GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. METHODS: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. RESULTS: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. CONCLUSIONS: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

An auxiliary diagnostic tool for common fundus diseases based on fundus color photography and light-weight classification models.

OBJECTIVE: To evaluate the performance of two lightweight neural network models in the diagnosis of common fundus diseases and make comparison to another two classical models. METHODS: A total of 16,000 color fundus photography were collected, including 2000 each of glaucoma, diabetic retinopathy (DR), high myopia, central retinal vein occlusion (CRVO), age-related macular degeneration (AMD), optic neuropathy, and central serous chorioretinopathy (CSC), in addition to 2000 normal fundus. Fundus photography was obtained from patients or physical examiners who visited the Ophthalmology Department of Beijing Tongren Hospital, Capital Medical University. Each fundus photography has been diagnosed and labeled by two professional ophthalmologists. Two classical classification models (ResNet152 and DenseNet121), and two lightweight classification models (MobileNetV3 and ShufflenetV2), were trained. Area under the curve (AUC), sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were used to evaluate the performance of the four models. RESULTS: Compared with the classical classification model, the total size and number of parameters of the two lightweight classification models were significantly reduced, and the classification speed was sharply improved. Compared with the DenseNet121 model, the ShufflenetV2 model took 50.7% less time to make a diagnosis on a fundus photography. The classical models performed better than lightweight classification models, and Densenet121 showed highest AUC in five out of the seven common fundus diseases. However, the performance of lightweight classification models is satisfying. The AUCs using MobileNetV3 model to diagnose AMD, diabetic retinopathy, glaucoma, CRVO, high myopia, optic atrophy, and CSC were 0.805, 0.892, 0.866, 0.812, 0.887, 0.868, and 0.803, respectively. For ShufflenetV2model, the AUCs for the above seven diseases were 0.856, 0.893, 0.855, 0.884, 0.891, 0.867, and 0.844, respectively. CONCLUSION: The training of light-weight neural network models based on color fundus photography for the diagnosis of common fundus diseases is not only fast but also has a significant reduction in storage size and parameter number compared with the classical classification model, and can achieve satisfactory accuracy.

The association between systemic inflammatory response index and contrast-associated acute kidney injury in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: The systemic inflammatory response index (SIRI), served as a novel inflammatory biomarker, is the synthesis of neutrophils, monocytes and lymphocytes. AIMS: We hypothesized that SIRI has predictive value for contrast-associated acute kidney injury (CA-AKI) and long-term mortality in patients undergoing elective percutaneous coronary intervention (PCI). METHODS: We retrospectively observed 5685 patients undergoing elective PCI from January 2012 to December 2018. Venous blood samples were collected to obtain the experimental data on the day of admission or the morning of the next day. SIRI = neutrophil count × monocyte count/lymphocyte count. CA-AKI was defined as an increase of 50% or 0.3 mg/dl in SCr from baseline within 48 h after contrast exposure. RESULTS: The incidence of CA-AKI was 6.1% (n = 352). The best cutoff value of SIRI for predicting CA-AKI was 1.39, with a sensitivity of 52.3% and a specificity of 67.3%. [AUC: 0.620, 95% confidence interval (CI): 0.590-0.651, p < 0.001]. After adjusting for potential confounders, multivariate analysis showed that the high SIRI group (SIRI > 1.39) was a strong independent predictor of CA-AKI in patients undergoing elective PCI compared with the low SIRI group (SIRI ≤ 1.39) (odds ratio = 1.642, 95% CI: 1.274-2.116, p < 0.001). Additionally, COX regression analysis showed that SIRI > 1.39 was significantly associated with long-term mortality at a median follow-up of 2.8 years. [Hazard ratio (HR)=1.448, 95%CI: 1.188-1.765; p < 0.001]. Besides, Kaplan-Meier survival curve also indicated that the cumulative rate of mortality was considerably higher in the high SIRI group. CONCLUSIONS: High levels of SIRI are independent predictors of CA-AKI and long-term mortality in patients undergoing elective PCI.

Bidirectional Solid-State Fermentation of Highland Barley by Edible Fungi to Improve Its Functional Components, Antioxidant Activity and Texture Characteristics.

In food industry, the characteristics of food substrate could be improved through its bidirectional solid-state fermentation (BSF) by fungi, because the functional components were produced during BSF. Six edible fungi were selected for BSF to study their effects on highland barley properties, such as functional components, antioxidant activity, and texture characteristics. After BSF, the triterpenes content in Ganoderma lucidum and Ganoderma leucocontextum samples increased by 76.57 and 205.98%, respectively, and the flavonoids content increased by 62.40% (Phellinus igniarius). Protein content in all tests increased significantly, with a maximal increase of 406.11% (P. igniarius). Proportion of indispensable amino acids increased significantly, with the maximum increase of 28.22%. Lysine content increased largest by 437.34% to 3.310 mg/g (Flammulina velutipes). For antioxidant activity, ABTS radical scavenging activity showed the maximal improvement, with an increase of 1268.95%. Low-field NMR results indicated a changed water status of highland barley after fermentation, which could result in changes in texture characteristics of highland barley. Texture analysis showed that the hardness and chewiness of the fermented product decreased markedly especially in Ganoderma lucidum sample with a decrease of 77.96% and 58.60%, respectively. The decrease indicated a significant improvement in the taste of highland barley. The results showed that BSF is an effective technology to increase the quality of highland barley and provide a new direction for the production of functional foods.

APT1-Mediated Depalmitoylation Regulates Hippocampal Synaptic Plasticity.

Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders.SIGNIFICANCE STATEMENT Fear-related anxiety disorders, including post-traumatic stress disorder, are prevalent psychiatric conditions, and fear memory is associated with hyperexcitability in the hippocampal CA1 region. Palmitoylation is involved in learning and memory, but mechanisms coupling palmitoylation with fear memory acquisition remain poorly understood. This study demonstrated that palmitoylation is essential for postsynapse density-95 clustering and hippocampal glutamatergic synaptic transmission, and APT1-mediated depalmitoylation plays critical roles in the regulation of synaptic plasticity. Our study revealed that molecular mechanism about downregulation of APT1 leads to enhancement of AMPAR-mediated synaptic transmission, and that palmitoylation cycling is implicated in fear conditioning-induced synaptic strengthening and fear memory formation.

Upregulation of dynorphin/kappa opioid receptor system in the dorsal hippocampus contributes to morphine withdrawal-induced place aversion.

Aversive emotion of opioid withdrawal generates motivational state leading to compulsive drug seeking and taking. Kappa opioid receptor (KOR) and its endogenous ligand dynorphin have been shown to participate in the regulation of aversive emotion. In the present study, we investigated the role of dynorphin/KOR system in the aversive emotion following opioid withdrawal in acute morphine-dependent mice. We found that blockade of KORs before pairing by intracerebroventricular injection of KOR antagonist norBNI (20, 40 µg) attenuated the development of morphine withdrawal-induced conditioned place aversion (CPA) behavior. We further found that morphine withdrawal increased dynorphin A expression in the dorsal hippocampus, but not in the amygdala, prefrontal cortex, nucleus accumbens, and thalamus. Microinjection of norBNI (20 µg) into the dorsal hippocampus significantly decreased morphine withdrawal-induced CPA behavior. We further found that p38 MAPK was significantly activated in the dorsal hippocampus after morphine withdrawal, and the activation of p38 MAPK was blocked by pretreatment with norBNI. Accordingly, microinjection of p38 MAPK inhibitor SB203580 (5 µg) into the dorsal hippocampus significantly decreased morphine withdrawal-produced CPA behavior. This study demonstrates that upregulation of dynorphin/KOR system in the dorsal hippocampus plays a critical role in the formation of aversive emotion associated with morphine withdrawal, suggesting that KOR antagonists may have therapeutic value for the treatment of opioid withdrawal-induced mood-related disorders.

[Research progress of ferroptosis in hypoxia-associated brain injury].

Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.

Six-month repeated irradiation of 650 nm low-level red light reduces the risk of myopia in children: a randomized controlled trial.

PURPOSE: To evaluate whether the six-month repeated irradiation of 650 nm low-level red light (LLRL) decreases the risk of myopia onset in children. METHODS: This was a single-masked, randomized controlled trial. A total of 112 children (aged 6-12 years) were enrolled and randomized to the treatment group or control group in a 1:1 ratio. The cycloplegic spherical equivalent error (SER) of children at baseline was -0.5 diopter (D) to 3D. Children in the treatment group were irradiated with the 650 nm LLRL for 6 min daily. No intervention was given to the control. The primary outcomes are myopia incidence, change in cycloplegic SER, and change in axial length (AL). RESULTS: For the treatment group and control group, the six-month myopia incidence rates were 1.8% (95% confidence interval, CI: 0.2-4.9%) and 12.5% (95% CI: 5.5-21.9%), respectively. The difference was significant (p = 0.028). The median changes in AL for the treatment group and control group were -0.02 (interquartile range, IQR: -0.12 to 0.06) mm, and 0.09 (IQR: 0-0.18) mm, respectively. The difference was significant (p < 0.001). The median changes in cycloplegic SER for the treatment group and control group were 0 (IQR: 0-0.25) D, and -0.125 (IQR: -0.375 to 0) D, respectively. The difference was significant (p < 0.001). There was no adverse event. CONCLUSION: The repeated irradiation of 650 nm LLRL may have a strong effect for myopia prevention in children, without risk of adverse events. TRIAL REGISTRATION: this trial is retrospectively registered in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ), the registration number is ChiCTR2200058963.

Using Both Plasma and Urine Donor-Derived Cell-Free DNA to Identify Various Renal Allograft Injuries.

BACKGROUND: This study was designed to investigate the association between donor-derived cell-free DNA (dd-cfDNA) and renal allograft injuries. METHODS: This single-center study enrolled 113 adult kidney transplant recipients with kidney biopsies. Plasma and urine dd-cfDNA was detected by target region capture sequencing. RESULTS: Plasma dd-cfDNA fraction was increased in multiple types of injuries, but most significantly in antibody-mediated rejection. Plasma dd-cfDNA fraction in isolated antibody-mediated rejection (1.94%, IQR: 1.15%, 2.33%) was higher than in T cell-mediated rejection (0.55%, IQR: 0.50%, 0.73%, P = 0.002) and negative biopsies (0.58%, IQR: 0.42%, 0.78%, P < 0.001), but lower than in mixed rejection (2.49%, IQR: 1.16%, 4.90%, P = 0.342). Increased urine dd-cfDNA concentration was associated with several types of injury, but most significantly with BK polyomavirus-associated nephropathy. Urine dd-cfDNA concentration in BK polyomavirus-associated nephropathy (12.22 ng/mL, IQR: 6.53 ng/mL, 31.66 ng/mL) was respectively higher than that in T cell-mediated rejection (5.24 ng/mL, IQR: 3.22 ng/mL, 6.99 ng/mL, P = 0.001), borderline change (3.93 ng/mL, IQR: 2.45 ng/mL, 6.30 ng/mL, P < 0.001), and negative biopsies (3.09 ng/mL, IQR: 1.94 ng/mL, 5.05 ng/mL, P < 0.001). Plasma dd-cfDNA fraction was positively associated with glomerulitis (r = 0.365, P < 0.001) and peri-tubular capillaritis (r = 0.344, P < 0.001), while urine dd-cfDNA concentration correlated with tubulitis (r = 0.302, P = 0.002). CONCLUSIONS: Both plasma and urine dd-cfDNA are sensitive markers for renal allograft injuries. The interpretation of a specific disease by dd-cfDNA should be combined with other clinical indicators.

Facile in Situ Transformation of NiOOH into MOF-74(Ni)/NiO OH Heterogeneous Composite for Enchancing Electrocatalytic Methanol Oxidation.

A new MOF-74(Ni)/NiOOH heterogeneous composite was synthesized via NiOOH microsphere precursor. The electrocatalytic methanol oxidation reactions' (MOR) performance was assessed. The as-prepared MOF-74(Ni)/NiOOH exhibited excellent activity with high peak current density (27.62 mA·cm-2) and high mass activity (243.8 mA·mg-1). The enhanced activity could be a result of the synergistic effect of the MOF-74(Ni)/NiOOH heterocomposite providing more exposed active sites, a beneficial diffusion path between the catalyst surface and electrolyte, and improved conductivity, favorable for improving MOR performance.

[Curcumin improves cardiac fibrosis by inhibiting endothelial-mesenchymal transition through NRF2-DDAH-ADMA-NO pathway].

The present study analyzed the correlations between curcumin(Cur), nuclear factor E2 related factor 2(NRF2)-dimethylarginine dimethylaminohydrolase(DDAH)-asymmetric dimethylarginine(ADMA)-nitric oxide(NO) pathway, and endothelial-mesenchymal transition(EndMT) based on SD rats with cardiac fibrosis, and explored the effect and mechanism of Cur in resisting cardiac fibrosis to provide an in-depth theoretical basis for its clinical application in the treatment of heart failure. The cardiac fibrosis model was induced by subcutaneous injection of isoprenaline(Iso) in rats. Thirty-two rats were randomly divided into a control group, a model group, a low-dose Cur group(100 mg·kg~(-1)·d~(-1)), and a high-dose Cur group(200 mg·kg~(-1)·d~(-1)), with eight in each group. After 21 days of treatment, cardiac function was detected by echocardiography, degree of cardiac fibrosis by Masson staining, expression of CD31 and α-SMA by pathological staining, expression of VE-cadherin, vimentin, NRF2, and DDAH by Western blot, and ADMA level by HPLC. Compared with the model group, the Cur groups showed alleviated cardiac fibrosis, accompanied by increased CD31 and VE-cadherin expression and decreased α-SMA and vimentin expression, indicating relieved EndMT. Additionally, DDAH and NRF2 levels were elevated and ADMA and NO expression declined. Cur improves cardiac fibrosis by inhibiting EndMT presumedly through the NRF2-DDAH-ADMA-NO pathway.

Effect of lens capsular tension ring on preventing capsular contraction syndrome in the surgery of retinitis pigmentosa combined with cataract: Retrospective case series.

PURPOSE: To observe the effect of phacoemulsification and intraocular lens (IOL) implantation with or without lens capsular tension ring (CTR) on retinitis pigmentosa (RP) combined with cataract patients. DESIGN: Retrospective cases series study. METHODS: Sixty-three cases (84 eyes) of RP with cataract were collected, including 30 males and 33 females. Phacoemulsification with 3.0 mm clear corneal incision was performed in all the patients. IOL and CTR implantation were performed in 44 eyes, and IOL implantation alone was performed in 40 eyes. All cases were followed up at 1 day, 1 week and 1, 3, 6,12 months after the surgery to compare the best-corrected visual acuity (BCVA), intraocular pressure (IOP), corneal endothelial cell count (ECC) and complications before and after the surgery. RESULTS: All surgery were successfully completed by the same physician, and IOL and CTR were all implanted in capsule without complications. The BCVA at 6 months after surgery was 0.91 ± 0.88 LogMAR, showing an improvement compared with the BCVA(1.3 ± 0.7LogMAR) before surgery and there was a statistically significant difference (P = .003). Four cases of capsule contraction syndrome (CCS) occurred in no CTR implantation group and there was no CCS in CTR group. There was a statistically significant difference in the incidence of CCS between two groups (P = .047). CONCLUSIONS: Phacoemulsification for RP combined with cataract is safe and reliable, and CTR implantation is conducive to reducing the complications caused by capsule contraction.

Diagnostic Value of Optical Coherence Tomography Angiography for Choroidal Neovascularization in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to evaluate the diagnostic value of optical coherence tomography angiography (OCTA) in detecting the choroidal neovascularization (CNV) in age-related macular degeneration (AMD). METHODS: A systematic review and meta-analysis was performed by searching Pubmed, Science Direct, Embase, and Web of Science. The pooled sensitivity and specificity with 95% confidence intervals (CIs), area under the summary receiver operator characteristic curve (sROC), and the total accurate classification rate were used to evaluate OCTA's diagnostic value of CNV in AMD patients. RESULTS: Seven studies involving 517 eyes were included in the analysis. The mean age of subjects in each study ranged from 58.5 years to 81.7 years. Fluorescein angiography was applied as the gold standard in 5 studies. There were 350 eyes diagnosed with CNV, OCTA detected 301 eyes correctly, while among the 167 eyes without CNV, OCTA identified 150 correctly. The total accurate classification rate was 87.23%. The Spearman's rank correlation coefficient was 0.5, indicating that there was no significant threshold effect in the current study (S = 8, p = 0.103). The pooled sensitivity and pooled specificity were 0.89 (95% CI: 0.82, 0.94) and 0.96 (95% CI: 0.85, 1.00), respectively. The area under sROC was up to 0.911. CONCLUSION: The specificity of OCTA for the detection of CNV in AMD patients is extremely high; however, the sensitivity still needs to be improved. In general, the meta-analysis revealed that OCTA had a high diagnostic value for the detection of CNV in AMD patients.

New prenylflavonol glycosides with xanthine oxidase inhibitory activity from the leaves of Cyclocarya paliurus.

Eight new prenylflavonol glycosides (1-8), along with five known analogues (9-13) were isolated from the n-butanol extract of the dried leaves of Cyclocarya paliurus (family Juglandaceae) for the first time. The structures of these compounds were characterized by comprehensive analysis of 1D, 2D NMR, HRESIMS, UV data and acid hydrolysis. In bioassay, all these thirteen prenylflavonol glycosides exhibited inhibitory effects on xanthine oxidase (XOD) activity. Especially compounds 2 and 7, showed outstanding IC50 values of 31.81 ± 2.20 and 29.71 ± 3.69 µM, respectively.

Glomerular Parietal Epithelial Cells Infection Is Associated With Poor Graft Outcome in Kidney Transplant Recipients With BK Polyomavirus-Associated Nephropathy.

BACKGROUND: The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN). METHODS: A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121 without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared between the groups. RESULTS: The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001). At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43-8.76; P = .006). CONCLUSIONS: GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.

[Clinical features of catch-up growth after kidney transplantation in children].

OBJECTIVE: To study the clinical features of catch-up growth of body height after kidney transplantation in children and related influencing factors. METHODS: A retrospective analysis was performed from the chart review data of 15 children who underwent kidney transplantation in Guangzhou Women and Children's Medical Center from July 2017 to November 2019. According to whether the increase in height standard deviation score (ΔHtSDS) in the first year after kidney transplantation reached ≥0.5, the children were divided into a catch-up group with 8 children and a non-catch-up group with 7 children. According to whether final HtSDS was ≥-2, the children were divided into a standard group with 6 children and a non-standard group with 9 children. The features of catch-up growth of body height and related influencing factors were compared between groups. RESULTS: The data showed that median ΔHtSDS was 0.8 in the first year after transplantation, which suggested catch-up growth of body height. There was a significant difference in HtSDS between the non-catch-up and catch-up groups (P<0.05). Baseline HtSDS before transplantation was positively correlated with HtSDS at the end of follow-up (r=0.622, P<0.05) and was negatively correlated with ∆HtSDS in the first year after transplantation (r=-0.705, P<0.05). Age of transplantation and mean dose of glucocorticoid (GC) per kg body weight were risk factors for catch-up growth after kidney transplantation (OR=1.23 and 1.74 respectively; P<0.05), while baseline HtSDS and use of antihypertensive drugs were independent protective factors for catch-up growth (OR=0.08 and 0.18 respectively; P<0.05); baseline HtSDS and ΔHtSDS in the first year after kidney transplantation were influencing factors for final HtSDS (ß=0.984 and 1.271 respectively; P<0.05). CONCLUSIONS: Kidney transplantation should be performed for children as early as possible, growth retardation before transplantation should be improved as far as possible, and multiple treatment methods (including the use of GC and antihypertensive drugs) should be optimized after surgery, in order to help these children achieve an ideal body height.

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus.

AIMS: Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODS: The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTS: Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONS: The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.

In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response.

Koumine Attenuates Neuroglia Activation and Inflammatory Response to Neuropathic Pain.

Despite decades of studies, the currently available drugs largely fail to control neuropathic pain. Koumine-an alkaloidal constituent derived from the medicinal plant Gelsemium elegans Benth.-has been shown to possess analgesic and anti-inflammatory properties; however, the underlying mechanisms remain unclear. In this study, we aimed to investigate the analgesic and anti-inflammatory effects and the possible underlying mechanisms of koumine. The analgesic and anti-inflammatory effects of koumine were explored by using chronic constriction injury of the sciatic nerve (CCI) neuropathic pain model in vivo and LPS-induced injury in microglia BV2 cells in vitro. Immunofluorescence staining and Western blot analysis were used to assess the modulator effect of koumine on microglia and astrocyte activation after CCI surgery. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the levels of proinflammatory cytokines. Western blot analysis and quantitative real-time polymerase chain reaction (qPCR) were used to examine the modulator effect of koumine on microglial M1 polarization. We found that single or repeated treatment of koumine can significantly reduce neuropathic pain after nerve injury. Moreover, koumine showed inhibitory effects on CCI-evoked microglia and astrocyte activation and reduced proinflammatory cytokine production in the spinal cord in rat CCI models. In BV2 cells, koumine significantly inhibited microglia M1 polarization. Furthermore, the analgesic effect of koumine was inhibited by a TSPO antagonist PK11195. These findings suggest that the analgesic effects of koumine on CCI-induced neuropathic pain may result from the inhibition of microglia activation and M1 polarization as well as the activation of astrocytes while sparing the anti-inflammatory responses to neuropathic pain.

Impact of acute kidney injury in donors on renal graft survival: a systematic review and Meta-Analysis.

The acute kidney injury (AKI) of deceased donors was an important strategy to address donor shortage. This meta-analysis was conducted to explore the clinical effect of kidney transplantation from donors with AKI. PubMed, Embase, and Cochrane Library were searched through July 2017. Fourteen cohort studies, involving a total of 15,345 donors, were included. Studies were pooled, and the hazard ratio (HR), relative risk (RR), weighted mean difference (WMD), and their corresponding 95% confidence interval (CI) were calculated. The present meta-analysis showed no significant difference in allograft survival between the AKI and non-AKI groups (HR = 1.16, 95% CI = 0.99-1.37, Pheterogeneity = 0.238, I2 = 21.6%) from 12 months to 120 months after kidney transplantation. However, the time of hospital stay was significantly longer (WMD = 2.49, 95% CI = 1.06-3.92, Pheterogeneity = 0.458, I2 = 0%) and the incidence of delayed graft function (DGF) was significantly higher (RR = 1.76, 95% CI = 1.52-2.04, Pheterogeneity < 0.001, I2 = 71.2%) in the AKI group than in the non-AKI group. We concluded that even though hospital stay time was longer and the incidence of DGF was significantly higher in the AKI group, there is no significant difference in allograft survival between the two groups.