Hipotensión intracraneal espontánea. Una puesta al día

Introducción: La hipotensión intracraneal espontánea es un síndrome causado por la disminución del volumen de líquido cefalorraquídeo consecuencia de su fuga al espacio extradural. Aunque la ICHD-3 proporciona un alto nivel de especificidad diagnóstica, esta enfermedad puede manifestarse de forma atípica. Hasta en un 30% no es posible establecer el punto de escape, pero con el refinamiento de los exámenes de imágenes este porcentaje se ha reducido a un 15%-20%. Actualmente, su manejo no se encuentra estandarizado y las recomendaciones se basan en evidencia de limitada calidad metodológica, además de la variabilidad de protocolos entre distintos centros. Desarrollo En esta revisión actualizamos los procedimientos diagnósticos y terapéuticos. Por un lado, analizamos el rol de la resonancia nuclear magnética de encéfalo y médula espinal completa como primer paso diagnóstico y, por otro lado, señalamos los exámenes destinados a determinar la fuga de líquido cefalorraquídeo. Tal es el caso de la mielo-resonancia, la mielo-tomografía computarizada, tanto estándar, dinámica y por sustracción digital, además de la cisternografía con 111-Indium-DPTA. Sin embargo, determinar cuál de estos exámenes es el óptimo es objeto de debate. Lo mismo ocurre con el tratamiento: reposo; parche sanguíneo epidural a ciegas, parche guiado por fluoroscopia o tomografía computarizada, parche de fibrina; o cirugía. Conclusiones Se requiere de una mayor investigación, especialmente con trabajos multicéntricos controlados, para una mejor comprensión de la fisiopatología, el diagnóstico por imágenes, los enfoques terapéuticos y evaluación objetiva de los resultados clínicos. Solo así se establecerán pautas diagnósticas y de tratamiento validadas.

Introducction: Spontaneous intracranial hypotension is a syndrome caused by decreased CSF volume secondary to its leakage into the extradural space Although ICHD-3 provides a high level of diagnostic specificity, manifestations may be atypical, making diagnosis challenging. The site of leakage may be undetermined in point Up to 30% of cases, although with recent refinement of imaging, this percentage has been reduced to 15-20%. Currently, management is not standardized and recommendations are based on inconclusive evidence, with variability of protocols between centres. Development. In this review, we update diagnostic and therapeutic procedures. We analyse the role of whole brain and spinal cord MRI as a first investigation and review tests aimed at determining cerebrospinal fluid leakage, such as MRI myelography, conventional CT myelography, dynamic CT myelography, and digital subtraction CT myelography, as well as 111-Indium-DPTA cisternography. Determining optimal use of these investigations remains a matter of debate. The same is true for treatment: rest, blind epidural blood patch, fluoroscopy or CT-guided epidural blood patch, fibrin patch and surgery are discussed. Conclusión: Further research, especially multicentre controlled studies, is required to improve understanding of pathophysiology, diagnostic imaging, therapeutic approaches and to objectively assess clinical outcomes. Only then will diagnostic and treatment guidelines be evidence-based.

Safety of G-CSF in patients with COVID-19 / 中国临床药理学与治疗学

COVID-19, a disease caused by SARSCoV-2 infection, has caused a global pandemic in a short time. The key immunopathological features of COVID-19 include lymphopenia, neutropenia, cytokine storm and related Immune damage to parenchymal organs such as lung. Granulocyte colony stimulating factor (G-CSF) can cause excessive inflammatory reaction, which may aggravate the condition of some patients. Therefore, it is controversial whether COVID-19 should be treated with G-CSF, and clinicians need to evaluate the effectiveness and safety of G-CSF according to the specific conditions of each patient.

Frecuencia de agentes patógenos en meningitis neonatal en Lima, Perú, entre los años 2001 y 2021 / Frequency of pathogens in neonatal meningitis in Lima, Perú, between 2001 and 2021

RESUMEN Objetivo : Describir los agentes patógenos más frecuentes de la meningitis neonatal en el Perú. Material y métodos : Estudio descriptivo, comparativo y de corte transversal. Se realizó una búsqueda bibliográfica en las bases de datos de PubMed y SciELO con las palabras clave «meningitis¼, «neonatal¼ y «Perú¼, y en los repositorios virtuales de las facultades de Medicina del Perú con las palabras clave «meningitis¼ y «neonatal¼, entre los años 2001 y 2021. Asimismo, dos revisores independientes evaluaron los títulos y abstracts de los artículos para su inclusión. Resultados : Se encontraron 477 artículos, de los cuales cinco fueron incluidos. De estos últimos, dos fueron excluidos por falta de datos descriptivos de los gérmenes, quedando tres elegidos. Conclusiones : Los microorganismos más frecuentes fueron Listeria monocytogenes, Staphylococcus coagulasa-negativo y Escherichia coli, con predominio de bacterias grampositivas. La etiología viral fue poco frecuente y de presentación tardía. Solo se registró un caso por Candida albicans. No se encontraron registros de vigilancia epidemiológica de meningitis neonatal.

ABSTRACT Objective : To describe the most frequent pathogenic agents identified in neonatal meningitis in Peru. Material and methods : Descriptive, comparative, cross-sectional study based on data bases from PubMed and SciELO, using the key words "Neonatal", "Meningitis" and "Perú", and from virtual repositories of medical schools in Peru, with the key words "Neonatal" and "Meningitis", between 2001 and 2021. Two independent reviewers assessed the articles' titles and abstracts to be included. Results : 477 articles were found from which only 5 were included; 2 studies were excluded due to lack of descriptive identification of the microorganisms, so that only 3 studies were finally selected. Conclusions : The most frequently found microorganisms were Listeria monocytogenes, coagulada-negative Staphylococcus and Escherichia coli, predominantly grampositive bacterias. The viral etiology was uncommon, and all cases had a late onset. There was only 1 case due to Candida albicans. An epidemiologic monitoring of neonatal meningitis is not established in Peru.

PERIOPERATIVE CONCERNS OF VENTRICULOATRIAL SHUNT-A RETROSPECTIVE ANALYSIS OF 40 CASES.

Background: Ventriculo -peritoneal [VP] shunt is the most commonly used cerebrospinal ?uid (CSF) diversion procedure for the management of hydrocephalus. However, when the absorption of CSF from the peritoneum is defective, it results in abdominal distension with CSF ascites. In such cases, an alternate diversion procedure - the ventriculo-atrial [VA] shunt – may be performed. However, this procedure is also associated with several perioperative problems like arrhythmias, air embolism and infection. Materials and methods: A retrospective analysis of 40 cases on the perioperative concerns of VA shunt procedures, performed in our institute, was done. Indication of the shunt, preoperative status & work -up, intraoperative adverse events & management and immediate post-operative complications were assessed. Out of the 40 patients, there were 25 male Results: s and 15 females and there were a total of 12 paediatric patients. Blocked shunt, abdominal infection and CSF ascites were common indications for VA shunt. All patients received general endotracheal anaesthesia with preoperative hypovolemia correction. Intraoperative tachycardia and arrhythmia were noted. Various Conclusion : preoperative concerns like distended abdomen and compromised respiration increase risk of VA shunt procedures. A better understanding of the underlying disease pathology and anticipation of related complications along with cautious and meticulous management can help prevent most of the complications of VA shunt procedure and thereby improve outcome

Inmunodeficiencias secundarias relacionadas con la presencia de autoanticuerpos anticitocinas / Secondary immunodeficiencies related to the presence of anti-cytokine autoantibodies

Resumen Los autoanticuerpos anticitocinas (ACAA) han sido reportados como causa importante de inmunodeficiencias secundarias. Altos títulos de autoanticuerpos neutralizantes pueden causar susceptibilidad a diferentes enfermedades infecciosas potencialmente mortales. Por ejemplo, se ha informado que autoanticuerpos neutralizantes contra IFNγ se correlacionan con susceptibilidad a infecciones micobacterianas y patógenos fúngicos intracelulares. Autoanticuerpos contra IL-6 se detectaron en pacientes con abscesos subcutáneos y celulitis estafilocócica recurrente; asimismo, pacientes con criptococosis, nocardiosis y proteinosis alveolar pulmonar fueron positivos a autoanticuerpos contra GM-CSF. También se ha establecido una relación entre los autoanticuerpos contra IL-17 e IL-22 y las infecciones crónicas por Candida en mucosas, que se han identificado en pacientes con poliendocrinopatía autoinmune tipo 1 o timoma. Recientemente se han reportado autoanticuerpos contra interferón tipo I durante el inicio de COVID-19 aguda. Estos ACAA se asemejan a defectos genéticos en citocinas o en sus rutas de señalización. Por ello, pueden considerarse fenocopias de inmunodeficiencias primarias. De esta forma, la detección de ACAA podría ser importante en el diagnóstico, particularmente en pacientes con enfermedades de aparición tardía, para decidir los tratamientos apropiados. Esta revisión presenta una descripción general de la comprensión actual de las inmunodeficiencias secundarias asociadas a ACAA.

Abstract Anti-cytokine autoantibodies (ACAA) have been reported to be an important cause of secondary immunodeficiencies. High titers of neutralizing autoantibodies may cause susceptibility to different life-threatening infectious diseases. For example, neutralizing autoantibodies against IFNγ have been reported to be correlated with susceptibility to mycobacterial infections and intracellular fungal pathogens. Autoantibodies against IL-6 were detected in patients with subcutaneous abscesses and recurrent staphylococcal cellulitis; on the other hand, patients with cryptococcosis, nocardiosis, and pulmonary alveolar proteinosis were positive for autoantibodies to GM-CSF. A relationship has also been established between autoantibodies against IL-17 and IL-22 and chronic mucosal Candida infections, which have been identified in patients with APECED or thymoma. Autoantibodies against type-I IFN have been recently reported during the onset of acute COVID-19. These ACAAs resemble genetic defects in cytokines or their signaling pathways. Therefore, they may be considered to be primary immunodeficiencies phenocopies. Consequently, the detection of ACAA could be important in the diagnosis of patients, particularly in the case of late-onset diseases, in order to decide appropriate treatments. This review presents an overview of current understanding of ACAA-associated secondary immunodeficiencies.

Neumoencéfalo recurrente post quirúrgico, a raíz de dos casos / Post-surgical late pneumoencephalus, based on two cases

El neumoencéfalo es una patología que comúnmente se presenta después de cirugía neuroquirúrgica y ocasionalmente endonasal. Estos se suelen manejar de manera conservadora, sin embargo, se pueden asociar a distintas etiologías las cuales los hacen recurrir. En este reporte presentamos dos casos de neumoencéfalo tardío post quirúrgico asociado a fístulas de LCR de bajo flujo, donde se discute su clínica, etiología y manejo posterior.

Pneumocephalus is a pathology that commonly occurs after endonasal surgery, these are usually managed conservatively, however they can be associated with different etiologies which make them recur. In this report we present two cases of post-surgical late pneumocephalus associated with low-flow CSF fistulae, where its symptoms, etiology, and subsequent management are discussed.

Headache attributed to spontaneous intracranial hypotension and associated possible causes / Cefaleia atribuída à hipotensão intracraniana espontânea e possíveis causas associadas

Bem Junior and coworkers published a very interesting and opportunely case report on spontaneous intracranial hypotension, associated with cerebrospinal fluid (CSF) fistula in this issue. In recent decades, many publications have been addressing the subject. Spontaneous intracranial hypotension is little known among physicians, and the diagnosis is difficult even considering neurologists. Many patients progress without the correct diagnosis for weeks or even months. The clinical expression is classically similar to that found in post-dural puncture headache syndrome, an entity prevalent after spinal anesthesia. The most frequent symptom presentation is orthostatic headache, which worsens in the upright position and subsides after lying down.

Bem Junior e colaboradores publicaram nesta edição um relato de caso muito interessante e oportuno sobre hipotensão intracraniana espontânea, associada à fístula do líquido cefalorraquidiano (LCR). Nas últimas décadas, muitas publicações têm abordado o assunto. A hipotensão intracraniana espontânea é pouco conhecida entre os médicos e o diagnóstico é difícil mesmo entre neurologistas. Muitos pacientes evoluem sem o diagnóstico correto por semanas ou até meses. A expressão clínica é classicamente semelhante à encontrada na síndrome da cefaleia pós-punção dural, entidade prevalente após raquianestesia. O sintoma mais frequente é a cefaleia ortostática, que piora na posição ortostática e cede após deitar.

Effect of cryopreservation on biological activity of national standard of human granulocyte colony-stimulating factor after reconstitution / 中国生物制品学杂志

@#ObjectiveTo investigate the effect of cryopreservation on the biological activity of the national standard of human granulocyte colony-stimulating factor(hG-CSF)after reconstitution,so as to provide a reference for the use of the national standard of hG-CSF.MethodsThe biological activity of the standard was determined according to the general rule 3525 of Chinese Pharmacopoeia(Volume Ⅲ,2020 edition);The reconstituted hG-CSF national standard was aliquoted and stored at-80 ℃,-40 ℃ and-20 ℃,and then sampled at 1,2,3,5 and 6 months to detect the biological activity. The standards reconstituted before use were used to quantify the standards stored at -80 ℃ for different time durations,and the standards stored at -80 ℃ were defined as the reference of 100% activity to quantify the relative biological activity of the other samples.ResultsThe Eyrlng equation fitted by the thermal acceleration stability experiment was:ln {k(t)} = 6. 75-3 772. 20/T + ln(T),R~2= 0. 969. The biological activity of hG-CSF national standard was predicted to decrease by 5% after about 93. 4 months storage at -80 ℃；The biological activity of reconstituted standards frozen at -80 ℃ decreased by about 24%.ConclusionThe aliquoted reconstituted hG-CSF national standard can be stored at -80 ℃ stably for more than half a year. However,freezing and thawing will cause the activity value to drop by more than 20%,so it is not recommended to reuse after reconstitution.

Clinical application value of pegylated recombinant human granulocyte-colony stimulating factor in neutropenia after chemotherapy / 中国生物制品学杂志

@#During chemotherapy of malignant tumors,neutropenia is the most important adverse event caused by myelosuppressive chemotherapeutics,of which the degree and duration are closely related to the risk of infection and even death.Granulocyte-colony stimulating factor(G-CSF) is an endogenous hematopoietic growth factor that can stimulate the proliferation and differentiation of neutrophil precursors,and increase the survival rate and activity of mature neutrophils.Recombinant human granulocyte-colony stimulating factor(rhG-CSF) is an artificially synthesized cytokine with G-CSF biological activity.It is used clinically for the prevention and treatment of neutropenia after treatment with cytotoxic chemotherapeutics,requiring multiple medications and repeated injections during application for its short half-life.Pegylated recombinant human granulocyte-colony stimulating factor(PEG-rhG-CSF) is its long-acting dosage form,and patients only need to be administered once per cycle of chemotherapy,which has been widely used in clinical practice because of its stability and convenience.This paper systematically described the clinical application value of PEG-rhG-CSF in neutropenia after chemotherapy,aiming to provide a reference for its further clinical application.

Clinical efficacy of small incision conjoint fascial sheath suspension in treatment of severe congenital blepharoptosis / 中华医学美学美容杂志

Objective:To analyze the clinical effect of small incision approach conjoint fascial sheath (CFS) suspension in the treatment of congenital severe blepharoptosis, and to discuss its advantages and disadvantages compared with conventional CSF suspension.Methods:From February 2020 to August 2022, 42 cases of severe blepharoptosis in the Department of Burn, Plastic and Cosmetic Surgery, Shaanxi Provincial People's Hospital were divided into the observation group (23 cases, 39 eyes) and the control group (19 cases, 37 eyes). The observation group was treated with small incision CFS suspension surgery, while the control group was treated with conventional CFS suspension surgery. The correction effect, complications, recovery time and other conditions between the two groups at different times after surgery were compared.Results:During postoperative follow-up at 1 week, 1 month, 3 months, and 6 months, there was no significant difference in the corrective effect between the two surgical methods at each time point (all P>0.05). The incidence of complications in the observation group at each time point that was 26.3%, 15.7%, 10.5%, and 5.2%, respectively, while the incidence of complications in the control group was 60.0%, 20.0%, 14.2%, and 8.6%, with statistical differences in the first week after surgery (χ 2=8.74, P=0.011). The average postoperative swelling time in the observation group was 4.2 days, which was less than 5.8 days in the control group. During a 6-month follow-up, it was found that there was a decrease in scar hyperplasia in the observation group of 9.1% (2/22) compared to the control group of 16.7% (3/18) (χ 2=0.023, P=0.878). The difference was of no statistical significance. Conclusions:CFS suspension with small incision in the treatment of moderate and severe blepharoptosis has the advantages of ideal correction effect, small damage range, and few postoperative complications, but the operation area is small, the operation is difficult, and the surgeon has higher requirements.

The Brain Structure Volume Estimation Based on Synthetic MRI in Pediatric Acute Lymphoblastic Leukemia / 中山大学学报(医学科学版)

ObjectiveCentral nervous system （CNS） infiltration commonly occurs in children with acute lymphoblastic leukemia （ALL）. Early subclinical CNS infiltration in pediatric ALL is hard to detect with conventional methods. This study aimed to investigate the changes of brain structure volume parameters based on Synthetic MRI （SyMRI） in pediatric ALL without clinically diagnosed CNS infiltration. MethodsThirty-six ALL and twenty-nine typically developing （TD） children were prospectively collected and all underwent SyMRI. The Synthetic MR software was used to obtain brain volumetric parameters including total white matter volume （WMV）， gray matter volume （GMV）， cerebrospinal fluid （CSF） volume， etc. and their within-group differences were assessed by analysis of covariance. The Spearman correlation analysis was used to examine the correlation between biological characteristics and statistically significant brain volume parameters. ResultsALL children showed increased CSF volume （PFDR-corrected = 0.009） and decreased GMV （PFDR-corrected = 0.027） when compared to TD children. We also found a moderately negative association between GMV/intracranial volume and risk classification in pediatric ALL （rs = -0.380， P = 0.022）. ConclusionsPediatric ALL without clinically diagnosed CNS infiltration presented with accumulation of CSF and reduction of gray matter. The brain volumetric changes in subclinical CNS infiltration of pediatric ALL provides a new attempt for exploring the underlying mechanism and early detection of CNS infiltration in pediatric ALL.

Effect Mechanism of Modified Baitouwengtang Treating Colorectal Cancer by Regulating CSF1R/STING/TBK1 Signaling to Polarize Phenotype of Tumor-associated Macrophages （TAMs） / 中国实验方剂学杂志

ObjectiveThis study aims to investigate the effect of modified Baitouwengtang （MBTWD） on tumor growth and the number of tumor-associated macrophages （TAMs） in tumor tissue of MC38 cell tumor-bearing mice with colorectal cancer and explores whether MBTWD mediates the remodeling of TAM phenotype to play an immunologically antitumor effect. MethodFirstly， The C57BL/6 mouse tumor model grafted subcutaneously was established， and then model mice were classified into a model group， positive control group（3 mg·kg-1）， and MBTWD groups with high and low dosages（23.43、46.86 g·kg-1）， with 10 mice in each group. In addition， 10 healthy mice were set as the blank group， and the changes in body weight， tumor volume， and survival status of mice in each group were observed. Tumor tissue， spleen， and peripheral blood were collected to calculate the tumor volume change， tumor inhibition rate， and spleen mass. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissue， and an immunofluorescence assay was used to detect the expression levels of CD4， CD8， and CD206 in tumor tissues of tumor-bearing mice. The secretion levels of transforming growth factor （TGF）-β， interleukin （IL）-6， and chemokine （C-C Motif） ligand 2 （CCL2） in peripheral serum were measured by using enzyme-linked immunosorbent assay （ELISA）. Secondly， a co-culture model induced by IL-4 in vitro of MC38 cells and murine monocytic macrophage RAW264.7 cells was established. Cell proliferation and activity assay （CCK-8） was used to detect the inhibitory effect of MBTWD containing serum on cell proliferation. A transwell experiment was used to detect the effect of IL-4-induced M2 macrophages on the invasion of MC38 cells. Flow cytometry was used to detect the expression of CD86 on the membrane of M2 macrophages induced by IL-4 with MBTWD containing serum. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the effect of MBTWD containing serum on the mRNA expression levels of M1 macrophage-related polarization factors CD86， nitric oxide synthase （iNOS）， and IL-12， as well as M2 macrophage-related polarization factors CD206， CD163， and IL-10 after co-cultivation. Finally， the protein expression levels of colony-stimulating factor 1 receptor （CSF1R）， stimulator of interferon genes （STING）， and TANK binding kinase 1 （TBK1） in tumor tissues of tumor-bearing mice were detected by Western blot. ResultIn vivo experimental results show that compared with the model group， the MBTWD can significantly inhibit the tumor growth of tumor-bearing mice. Immunofluorescence experiments show that the MBTWD can increase the number of CD8+ T cell infiltration in tumor tissue of tumor-bearing mice， reduce the number of CD206+ TAMs infiltration， and down-regulate the secretion levels of cytokines IL-6， TGF-β， and CCL2 in peripheral blood of tumor-bearing mice. The results of in vitro experiments show that the MBTWD containing serum has no obvious inhibitory effect on cell proliferation， but the cell supernatant after co-cultivation with RAW264.7 cells can inhibit the proliferation activity of MC38 cells， and the invasion ability of MC38 cells is enhanced by IL-4-induced M2 macrophages. However， this effect can be inhibited in a concentration-dependent manner by the MBTWD containing serum. At the same time， the results of Real-time PCR show that the MBTWD containing serum can up-regulate the mRNA expression levels of M1 macrophage-related polarization factors CD86， iNOS， and IL-12 and down-regulate those of M2 macrophage-related polarization factors CD206， CD163， and IL-10. Flow cytometry results also confirm that the MBTWD containing serum can increase the number of repolarized CD86+ M1 macrophages， indicating that MBTWD can induce M2 macrophages to repolarized M1 macrophages to play an anti-tumor growth role. Finally， Western blot results show that MBTWD can down-regulate the expression of CSF1R protein and up-regulate that of STING and TBK1 proteins in tumor tissue of tumor-bearing mice. ConclusionMBTWD can down-regulate the infiltration number of CD206+ TAMs and increase the infiltration of CD8+ T cells， thereby playing an immunologically antitumor effect on the growth inhibition of colorectal cancer， which may be related to regulating CSF1R signaling and then activating STING/TBK1 signaling pathway to induce phenotypic remodeling of TAMs.

Clinical significance of Epstein-Barr Virus detection in the cerebrospinal fluid of patients who underwent hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To analyze the detection rate, clinical significance, and prognosis of Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of patients following allogeneic hematopoietic stem cell transplantation. Methods: A retrospective analysis was performed on 1100 patients who underwent the CSF virus test after allogeneic hematopoietic stem cell transplantation in Peking University People's Hospital between January 2017 and June 2022. Among them, 19 patients were screened positive for EBV in their CSF, and their clinical characteristics, treatment, and prognosis were analyzed. Results: Among 19 patients with EBV-positive cerebrospinal fluid, 12 were male and 7 were female, with 5 patients aged <18 years and 12 aged ≥18 years, with a median age of 27 (5-58) years old. There were 7 cases of acute myeloid leukemia, 8 of acute lymphocytic leukemia, 2 of aplastic anemia, 1 of Hodgkin's lymphoma, and 1 of hemophagocytic syndrome. All 19 patients underwent haploid hematopoietic stem cell transplantation, including 1 secondary transplant. Nineteen patients had neurological symptoms (headache, dizziness, convulsions, or seizures), of which 13 had fever. Ten cases showed no abnormalities in cranial imaging examination. Among the 19 patients, 6 were diagnosed with EB virus-related central nervous system diseases, with a median diagnosis time of 50 (22-363) days after transplantation. In 9 (47.3%) patients, EBV was detected in their peripheral blood, and they were treated with intravenous infusion of rituximab (including two patients who underwent lumbar puncture and intrathecal injection of rituximab). After treatment, EBV was not detected in seven patients. Among the 19 patients, 2 died from EBV infection and 2 from other causes. Conclusion: In patients who exhibited central nervous system symptoms after allogeneic hematopoietic stem cell transplantation, EBV should be screened as a potential pathogen. EBV detected in the CSF may indicate an infection; however, it does not confirm the diagnosis.

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

JAK inhibition ameliorated experimental autoimmune encephalomyelitis by blocking GM-CSF-driven inflammatory signature of monocytes

Monocytes are key effectors in autoimmunity-related diseases in the central nervous system (CNS) due to the critical roles of these cells in the production of proinflammatory cytokines, differentiation of T-helper (Th) cells, and antigen presentation. The JAK-STAT signaling is crucial for initiating monocytes induced immune responses by relaying cytokines signaling. However, the role of this pathway in modulating the communication between monocytes and Th cells in the pathogenesis of multiple sclerosis (MS) is unclear. Here, we show that the JAK1/2/3 and STAT1/3/5/6 subtypes involved in the demyelination mediated by the differentiation of pathological Th1 and Th17 and the CNS-infiltrating inflammatory monocytes in experimental autoimmune encephalomyelitis (EAE), a model for MS. JAK inhibition prevented the CNS-infiltrating CCR2-dependent Ly6Chi monocytes and monocyte-derived dendritic cells in EAE mice. In parallel, the proportion of GM-CSF+CD4+ T cells and GM-CSF secretion were decreased in pathological Th17 cells by JAK inhibition, which in turns converted CNS-invading monocytes into antigen-presenting cells to mediate tissue damage. Together, our data highlight the therapeutic potential of JAK inhibition in treating EAE by blocking the GM-CSF-driven inflammatory signature of monocytes.

Genetic Architecture and Functional Implications of the CSF-Contacting Nucleus / 神经科学通报·英文版

We previously identified a unique nucleus, the cerebrospinal fluid (CSF)-contacting nucleus. This study aims to understand its gene architecture and preliminarily suggest its functions. The results showed that there were about 19,666 genes in this nucleus, of which 913 were distinct from the dorsal raphe nucleus (non-CSF contacting). The top 40 highly-expressed genes are mainly related to energy metabolism, protein synthesis, transport, secretion, and hydrolysis. The main neurotransmitter is 5-HT. The receptors of 5-HT and GABA are abundant. The channels for Cl-, Na+, K+, and Ca2+ are routinely expressed. The signaling molecules associated with the CaMK, JAK, and MAPK pathways were identified accurately. In particular, the channels of transient receptor potential associated with nociceptors and the solute carrier superfamily members associated with cell membrane transport were significantly expressed. The relationship between the main genes of the nucleus and life activities is preliminarily verified.

Needle caliber and design are associated with the risk of post-dural puncture headache after diagnostic lumbar puncture / O calibre e o design da agulha estão associados ao risco de cefaleia pós-punção dural após punção lombar diagnóstica

Introduction:Post-dural puncture headache (PDPH) is defined as an orthostatic headache that develops within the first few days after performing a spinal tap and it is related to extravasation of cerebrospinal fluid (CSF) into the epidural space, resulting in CSF hypovolemia and hypotension. The risk factors for PDPH are not yet fully understood. Objective:To evaluate the risk of spontaneously reported PDPH according to the size and type of spinal tap needle. Methods:A total of 4589 patients undergoing outpatient lumbar puncture (LP) were included. All CSF collections were performed at Senne Liquor Diagnostico, a laboratory specialized in CSF collection and analysis. Patients were instructed to report by telephone if they had orthostatic headache during the first 7 days after LP to the medical team of the laboratory. Patients with previous headache were instructed to report any change in the headache pattern during the same period. Needle gauge was classified into two groups: 1) 25 G or less and 2) greater than 25 G. Two types of needles were used and compared: 1) Pencil point and 2) Quincke. Comparisons of the percentages of spontaneous reports of PDPH were made using the chi-square test. Results:141 patients (3.07%) reported PDPH to the laboratory's medical team. Needles of 25G gauge or less were used in 31.8% of cases. The percentage of patients reporting PHD in the group of 25G or less needles was 1.9% versus 3.6% in the group of larger than 25G needles (p=0.003). Pencil point needles were used in 10.6% of cases. The percentage of PHD among pencil point group was 1.4% versus 3.2% in Quincke group (p=0.026). Conclusion:25 G or finer gauge needles as well as pencil point type needles significantly reduced the risk of spontaneously reported PHD.

Introdução: A cefaleia pós-punção dural (CPPD) é definida como uma cefaleia ortostática que se desenvolve nos primeiros dias após a realização de uma punção lombar e está relacionada ao extravasamento de líquido cefalorraquidiano (LCR) para o espaço peridural, resultando em hipovolemia do LCR e hipotensão. Os fatores de risco para CPPD ainda não são totalmente compreendidos. Objetivo:Avaliar o risco de CPPD relatada espontaneamente de acordo com o tamanho e tipo de agulha de punção lombar. Métodos: Foram incluídos 4.589 pacientes submetidos à punção lombar (PL) ambulatorial. Todas as coletas de LCR foram realizadas no Senne Liquor Diagnostico, laboratório especializado em coleta e análise de LCR. Os pacientes foram orientados a relatar por telefone à equipe médica do laboratório se apresentassem cefaleia ortostática nos primeiros 7 dias após a PL. Pacientes com cefaleia prévia foram orientados a relatar qualquer alteração no padrão de cefaleia durante o mesmo período. O calibre da agulha foi classificado em dois grupos: 1) 25 G ou menos e 2) maior que 25 G. Dois tipos de agulhas foram utilizados e comparados: 1) ponta de lápis e 2) Quincke. As comparações dos percentuais de notificações espontâneas de CPPD foram feitas por meio do teste do qui-quadrado. Resultados:141 pacientes (3,07%) relataram CPPD à equipe médica do laboratório. Agulhas de calibre 25G ou menos foram utilizadas em 31,8% dos casos. A porcentagem de pacientes que relataram HDP no grupo de agulhas 25G ou menos foi de 1,9% versus 3,6% no grupo de agulhas maiores que 25G (p=0,003). Agulhas com ponta de lápis foram utilizadas em 10,6% dos casos. O percentual de DPH no grupo ponta de lápis foi de 1,4% versus 3,2% no grupo Quincke (p=0,026). Conclusão: Agulhas de calibre 25 G ou mais fino, bem como agulhas tipo ponta de lápis reduziram significativamente o risco de HP relatado espontaneamente.

Management of coexistent sinonasal pathology in patients undergoing endoscopic cerebrospinal fluid rhinorrhea repair / Manejo de doenças nasossinusais coexistentes em pacientes submetidos a tratamento cirúrgico endoscópico de fístula liquórica

Abstract Introduction Patients who undergo endoscopic cerebrospinal fluid rhinorrhea repair may occasionally present with coexistent sinonasal pathology which may or may not need to be addressed prior to surgical repair. Some patients may develop new onset nasal morbidity related to endoscopic repair. Objective To study the prevalence and management of additional sinonasal pathology in patients who undergo endoscopic repair of cerebrospinal fluid rhinorrhea Methods A retrospective review of patients who underwent endoscopic cerebrospinal fluid leak repair was conducted to note the presence of coexistent sinonasal morbidity preoperatively and in the followup period. Results Of a total of 153 patients who underwent endoscopic closure of cerebrospinal fluid leak, 97 (63.4%) were female and 56 (36.6%) males. Most patients (90.2%) were aged between 21 and 60 years, with a mean of 40.8 years. Sixty-four patients (41.8%) were found to have coexistent sinonasal morbidity preoperatively, the commonest being symptomatic deviated nasal septum (17.6%), chronic rhinosinusitis without polyps (11.1%) and chronic rhinosinusitis with polyps (3.3%). Rare instances of septal hemangioma (0.7%) and inverting papilloma (0.7%) were also seen. Postoperatively, there was cessation of cerebrospinal fluid rhinorrhea in 96.7% which rose to 100% after revision surgery in those with recurrence. Resolution of coexistent sinonasal pathology occurred in all patients with followup ranging from 10 to 192 months. New onset sinonasal morbidity which developed postoperatively included synechiae between middle turbinate and lateral nasal wall (5.9%) and sinonasal polyposis (1.3%). Conclusion Patients who undergo endoscopic cerebrospinal fluid leak repair may have coexistent sinonasal pathology which needs to be addressed prior to or along with repair of the dural defect. New onset sinonasal morbidity, which may arise in a few patients postoperatively, may require additional treatment. A protocol for the management of coexistent sinonasal conditions ensures a successful outcome.

Resumo Introdução Pacientes submetidos a tratamento cirúrgico endoscópico de fístula liquórica podem ocasionalmente apresentar coexistência de outras doenças comuns que podem ou não precisar ser tratadas antes do procedimento. Alguns pacientes podem desenvolver nova morbidade nasal relacionada ao tratamento da fístula. Objetivo Estudar a prevalência e o manejo de doenças nasossinusais adicionais em pacientes submetidos ao reparo endoscópico de fístula liquórica. Método Uma revisão retrospectiva de pacientes submetidos ao reparo endoscópico de fistula liquórica foi feita para avaliar a presença de outras morbidades nasossinusais coexistentes no pré‐operatório e no período de seguimento. Resultados De 153 pacientes submetidos ao tratamento endoscópico do fistula liquórica, 97 (63,4%) eram do sexo feminino e 56 (36,6%) do masculino. A maioria dos pacientes (90,2%) tinha entre 21 e 60 anos, com média de 40,8. Verificou‐se que 64 pacientes (41,8%) apresentavam coexistência de morbidade nasossinusal no pré‐operatório, as mais comuns eram desvio de septo nasal sintomático (17,6%), rinossinusite crônica sem pólipos (11,1%) e rinossinusite crônica com pólipos (3,3%). Casos raros de hemangioma septal (0,7%) e papiloma invertido (0,7%) também foram observados. No pós‐operatório, inicialmente obteve‐se fechamento da fístula liquórica em 96,7%, que aumentou para 100% após a cirurgia de revisão nos pacientes com recorrência. A resolução das outras doenças nasossinusais coexistentes foi obtida em todos os pacientes, o seguimento variou de 10 a 192 meses. A ocorrência de uma nova morbidade nasossinusal no pós‐operatório incluiu sinéquias entre a concha média e a parede lateral do nariz (5,9%) e polipose nasossinusal (1,3%). Conclusão Pacientes submetidos a tratamento endoscópico de fistula liquórica podem apresentar coexistência de outras doenças nasossinusais que necessitam de tratamento prévio ou concomitante ao reparo do defeito dural. Outras morbidades nasossinusais que surgem durante o pós‐operatório podem exigir tratamento adicional. Um protocolo para o manejo das condições nasossinusais coexistentes garante um desfecho bem‐sucedido.

Liquid biopsy in CNS tumors: Current status & future perspectives

Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.

Investigation of therapeutic effects in the wound healing of chitosan/pGM-CSF complexes

Abstract Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to promote the growth, proliferation, and migration of endothelial and keratinocyte cells. Chitosan has been widely used as a biopolymer in wound-healing studies. The aim of this study was to investigate the in vitro proliferative effects of chitosan/pGM-CSF complexes as well as the therapeutic role of the complexes in an in vivo rat wound model. The effect of complexes on cell proliferation and migration was examined. Wounds were made in Wistar-albino rats, and examined histopathologically. The cell proliferation and migration were increased weight ratio- and time-dependently in HaCaT and NIH-3T3 cell lines. Wound healing was significantly accelerated in rats treated with the complexes. These results showed that the delivery of pGM-CSF using chitosan complexes could play an accelerating role in the cell proliferation, migration, and wound-healing process.