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A family carrying a homozygous variant of DNAJB2 gene C.91C>T (p.His31Tyr) with distal hereditary motor neuropathy (dHMN) associated with early-onset Parkinson′s disease was reported. The patient presented with distal limb weakness and atrophy at the early stage of the disease, and developed Parkinson′s symptoms more than 10 years later. Neuroelectrophysiological examination suggested motor and sensory axonal involvement. This mutation site had not been reported and was considered to be a neogenic mutagenicity of dHMN, excluding other mutations that can cause early-onset Parkinson′s disease.
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Objective To evaluate the role and potential mechanism of interleukin (IL)-18/IL-18 binding protein (BP) in mediating the killing effect of natural killer (NK)-92MI cells upon endothelial cells from α-1, 3- galactosyltransferase gene-knockout (GTKO) porcine models. Methods NK-92MI cells were divided into the NK, NK+IL-18, NK+GTKO, IL-18+NK+GTKO and IL-18+IL-18BP+NK+GTKO groups. The messenger ribonucleic acid (mRNA) levels of inflammation-related genes in NK-92MI cells were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The killing effect of NK-92MI cells on endothelial cells from GTKO porcine models was evaluated by lactate dehydrogenase (LDH) assay. The apoptosis of endothelial cells from GTKO porcine models was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The expression levels of proteins with killing effect and apoptosis-related proteins were determined by Western blot. Results Compared with the NK, NK+IL-18 and NK+GTKO groups, the expression levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-8, IL-3, IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA were up-regulated in NK-92MI cells in the IL-18+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the IL-18+NK+GTKO group, the expression levels of IFN-γ, TNF-α, IL-8, IL-3, IL-6 and GM-CSF mRNA were down-regulated in NK-92MI cells in the IL-18+IL-18BP+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the NK+GTKO group, the expression levels of perforin, granzyme B and IFN-γ proteins in NK-92MI cells were up-regulated, the killing rate of NK-92MI cells against endothelial cells from GTKO porcine models was enhanced, the apoptosis rate of endothelial cells from GTKO porcine models was increased, and the ratios of B cell lymphoma-2 (Bcl-2)-associated X protein (Bax)/Bcl-2 and cleaved Caspase-3/Caspase-3 in endothelial cells from GTKO porcine models were elevated in the IL-18+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Compared with the IL-18+NK+GTKO group, the expression levels of perforin, granzyme B and IFN-γ proteins were down-regulated, the killing rate of NK-92MI cells against endothelial cells from GTKO porcine models was decreased, the apoptosis rate of endothelial cells from GTKO porcine models was decreased, and the ratios of Bax/Bcl-2 and cleaved Caspase-3/Caspase-3 in endothelial cells from GTKO porcine models were declined in the IL-18+IL-18BP+NK+GTKO group, and the differences were statistically significant (all P < 0.05). Conclusions IL-18BP may block the expression of inflammation-related genes in NK-92MI cells induced by IL-18 and the killing effect of NK-92MI cells on endothelial cells from GTKO porcine models.
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Neurexin-3α, discovered in 2016, is a new type of autoimmune encephalitis antibody. Anti-neurexin-3α antibody-associated encephalitis is generally associated with prodromal symptoms or mood changes, having main clinical manifestations as seizures, memory disorders, confusion or loss of consciousness, central ventilation insufficiency, abnormal behavior, and speech disorders. This paper reviews the relevant research progress at home and abroad about pathogenesis, diagnosis and differential diagnosis, treatment and prognosis of anti-neurexin-3α antibody-associated encephalitis, so as to expand the understanding of clinicians for this disease.
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Anti- N-methyl- D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system mediated by NMDAR antibodies. Movement disorder is one of the clinical features of anti-NMDAR encephalitis, with various manifestations such as orofacial involuntary movements and limbs stereotypies, which can indicate the disease diagnosis. Currently, the clinical understanding and attention to movement disorder are insufficient, with few treatment strategies. This article reviews the research progress on characteristics and treatment methods of movement disorder of anti-NMDAR encephalitis, aiming to further effectively recognize and treat movement disorder.
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【Objective】 To explore the perioperative blood management in patients with pancreatic pseudocyst combiend with coagulation factor Ⅴ(FⅤ) deficiency. 【Methods】 Preoperative: In order to determine the effect of cryoprecipitated antihemophilic factor and fresh frozen plasma (FFP) on the elevation level of factor Ⅴ, we alternately infused cryoprecipitate and FFP in the resting state. TEG, coagulation function and coagulation factor activity were monitored before and 1 h, 24 h and 48 h after infusion, and intraoperative and postoperative blood transfusion strategies were formulated. FFP 600 mL and cryoprecipitate 10 U were supplemented preoperatively. Intraoperative: The operation procedure was performed for 7 hours with an infusion of 600 mL FFP without significant bleeding. Postoperative: FFP was infused. 【Results】 Preoperative: The coagulation factor Ⅴ activity on pre-operation was 1.9% and 1.8%. After alternating infusion cryoprecipitate 10 U and FFP 1 200 mL, the FⅤactivity increased to 5.1% and 6.0%, respectively. There was no significant difference in TEG parameters, PT and ATPP results were decreased to varying degrees. Intraoperative: The operation was successful without obvious bleeding. Postoperative: FFP 500 mL was infused 2 h after operation, and FFP 250-500 mL was injected daily from 1 to 7 days after surgery. No significant bleeding was observed in the wound, the results of TEG, PT, APTT and hemoglobin (Hb) did not change significantly compared with those before surgery. The patient was discharged successfully 12 days after surgery. The genetic test results showed that he had inherited coagulation factor Ⅴ deficiency, which was a compound heterozygous variation. 【Conclusion】 Perioperative blood management in patients with FⅤ deficiency combined with surgical disease, requiring pre-transfusion evaluation and post-transfusion evaluation in combination with laboratory investigations and clinical manifestations, cryoprecipitate and fresh frozen plasma can be effective in supplementing coagulation factors. The TEG seems to be better than the Seven items of coagulation function in judging the clotting status of patients with FⅤ deficiency.
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Cerebral amyloid angiopathy-related inflammation is an inflammatory reaction process caused by beta-amyloid protein deposited in the cortical and leptomeningeal vessels, which is a rare type of cerebral amyloid angiopathy. Most of the patients are middle-aged and elderly, and manifest as progressive cognitive impairment, headache, seizures, and focal neurological deficits. Brain magnetic resonance imaging shows asymmetric T 2/fluid attenuated inversion recovery hyperintensity in cortical and subcortical white matter, in addition to multiple cerebral microbleeds. The disease often needs to be differentiated from primary angiitis of the central nervous system, glioma, and varicella-zoster virus encephalitis. Although the disease is rare, prompt treatment with glucocorticoids and immune suppressants can reduce death and disability and significantly improve outcome. Therefore, it is necessary to improve the ability of early diagnosis and treatment of this disease.
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@#To compared the clinical characteristics and surgical outcomes of temporal lobe epilepsy （TLE） patients with different auras，so as to provide more theoretical reference for the clinical diagnosis and treatment of TLE. Methods We retrospectively analyzed the clinical data of 408 TLE patients who underwent surgical treatment. The auras were divided into mesial temporal auras，lateral temporal auras，extratemporal auras and unspecific auras，and the age at seizure onset，gender，febrile seizures （FS），MRI，distribution of interictal epileptiform discharges （IEDs），secondary general tonicclonic seizures （SGTCS），operation side and surgical outcomes were compared in patients with different auras. Results 60.8% （248/408） of the TLE patients had auras，of which 37.7% were medial temporal auras，7.6% were lateral temporal auras，4.7% were extratemporal auras and 10.8% were unspecific auras. There was no significant difference in age at onset，gender，febrile seizures，MRI，distribution of IEDs，SGTCS and operation side in patients with or without auras（all P>0.05）. However，among patients with auras，those with mesial temporal auras had higher odds of focal IEDs （57.1% vs. 43.6%，P=0.039），and those with extratemporal auras had higher odds of FS and left side surgery （52.1% vs. 21.8%，P=0.006 and 73.7% vs. 49.3%，P=0.041，respectively）. The mean postoperative follow-up was 41.5±22.9 months and 75.4% （254/337） of patients were seizure free. There was no statistical difference in surgical outcomes among patients with different type of auras or no auras（P=0.483）.Conclusion The clinical characteristics including FS，lateralization of epileptogenic focus and distribution of IEDs in TLE patients with different type of auras had certain differences.However，there was no difference in surgical outcomes among TLE patients with no aura or different type of auras.
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In clinic, it is very common that a variety of drugs are used in the treatment of diseases. However, the combination of drugs can easily lead to the occurrence of drug-drug interaction (DDI), which can lead to the reduction or loss of drug efficacy, the increase of adverse reactions, and even lead to serious adverse reactions. Drug transporters play an important role in the occurrence and development of DDI by influencing the disposal process of combined drugs in vivo. In this paper, the relationship between DDI and transporter was summarized. The effects of transporter-mediated DDI on the drug disposal process in vivo, and the relations of DDI and disease or multidrug resistance were reviewed. The current guiding principles of DDI research in China were briefly introduced. The purpose was to remind clinical medical workers to pay attention to transporter-mediated DDI and improve the safety of drug combination, further to provide a new vision and ideas for disease treatment and avoiding multidrug resistance.
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OBJECTIVE@#To establish a secondary hemophagocytic lymphohistiocytosis(HLH) mouse model, and to investigate the effect of ruxolitinib on the disease manifestation of model mice.@*METHODS@#Wild type C57BL/6 mice were randomly divided into 4 groups: two groups of mice were intraperitoneally injected with CpG oligodeoxynucleotide 1826 (CpG-ODN1826) every other day to induce HLH, and other two groups were control groups. One group of the CpG-ODN1826 groups and one of the control groups were given ruxolitinib, and other two groups were given the same amount of PBS. Blood samples, serum ferritin and hepatic/spleen weights of experimental mice were detected and serum cytokine levels were measured by ELISA.@*RESULTS@#Compared with the control groups, the levels of white blood cells, hemoglobin and platelets in the CpG-ODN1826 groups were significantly lower (P＜0.05); and liver/body weight, spleen/body weight, serum ferritin, sCD25, IL-10, IL-1β, IFN-Ƴ, IL-12p70, GM-CSF, TNF-α and IL-18 levels significantly increased (P＜0.05). There was no significant difference in the levels of IL-2, IL-4, IL-5, IL-6, IL-22, IL-13, IL-27 and IL-23 between the two groups (P＞0.05). The spleen in CpG group had disordered internal structure, expanding red pulp and hyperplastic nucleated cells. The liver had severe perivascular inflammations. The spleen/weight of the ruxolitinib-treated mice in the CpG-ODN1826 group was significantly smaller than that of the unapplied ruxolitinib (P＜0.05).@*CONCLUSION@#The CpG-ODN1826 can induce secondary HLH symptoms in wild type C57BL/6 mice. Ruxolitinib can alleviate the symptoms of splenomegaly in HLH model mice.
الموضوعات
Animals , Mice , Disease Models, Animal , Lymphohistiocytosis, Hemophagocytic , Mice, Inbred C57BL , Pyrazolesالملخص
Objective:To investigate the changes of c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 (MMP-9) expressions after cerebral ischemia-reperfusion in rats and whether JNK inhibitor SP600125 can protect the cerebral ischemia-reperfusion injury by down-regulating the expression of MMP-9. Methods:Eighty-five adult male SD rats were divided into sham-operated group ( n=35), ischemia group ( n=35) and SP600125 group ( n=15). The middle cerebral artery occlusion models in rats of ischemia group and SP600125 group were established by thread embolism method, and reperfusion was performed one h after ischemia. Rats in the SP600125 group were injected with SP600125 solvent (being dissolved in 10% dimethyl sulfoxide with final concentration of 20 mmol/L) in the lateral ventricle 30 min before cerebral ischemia. At 48 h after reperfusion, neurological impairment scale scores, volume ratio of ischemic lesion, and moisture content of brain tissues in rats from each group were evaluated. The protein expression levels of phosphorylated (p)-JNK, JNK and MMP-9 in the ischemic cortex were detected by Western blotting in rats from the sham-operated group and ischemic group at 3, 6, 24 and 48 h after reperfusion, and in rats from SP600125 group at 48 h after reperfusion. Results:As compared with the sham-operated group, rats in the ischemia group had significantly decreased neurological impairment scale scores, and significantly increased infarction volume ratio and moisture content of brain tissues 48 h after reperfusion. At 24 and 48 h after reperfusion, the p-JNK/JNK values and MMP-9 protein level in the ischemia group were significantly increased as compared with those in the sham-operated group ( P<0.05). As compared with the ischemia group, at 48 h after reperfusion, rats in the SP600125 group had significantly increased neurological impairment scale scores, and significantly reduced volume ratio of ischemic lesion and moisture content of brain tissues, and significantly reduced p-JNK/JNK values and MMP-9 protein level in the ischemic cortex ( P<0.05). Conclusion:The expressions of JNK and MMP-9 are increased after cerebral ischemia-reperfusion, and the JNK inhibitor SP600125 may decrease MMP-9 expression to reduce the degrees of cerebral infarction after cerebral ischemia-reperfusion, thereby playing a role in brain protection.
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@#Objective To investigate the electro-clinical characteristics of epilepsy patients with double cortex syndrome（DCS）. Methods We retrospectively analyzed the history，imaging，electrophysiology，seizure type and clinical treatment of 4 epilepsy patients with DCS. Results All 4 patients were female，and the onset age was 1 to 13 years old. All had different degrees of mental development disorders. The EEG background rhythm was significantly slower in 2 patients. In 3 patients，the interictal epileptic discharges were mainly located in the temporo-parieto-occipital area bilaterally，appeared synchronously or alternately，and could also be mainly distributed on one side. In 3 patients who had seizures all had a widespread seizure origin. All 4 patients had multiple seizure types，and secondary general tonic or general tonic-clonic can be well controlled in 3 patients. Conclusion The incidence of epilepsy patients with DCS has obvious female gender advantage，and the earlier the onset age，the greater the impact on intellectual development. Interictal epileptic discharges in these patients were mainly located on posterior head bilaterally. Furthermore，it has the characteristics of wide distributed seizure onset zone，various seizure types，and well controlled seizure type of general tonic or general tonic-clonic by antiepileptic drugs.
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Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I (DHP-I), was developed. In present study, the potential roles of renal organic anion transporters (OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated and in rabbits. Our results indicated that imipenem and cilastatin were substrates of hOAT1 and hOAT3. Cilastatin inhibited hOAT1/3-mediated transport of imipenem with IC values comparable to the clinical concentration, suggesting the potential to cause a clinical drug-drug interaction (DDI). Moreover, imipenem exhibited hOAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.
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OBJECTIVE@#To investigate the clinical features of acute myeloid leukemia patients aged over 80 years.@*METHODS@#The clinical data from 24 cases of acute myeloid leukemia (non-M3) aged over 80 years were analyzed retrospectively. Clinical characteristics, therapeutic efficacy and overall survival rate of the patients received low dose chemotherapy and/or decitabine were compared with that received only supportive care.@*RESULTS@#According to FAB classification, the 10 patients were M2 subtypes (41.7%), the 7 patients were M4 subtypes (29.2%), the 4 patiens were M5 (16.7%), the 3 patients were unclassifed (16.5%). 22 patients (91.0%) were complicated with underling diseases. Among 13 patients received low dose chemotherapy or decitabine, 8 cases (61.5%) achived partial remission or higher remission. The median survival time of patients who reseived chemotherapy was 30 weeks, and signicantly longer than that of patients received supportive care (median survival time was 9 weeks (P<0.05)). The univariated analysis showed that WBC≥50×10/L, ECOG≥2 and received supportive care were unfavonrable prognostic factors for overall survival.@*CONCLUSION@#More than half of patients aged over 80 years who received individudized treatment can achieve partial remission or higher remission, and can have more longer survival time..
الموضوعات
Aged, 80 and over , Humans , Decitabine , Leukemia, Myeloid, Acute , Retrospective Studies , Survival Rate , Treatment Outcomeالملخص
Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.
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Objective To investigate the mechanism of action of toll-like receptor 2 (TLR2),myeloid differentiation factor 88 (MyD88),and matrix metalloproteinase-9 (MMP-9) in cerebral ischemia-reperfusion injury in rats.Methods One hundred twenty-fiwe adult male SD rats were randomly divided into sham operation group,cerebral ischemia group and T2.5 (TLR2 antagonist) treatment group.A model of middle cerebral artery occlusion was induced by suture method.T2.5 (0.121 2 μg/g) was injected into jugular vein at the beginning of reperfusion in the T2.5 treatment group.Cerebral infarction volume,brain edema,bloodbrain barrier permeability and neurological deficit score were measured at 24 h after reperfusion.Western blotting was used to determine the expression levels of TLR2,MyD88 and MMP-9 at different time points in the ischemic cortex.Results Western blot analysis showed that compared with the sham operation group,the expression levels of TLR2 and MyD88 in the ischemic group increased significantly from 6 h after ischemia-reperfusion and lasted for 24 h (all P ＜ 0.05),while MMP-9 increased significantly at 24 h after ischemia-reperfusion (P ＜ 0.05).At 24 h after ischemia-reperfusion,the blood-brain barrier permeability,brain edema degree,cerebral infarction volume,and neurological deficit score in the ischemic group were significantly higher than those in the sham operation group (all P ＜0.05);at this time,the expression levels of TLR2,MyD88 and MMP-9 in the T2.5 treatment group were significantly lower than those in the ischemic group (all P＜ 0.05),and the blood-brain barrier permeability,brain edema degree,cerebral infarction volume,and neurological deficit score were significantly reduced (all P＜ 0.05).Conclusion TLR2,MyD88 and MMP-9 might be involved in cerebral ischemia-reperfusion injury.TLR2 antagonist T2.5 might inhibit the expression of MMP-9 through TLR2-MyD88 signaling pathway,thus alleviating cerebral ischemia-reperfusion injury.
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Objective To investigate the effect of thyroid stimulating hormone (TSH) on the expression of endothelial nitric oxide synthase (eNOS) and its mechanism in human microvascular endothelial cells (HMEC-1) in vitro culture.Methods Different concentrations of TSH (0,10,50 mIU/ml) were used to intervene HMEC-1.The expression of eNOS mRNA was detected with quantitative polymerase chain reaction (qPCR) method.The protein expressions of eNOS,phosphorylated protein kinase B (p-AKT),protein kinase B (AKT),phosphorylated extracellular signal-regulated kinase (P-ERK),and extracellular signal-regulated kinase (ERK) were determined with Western Blot.Results (1) The expression level of eNOS was significantly decreased by TSH in dose-dependent manner (P ＜ 0.05).(2) TSH could promote the phosphorylation of AKT and ERK (P ＜ 0.05).Conclusions Thyroid-stimulating hormone may inhibit the expression of nitric oxide synthase in human microvascular endothelial cells by activating AKT and ERK signaling pathways.
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Objective To study the effect of hyperthermia-induced MMP-9 on expression of claudin-1 in in vitro BBB model.Methods BMEC and astrocytes were cultured.An in vitro BBB model was established with its permeability assayed by LY test.The BBB model was randomly divided into 37℃ group,39℃ group,37℃+MMP-9 group and 39℃+MMP-9 group.The permeability of BBB model was recorded at 30,60 and 90 min respectively.Expression of claudin-1 in BMEC was detected by Western blot with immunocytochemical staining.Results The permeability of BBB model was higher in 39℃ group than in 37℃ group (P＜0.05) and was significantly higher in 39℃ +MMP-9 group than in 37℃ group (P＜0.05).The number of claudin-1 positive BMEC was smaller in 39℃ +MMP-9 group than in 37℃ group at the same time points (P＜0.05) and in 39℃ +MMP-9 group than in 39℃ group at 90 min (75.0±12.8/HP vs 97.0±6.1/HP,P＜0.05).The expression level of claudin-1 was lower in 39℃ group than in 37℃ group (P＜0.05) and was significantly higher in 39℃ +MMP-9 group than in 37℃ group (P＜0.05),which further increased with the increasing time.Conclusion Hyperthermia can downregulate the expression of claudin-1 in in vitro BBB model and upregulate the permeability of in vitro BBB model.Adding MMP-9 can further aggrevate the damage of in vitro BBB model,indicating that hyperthermia can aggrevate the damage of in vitro BBB model through MMP-9.
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Cholestatic liver injury,which is mainly caused by the disruption of bile acids,is common in the clinic.The pathogenesis of cholestatic liver injury is directly related to the changes of bile acid-related transporters,synthetic and metabolic enzymes.Nuclear receptors play a crucial part in cholestatic liver injury by regulating the expression of transporters and metabolic enzymes that maintaining the homeostasis of bile acids.In this review,we focus on the role of hepatic transporters and metabolic enzymes in cholestatic liver injury and the mechanism of nuclear receptors on the regulation of transporters and metabolic enzymes.
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Liver is an important metabolic and detoxification organ in the body.Hepatic transporters are a series of functional membrane proteins that are extensively expressed in the liver.They are responsible for the uptake of endogenous and exogenous substances such as medicines into hepatocytes and excretion of their metabolic products into bile.Recent studies have provided that transporters and metabolic enzymes play important roles in the chemical substances-induced liver injury,and its various regulatory mechanisms have become hot topics of research.In this paper,we summarize the classification of hepatic transporters and metabolic enzymes and the changes of transporters and metabolic enzymes in the chemical substances-induced liver injury and its regulatory mechanism.
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Elevated thyroid stimulating hormone (TSH) level is an early manifestation of subclinical hypothyroidism (SCH). In the early stages of SCH, patients did not have significant clinical symptoms and were therefore often not taken seriously.However, more and more studies have shown that changes in TSH levels are closely related to human health in recent years. This paper summarizes and analyzes the literature about the effect of TSH on the health, summarizes the research progress of TSH and health relationship in recent 10 years, and provides a new way for the diagnosis and treatment of human diseases.