Biomarkers for neuromyelitis optica:a visual analysis of emerging research trends

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system that differs from multiple sclerosis.Over the past 20 years,the search for biomarke rs for neuromyelitis optica has been ongoing.Here,we used a bibliometric approach to analyze the main research focus in the field of biomarkers for neuromyelitis optica.Research in this area is consistently increasing,with China and the United States leading the way on the number of studies conducted.The Mayo Clinic is a highly reputable institution in the United States,and was identified as the most authoritative institution in this field.Furthermore,Professor Wingerchuk from the Mayo Clinic was the most authoritative expe rt in this field.Keyword analysis revealed that the terms "neuro myelitis optica"(261 times), "multiple sclerosis"(220 times), "neuromyelitis optica spectrum disorder"(132 times), "aquaporin4"(99 times),and "optical neuritis"(87 times) were the most frequently used keywords in literature related to this field.Comprehensive analysis of the classical literature showed that the majority of publications provide conclusive research evidence supporting the use of aquaporin-4-IgG and neuromyelitis optica-IgG to effectively diagnose and differentiate neuromyelitis optica from multiple sclerosis.Furthermore,aquaporin-4-IgG has emerged as a highly specific diagnostic biomarker for neuromyelitis optica spectrum disorder.Myelin oligodendrocyte glycoprotein-IgG is a diagnostic biomarke r for myelin oligodendrocyte glycoprotein antibody-associated disease.Recent biomarkers for neuromyelitis optica in clude cerebrospinal fluid immunological biomarkers such as glial fibrillary acidic protein,serum astrocyte damage biomarkers like FAM19A5,serum albumin,and gammaaminobutyric acid.The latest prospective clinical trials are exploring the potential of these biomarkers.Preliminary results indicate that glial fibrillary acidic protein is emerging as a promising candidate biomarker for neuromyelitis optica spectrum disorder.The ultimate goal of future research is to identify non-invasive biomarkers with high sensitivity,specificity,and safety for the accurate diagnosis of neuro myelitis optica.

Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis

AIM: To investigate the role that the hedgehog (Hh) signaling pathway, which includes sonic hedgehog (Shh), Patched (Ptc), Smoothened (Smo) and Gli-1, plays in hu- man gastrointestinal stromal tumors (GISTs). METHODS: Surgically resected specimens from pa- tients with GISTs, leiomyomas and schwannomas were examined by immunohistochemical staining for aberrant expression of hedgehog signaling components, Shh, Ptc, Smo and Gli-1, respectively. RESULTS: In GISTs, 58.1% (18 of 31), 77.4% (24 of 31), 80.6% (25 of 31) and 58.1% (18 of 31) of the specimens stained positive for Shh, Ptc, Smo and Gli-1, respectively. In leiomyomas, 92.3% (12 of 13), 92.3% (12 of 13), 69.2% (9 of 13) and 92.3% (12 of 13) stained positive for Shh, Ptc, Smo and Gli-1, respectively. In schwannomas, 83.3% (5 of 6), 83.3% (5 of 6), 83.3% (5 of 6) and 100% (6 of 6) stained positive for Shh, Ptc, Smo and Gli-1, respectively. Immunohistochemistry revealed that the expressions of Shh and Gli-1 were sig- nificantly higher in leiomyomas than in GISTs (P < 0.05, respectively). Shh expression strongly correlated with the grade of tumor risk category and with tumor size (P < 0.05, respectively). However, the expressions of Ptc and Smo did not correlate with histopathological differentiation. CONCLUSION: These results suggest that the Hh sig- naling pathway may play an important role in myogenic differentiation and the malignant potential of human in-testinal stromal tumors.

Expression of vascular endothelial growth factor and its receptors VEGFR-1 and 2 in gastrointestinal stromal tumors,leiomyomas and schwannomas

AIM： To investigate the role of vascular endothelial growth factor （VEGF/and its receptors VEGFR-1 and 2 in the growth and differentiation of gastrointestinal strornal tumors （GISTs）. METHODS： Thirty-three GISTs, 15 leiomyomas and 6 schwannomas were examined by immunohistochemistry in this study. RESULTS： VEGF protein was expressed in the cytoplasm of tumor cells, and VEGFRol and 2 were expressed both in the cytoplasm and on the membrane of all tumors. Irnrnunohistochernical staining revealed that 26 GISTs （78.8%）, 9 leiornyornas （60.0%） and 3 schwannornas （50.0%/were positive for VEGF; 24 GISTs （72.7%/, 12 leiornyornas （80.0%） and 4 schwannornas （66.7%） were positive for VEGFR-1; 30 GISTs （90.9%/, 5 leiornyornas （33.3%/and 4 schwannornas （66.7%） were positive for VEGFR-2. VEGFR-2 expression was statistically different between GISTs and leiomyomas （P 〈 0.0001）. However, there was no correlation between the expression of VEGF pathway componenets and the clinical risk categories. CONCLUSION： Our results suggest that the VEGF pathway may play an important role in the differentiation of GISTs, leiomyomas and schwannomas.

Expression of Angiopoietin-1, 2 and 4 and Tie-1 and 2 in gastrointestinal stromal tumor, leiomyoma and schwannoma

AIM: To investigate the role of angiopoietin (Ang) -1, -2 and -4 and its receptors, Tie-1 and -2, in the growth and differentiation of gastrointestinal stromal tumors (GISTs).METHODS: Thirty GISTs, seventeen leiomyomas and six schwannomas were examined by immunohistochemistry in this study.RESULTS: Ang-1, -2 and -4 proteins were expressed in the cytoplasm of tumor cells, and Tie-1 and -2 were expressed both in the cytoplasm and on the membrane of all tumors. Immunohistochemical staining revealed that 66.7% of GISTs (20 of 30), 76.5% of leiomyomas (13 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-1. 83.3% of GISTs (25 of 30), 82.4% of leiomyomas (14 of 17) and 100% of schwannomas (6 of 6) were positive for Ang-2. 36.7% of GISTs (11 of 30), 58.8% of leiomyomas (10 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-4. 60.0% of GISTs (18 of 30), 82.4% of leiomyomas and 100% of schwannomas (6 of 6) were positive for Tie-1. 10.0% of GISTs (3 of 30), 94.1% of leiomyomas (16 of 17) and 33.3% of schwannomas (2 of 6) were positive for Tie-2. Tie-2 expression was statistically different between GISTs and leiomyomas (P < 0.001). However, there was no correlation between expression of angiopoietin pathway components and clinical risk categories.CONCLUSION: Our results suggest that the angiopoietin pathway plays an important role in the differentiation of GISTs, leiomyomas and schwannomas.

Serum metabolic profiling of targeted bile acids reveals potentially novel biomarkers for primary biliary cholangitis and autoimmune hepatitis

BACKGROUND Primary biliary cholangitis(PBC)and autoimmune hepatitis(AIH)are two unexplained immune diseases.The golden standard for diagnosis of these diseases requires a liver biopsy.Liver biopsy is not widely accepted by patients because of its invasive nature,and atypical liver histology can confuse diagnosis.In view of the lack of effective diagnostic markers for PBC and AIH,combined with the increasingly mature metabolomics technologies,including full-contour metabolomics and target.AIM To determine non-invasive,reliable,and sensitive biochemical markers for the differential diagnosis of PBC and AIH.METHODS Serum samples from 54 patients with PBC,26 patients with AIH and 30 healthy controls were analyzed by Ultra-high performance liquid chromatographytandem mass spectrometry serum metabolomics.The metabolites and metabolic pathways were identified,and the metabolic changes,metabolic pathways and inter-group differences between PBC and AIH were analyzed.Fifteen kinds of target metabolites of bile acids(BAs)were quantitatively analyzed by SRM,and the differential metabolites related to the diagnosis of PBC were screened by receiver operating characteristic curve analysis.RESULTS We found the changes in the levels of amino acids,BAs,organic acids,phospholipids,choline,sugar,and sugar alcohols in patients with PBC and AIH.Furthermore,the SRM assay of BAs revealed the increased levels of chenodeoxycholic acid,lithocholic acid(LCA),taurolithocholic acid(TLCA),and LCA+TLCA in the PBC group compared with those in the AIH group.The levels of BAs may be used as biomarkers to differentiate PBC from AIH diseases.The levels of glycochenodeoxycholic acid,glycochenodeoxycholic sulfate,and taurodeoxycholic acid were gradually elevated with the increase of Child-Pugh class,which was correlated with the severity of disease.CONCLUSION The results demonstrated that the levels of BAs could serve as potential biomarkers for the early diagnosis and assessment of the severity of PBC and AIH.

Use of lectin microarray to differentiate gastric cancer from gastric ulcer

AIM: To investigate the feasibility of lectin microarray for differentiating gastric cancer from gastric ulcer. METHODS: Twenty cases of human gastric cancer tissue and 20 cases of human gastric ulcer tissue were collected and processed. Protein was extracted from the frozen tissues and stored. The lectins were dissolved in buffer, and the sugar-binding specificities of lectins and the layout of the lectin microarray were summarized. The median of the effective data points for each lectin was globally normalized to the sum of medians of all effective data points for each lectin in one block. Formalin-fixed paraffin-embedded gastric cancer tissues and their corresponding gastric ulcer tissues were subjected to Ag retrieval. Biotinylated lectin was used as the primary antibody and HRP-streptavidin as the secondary antibody. The glycopatterns of glycoprotein in gastric cancer and gastric ulcer specimens were determined by lectin microarray, and then validated by lectin histochemistry. Data are presented as mean +/- SD for the indicated number of independent experiments. RESULTS: The glycosylation level of gastric cancer was significantly higher than that in ulcer. In gastric cancer, most of the lectin binders showed positive signals and the intensity of the signals was stronger, whereas the opposite was the case for ulcers. Significant differences in the pathological score of the two lectins were apparent between ulcer and gastric cancer tissues using the same lectin. For MPL and VVA, all types of gastric cancer detected showed stronger staining and a higher positive rate in comparison with ulcer, especially in the case of signet ring cell carcinoma and intra-mucosal carcinoma. GalNAc bound to MPL showed a significant increase. A statistically significant association between MPL and gastric cancer was observed. As with MPL, there were significant differences in VVA staining between gastric cancer and ulcer. CONCLUSION: Lectin microarray can differentiate the different glycopatterns in gastric cancer and gastric ulcer, and the lectins MPL and VVA can be used as biomarkers. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Association of UCP3,APN,and TNF-α Gene Polymorphisms with Type 2 Diabetes in a Population of Northern Chinese Han Patients

We observed the polymorphism distribution and coaction of uncoupling protein 3（UCP3）-55C/T,adiponectin（APN）＋45T/G and tumor necrosis factor（TNF）-α-308G/A on the onset and development of T2DM in a Northern Chinese Han population of 213[100 type 2 diabete（T2DM） patients and 113 health control subjects] by polymerase chain reaction-restriction fragment length polymorphisum（PCR-RFLP） method.Results demonstrate the polymorphism of UCP3-55C/T,APN＋45T/G,and TNF-α-308G/A related to T2DM onset and developement.And the individuals carrying UCP3-55T,APN＋45G and TNF-α-308A allele had higher T2DM risk.Those results are the first report to evaluate the association of the coaction of UCP3,APN,TNF-α genes polymorphism on T2DM risk and the susceptibility of T2DM in the Northern Chinese Han population.

Oxidative phosphorylated neurofilament protein M protects spinal cord against ischemia/reperfusion injury

Previous studies have shown that neurofilament protein M expression is upregulated in the early stage of spinal cord ischemia/reperfusion injury, indicating that this protein may play a role in the injury process. In the present study, we compared protein expression in spinal cord tissue of rabbits after 25 minutes of ischemia followed by 0, 12, 24, or 48 hours of reperfusion with that of sham operated rabbits, using proteomic two-dimensional gel electrophoresis and mass spec- trometry. In addition, the nerve repair-related neurofilament protein M with the unregulated expression was detected with immunohistochemistry and western blot analysis. Two-dimen- sional gel electrophoresis and mass spectrometry showed that, compared with the sham group, upregulation of protein expression was most significant in the spinal cords of rabbits that had undergone ischemia and 24 hours of reperfusion. Immunohistochemical analysis revealed that neurofilament protein M was located in the membrane and cytoplasm of neuronal soma and axons at each time point after injury. Western blot analysis showed that neurofilament protein M expression increased with reperfusion time until it peaked at 24 hours and returned to baseline level after 48 hours. Furthermore, neurofilament protein M is phosphorylated under oxidative stress, and expression changes were parallel for the phosphorylated and non-phosphorylated forms. Neurofilament protein M plays an important role in spinal cord ischemia/reperfusion injury, and its functions are achieved through oxidative phosphorylation.

Morphological changes of gonadotropin-releasing hormone neurons in the rat preoptic area across puberty

Gonadotropin-releasing hormone （GnRH） neurons in the preoptic area may undergo morphological changes during the pubertal period when their activities are upregulated. To clarify the regulatory mechanism of puberty onset, this study aimed to investigate the morphological changes of GnRH neurons in the preoptic area of GnRH-enhanced green fluorescent protein transgenic rats. Under confocal laser microscopy, pubertal GnRH neurons exhibited an inverted Y distribution pattern. Prepubertal GnRH neurons were generally unipolar and bipolar, and were distinguished as smooth type cells with few small processes or irregular type cells with many spine-like processes in the proximal dendrites. The number of GnRH neurons in the preoptic area and spine-like processes were increased during the course of reproductive maturation. There was no significant difference between male and female rats. Immunofluorescence staining revealed synaptophysin punctae close to the distal end of GnRH neurons, indicating that some presynaptic terminals may form a synaptic linkage with these neurons.

Effects of glucocorticoid dexamethasone on serum nitric oxide synthase activity and nitric oxide levels in a rat model of lung disease-induced brain injury

In this study, we investigated the effects of dexamethasone, pertussis toxin （a Gi protein inhibitor） and actinomycin （a transcription inhibitor） on serum nitric oxide synthase activity and nitric oxide content in a rat model of lung disease-induced brain injury. High-dose dexamethasone （13 mg/kg） and dexamethasone ＋ actinomycin reduced lung water content, increased serum nitric oxide synthase activity and nitric oxide content, diminished inflammatory cell infiltration in pulmonary alveolar interstitium, attenuated meningeal vascular hyperemia, reduced glial cell infiltration, and decreased cerebral edema. These results demonstrate that high-dose glucocorticoid treatment can reduce the severity of lung disease-induced brain injury by increasing nitric oxide synthase activity and nitric oxide levels.

Design of Implant Prosthesis for Bone Injury Repair Considering Stress Shielding Effect

The failure of bone injury repair surgery is mostly due to the stress shielding effect caused by the difference of elastic modulus between the implant prosthesis and human bone,result-ing in a great damage to patients.To solve this problem,in this study,the influencing factors of the elastic modulus of implant prosthesis were investigated,the relationship between the elastic modulus of the implanted prosthesis and the influencing factors was analyzed,and then a design method of the implant prosthesis to reduce the stress shielding effect by adjusting the unit module to control the elastic modulus was established.This method was used for the biomechanical simula-tion to simulate the displacement and stress distribution between the implant prosthesis and the surrounding bone tissue,and then the reliability of the method was verified.The implant prosthe-sis with an elastic modulus consistent with that of the experimental dog bone was made by this method,and used for the animal experiments.The effects of implant prosthesis with different mod-ulus on the growth of surrounding bone tissue were observed,and at the same time,the reliability of the implant design method and the results of biomechanical simulation were verified.It is con-firmed that this method can effectively reduce the stress concentration of implant prosthesis by more than 15.4%and increase the growth of bone tissue by more than 21%.

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).

Publication trends in studies examining radix notoginseng as a treatment for ischemic brain injury

Acute ischemic stroke has become a major disease burden with high mortality and morbidity rates. There is a lack of evidence-based medicine confirming the efficacy of common treatments. Panax notoginseng saponins, the main active ingredient of radix notoginseng, have a neuro- protective role in ischemic brain injury, and have been popularized as a maintenance treatment for acute cerebral infarction and its sequelae. We conducted literature searches on the Web of Science, ClinicalTrials.gov, Cochrane Collaboration, CNKI, Wanfang and the China Scientific ＆ Technological Achievements Database and analyzed the experimental and clinical outcomes of studies investigating the use of radix notoginseng in the treatment of ischemic brain injury to improve the understanding of relevant research trends and existing problems. We found that over the past 10 years, China has maintained its interest in Panax notoginseng research, while such studies are scarce on the Web of Science. However, Chinese researchers often focus on the neuroprotective role of radix notoginseng in ischemic brain injury, but there are no large-scale clinical data to confirm its efficacy and safety. There remains a need for more rigorous large-sample randomized controlled clinical trials with long-term follow-up, to determine whether radix notoginseng lowers stroke recurrence and improves patient＇s quality of life.

Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis

Stem cells have been confirmed to be involved in the occurrence and development of diabetic retinopathy;however,the underlying mechanisms remain unclear.In this study,we used Citespace software to visually analyze 552 articles exploring the stem cell-based treatment of diabetic retinopathy over the past 20 years,which were included in the Web of Science Core Collection.We found the following:(1)a co-citation analysis of the references cited by all 552 articles indicated 15 clusters.In cluster#0,representing the stem cell field,some highly cited landmark studies emerged between 2009–2013.For example,endothelial progenitor cells and diabetic retinopathy gradually received the full attention of scholars,in terms of their relationship and therapeutic prospects.Some researchers also verified the potential of adipose-derived stem cells to differentiate into stable retinal perivascular cells,using a variety of animal models of retinal vascular disease.All of these achievements provided references for the subsequent stem cell research.(2)An analysis of popular keywords among the 552 articles revealed that,during the past 20 years,a relative increase in basic research articles examining stem cells and endothelial progenitor cells for the treatment of diabetic retinopathy was observed.The contents of these articles primarily involved the expression of vascular endothelial growth factor,vascular regeneration,oxidative stress,and inflammatory response.(3)A burst analysis of keywords used in the 552 articles indicated that genetic and cytological research regarding the promotion of angiogenesis was an issue of concern from 2001 to 2012,including several studies addressing the expression of various growth factor genes;from 2014 to 2020,mouse models of diabetic retinopathy were recognized as mature animal models,and the most recent research has focused on macular degeneration,macular edema,neurodegeneration,and inflammatory changes in diabetic animal models.(4)Globally,the current authoritative studies have focused on basic research towards the stem cell treatment of diabetic retinopathy.Existing clinical studies are of low quality and have insufficient evidence levels,and their findings have not yet been widely accepted in clinical practice.Major challenges during stem cell transplantation remain,including stem cell heterogeneity,cell delivery,and the effective homing of stem cells to damaged tissue.However,clinical trials examining potential stem cell-based treatments of diabetic retinopathy,including the use of pluripotent stem cells,retinal pigment epithelial cells,bone marrow mesenchymal stem cells,and endothelial progenitor cells,are currently ongoing,and high-quality clinical evidence is likely to appear in the future,to promote clinical transformation.

Angioarchitecture and prognosis of pediatric intracranial pial arteriovenous fistula

Objective Pial arteriovenous fistulas(PAVFs)are rare and mostly observed in children.However,the overall angioarchitecture,clinical features,treatments and long-term prognosis for pediatric patients remain unclear.Methods Clinical data of consecutive 42 pediatric PAVFs were documented and analysed.According to the differences of age distribution and clinical features,they were split into a younger group(≤3 years old;20 cases)and an older group(3-14 years old;22 cases).Results Their mean age was 4.9±3.9 years,and the mean preoperative modified Rankin Scale(mRS)score was 1.64±1.57.Fourteen patients(33.3%)were asymptomatic,followed by epilepsy(21.4%),intracranial haemorrhage(16.7%),hydrocephalus(9.5%),developmental delay(7.1%),intermittent headache(7.1%)and congestive heart failure(4.8%).Annual bleeding rate and rebleeding rate before treatment reached 3.86%and 3.17%.Poor venous drainage including sinus dynamic obstruction(21 cases,50.0%)and sinus occlusion(17 cases,40.48%)were found with high frequency among these patients.Finally,33 cases were cured(78.57%),and 4 cases faced surgery-related complications(9.52%).During 24-140 months’follow-up,the mean mRS score reduced to 0.57±0.40.However,only 22 cases(52.38%)recovered to absolutely normal,and poor venous drainage was the risk factor for patients’incomplete recovery(p=0.028,Exp(B)=14.692,95%CI 1.346 to 160.392).Compared with the older group,younger group showed more chronic symptoms,more secondary pathological changes,more times treatment and worse prognosis(p=0.013,0.002,0.000 and 0.032,respectively).Conclusions Pediatric PAVF has different angioarchitectures,clinical features and prognoses in different age groups.Poor venous drainage is an important factor leading to poor prognosis,and it accounts for incomplete recovery in nearly half of patients.