Tyrosine kinase inhibitor-induced hypothyroidism: mechanism and clinical implications.

INTRODUCTION: Since the first experimentally proven tyrosine kinase inhibitor (TKI) imatinib was introduced in the clinical setting, TKIs have attracted widespread attention because of their remarkable therapeutic effects and improvement of survival rates. TKIs are small-molecule, multi-target, anti-cancer agents that target different tyrosine kinases and block downstream signaling. ADVERSE REACTIONS AND CONCERNS: However, with in-depth research on TKI drugs, the adverse reactions-for example, thyroid dysfunction-have become a concern and thus have attracted the attention of numerous researchers. Thyroid dysfunction, especially hypothyroidism, that occurs in high incidence during TKI therapy has a close relationship with treatment efficacy, but the mechanism of TKI-induced thyroid dysfunction is obscure. DISCUSSION: This review discusses the epidemiology, possible mechanisms, and clinical significance of hypothyroidism in cancer patients treated with TKI.

Predicting fluid responsiveness in spontaneously breathing parturients undergoing caesarean section via carotid artery blood flow and velocity time integral measured by carotid ultrasound: a prospective cohort study.

BACKGROUND: Present evidence suggests that the Doppler ultrasonographic indices, such as carotid artery blood flow (CABF) and velocity time integral (VTI), had the ability to predict fluid responsiveness in non-obstetric patients. The purpose of this study was to assess their capacity to predict fluid responsiveness in spontaneous breathing parturients undergoing caesarean section and to determine the effect of detecting and management of hypovolemia (fluid responsiveness) on the incidence of hypotension after anaesthesia. METHODS: A total of 72 full term singleton parturients undergoing elective caesarean section were enrolled in this study. CABF, VTI, and hemodynamic parameters were recorded before and after fluid challenge and assessed by carotid artery ultrasonography. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. RESULTS: Thirty-one (43%) patients were fluid responders. The area under the ROC curve to predict fluid responsiveness for CABF and VTI were 0.803 (95% CI, 0.701-0.905) and 0.821 (95% CI, 0.720-0.922). The optimal cut-off values of CABF and VTI for fluid responsiveness was 175.9 ml/min (sensitivity of 74.0%; specificity of 78.0%) and 8.7 cm/s (sensitivity of 67.0%; specificity of 90.0%). The grey zone for CABF and VTI were 114.2-175.9 ml/min and 6.8-8.7 cm/s. The incidence of hypotension after the combined spinal-epidural anaesthesia (CSEA) was significantly higher in the Responders group 25.8% (8/31) than in the Non-Responders group 17.1(7/41) (P < 0.001). The total incidence of hypotension after CSEA of the two groups was 20.8% (15/72). CONCLUSIONS: Ultrasound evaluation of CABF and VTI seem to be the feasible parameters to predict fluid responsiveness in parturients undergoing elective caesarean section and detecting and management of hypovolemia (fluid responsiveness) could significantly decrease incidence of hypotension after anaesthesia. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR) ( www.chictr.org ), registration number was ChiCTR1900022327 (The website link: https://www.chictr.org.cn/showproj.html?proj=37271 ) and the date of trial registration was in April 5, 2019. This study was performed in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Women's Hospital, Zhejiang University School of Medicine (20,180,120).

Predicting Severity in Hypertriglyceridemia-Induced Acute Pancreatitis: The Role of Neutrophils, Calcium, and Apolipoproteins.

BACKGROUND Hypertriglyceridemia-induced acute pancreatitis (HTG-AP), representing 10% of all acute pancreatitis cases, is characterized by younger onset age and more severe progression, often leading to higher ICU admission rates. This condition poses a significant challenge due to its rapid progression and the potential for severe complications, including multiple organ failure. HTG-AP is distinct from other forms of pancreatitis, such as those caused by cholelithiasis or alcohol, in terms of clinical presentation and outcomes. It's essential to identify early markers that can predict the severity of HTG-AP to improve patient management and outcomes. MATERIAL AND METHODS This study divided 127 HTG-AP patients into mild acute pancreatitis (MAP, n=71) and moderate-to-severe acute pancreatitis (MSAP/SAP, n=56) groups. Blood biological indicators within the first 24 hours of admission were analyzed. Risk factors for HTG-AP progression were determined using binary logistic regression and ROC curves. RESULTS Elevated levels of HCT, NLR, TBI, DBI, AST, Cre, and AMS were noted in the MSAP/SAP group, with lower levels of LYM, Na⁺, Ca²âº, ApoA, and ApoB compared to the MAP group (p<0.05). NEUT%, Ca²âº, ApoA, and ApoB were significantly linked with HTG-AP severity. Their combined ROC analysis yielded an area of 0.81, with a sensitivity of 61.8% and specificity of 90%. CONCLUSIONS NEUT%, Ca²âº, ApoA, and ApoB are significant risk factors for progressing to MSAP/SAP in HTG-AP. Their combined assessment provides a reliable predictive measure for early intervention in patients at risk of severe progression.

Low-dose nifedipine rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice.

It is of great clinical significance to develop potential novel strategies to prevent diabetic cardiovascular complications. Endothelial progenitor cell (EPC) dysfunction is a key contributor to diabetic vascular complications. In the present study we evaluated whether low-dose nifedipine could rescue impaired EPC-mediated angiogenesis and prevent cardiovascular complications in diabetic mice. Diabetes was induced in mice by five consecutive injections of streptozotocin (STZ, 60 mg·kg-1·d-1, i.p.). Diabetic mice were treated with low-dose nifedipine (1.5 mg·kg-1·d-1, i.g.) for six weeks. Then, circulating EPCs in the peripheral blood were quantified, and bone marrow-derived EPCs (BM-EPCs) were prepared. We showed that administration of low-dose nifedipine significantly increased circulating EPCs, improved BM-EPCs function, promoted angiogenesis, and reduced the cerebral ischemic injury in diabetic mice. Furthermore, we found that low-dose nifedipine significantly increased endothelial nitric oxide synthase (eNOS) expression and intracellular NO levels, and decreased the levels of intracellular O2.- and thrombospondin-1/2 (TSP-1/2, a potent angiogenesis inhibitor) in BM-EPCs of diabetic mice. In cultured BM-EPCs, co-treatment with nifedipine (0.1, 1 µM) dose-dependently protected against high-glucose-induced impairment of migration, and suppressed high-glucose-induced TSP-1 secretion and superoxide overproduction. In mice with middle cerebral artery occlusion, intravenous injection of diabetic BM-EPCs treated with nifedipine displayed a greater ability to promote local angiogenesis and reduce cerebral ischemic injury compared to injection of diabetic BM-EPCs treated with vehicle, and the donor-derived BM-EPCs homed to the recipient ischemic brain. In conclusion, low-dose nifedipine can enhance EPCs' angiogenic potential and protect against cerebral ischemic injury in diabetic mice. It is implied that chronic treatment with low-dose nifedipine may be a safe and economic manner to prevent ischemic diseases (including stroke) in diabetes.

Poly-γ-glutamic acid enhanced the drought resistance of maize by improving photosynthesis and affecting the rhizosphere microbial community.

BACKGROUND: Compared with other abiotic stresses, drought stress causes serious crop yield reductions. Poly-γ-glutamic acid (γ-PGA), as an environmentally friendly biomacromolecule, plays an important role in plant growth and regulation. RESULTS: In this project, the effect of exogenous application of γ-PGA on drought tolerance of maize (Zea mays. L) and its mechanism were studied. Drought dramatically inhibited the growth and development of maize, but the exogenous application of γ-PGA significantly increased the dry weight of maize, the contents of ABA, soluble sugar, proline, and chlorophyll, and the photosynthetic rate under severe drought stress. RNA-seq data showed that γ-PGA may enhance drought resistance in maize by affecting the expression of ABA biosynthesis, signal transduction, and photosynthesis-related genes and other stress-responsive genes, which was also confirmed by RT-PCR and promoter motif analysis. In addition, diversity and structure analysis of the rhizosphere soil bacterial community demonstrated that γ-PGA enriched plant growth promoting bacteria such as Actinobacteria, Chloroflexi, Firmicutes, Alphaproteobacteria and Deltaproteobacteria. Moreover, γ-PGA significantly improved root development, urease activity and the ABA contents of maize rhizospheric soil under drought stress. This study emphasized the possibility of using γ-PGA to improve crop drought resistance and the soil environment under drought conditions and revealed its preliminary mechanism. CONCLUSIONS: Exogenous application of poly-γ-glutamic acid could significantly enhance the drought resistance of maize by improving photosynthesis, and root development and affecting the rhizosphere microbial community.

Choline deficiency-related multi-omics characteristics are susceptible factors for chemotherapy-induced thrombocytopenia.

The XELOX chemotherapy protocol that includes capecitabine and oxaliplatin is the routine treatment for colorectal cancer (CRC), but it can cause chemotherapy-related adverse events such as thrombocytopenia (TCP). To identify predictive biomarkers and clarify the mechanism of TCP susceptibility, we conducted integrative analysis using normal colorectal tissue (CRT), plasma, and urine samples collected before CRC patients received adjuvant XELOX chemotherapy. RNA-sequencing and DNA methylation arrays were performed on CRT samples, while liquid chromatography-mass spectrometry was performed on CRT, plasma, and urine samples. Differentially expressed features (DEFs) from each uni-omics analysis were then subjected to integrative analysis using Multi-Omics Factor Analysis (MOFA). Choline-deficiency in plasma and CRT was found as the most critical TCP-related feature. Based on bioinformatic analysis and literature research, we further concluded that choline-deficiency was the possible reason for most of the other TCP-related multi-omics DEFs, including metabolites representing reduced sphingolipid de novo synthesis and elevated solute carrier-mediated transmembrane transportation in CRT and plasma, DNA hypermethylation and elevated expression of genes involved in neuronal system genes. In terms of thrombocytopoiesis, these TCP-related DEFs may cause atypical maintenance and differentiation of megakaryocyte, resulting a suppressed ability of thrombocytopoiesis, making patients more susceptible to chemotherapy-induced TCP. At last, prediction models were developed and validated with reasonably good discrimination. The area under curves (AUCs) of training sets were all > 0.9, while validation sets had AUCs between 0.778 and 0.926. In conclusion, our results produced reliable marker systems for predicting TCP and promising target for developing precision treatment to prevent TCP.

Gut Microbiome-Derived Uremic Toxin Levels in Hemodialysis Patients on Different Phosphate Binder Therapies.

INTRODUCTION: Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. METHODS: Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. RESULTS: The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, p < 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5-7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. CONCLUSION: There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.

Corrected flow time and respirophasic variation in blood flow peak velocity of radial artery predict fluid responsiveness in gynecological surgical patients with mechanical ventilation.

BACKGROUND: Recent evidence suggests that ultrasound measurements of carotid and brachial artery corrected flow time (FTc) and respirophasic variation in blood flow peak velocity (ΔVpeak) are valuable for predicting fluid responsiveness in mechanical ventilated patients. We performed the study to reveal the performance of ultrasonic measurements of radial artery FTc and ΔVpeak for predicting fluid responsiveness in mechanical ventilated patients undergoing gynecological surgery. METHODS: A total of eighty mechanical ventilated patients were enrolled. Radial artery FTc and ΔVpeak, and non-invasive pulse pressure variation (PPV) were measured before and after fluid challenge. Fluid responsiveness was defined as an increase in stroke volume index (SVI) of 15% or more after the fluid challenge. Multivariate logistic regression analyses and receiver operating characteristic (ROC) curve were used to screen multivariate predictors of fluid responsiveness and identify the predictive abilitie of non-invasive PPV, ΔVpeak and FTc on fluid responsiveness. RESULTS: Forty-four (55%) patients were fluid responders. Multivariate logistic regression analysis showed that radial artery FTc, ΔVpeak, and non-invasive PPV were the independent predictors of fluid responsiveness, with odds ratios of 1.152 [95% confidence interval (CI) 1.045 to 1.270], 0.581 (95% CI 0.403 to 0.839), and 0.361 (95% CI, 0.193 to 0.676), respectively. The area under the ROC curve of fluid responsiveness predicted by FTC was 0.802 (95% CI, 0.706-0.898), and ΔVpeak was 0.812 (95% CI, 0.091-0.286), which were comparable with non-invasive PPV (0.846, 95%CI, 0.070-0.238). The optimal cut-off values of FTc for fluid responsiveness was 336.6 ms (sensitivity of 75.3%; specificity of 75.9%), ΔVpeak was 14.2% (sensitivity of 88.2%; specificity of 67.9%). The grey zone for FTc was 313.5-336.6 ms and included 40 (50%) of the patients, ΔVpeak was 12.2-16.5% and included 37(46%) of the patients. CONCLUSIONS: Ultrasound measurement of radial artery FTc and ΔVpeak are the feasible and reliable methods for predicting fluid responsiveness in mechanically ventilated patients. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR)(www.chictr.org), registration number ChiCTR2000040941.

Effect of Statewide Lockdown in Response to COVID-19 Pandemic on Physical Activity Levels of Hemodialysis Patients.

BACKGROUND/OBJECTIVES: On March 22, 2020, a statewide stay-at-home order for nonessential tasks was implemented in New York State. We aimed to determine the impact of the lockdown on physical activity levels (PAL) in hemodialysis patients. METHODS: Starting in May 2018, we are conducting an observational study with a 1-year follow-up on PAL in patients from 4 hemodialysis clinics in New York City. Patients active in the study as of March 22, 2020, were included. PAL was defined by steps taken per day measured by a wrist-based monitoring device (Fitbit Charge 2). Average steps/day were calculated for January 1 to February 13, 2020, and then weekly from February 14 to June 30. RESULTS: 42 patients were included. Their mean age was 55 years, 79% were males, and 69% were African Americans. Between January 1 and February 13, 2020, patients took on average 5,963 (95% CI 4,909-7,017) steps/day. In the week prior to the mandated lockdown, when a national emergency was declared, and in the week of the shutdown, the average number of daily steps had decreased by 868 steps/day (95% CI 213-1,722) and 1,222 steps/day (95% CI 668-2300), respectively. Six patients were diagnosed with COVID-19 during the study period. Five of them exhibited significantly higher PAL in the 2 weeks prior to showing COVID-19 symptoms compared to COVID-19 negative patients. CONCLUSION: Lockdown measures were associated with a significant decrease in PAL in hemodialysis patients. Patients who contracted COVID-19 had higher PAL during the incubation period. Methods to increase PAL while allowing for social distancing should be explored and implemented.

Predictors of treatment failure after top-hat procedure in squamous intraepithelial lesion.

AIM: The value of top-hat procedure during loop electrosurgical excision procedure (LEEP) for squamous intraepithelial lesions had remained controversial. This study aimed to evaluate whether top-hat specimens positive for cervical intraepithelial neoplasia (CIN) on histopathology can serve as an independent risk factor to predict treatment failure. METHODS: We reviewed the medical records of patients who underwent LEEP and top-hat procedures in Peking University First Hospital between 2011 and 2016 and collected their follow-up data until January 2019. We compared the pathological risk factor of treatment failure. Multivariate analysis was carried out to clarify the independent determinant of treatment failure. A Cox model was used to assess the influence of different variables on cumulative treatment failure rates. RESULTS: This study included 295 cases for short-term treatment failure, and among them, 178 cases were used to study the long-term. The presence of CIN in top-hat was relevant to short-term treatment failure (OR = 9.64, 95% CI 2.55-36.4) despite a clear margin. On multivariate analysis, top-hat result (OR = 3.58, 95% CI 1.30-9.89), age ≥ 50 (OR = 10.2, 95%CI 3.64-28.3) and post-treatment HPV 16/18 infection (OR = 2.35, 95%CI 1.19-4.63) were independent risk factors in predicting short-term failure. In the Cox model, these factors were also associated with higher cumulative failure rates. CONCLUSION: The current study supported the predictive value of top-hat procedure in short-term failure after LEEP. Typically, women with positive top-hat need closer follow-up despite their negative margin status. Older women with positive top-hat findings and HPV 16/18 infections after the treatment suffer a higher risk of short-term failure.

Zinc finger protein A20 regulates the development and progression of osteoarthritis by affecting the activity of NF-κB p65.

OBJECTIVE: To investigate the role of Zinc finger protein A20 in osteoarthritis (OA) by regulating NF-κB p65. METHODS: A20, MMP1, MMP13 and IL-1ß expressions in human OA cartilage samples were detected by qRT-PCR. IL-1ß-induced chondrocyte was treated with A20 lentivirus activation particle, pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor) with/without A20 siRNA. IL-6, TNF-α, and PGE2 levels were measured by ELISA, and NO production by Greiss reaction. Destabilization of the medial meniscus (DMM) surgery was used to construct the OA models, followed by injection of A20 adenovirus. MMP1 and MMP13 expression was measured by immunohistochemistry. The mRNA and protein expression were performed by qRT-PCR and western blotting, respectively. RESULTS: A20 was down-regulated in human OA cartilage samples, and negatively correlated with the expressions of MMP1, MMP13 and IL-1ß. The IL-1ß-induced chondrocyte manifested decreased A20 with increased NF-κB p65 activity. A20 overexpression suppressed the NF-κB p65 activity in IL-1ß-induced chondrocyte. Furthermore, PDTC decreased IL-1ß-induced chondrocyte apoptosis with the upregulated COL1A1, COL2A1, COL10A1 and ACAN, as well as the down-regulated MMP1, MMP13, COX2, iNOS, IL-6, TNF-α, NO and PGE2, which was reversed by A20 siRNA. In vivo, OA mice gained higher OARSI score and Mankin's score, exhibited up-regulations of MMP1 and MMP13, and decreased NF-κB p65 activity, which was improved after injection of A20 adenovirus. CONCLUSION: A20 was reduced in OA cartilage samples, and its overexpression, by suppressing the activity of NF-κB p65, could improve IL-1ß-induced chondrocyte degradation and apoptosis in vitro, as well as mitigate the inflammation in OA mice.

Difference Between Medical and Nonmedical Students on Knowledge, Practice, and Attitude Towards the Human Papillomavirus Vaccine in China: a Cross-Sectional Study.

HPV vaccine can prevent HPV infection effectively. The college student's vaccination status is unclear in mainland China. We assessed the knowledge, practice, and attitude towards HPV vaccine and compared the differences between medical and nonmedical students. It was a cross-sectional study using self-administered anonymous questionnaires. Nine-hundred sixty full-time college students were recruited randomly at Peking University in China. The medical students had higher level of knowledge of HPV and its vaccine than the nonmedical students (p < 0.001). The vaccinated female students were 9.0%. The high-grade clinical students had a higher uptake rate than the nonmedical students (19.5 vs 8.6%, p < 0.05). Awareness of HPV (p < 0.01), awareness of the vaccine (p < 0.001), and vaccinated family members or friends (p < 0.001) were related to the nonmedical students' vaccination. Vaccinated family members or friends were significant predictor for students' vaccination status (p < 0.001). Medical students knew more about HPV and its vaccine than nonmedical students. Female students' vaccinated rate was low, and the high-grade clinical students had a higher uptake rate than the nonmedical students.

Carboxymethyl cellulose/okara protein influencing microstructure, rheological properties and stability of O/W emulsions.

BACKGROUND: The role of protein-polysaccharide interactions and their mixtures has been a vital factor affecting the formation and stability of food emulsions. Okara protein (OP), which is extracted from the by-product of soybean processing, has received much attention because of its abundant sources and potential attributes with respect to food formulation. Carboxymethyl cellulose (CMC), a well-known food-grade polysaccharide additive, has been widely utilized in the protein-polysaccharide system, whereas, among the proteins, the role of OP has not yet been explored. RESULTS: The present study first assessed the ζ-potential and hydrodynamic diameter of aqueous mixtures containing OP (1.0 wt%) and CMC (0-0.5 wt%), followed by the investigation of OP-CMC mixtures stabilized O/W emulsions. As CMC increased, oil droplet size, surface protein adsorption, apparent viscosity and storage modulus increased, whereas the loss tangent decreased. CONCLUSION: CMC resulted in emulsion destabilization compared to emulsions without CMC, whereas a higher concentration of CMC promoted emulsion stability against creaming for emulsions in the presence of CMC. The results provide information with respect to OP and CMC being incorporated into food formulations and also strengthen our understanding of the related mechanism, in addition to facilitating the further utilization of OP. © 2020 Society of Chemical Industry.

The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke.

BACKGROUND: Spontaneous functional recovery occurs during the acute phase after stroke onset, but this intrinsic recovery remains limited. Therefore, exploring the mechanism underlying spontaneous recovery and identifying potential strategies to promote functional rehabilitation after stroke are very important. The CD200/CD200R signaling pathway plays an important role in neurological recovery by modulating synaptic plasticity during multiple brain disorders. However, the effect and mechanism of action of the CD200/CD200R pathway in spontaneous functional recovery after stroke are unclear. METHODS: In this study, we used a transient middle cerebral artery occlusion (MCAO) model in rats to investigate the function of CD200/CD200R signaling in spontaneous functional recovery after stroke. We performed a battery of behavioral tests (Longa test, adhesive removal test, limb-use asymmetry test, and the modified grip-traction test) to evaluate sensorimotor function after intracerebroventricular (i.c.v.) injection with CD200 fusion protein (CD200Fc) or CD200R blocking antibody (CD200R Ab) post-stroke. Density and morphology of dendritic spines were analyzed by Golgi staining. Microglia activation was evaluated by immunofluorescence staining. Western blot was used to detect the levels of protein and the levels of mRNA were measured by qPCR. RESULTS: Our study demonstrated that sensorimotor function, synaptic proteins, and structures were gradually recovered and CD200R was transiently upregulated in ipsilateral cortex after stroke. Synapse-related proteins and dendritic spines were preserved, accompanied by sensorimotor functional recovery, after stereotaxic CD200Fc injection post-stroke. In addition, CD200Fc restrained microglia activation and pro-inflammatory factor release (such as Il-1, Tnf-α, and Il-6) after MCAO. On the contrary, CD200R Ab aggravated sensory function recovery in adhesive removal test and further promoted microglia activation and pro-inflammatory factor release (such as Il-1) after MCAO. The immune-modulatory effect of CD200/CD200R signaling might be exerted partly by its inhibition of the MAPK pathway. CONCLUSIONS: This study provides evidence that the CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity via inhibition of microglia activation and inflammatory factor release.

Neurogenesis promoted by the CD200/CD200R signaling pathway following treadmill exercise enhances post-stroke functional recovery in rats.

Stroke is a leading cause of long-term disability worldwide; survivors often show sensorimotor and cognitive deficits. Therapeutic exercise is the most common treatment strategy for rehabilitating patients with stroke via augmentation of neurogenesis, angiogenesis, neurotrophic factors expression, and synaptogenesis. Neurogenesis plays important roles in sensorimotor and cognitive functional recovery, and can be promoted by exercise; however, the mechanism underlying this phenomenon remains unclear. In this study, we explored the effects of treadmill exercise on sensorimotor and cognitive functional recovery, as well as the potential molecular mechanisms underlying the promotion of neurogenesis in a rat model of transient middle cerebral artery occlusion (tMCAO). We found that treadmill exercise facilitated sensorimotor and cognitive functional recovery after tMCAO, and that neural stem/progenitor cell proliferation, differentiation, and migration were enhanced in the ipsilateral subventricular and subgranular zones after tMCAO. Meanwhile, the newborn neurons induced by treadmill exercise after tMCAO had the similar function with pre-existing neurons. Treadmill exercise significantly increased CD200 and CD200 receptor (CD200R) levels in the ipsilateral hippocampus and cortex. Further study revealed that treadmill exercise-induced neurogenesis and functional recovery were clearly inhibited, while Il-ß and Tnf-α expression were upregulated, following lentivirus (LV)-induced suppression of post-stroke CD200R expression. Consistent with the effect of treadmill exercise, CD200Fc (a CD200R agonist) markedly promoted neurogenesis and functional recovery after stroke. In addition, CD200Fc could further enhance the functional recovery induced by treadmill exercise after stroke. Our results demonstrate the beneficial role of treadmill exercise in promoting neurogenesis and functional recovery via activating the CD200/CD200R signaling pathway and improving the inflammatory environment after stroke. Thus, the CD200/CD200R signaling pathway is a potential therapeutic target for functional recovery after stroke.

Value of top-hat procedure in management of squamous intraepithelial lesion.

AIM: To investigate the features of skip lesions and evaluate value of top-hat procedure in management of squamous intraepithelial lesion. METHODS: We reviewed the records of patients who underwent loop electrosurgical excision procedure (LEEP) in Peking University First Hospital between 2011 and 2016. Patients were confirmed to have CIN1-3. The term 'skip lesion' refers to lesion lying deep in cervical canal discontiguous with other lesions in transformation zone and was confirmed by top-hat. We compared their lesion grade in patients with or without skip lesion using logistic regression. We further reviewed patients who underwent subsequent hysterectomy within 6 months following LEEP and evaluated if top-hat procedure led to less residual lesions or was able to predict residual lesions. RESULTS: A total of 2260 patients were included and 595 underwent top-hat procedure. Thirty-nine out of 595 patients had skip lesions (6.5%), among whom two patients had CIN1 (5.1%), eight had CIN2 (20.5%) and 29 had CIN3 (74.4%). Logistical regression showed CIN3 was associated with higher risk of skip lesions compared to CIN1 (OR = 4.433, 95%CI: 1.036-18.964), while CIN2 was not (OR = 1.762, 95%CI: 0.366-8.471). Sixty-two patients underwent hysterectomy within 6 months following LEEP (CIN1-3), 24 underwent top-hat. Analysis revealed top-hat procedure did not result in less residual lesions. Colposcopy impression or prior HPV test was unable to predict skip lesions. CONCLUSION: About 9.4% patients with CIN3 had skip lesions in the study, which is associated with elevated risk for residual lesion. Top-hat procedure is able to detect skip lesions, but should not be performed on routinely because its prognostic value is not proved.

Preventive Cold Acclimation Augments the Reparative Function of Endothelial Progenitor Cells in Mice.

BACKGROUND/AIMS: Chronic cold exposure may increase energy expenditure and contribute to counteracting obesity, an important risk factor for cerebrocardiovascular diseases. This study sought to evaluate whether preventive cold acclimation before ischemia onset might be a promising option for preventing cerebral ischemic injury. METHODS: After a 14-day cold acclimation period, young and aged mice were subjected to permanent cerebral ischemia, and histological analyses and behavioral tests were performed. Mouse endothelial progenitor cells (EPCs) were isolated, their function and number were determined, and the effects of EPC transplantation on cerebral ischemic injury were investigated. RESULTS: Preventive cold acclimation before ischemia onset increased EPC function, promoted ischemic brain angiogenesis, protected against cerebral ischemic injury, and improved long-term stroke outcomes in young mice. In addition, transplanted EPCs from cold-exposed mice had a greater ability to reduce cerebral ischemic injury and promote local angiogenesis compared to those from control mice, and EPCs from donor animals could integrate into the recipient ischemic murine brain. Furthermore, transplanted EPCs might exert paracrine effects on cerebral ischemic injury, which could be improved by preventive cold acclimation. Moreover, preventive cold acclimation could also enhance EPC function, promote local angiogenesis, and protect against cerebral ischemic injury in aged mice. CONCLUSIONS: Preventive cold acclimation before ischemia onset improved long-term stroke outcomes in mice at least in part via promoting the reparative function of EPC. Our findings imply that a variable indoor environment with frequent cold exposure might benefit individuals at high risk for stroke.

The adhesion and migration of microglia to ß-amyloid (Aß) is decreased with aging and inhibited by Nogo/NgR pathway.

BACKGROUND: Alzheimer's disease is characterized by progressive accumulation of ß-amyloid (Aß)-containing amyloid plaques, and microglia play a critical role in internalization and degradation of Aß. Our previous research confirmed that Nogo-66 binding to Nogo receptors (NgR) expressed on microglia inhibits cell adhesion and migration in vitro. METHODS: The adhesion and migration of microglia isolated from WT and APP/PS1 mice from different ages were measured by adhesion assays and transwells. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in APP/PS1 transgenic mice, microglial recruitment toward Aß deposits and CD36 expression were determined. RESULTS: In this paper, we found that aging led to a reduction of microglia adhesion and migration to fAß1-42 in WT and APP/PS1 mice. The adhesion and migration of microglia to fAß1-42 were downregulated by the Nogo, which was mediated by NgR, and the increased inhibitory effects of the Nogo could be observed in aged mice. Moreover, Rho GTPases contributed to the effects of the Nogo on adhesion and migration of microglia to fAß1-42 by regulating cytoskeleton arrangement. Furthermore, blocking the Nogo/NgR pathway enhanced recruitment of microglia toward Aß deposits and expression of CD36 in APP/PS1 mice. CONCLUSION: Taken together, Nogo/NgR pathway could take part in Aß pathology in AD by modulating microglial adhesion and migration to Aß and the Nogo/NgR pathway might be an important target for treating AD.

A preventive injection of endothelial progenitor cells prolongs lifespan in stroke-prone spontaneously hypertensive rats.

There is a pressing need for new approaches to prevent stroke. Endothelial progenitor cells (EPCs) promote vascular repair and revascularization in the ischemic brain. The present study sought to evaluate whether preventive delivery of EPCs could prevent or protect against stroke. Stroke-prone spontaneously hypertensive rats (SHR-SP) received a single injection of EPCs, and their survival time was monitored. In addition, at 28 and/or 42 days after a single injection of EPCs, SHR-SP and mice were subjected to cerebral ischemia, and cerebral ischemic injury, local angiogenesis and in vivo EPC integration were determined. Other experiments examined the effects of EPC conditioned medium, and the distribution of donor EPCs taken from GFP transgenic mice. It was found that EPC-pretreated SHR-SP showed longer lifespans than untreated controls. A single preventive injection of EPCs could produce persistent protective effects against cerebral ischemic injury (lasting at least 42 days), and promote local angiogenesis in the ischemic brain, in two types of animals (SHR-SP and normotensive mice). EPCs of donor origin could be detected in the recipient peripheral blood, and integrated into the recipient ischemic brains. Furthermore, it was suggested that mouse EPCs might exert paracrine effects on cerebral ischemic injury in addition to their direct angiogenic effects. In conclusion, a single preventive injection of EPCs prolonged the lifespan of SHR-SP, and protected against cerebral ischemic injury for at least 7 weeks. It is implied that EPC injection might be a promising candidate for a preventive role in patients at high risk for stroke.

Targeted metabolomic analysis of 33 amino acids and biogenic amines in human urine by ion-pairing HPLC-MS/MS: Biomarkers for tacrolimus nephrotoxicity after renal transplantation.

Calcineurin inhibitor nephrotoxicity, especially for the widely used tacrolimus, has become a major concern in post-transplant immunosuppression. Multiparametric amino acid metabolomics is useful for biomarker identification of tacrolimus nephrotoxicity, for which specific quantitative methods are highlighted as a premise. This article presents a targeted metabolomic assay to quantify 33 amino acids and biogenic amines in human urine by high-performance liquid chromatography coupled with tandem mass spectrometry. Chromatographic separation was carried out on an Agilent Zorbax SB-C18 column (3.0 × 150 mm, 5 µm) with addition of an ion-pairing agent in the mobile phase, and MS/MS detection was achieved in both the positive and negative multiple reaction monitoring modes. Good correlation coefficients (r2 > 0.98) were obtained for most analytes. Intra- and inter-day precision, stability, carryover and incurred sample reanalysis met with the acceptance criteria of the guidance of the US Food and Drug Administration. Analysis on urine from healthy volunteers and renal transplantation patients with tacrolimus nephrotoxicity confirmed symmetric dimethylarginine and serine as biomarkers for kidney injury, with AUC values of 0.95 and 0.81 in receiver operating characteristic analysis, respectively. Additionally, symmetric dimethylarginine exhibited a tight correlation with serum creatinine, and was therefore indicative of renal function. The targeted metabolomic assay was time and cost prohibitive for amino acid analysis in human urine, facilitating the biomarker identification of tacrolimus nephrotoxicity.