110 cases were divided into control and observation groups with 55 cases each.The control group received routine perioperative care,and the observation group received perioperative care along with comprehensive nursing care.The two groups’disease cognition levels,anxiety,symptoms,daily living ability scores,and postoperative complication rates were compared.Results:The anxiety score and total postoperative complications of the observation group upon discharge were lower than that of the control group,and the disease cognition level and daily living ability upon discharge were higher than that of the control group(P<0.05).Conclusion:Applying the comprehensive nursing model in conjunction with perioperative care for patients undergoing surgery can effectively improve their anxiety,strengthen activities of daily living,and reduce the risk of postoperative complications.

Enhancement Expression of bFGF in Chinese Patients with Moyamoya Disease

Objective To detect the content of the basic fibroblast growth factor in blood samples of patients with Moyamoya disease, and investigate the relationship between Moyamoya disease and the basic fibroblast growth factor. Methods This tissue microarray study included 24 cases of superficial temporal artery samples, 15 cases of Moyamoya disease, and 9 cases of normal arteries as control, and bFGF immunofluorescence assay was applied to test the samples. The number of positive cells and total cells of the muscular layer and the endothelium layer were counted separately in every picture, the positive rates were calculated, and the experimental data were analyzed statistically. Results The bFGF immunofluorescence staining of smooth muscular layer cells, intima cells and endothelial cells from the moyamoya disease group were obviously stronger than that from the control group （P0.01）. Conclusion The enhancement expression of bFGF in the Moyamaya disease group implicates that bFGF plays an important part in the pathogenesis of Moyamoya disease.

Cloning and Analysis of a Disease Resistance Gene Homolog from Soybean

Conserved domains e.g. nucleotide binding site (NBS) were found in several cloned plant disease resistance genes. Based on the NBS domain, resistance gene analogs (RGAs) have been isolated previously and were used as probes to screen a soybean (Glycine max L. Merr.) cDNA library. A full-length cDNA, KR3, was obtained by screening the library and rapid amplification of cDNA ends (RACE) method. Sequence analysis revealed that the cDNA is 2 353 bp in length and the open reading frame (ORF) codes for a polypeptide of 636 amino acids with a Toll-Interleukin-1 receptor (TIR) and a NBS domain. Sequence alignment showed that it was similar to N gene of tobacco. The phylogenetic tree analysis of R proteins with NBS from higher plants was performed. The KR3 gene has low copies in soybean genome and its expression was induced by exogenous salicylic acid (SA).

Significance of Cyclooxygenase-2 Elevation in Middle Cerebral Artery for Patients with Hemorrhagic Moyamoya Disease

The etiology and pathogenesis of moyamoya disease（MMD） remain elusive. Some inflammatory proteins, such as cyclooxygenase（COX）-2, are believed to be implicated in the development of MMD. So far, the relationship between COX-2 and MMD is poorly understood and reports on the intracranial vessels of MMD patients are scanty. In this study, tiny pieces of middle cerebral artery（MCA） and superficial temporal artery（STA） from 13 MMD patients were surgically harvested. The MCA and STA samples from 5 control patients were also collected by using the same technique. The expression of COX-2 was immunohistochemically detected and the average absorbance（A） of positively-stained areas was measured. High-level COX-2 expression was found in all layers of the MCA samples from all 5 hemorrhagic MMD patients, while positive but weak expression of COX-2 was observed only in the endothelial layer of the MCA samples from most ischemic MMD patients（6/8, 75%）. The average A values of COX-2 in the hemorrhagic MMD patients were substantially higher than those in their ischemic counterparts（t=4.632, P=0.001）. There was no significant difference in the COX-2 expression among the ＂gender＂ groups, or ＂radiographic grade＂ groups, or ＂lesion location＂ groups（P0.05 for all）. The COX-2 expression was detected neither in the MCA samples from the controls nor in all STA specimens. Our results suggested that COX-2 was up-regulated in the MCA of MMD patients, especially in hemorrhagic MMD patients. We are led to speculate that COX-2 may be involved in the pathogenesis of MMD and even contribute to the hemorrhagic stroke of MMD patients.

Histopathological Features of Middle Cerebral Artery and Superficial Temporal Artery from Patients with Moyamoya Disease and Enlightenments on Clinical Treatment

The histopathological features of the middle cerebral artery（MCA） and superficial temporal artery（STA） from moyamoya disease（MMD） and their relationships with gender,age,angiography stage were explored.The causes and the clinical significance of vasculopathy of STA were also discussed.The clinical data and specimens of MCA and STA from 30 MMD patients were collected.Twelve samples of MCA and STA from non-MMD patients served as control group.Histopathological examination was then performed by measuring the thickness of intima and media,and statistical analysis was conducted.The MCA and STA specimens from MMD group had apparently thicker intima and thinner media than those from the control group.There was no significant pathological difference between the hemorrhage group and non-hemorrhage group,and between the males and females in MMD patients.Neither the age nor the digital subtraction angiography（DSA） stage was correlated with the thickness of intima in MCA and STA.MMD is a systemic vascular disease involving both intracranial and extracranial vessels.Preoperative external carotid arteriography,especially super-selective arteriography of the STA,benefits the selection of donor vessel.

Spectral Domain Optical Coherence Tomography of Vogt-Koyanagi-Harada Disease: Novel Findings and New Insights into the Pathogenesis

Objective To provide novel spectral domain optical coherence tomography (SD OCT) findings of Vogt-Koyanagi-Harada (VKH) disease as well as new insights into the pathogenesis of this disease. Methods Detailed SD OCT and fluorescein angiography (FA) findings of 18 consecutive VKH patients (11 women and 7 men) from December 2007 to April 2009 who were in acute uveitic stage at presentation were reviewed. All the patients had been followed up for at least 6 months with reevaluation(s) of SD OCT performed in 10 patients. Results Intraretinal cysts were found to be located in various layers of the outer retina. In addition to the photoreceptor layer, they could also be found between the outer plexiform layer and the outer nuclear layer, or spanning the external limiting membrane. On FA, intraretinal cysts could be hypofluorescent, normofluorescent, or hyperfluorescent. Some intraretinal cysts had a characteristic FA pattern, in which a small round hypofluorescent area was surrounded by a ring of hyperfluorescence (donut-shaped dye pooling). Subretinal fibrinoid deposit appeared in acute uveitic stage in two severe VKH patients and seemed to develop from subretinal exudates and evolved into typical subretinal fibrosis. Gradual transfiguration/migration and progressive proliferation/pigmentation of the subretinal fibrinoid deposit/subretinal fibrosis was observed in one patient. Conclusions Intraretinal cysts could form in various layers of the outer retina and may result from extension of choroidal inflammation. Subretinal fibrosis may develop from subretinal exudates in VKH patients and may cause substantial visual impairment.

Recognition of moyamoya disease and its hemorrhagic risk using deep learning algorithms:sourced from retrospective studies

Although intracranial hemorrhage in moyamoya disease can occur repeatedly,predicting the disease is difficult.Deep learning algorithms developed in recent years provide a new angle for identifying hidden risk factors,evaluating the weight of different factors,and quantitatively evaluating the risk of intracranial hemorrhage in moyamoya disease.To investigate whether convolutional neural network algorithms can be used to recognize moyamoya disease and predict hemorrhagic episodes,we retrospectively selected 460 adult unilateral hemispheres with moyamoya vasculopathy as positive samples for diagnosis modeling,including 418 hemispheres with moyamoya disease and 42 hemispheres with moyamoya syndromes.Another 500 hemispheres with normal vessel appearance were selected as negative samples.We used deep residual neural network(ResNet-152)algorithms to extract features from raw data obtained from digital subtraction angiography of the internal carotid artery,then trained and validated the model.The accuracy,sensitivity,and specificity of the model in identifying unilateral moyamoya vasculopathy were 97.64±0.87%,96.55±3.44%,and 98.29±0.98%,respectively.The area under the receiver operating characteristic curve was 0.990.We used a combined multi-view conventional neural network algorithm to integrate age,sex,and hemorrhagic factors with features of the digital subtraction angiography.The accuracy of the model in predicting unilateral hemorrhagic risk was 90.69±1.58%and the sensitivity and specificity were 94.12±2.75%and 89.86±3.64%,respectively.The deep learning algorithms we proposed were valuable and might assist in the automatic diagnosis of moyamoya disease and timely recognition of the risk for re-hemorrhage.This study was approved by the Institutional Review Board of Huashan Hospital,Fudan University,China(approved No.2014-278)on January 12,2015.

Acute recurrent cerebral infarction caused by moyamoya disease complicated with adenomyosis:A case report

BACKGROUND Moyamoya disease is essentially an ischemic cerebrovascular disease.Here,we describe a case of acute recurrent cerebral infarction caused by moyamoya disease with concurrent adenomyosis which,to our knowledge,is the first in the literature.A literature review is also presented.CASE SUMMARY A 38-year-old female presented to the Research and Treatment Center of Moyamoya Disease in our hospital with"left limb weakness"as the main symptom.She was diagnosed with acute cerebral infarction and moyamoya disease through magnetic resonance imaging and digital subtraction angiography.Prior to this,she had experienced a prolonged menstrual period of one-month duration.This was investigated and adenomyosis was diagnosed.After passing the acute cerebral infarction phase,the patient underwent surgery for adenomyosis followed by combined cerebral revascularization.During the postoperative follow-up,improvements of the perfusion imaging stage and modified Rankin Scale were observed.A review of the literature showed only 16 reported cases of gynecological diseases complicated with stroke.The clinical characteristics,pathogenesis,therapeutic effects,and long-term prognosis of these cases have been studied and discussed.CONCLUSION In patients with moyamoya disease,early management of gynecological-related bleeding disorders is essential to prevent the complications of cerebral events.

Mitochondrial malfunction in vanishing white matter disease： a disease of the cytosolic translation machinery

Vanishing white matter （VWM） disease - a disease of the cytosolic translation machinery： VWM is a recessive genet- ic neurodegenerative disease caused by mutations in any of the five genes encoding the subunits of translation initiation factor 2B （eIF2B） （Leegwater et al., 2001; OMIM 306896）.

A Novel Framework for Multi-Classification of Guava Disease

Guava is one of the most important fruits in Pakistan,and is gradually boosting the economy of Pakistan.Guava production can be interrupted due to different diseases,such as anthracnose,algal spot,fruit fly,styler end rot and canker.These diseases are usually detected and identified by visual observation,thus automatic detection is required to assist formers.In this research,a new technique was created to detect guava plant diseases using image processing techniques and computer vision.An automated system is developed to support farmers to identify major diseases in guava.We collected healthy and unhealthy images of different guava diseases from the field.Then image labeling was done with the help of an expert to differentiate between healthy and unhealthy fruit.The local binary pattern(LBP)was used for the extraction of features,and principal component analysis(PCA)was used for dimensionality reduction.Disease classification was carried out using multiple classifiers,including cubic support vector machine,Fine K-nearest neighbor(F-KNN),Bagged Tree and RUSBoosted Tree algorithms and achieved 100%accuracy for the diagnosis of fruit flies disease using Bagged Tree.However,the findings indicated that cubic support vector machines(C-SVM)was the best classifier for all guava disease mentioned in the dataset.

Polyphenols for the prevention and treatment of dementia diseases

The greatest risk factor for neurodegeneration is aging.However genetics at birth only contributes 20-25%to the determinants of lifespan,so we actually have around 75%control over how well individuals age in body and brain.Health is the real wealth and that everyone can significantly control/achieve sustainable health and quality of life through lifestyle choices needs to be better promoted. Dementia is predominantly a disease of aging with millions of people suffering from dementia and Alzheimer＇s disease （AD） and in recent years little has happened to change and improve the cognitive functions of elderly people （2015 Alzheimer＇s disease facts and figures）. Every 4 seconds there is a new case of dementia in the world and with 7.7 mil- lion cases annually, the estimated global cost of AD and demen- tia disease is $604 billion.

Optical coherence tomography angiography in incomplete acute Vogt-Koyanagi-Harada disease

Dear Editor,Vogt-Koyanagi-Harada（VKH）disease is a cell-mediated autoimmune syndrome directed against melanocytes.It is considered a multisystem disorder characterized by granulomatous panuveitis often associated with neurologic and cutaneous manifestations.

Spectrum and visual outcomes of Vogt-Koyanagi-Harada disease in Argentina

AIM： To review all cases of Vogt-Koyanagi-Harada （VKH） disease in an Inflammatory Eye Disease Service in Argentina and to describe the clinical profile and outcomes of treatment.METHODS： The records from patients with VKH disease between January 1980 and December 2008 were retrospectively analyzed for clinical profile, complications, and treatment. Patients were classified according to their initial treatment in group 1： high corticosteroid dose [≥1 mg/（kg·d）] within 2wk of illness onset; group 2： high corticosteroid dose, 2 to 4wk of onset and group 3： patients who received the high dose after 1mo of illness onset, patients who received lower oral doses than 1 mg/（kg·d） without regarding the time of beginning of the disease.RESULTS： A total of 210 eyes of 105 patients were included. The mean age at presentation was 32.6±13y （range： 10-74y）, and 86.7% were female. The mean duration of follow up was 144±96.6mo. Patients in the group 1 had significantly higher visual acuity than the other groups （P〈0.0001）, none had （loss of, or no） light perception at the end of follow up, whereas 24.7% patients in group 3 ended in light perception （P〈0.004）.CONCLUSION： Patients with early high dose corticosteroid treatment have better visual acuity and fewer complications. Proper timing in referral and treatment is critical for better visual outcome in VKH disease.

Clinical manifestations and cerebral angiographic findings of moyamoya disease

Objective To study the clinical features and angiographic findings of moyamoya disease (MMD) as well as their relationship. Methods A total of 22 MMD patients received routine digital substraction angiography (DSA). The clinical manifestations and angiographic findings were analyzed. Results Clinical manifestations varied and each patient often had multiple symptoms,including cerebral infarction in 9 patients with an average age of 23.6 (13-39 years) and cerebral hemorrhage in 7 patients with an average age of 31.2 (28-46 years). Angiographic examination found that all the diseased sides showed MMD blood vessels. The patients who received encephalo-myo-arterio-synangiosis (EMAS) had better prognosis than those without receiving the treatment. Conclusion Cerebral infarction is frequent in children and adolescents with MMD,whereas cerebral hemorrhage is common in adults. DSA is a golden criterion for diagnosing MMD. Surgical treatment,EMAS blood supply reconstruction in particular,should be prescribed.

Making Ecology a Priority

China’s outstanding economic achievements in recent years have been partly based on an excessive consumption of its energy resources.From 1990 to 2001, the country’s oil consumption grew by 100 per cent from 118 million tons to 235 million tons; demand for natural gas increased by 140

A challenging case of tuberculosis-associated uveitis after corticosteroid treatment for Vogt-Koyanagi-Harada disease

Dear Editor,I am Dr.Tian-Wei Qian,from Shanghai General Hospital,Shanghai,China.I write to present one case report of tuberculosis（TB）-associated uveitis after corticosteroid treatment for Vogt-Koyanagi-Harada（VKH）disease.