Mechanosensitive channel of large conductance enhances the mechanical stretching-induced upregulation of glycolysis and oxidative metabolism in Schwann cells.

BACKGROUND: Physical exercise directly stretching the peripheral nerve promotes nerve regeneration; however, its action mechanism remains elusive. Our present study aimed to investigate the effects of mechanosensitive channel of large conductance (MscL) activated by mechanical stretching on the cultured Schwann cells (SCs) and explore the possible mechanism. METHODS: Primary SCs from neonatal mice at 3-5 days of age were derived and transfected with the lentivirus vector expressing a mutant version of MscL, MscL-G22S. We first detected the cell viability and calcium ion (Ca2+) influx in the MscL-G22S-expressing SCs with low-intensity mechanical stretching and the controls. Proteomic and energy metabolomics analyses were performed to investigate the comprehensive effects of MscL-G22S activation on SCs. Measurement of glycolysis- and oxidative phosphorylation-related molecules and ATP production were respectively performed to further validate the effects of MscL-G22S activation on SCs. Finally, the roles of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway in the mechanism of energy metabolism modulation of SCs by MscL-G22S activation was investigated. RESULTS: Mechanical stretching-induced MscL-G22S activation significantly increased the cell viability and Ca2+ influx into the SCs. Both the proteomic and targeted energy metabolomics analysis indicated the upregulation of energy metabolism as the main action mechanism of MscL-G22S-activation on SCs. MscL-G22S-activated SCs showed significant upregulation of glycolysis and oxidative phosphorylation when SCs with stretching alone had only mild upregulation of energy metabolism than those without stimuli. MscL-G22S activation caused significant phosphorylation of the PI3K/AKT/mTOR signaling pathway and upregulation of HIF-1α/c-Myc. Inhibition of PI3K abolished the MscL-G22S activation-induced upregulation of HIF-1α/c-Myc signaling in SCs and reduced the levels of glycolysis- and oxidative phosphorylation-related substrates and mitochondrial activity. CONCLUSION: Mechanical stretching activates MscL-G22S to significantly promote the energy metabolism of SCs and the production of energic substrates, which may be applied to enhance nerve regeneration via the glia-axonal metabolic coupling.

A novel classification model based on cerebral 18F-FDG uptake pattern facilitates the diagnosis of acute/subacute seropositive autoimmune encephalitis.

PURPOSE: To explore the intrinsic alteration of cerebral 18F-FDG metabolism in acute/subacute seropositive autoimmune encephalitis (AE) and to propose a universal classification model based on 18F-FDG metabolic patterns to predict AE. METHODS: Cerebral 18F-FDG PET images of 42 acute/subacute seropositive AE patients and 45 healthy controls (HCs) were compared using voxelwise and region of interest (ROI)-based schemes. The mean standardized uptake value ratios (SUVRs) of 59 subregions according to a modified Automated Anatomical Labeling (AAL) atlas were compared using a t-test. Subjects were randomly divided into a training set (70%) and a testing set (30%). Logistic regression models were built based on the SUVRs and the models were evaluated by determining their predictive value in the training and testing sets. RESULTS: The 18F-FDG uptake pattern in the AE group was characterized by increased SUVRs in the brainstem, cerebellum, basal ganglia, and temporal lobe, and decreased SUVRs in the occipital, and frontal regions with voxelwise analysis (false discovery rate [FDR] p<0.05). Utilizing ROI-based analysis, we identified 15 subareas that exhibited statistically significant changes in SUVRs among AE patients compared to HC (FDR p<0.05). Further, a logistic regression model incorporating SUVRs from the calcarine cortex, putamen, supramarginal gyrus, cerebelum_10, and hippocampus successfully enhanced the positive predictive value from 0.76 to 0.86 when compared to visual assessments. This model also demonstrated potent predictive ability, with AUC values of 0.94 and 0.91 observed for the training and testing sets, respectively. CONCLUSIONS: During the acute/subacute stages of seropositive AE, alterations in SUVRs appear to be concentrated within physiologically significant regions, ultimately defining the general cerebral metabolic pattern. By incorporating these key regions into a new classification model, we have improved the overall diagnostic efficiency of AE.

Impact of HPV vaccination on HPV infection and cervical related disease burden in real-world settings (HPV-RWS): protocol of a prospective cohort.

BACKGROUND: Cervical cancer is one of the most common cancers in women and could be prevented by human papilloma virus (HPV) vaccination. Cervarix, the first available HPV vaccine, has been widely administrated to Chinese women, while little was known about its effect on the prevention and control for HPV related diseases in China. The study aims to assess the impact of Cervarix on HPV infection and cervical related diseases in real world. METHODS: This is a prospective, multi-age birth cohort study to investigate the incidence and continuous status of HPV infection, and relevant cervical diseases by exposure status (with Cervarix vaccination history or without any HPV vaccination history). It is planned to recruit 12,118 eligible women at age of 9 to 45 years from vaccination clinics or hospital outpatient clinics, and then follow up them for three years. The standard questionnaire will be used to collect information such as demographic characteristics, menstruation and obstetrical histories, history of sexual behavior, personal behavior history, history of disease and pathogen infection, medication history, and family history at baseline. After three years, the changes of these behaviors will be investigated again, and other related health status information will be retrieved from the electronic health records during the follow-up period. If available physically and legally, the cervical cancer screening will be performed, including type-specific HPV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) testing and contingent thinprep cytologic test (TCT) and colposcopy. The free cervical cancer screening will be captured and uploaded timely to the Yinzhou Regional Health Information Platform (YRHIP); therefore, the long-term outcomes of participants will be monitored. DISCUSSION: This prospective cohort study will assess the impact of HPV vaccine on HPV infection and related cervical diseases in women aged 9-45 years, which makes up for the lack of evidence in Chinese women. The results of this study will provide support for understanding the impact of HPV vaccination in China, and make a contribution to increasing HPV vaccination and cervical cancer screening coverage in China. TRIAL REGISTRATION: This study has been retrospectively registered on clinicaltrials.gov (NCT05341284) on April 22, 2022.

The impact of pre-evacuation ultrasound examination in histologically confirmed hydatidiform mole in missed abortion.

BACKGROUND: Early detecting hydatidiform mole in missed abortion is challenge. In this retrospective observational study, we analysed the sensitivity of detecting hydatidiform mole by pre-evacuation ultrasound examination or naked eye after surgical uterine evacuation in missed abortion. METHODS: Data on 577 cases with histologically confirmed hydatidiform mole were collected over a 10-year period and analysed. Data included serum ß-hCG level before surgical evacuation, the ultrasound examination findings, histology findings and naked eye findings. In addition, serum ß-hCG level on 2398 cases without hydatidiform mole was also collected. RESULTS: The median maternal age was 29 (range, 17-53) years and the range of gestational age was 6 to 12 weeks. The sensitivity of detecting hydatidiform mole by ultrasound examination or by naked eye was 25% or 60% respectively. This sensitivity was not increased by the combination of ultrasound and naked eye. There was no difference in the sensitivity of detecting subtypes of hydatidiform mole. The higher ß-hCG level was seen in cases with hydatidiform mole, compared to cases without hydatidiform mole. However, there was a lot of overlap in the distributions of ß-hCG between the two groups. CONCLUSIONS: In this study, we found lower sensitivity of detecting hydatidiform mole by ultrasound in missed abortion. ß-hCG level was higher in hydatidiform mole than in non- hydatidiform mole in missed abortion. Although higher sensitivity of detecting hydatidiform mole is seen by naked eye (60%), in order to minimise missed opportunity of detecting hydatidiform mole, our study suggests that routine histopathological examination is necessary in missed abortion.

Dynein axonemal intermediate chain 2 plays a role in gametogenesis by activation of Stat3.

We previously identified the mouse dynein axonemal intermediate chain 2 (Dnaic2) gene. This gene expresses a component of the axonemal dynein complex that functions in cilia or flagella. We found that overexpression of Dnaic2 results in female subfertility and male infertility. In this study, we generated Dnaic2 knockdown (KD) mice and identified the potential regulatory mechanisms involved in Dnaic2 function. For phenotype analysis, we found that body weight was lighter and size was smaller in Dnaic2 KD mice than in wild-type mice. A total of 45% of these Dnaic2 KD mice were infertile due to sperm abnormalities in males, or had oocyte abnormalities and pathological changes in the tunica mucosa in the oviduct of females. Moreover, Dnaic2 overexpression enhanced the expression of proliferating cell nuclear antigen (PCNA) in the ovaries, which suggested that Dnaic2 stimulated proliferation of cells in the ovaries. However, PCNA expression in the testis of Dnaic2-overexpressed mice was lower than that in controls. Additionally, the ratio of Bax/B-cell lymphoma-2(Bcl-2) in the testis of Dnaic2-overexpressed mice was higher than that in controls, which suggested that Dnaic2 inhibited cellular proliferation in the testis. To examine the molecular action of Dnaic2, immunoprecipitation analysis was used and showed that Dnaic2 protein interacted with signal transducer and activator of transcription 3 (Stat3). Molecular modelling analysis showed that Dnaic2 bound with the linker and SH2 domains of Stat3. Furthermore, overexpression of Dnaic2 promoted phosphorylation of Stat3. In conclusion, our study suggests that Dnaic2 plays a role in oogenesis and spermatogenesis by activation of Stat3.

Interleukin-16 aggravates ovalbumin-induced allergic inflammation by enhancing Th2 and Th17 cytokine production in a mouse model.

Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.

Unstable Carotid Plaque is Associated With Coagulation Function and Platelet Activity Evaluated by Thrombelastography.

BACKGROUND: Rupture of unstable carotid plaque and consequently occlusive thrombus formation for the most part cause ischemic cerebral vascular event. Many researchers have been studying on the risk predictors of carotid plaque formation. But the risk factors for unstable carotid plaque have not been researched for so much. In the current study, we aimed to evaluate the association of coagulation function and carotid plaque especially unstable plaque by thrombelastography (TEG). METHODS: This was a cross-sectional study. Consecutive eligible patients with acute ischemic stroke were included and their TEG data were collected. Carotid plaque was evaluated by carotid ultrasound. Echolucent plaque and heterogeneous echo plaque in ultrasound were classified as unstable carotid plaque. Patients were classified according to being with carotid plaque or unstable plaque for comparison. RESULTS: Four hundred and seven patients were enrolled. Compared to those without carotid plaques, patients with carotid plaques had higher ages, higher incidence of hypertension and diabetes mellitus, lower k (P = .017) and higher angle (P = .021) on TEG. In the comparison between groups with unstable plaque and stable plaque, no significant difference was found in baseline characteristics; higher serum fibrinogen and higher maximum amplitude on TEG were significantly correlated to unstable carotid plaques (P = .051, P = .009). Multivariate logistic analysis revealed that age, hypertension, and smoking were independent risk factors of carotid plaques formation; higher serum fibrinogen was an independent risk factor of unstable plaques formation. CONCLUSIONS: This study demonstrates that carotid plaques formation in ischemic stroke patients has a link to abnormal coagulation function, while high platelet activity has an additional contribution to unstable plaque formation.

Risk Factors for Unsuccessful Office-Based Endometrial Biopsy: A Comparative Study of Office-Based Endometrial Biopsy (Pipelle) and Diagnostic Dilation and Curettage.

STUDY OBJECTIVE: To determine the risk factors for Pipelle diagnostic failure, which might help healthcare providers choose the appropriate protocol for endometrial evaluation individually. DESIGN: A single-center prospective study (Canadian Task Force classification II). SETTING: The Obstetrics and Gynecology Hospital of Fudan University. PATIENTS: Patients (n = 466) with an indication for endometrial biopsy. INTERVENTIONS: All patients received Pipelle and then diagnostic dilation and curettage. The samples were sent for histopathologic diagnosis separately. MEASUREMENTS AND MAIN RESULTS: The Pipelle procedure failed in 10 of 466 patients (2.146%). The general sample inadequacy and histopathologic diagnosis inconsistency of Pipelle was 5.921% (27/456) and 14.254% (65/456), respectively. Upon multivariate analysis, history of cervical operation(s) (odds ratio [OR], 26.510; 95% coefficient interval [CI], 2.932-239.784; p = .004), prior intrauterine procedure(s) (OR, .096; 95% CI, .017-.554; p = .009), and pinpoint cervical os (OR, 5.939; 95% CI, 1.134-31.108; p = .035) were significantly associated with Pipelle procedure failure. Meanwhile, uterine volume < 43 cm3 (OR, 8.229; 95% CI, 1.902-35.601; p = .005) and uneven endometrium detected by ultrasound (OR, .176; 95% CI, .042-.734; p = .017) had significant correlation with sample inadequacy. Pipelle detected all endometrial cancer cases, whereas only 50.000% (7/14) of endometrial hyperplasia with atypia, 26.471% (9/34) of polyps, and 18.182% (2/11) of polyps with endometrial hyperplasia without atypia cases were detected by Pipelle. CONCLUSION: Although Pipelle is the first-line method for endometrial biopsy, it might fail in women with risk factors identified in this study. More considerations should be taken when choosing Pipelle.

The HEP Score: A Nomogram-Derived Hematoma Expansion Prediction Scale.

BACKGROUND: Identification of intracerebral hemorrhage (ICH) patients at risk of substantial hematoma expansion (SHE) could facilitate the selection of candidates likely to benefit from therapies aiming to minimize ICH growth. We aimed to develop a grading tool that can be quickly used during the hyperacute phase to predict the risk of SHE. METHODS: We reviewed data from 237 spontaneous ICH patients who had baseline head CT scan within 12 h of symptom onset and follow-up CT during the following 72 h. We performed logistic regression analyses to determine the predictors of SHE (defined as an absolute increase in ICH volume >6 ml or an increase >33% on follow-up CT). We identified 6 predictors; each was assigned a point in the graphic interface of a nomogram which was used to construct a scoring system-The Hematoma Expansion Prediction (HEP) Score, varying from 0 to 18 points. We evaluated the ability of the model to predict the probability of SHE using c-statistics. RESULTS: SHE occurred in 74 patients (31.2%). The final model to predict SHE included 6 variables: time from onset to baseline CT (<3 vs. 3-12 h), history of dementia, current smoking, antiplatelet use, Glasgow Comma Scale score, and the presence of subarachnoid hemorrhage on baseline scan. The model had satisfactory discrimination ability with a bootstrap corrected c-index of 0.76 (95% CI 0.69-0.83) and good calibration. Patients with a total HEP score >3 were at greatest risk for SHE. CONCLUSIONS: We developed and internally validated a novel nomogram and an easy to use score which accurately predict the probability of SHE based on six easily obtainable parameters. This could be useful for treatment decision and stratification. External prospective validation of the HEP score is warranted before its application to other populations.

Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke.

BACKGROUND: Elevated maximal clot strength, measured by thrombelastography (TEG) maximum amplitude (MA) has been associated with a higher risk for ischemic events in patients with coronary artery diseases. However, it has not been investigated in patients with cerebrovascular diseases. In the current study, we aimed to evaluate the predictive ability of TEG-MA in assessing the risk for ischemic event recurrence and the functional outcome after index ischemic stroke. METHODS: This was a prospective observational study. Consecutive eligible patients with acute ischemic stroke were included and followed up for one year. Patients were stratified into tertile groups based on MA levels. TEG-hypercoagulability was defined as an MA of ≥ 69 mm. Ischemic events were defined as a composite of ischemic stroke, myocardial infarction, or vascular death (excluding hemorrhagic death). The functional outcome was evaluated by modified Rankin Scale (mRS). Unfavorable functional outcome was defined as mRS ≥ 2. RESULTS: Two hundred and eleven patients were enrolled with 27 lost to follow-up at one year contact. At baseline, 38 (18.0%) patients were TEG-hypercoagulopathy after the treatment of antiplatelets. Patients with higher tertile of MA were more likely to be females, and had lower hemoglobin levels, higher platelet counts, higher fibrinogen levels, higher white blood cell counts, as well as higher ESR and hsCRP levels. Patients in the third tertile group were more likely to have intracranial artery stenosis and large-vessel subtype stroke than those in the other two groups. Higher tertile of MA was also related to stroke severity in acute phase (higher NIHSS scores on admission and longer in-hospital stay). At one year of follow-up, a higher percentage of unfavorable functional outcome and a non-significant trend of higher ischemic event rate were observed in higher MA tertile groups. Multivariate logistic analysis revealed that higher MA level (OR = 1.192, p = 0.022) was an independent predictor for unfavorable one-year functional outcome. Other independent predictors included old age (OR = 1.119, p = 0.001), diabetes mellitus (DM) (OR = 4.280, p = 0.014), previous ischemic stroke/TIA history (OR = 4.953, p = 0.008), and higher NIHSS scores on admission (OR = 1.437, p = 0.001). CONCLUSIONS: We found that higher TEG-MA levels could predict an unfavorable functional outcome after index ischemic stroke. Further, large-scale studies are required to investigate the relationship between MA levels and risk of recurrent ischemic events in ischemic stroke patients.

Acute albumin administration as therapy for intracerebral hemorrhage: A literature review.

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality. Secondary brain injury after surviving the initial ictus leads to severe neurological deficits, and has emerged as an attractive therapeutic target. Human serum albumin (HSA), a pluripotent protein synthesized mainly in the liver, has shown remarkable efficacy by targeting secondary brain injury pathways in rodent models of ICH, while results from relevant clinical research on albumin therapy remain unclear. Preclinical studies have shown albumin-mediated neuroprotection may stem from its biological functions, including its major antioxidation activity, anti-inflammatory responses, and anti-apoptosis. HSA treatment provides neuroprotective and recovery enhancement effects via improving short and long-term neurologic function, maintaining blood-brain barrier (BBB) integrity and reducing neuronal oxidative stress and apoptosis. Retrospective clinical studies have shown that admission hypoalbuminemia is a prognostic factor for poor outcomes in patients with ICH. However, clinical trial was terminated due to poor enrollment and its potential adverse effects. This review provides an overview of the physiological properties of albumin, as well as its potential neuroprotective and prognostic value and the resulting clinical implications.

Giant Intrauterine Mass Because of Puerperal Infection: A Case Report.

Background: Puerperal infection is one of the four main causes of maternal mortality. A giant intrauterine mass caused by puerperal infection is a rare form of infection. The delay in treatment may result in the removal of the uterus. Case Presentation: We report a case of a large intrauterine mass resulting from puerperal infection, in which the uterus was salvaged through antibiotic treatment and curettage. The patient was a 27-year-old female, who presented with a large intrauterine mass, accompanied by fever and abdominal pain 35 days after vaginal delivery. The large intrauterine mass was ultimately pathologically confirmed to be necrotic smooth muscle tissue instead of residual pregnancy tissue. Conclusion: In most cases, the intrauterine mass after pregnancy is residual pregnancy tissue. Early identification and management are critical to ensure a good prognosis for patients. Obstetricians and pregnant women should be fully aware of the hazards of puerperal infections.

Immunosuppressive therapy and COVID-19 infection in patients with NMOSD.

INTRODUCTION: To evaluate whether treated with immunosuppressants in neuromyelitis optica spectrum disorder (NMOSD) shows an effect on the severity and outcomes of COVID-19 Omicron variant. METHODS: This is a substudy of a single-center clinical trial involving human umbilical cord mesenchymal stem cells (hUC-MSCs) in NMOSD patients. NMOSD patients with hUC-MSCs treatment, NMOSD patients without hUC-MSCs treatment, and matched healthy controls (HC) were included. Demographic information, NMOSD-related clinical features, comorbidities, use of disease-modifying therapy, COVID-19 vaccination status, COVID-19 clinical features, COVID-19 clinical outcomes, and NMOSD-related disease activity were obtained through online questionnaires or phone calls. RESULTS: The majority of NMOSD patients received long-term treatment with mycophenolate mofetil (68.8%) or azathioprine (22.9%), and 50% received oral glucocorticoid. During the epidemic, 97.4% of NMOSD patients infected with COVID-19 had asymptomatic or mild forms, with only two patients (2.6%) requiring hospitalization. None of these patients required tracheal intubation or admission to the intensive care unit. Clinical symptoms were found to be more prevalent in HC groups. Additionally, the HC groups had higher fever-recorded temperatures. NMOSD patients who received hUC-MSCs treatment had shorter disease duration than patients who did not receive hUC-MSCs treatment. DISCUSSION: Immunosuppressant-treated patients with NMOSD have a similar risk of COVID-19 infection as the general population, but the disease duration is shorter and the clinical symptoms are less severe. Among our NMOSD patients who received hUC-MSCs treatment, COVID-19 outcomes were favorable, with no increased risk of severe COVID-19. Prospective studies on immunotherapies are needed to help determine best treatment practices.

Serum Albumin Level Can Predict Immunotherapy Response of Neuromyelitis Optica Spectrum Disorders in the Acute Phase.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system. However, few biomarkers have been found to predict the outcome of immunotherapy. We investigated the relationship between the serum albumin (S-Alb) and response to immunotherapy in acute NMOSD patients. Methods: A total of 107 consecutive Chinese patients with acute NMOSD diagnosed between January 2013 and January 2022 were included in our prospective observational study. S-Alb was measured by the use of bromocresol green and immunoturbidimetric methods on admission. The immunotherapy response was assessed by the percentage change in the expanded disability status scale (EDSS) score from admission to discharge after treatment. We evaluated the association between S-Alb and immunotherapy response through multivariate logistic regression analysis. Results: S-Alb levels were significantly lower in patients who were resistant to immunotherapy than in those who were responsive to treatment (p<0.001). S-Alb levels were positively related to a favorable response to immunotherapy (r=0.386, p<0.001). The odds ratio (95% CI) for the association between S-Alb level and response to immunotherapy was 1.27 (95% CI=1.08, 1.50; p=0.004) after adjusting for potential factors. ROC analysis showed that patients with S-Alb levels lower than 40.85 g/L were likely to be resistant to immunotherapy. Conclusion: Our study indicated that a higher S-Alb was an independent indicator of response to immunotherapy in acute NMOSD patients.

Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System.

The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.

The effect of double filtration plasmapheresis and corticosteroids on patients with anti-dipeptidyl-peptidase-like protein 6 encephalitis.

INTRODUCTION: Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare condition with varied symptoms including gastrointestinal issues, weight loss, cognitive and mental dysfunction, and hyperexcitability of the central nervous system. METHODS: We studied five patients with anti-DPPX encephalitis who received immunotherapy, specifically DFPP, at our hospital. We analyzed their clinical symptoms, lab results, electrophysiological and imaging findings, and outcomes with immunotherapy. RESULTS: Patients presented with cognitive dysfunction, tremor, seizures, psychiatric disturbances, and cerebellar and brainstem dysfunction. Magnetic resonance imaging (MRI) showed brain abnormalities in one patient and elevated cerebrospinal fluid (CSF) protein levels in two patients. Antibodies against DPPX were detected in all patients and in CSF in two patients. One patient had antibodies against anti-CV2/contactin response mediator protein 5 (CRMP5). All patients responded well to DFPP and corticosteroids. CONCLUSION: DFPP may be an effective treatment for anti-DPPX encephalitis. Further research is needed to understand disease progression and evaluate immunotherapy efficacy.

Hypoxia-induced downregulation of miR-30c promotes epithelial-mesenchymal transition in human renal cell carcinoma.

MicroRNAs (miRNAs), which negatively regulate protein expression by binding protein-coding mRNAs, have been integrated into cancer development and progression as either oncogenes or tumor suppressor genes. miR-30c was reported to be downregulated in several types of cancer. However, its role in human renal cell carcinoma (RCC) remains largely unknown. Here, we show that miR-30c is significantly downregulated in human RCC tissues and cell lines. We found that miR-30c downregulation could be induced by hypoxia in RCC cells in a hypoxia-inducible factors (HIFs) dependent manner. Repression of miR-30c through its inhibitor resulted in reduction of E-cadherin production and promotion of epithelial-mesenchymal transition (EMT), while overexpression of miR-30c inhibited EMT in RCC cells. We identified Slug as a direct target of miR-30c in RCC cells. Slug was upregulated in RCC tissues and its expression could be induced by hypoxia, which is consistent with downregulation of miR-30c by hypoxia. Forced overexpression of Slug in 786-O cells reduced E-cadherin production, and promoted EMT as well as cell migration. Moreover, Slug overexpression abrogated the inhibitory role of miR-30c in regulating EMT and cell migration, indicating miR-30c regulates EMT through Slug in RCC cells. Our findings propose a model that hypoxia induces EMT in RCC cells through downregulation of miR-30c, which leads to subsequent increase of Slug expression and repression of E-cadherin production, and suggest a potential application of miR-30c in RCC treatment.

A new human DSG2-transgenic mouse model for studying the tropism and pathology of human adenoviruses.

We have recently reported that a group of human adenoviruses (HAdVs) uses desmoglein 2 (DSG2) as a receptor for infection. Among these are the widely distributed serotypes HAdV-B3 and HAdV-B7, as well as a newly emerged strain derived from HAdV-B14. These serotypes do not infect rodent cells and could not up until now be studied in small-animal models. We therefore generated transgenic mice containing the human DSG2 locus. These mice expressed human DSG2 (hDSG2) at a level and in a pattern similar to those found for humans and nonhuman primates. As an initial application of hDSG2-transgenic mice, we used a green fluorescent protein (GFP)-expressing HAdV-B3 vector (Ad3-GFP) and studied GFP transgene expression by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry subsequent to intranasal and intravenous virus application. After intranasal application, we found efficient transduction of bronchial and alveolar epithelial cells in hDSG2-transgenic mice. Intravenous Ad3-GFP injection into hDSG2-transgenic mice resulted in hDSG2-dependent transduction of epithelial cells in the intestinal and colon mucosa. Our findings give an explanation for clinical symptoms associated with infection by DSG2-interacting HAdVs and provide a rationale for using Ad3-derived vectors in gene therapy.

[Clinical features and prognostic factors in patients with leptomeningeal metastases].

OBJECTIVE: To investigate the clinical characteristics and prognostic factors of leptomeningeal metastases (LM) from solid tumors and to develop better treatment strategies. METHODS: The clinical characteristics and follow-up results of 77 cases of leptomeningeal metastases (LM) from solid tumors diagnosed and treated in our hospital from 2002 to 2011 were retrospectively analyzed. Clinical characteristics, treatment methods and overall survival were analyzed using Kaplan-Meier method and Cox regression model. RESULTS: The median survival time for all the patients was 88 days. KPS score, control of the primary tumor and systemic treatment were correlated with survival time for the patients (P < 0.05 for all). The median survival time of systemic treatment was 150 d and those without systemic treatment (chemotherapy and/or targeted therapy) after LM was 60 d (P = 0.001). Systemic therapy combined with local treatment (radiotherapy to the meninges or intrathecal chemotherapy) further improved the survival time of patients. Multivariate analysis showed that KPS and short-term therapeutic response for the LM were independent prognostic factors (P < 0.05 for both). CONCLUSIONS: KPS and short-term therapeutic response are independent prognostic factores for leptomeningeal metastases from solid tumors. Systemic chemotherapy or targeted therapy can prolong the survival time. Systemic treatment (chemotherapy and/or targeted therapy) combined with radiation therapy or intrathecal injection may further improve the clinical outcomes.

Drug-drug interaction between paxlovid and tacrolimus in a patient with myasthenia gravis and SARS-CoV-2 infection.

Patients with both myasthenia gravis (MG) and SARS-CoV-2 infection face treatment challenges due to potential drug interactions. One common immunosuppressant for MG, Tacrolimus, is primarily metabolized by the cytochrome P450. However, Paxlovid, an antiviral medication, inhibits cytochrome P450 activity, which can lead to increased Tacrolimus levels and potential toxicity when the two drugs are combined. In this case report, we present the case of a 39-year-old woman with early-onset MG who was initially treated with Tacrolimus. Later, she received Paxlovid for SARS-CoV-2 infection, which resulted in a sudden spike in Tacrolimus levels due to the drug interaction. This case emphasizes the importance of personalized treatment plans and close monitoring of drug interactions in patients with multiple health conditions. Clinicians should exercise vigilance regarding potential Tacrolimus interactions and regularly monitor blood levels to prevent adverse effects. Caution and close monitoring of Tacrolimus levels are essential when administering Paxlovid to patients on Tacrolimus therapy.