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Mendelian randomization (MR) approach is based on the Mendelian genetic law,which is called "Parental alleles that randomly assigned to the offspring".MR refers to the use of genetic variants to develop causal inferences from observational data,if the variant genotype isassociated with the phenotype and the variant genotype associated with the risk of disease of interest through the phenotype.Hence,the genotype can be used as Instrumental Variable (IV) to infer the causal relation between the phenotype and the risk of diseases.In recent years,MR approach is widely used in causal inference between the exposure factors and the risks of disease,along with the rapid development of statistical methods,big datasets of GWAS,epigenetics and the various "omics" techniques.This paper provides an overview of the MR strategies and addresses the related assumptions and implications,with reliability and limitations included.
ABSTRACT
Mendelian randomization (MR) approach is based on the Mendelian genetic law,which is called "Parental alleles that randomly assigned to the offspring".MR refers to the use of genetic variants to develop causal inferences from observational data,if the variant genotype isassociated with the phenotype and the variant genotype associated with the risk of disease of interest through the phenotype.Hence,the genotype can be used as Instrumental Variable (IV) to infer the causal relation between the phenotype and the risk of diseases.In recent years,MR approach is widely used in causal inference between the exposure factors and the risks of disease,along with the rapid development of statistical methods,big datasets of GWAS,epigenetics and the various "omics" techniques.This paper provides an overview of the MR strategies and addresses the related assumptions and implications,with reliability and limitations included.
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Objective To evaluate expression and significance of TLR4 and NF-κB on inflammatory injure after intracerebral hemorrhage in rats .Methods 60 Sprague Dawley maleness rats were randomly divided into Sham group ,12 h ,24 h ,72 h and 7 d af-ter ICH group(12 s) .The ICH was induced by injection of autologous blood in rats .The behavioral changes were detected by neu-rologic deficit score .The water content of the brain was used to evaluate brain edema changes .Number of TLR4 and NF-κB positive cells by Nissl staining and the expression of protein determined by immunohistochemistry and Western blot .Results After ICH 12 h ,expression of TLR4 and NF-κB positive cells around the hematoma were expressed ,with the extension of the time ,expression was gradually increasing ,and after ICH 72 h the expression of protein were the highest .Cerebral edema and severe neurological damage occurred .Western blot shows the amount of TLR4 expression and NF-κB were in line with the result .Conclusion After in-tracerebral hemorrhage in rat causing inflammatory injure of brain tissue around the hematoma .TLR4 may activate the expression of NF-κB involved in the secondary inflammatory injure after intracerebral hemorrhage in rats .
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<p><b>OBJECTIVE</b>To investigate the role of P38 mitogen-activated protein kinase (P38 MAPK) signaling pathway in regulating the expression of nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) in the substantia nigra (SN) of a mouse model of Parkinson's disease (PD).</p><p><b>METHODS</b>C57BL/6N mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish an subacute PD model, and the behavioral changes of the mice were observed. Immunohistochemistry and Western blotting were employed to detect the expressions of tyrosine hydroxylase (TH), NF-κB, iNOS and phosphorylated P38 (p-P38) in the midbrain before and after treatment with SB203580.</p><p><b>RESULTS</b>Compared with the control mice, the PD mouse models presented with typical symptoms of PD and showed significantly increased number of p-P38-, NF-κB-, and iNOS-positive cells in the SN area (P<0.01) with significantly reduced number of TH-positive neurons (P<0.01). After SB203580 treatment, the number of p-P38-, NF-κB-, and iNOS-positive cells was reduced obviously (P<0.01) and the number of TH-positive neurons in the SN increased significantly in the PD model mice (P<0.01).</p><p><b>CONCLUSION</b>P38 MAPK signaling pathway may play an important role in modulating NF-κB and iNOS expression in the SN in the early stage of MPTP-induced subacute PD, and SB203580 can inhibit P38 signaling pathway to protect the DA neurons in PD model mice.</p>
Subject(s)
Animals , Mice , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Disease Models, Animal , Imidazoles , MAP Kinase Signaling System , Mice, Inbred C57BL , Metabolism , NF-kappa B , Metabolism , Neurons , Nitric Oxide Synthase Type II , Metabolism , Parkinson Disease , Metabolism , Phosphorylation , Pyridines , Substantia Nigra , p38 Mitogen-Activated Protein Kinases , MetabolismABSTRACT
Objective To explore the effects of tanshinoneⅡA on the injury of dopaminergic neurons of Parkinson’s disease (PD)mouse model induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),and to clarify the possible mechanism of its protective effects on dopaminergic neurons.Methods 60 C57BL/6N mice were randomly divided into control group,PD model group and tanshinone ⅡA group(n=20).The mice in PD model group and tanshinone ⅡA group were treated with MPTP to establish PD models. The bebavior of the mice in various groups was observed.The number of tyrosine hydroxylase (TH),cd11b,p47-phox,and inducibleni tricoxidesynthase (iNOS)-positive cells,and the protein expression levels of TH,cd11b,p47-phox and iNOS in the substantia nigra (SN)of the midbrain of the mice in various groups were detected with immunohistochemistry, Western blotting and double-labeling immunofluorescence assay.Results Compared with control group,the mice in PD model group exhibited typical symptoms of PD, and the number of TH-positive cells and the protein expression level of TH in the substantia nigra of the mice in PD model group were reduced by about 45% and 50%;the number of cd11b,p47-phox,iNOS-positive cells and the protein expression levels of cd11b,p47-phox,iNOS were markedly increased (P<0.01 ). Compared with PD model group, the symptoms of PD of the mice in tanshinone ⅡA group were alleviated,the number of TH-positive cells and the expression level of TH protein in the SN were increased(P<0.01),and the number of cd11b,p47-phox and iNOS-positive cells and the TH protein expression levels were obviously decreased(P<0.01).Conclusion Tanshinone ⅡA could mitigate the loss of dopaminergic neurons in the PD mouse model induced by MPTP. The mechanism of neuprotective effect may be related to the inhibition of microglial activation,NADPH oxidase and iNOS expressions.
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Objective To study the relationship between clinical-biological significance and the expression of CD44v6 and Survivin in multifocal papillary thyroid carcinoma (PTC). Methods Immunohistochemical SP method was used to investigate the expression of CD44v6 and Survivin in 47 cases of multifocal PTC and adjacent tissues, and 122 cases of single focal PTC tissues. The expression of CD44v6 and Survivin and the risk factors among different clinical factors were analyzed between solitary PTC and multifocal PTC group. Results Tumor foci were found in 27.8 % (47/169) patients. The patients with multifocal were characterized by a higher ratio of family history of thymid tumor, lymph node metastasis and extra-thymidal extension (χ2 = 4.189, 6.159, 4.079, P ＜0.05), and not related with sex, age, size and the number of the tumors (P ＞0.05).The positive rates of CD44v6 and Survivin were 70.2 % (33/47) and 66.0 %(31/47), respectively, in multifocal PTC, both of which were significantly higher than that in nodular goiter,Hashimoto' s thyroiditis and normal thyroid tissues (χ2 =47.184, P ＜0.05). Overexpressions of CD44v6 and Survivin in multifocal PTC were related to the degree of the infiltration(χ2 = 4.723, P =0.030; χ2 =4.023,P =0.045) and lymph node metastasis (χ2 =5.771, P =0.016; χ2 =5.686, P =0.017), and not related with sex,age, family history and the number of the tumors (P ＞0.05).The expression of CD44v6 was correlated positively with Survivin (r =0.514, χ2 =10.15, P ＜0.01).There was no significant difference in expressions of CD44v6 and Survivin between multifocal and single focal PTC (P ＞0.05).By the sept.2010, the patients with single and mutiple focal PTC were all survival.Conclusion Multifocus is one of the clinical features of PTC.The high expressions of CD44v6 and Survivin in multifocal PTCs relate to the development, invasion and metastasis.
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Objective To investegate the effect of phosphorylated-P38 MAPK(mitogen-activated protein kinase) on the expression of caspase-3 in the substania nigra (SN) of MPTP-induced mouse model of(PD). Methods Mice were randomly divided into MPTP model group, which were treated with MPTP and inhibitor group. Once a day for 5 days; control group was treated with saline and DMSO as much as the model group received per day for 5 days. The behavioral were observed, immunohistochemistry and Western blot for TH, caspase-3 and phosphorylation of P38 MAPK were used to observe the change of positive cell number and the expression level in the SN of midbrain. Results Compared with the mice in control group, the model group showed typical symtoms of PD with decreased numbers of TH-positive neurons and the protein level of TH in SN of the midbrain by about 60% and 65% respec-tively(P<0.01) , the numbers of caspase-3 and phosphorylation of P38 MAPK immunoreactive cells and their protein level in the SN of the midbrain increased markedly (P<0.01). After giving SB203580, the above changes were reduced obviously (P <0. 01). Conclusion In the mouse model of subacute Parkinson's disease induced by MPTP, phosphorylated-P38 MAPK regulated caspase-3 in the SN of midbrain, the specific P38 MAPK inhibitor SB203580 is neurologically oprotective to the mouse model.
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Objective To explore the clinical value of combined detection of CA15-3, TSGF, OPN and CA125 in the diagnosis and treatment of breast cancer. Methods The serum specimens from 187 patients with breast cancer (cancer group) were collected, tumor markers CA15-3 and CA125 were detected with electrochemiluminescence method, TSGF was detected with chemocolorimetry, and OPN was detected with enzyme-linked immunosorbent assay. Compared with 50 cases of patients with benign breast disease (control group), The relationship between these marker and clinical stage, recurrence and metastasis of breast cancer were analyzed. Results The serum levels of CA15-3, CA125, TSGF and OPN in cancer group were significantly higher than those in control group (P ＜0.05). Four markers in high clinical stage(Ⅲ and Ⅳ stage)[(83.21±28.67), (89.13±32.34), (278.66±137.23) U/ml and (97.4±11.7) ng/ml, respectively] were higher than those in low stage( Ⅰ and Ⅱ stage) [(60.03±19.35), (58.21±17.56), (155.79±113.11) U/ml and (77.5±10.81) ng/ml,respectively] (P ＜0.05), and those in lymphnode metastasis patients and in recurrence patients were significantly higher than those in corresponding groups (P ＜0.05). The sensitivity and specificity of the combined detection of four tumor markers were 96.3 % (180/187) and 80.0 % (40/50), respectively. The average time of combined detection of serum tumor markers was 2 months ahead of the mammographic features in the recurrence patients with breast cancer. Conclusion The dynamic combined detection of CA15-3, TSGF, OPN and CA125 are better markers for monitoring recurrence and metastasis of breast cancer,which are benefit to early diagnosis and interference.
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Objective To investigate possible mechanism of Ginsenoside Rg1 on dopaminergic nigral neurons apoptosis of Parkinson's disease (PD) and its protective effect.Methods C57BL/6N mice were administrated with 1-Methy-4-phenyl-1,2,3,6-tetrahydropyri-dine (MPTP) to produce chronic PD model,PD mice were observed in behavioral changes.The expression levels of caspase-3 and TH in ventral midbrain were studied with immunohistochemistry and Western blotting.Apoptotic cell numbers were determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL).Results In group treated with Ginsenoside Rg1,the number of TH-positive neurons in SN was only decreased by 31% as compared with the control group (55%)(P<0.01),the expression of caspase-3 was apparently decreased and major expressed in the cytosol of nigral neurons and TUNEL positive cells in SN decreased (P<0.01).Conclusion The neuroprotective effect of Ginsenoside Rg1 on dopaminergic nigral neurons apoptosis of the mice model of Parkinson's disease induced by MPTP is significant,Decreased expression of Caspase-3 may be the major mechanism of Ginsenoside Rg1 for antiapoptosis.
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Objective To study the clinicopathological characteristics of hepatobiliary cystic neoplasms(cystadenoma and cystadenocarcinoma)in order to improve its diagnostic and therapeutic accuracy.Methods A retrospective analysis was done on the clinical materials of 9 cases of cystic biliary tumors hospitalized in the People's Hospital of Rizhao City from May 1993 to May 2007.All cases were confirmed by operation and pathologic biopsy.Results Six cases were biliary cystadenoma with muhilocular cyst.The other three cases were biliary cystadenocarcinoma,two with single cyst and one with multilocular cyst.Of the three cystadenocarcinorna,two cases had mural nodules and one case had papillary excrescences and cystic wall thickening.Irregular thickening of internal sept.was shown in the multilocular cyst cases.Two had calcification.Enhancement of the wall.internal septa and nlasses were seen in all the malignant tumors on CT scans. Metastatic lymph node was found in one cage. Conclusion There were no special clinical characteristics in difierentiation between hiliary cystadenoma and cystadenocarcinoma. Single cyst, mural nodules and papillary excrescences,irregular thickening of cystic wall and internal septa,coarse calcification and metastatic lymph node increase the likelihood of the diagnosis of the malignant tumors.But the diagnostic differentiation between cystadenoma and cystadenocarcinoma depends on pathology.
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Objective To study the clinicopathology characteristics of chronic lymphocytic thyroiditis (Hashimoto's thymiditis, HT) with occult papillary thyroid carcinoma (occult PTC) in order to improve its diagnostic and therapeutic accuracy. Methods A restrospective analysis was done on the clinical materials of 28 cases of HT with occult PTC from July 1999 to July 2005. All cases were confirmed by operation and pathologic biopsy. Clinical and gross findings were collected. All HE slides were reexamined and immunostains for CK19, galectin-3,and bcl-2 were performed (Envision method). Results In total 189 cases of chronic lymphocytic thyroiditis,28cases (14.8%,28/189)had coexistent occult papillary thyroid carcinoma. There were 19 females and 9 males with median age of 36.7 years old. Normal TSH presented in 11cases (39.3%), high in 8 cases(28.6%), and low in 9cases (32.1%). All tumor diameter was counted for <0.8 cm, 16 cases (57.1%) tumor diameter 0.2～0.5 cm, 12 cases (42.9%) >0.5 cm. Coarse calcification was seen in 6 cases(21.4%) in color ultrasonic exam and CT scans. Follow-up data showed that 28 patients were all alive with no evidence of recurrence or metastasis for 2 to 7 years by December 2007. Conclusion There are no special clinical characteristics in coexistent HT with occult PTC.Coarse calcification in HT in the group of middle-aged women increase the likelihood of the diagnosis. But the diagnosis depends on pathology. Because of the high incidence of occult PTC in HT population, it would be necessary to keep an eye on this particular type of thyroid carcinoma, and multiple sampling in suspected area of HT specimen is advised in the hope not to miss any small tumor in clinical practice.
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Purpose:Despite the declining trend of stomach cancer incidence, it is still the second important cancer in China and ranks first in Yangzhong City. We examined the role of green tea consumption on stomach cancer and chronic gastritis risks by case control study. Interaction between green tea drinking and potential risk factors of stomach cancer and chronic gastrotitis were also explored. Methods:A population based case control study was conducted in Yangzhong, China, with 143 stomach cancer patients, 166 chronic gastitis patients and 433 healthy controls. Epidemiological data were collected by standard questionnaire, and blood samples were obtained for measurement of Helicobacter pylori infection. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. Results:Inverse association was observed between green tea drinking and stomach cancer and chronic gastritis risks. After adjusting for potential confounding factors, ORs of green tea drinking were 0.46 (95%CI: 0.22—0.96) and 0,46 (95%CI: 0.27—0.77) for stomach cancer and chronic gastritis, respectively. The less ORs of stomach cancer and chronic gastritis, the more frequent the green tea drinking ( P for trend
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Objective To investigate the effect of nuclear factor-?B(NF-?B) on the regulation of cyclooxygenase-2(COX-2) and Caspase-3 in hippocampal neurons after traumatic brain injury(TBI) in rats,and explore the neuroprotective effect and the possible mechanism of progesterone(PROG) in hippocampal neurons after TBI.Methods Forty-five male Spraque-Dawley rats were randomly divided into 3 groups: sham-operated group(n=15),TBI group(n=15) and PROG-treated group(n=15,intraperitoneal injection of PROG 16 mg/kg in 1 and 6 h after injury).The rat model of TBI was duplicated with the improved Feeney's method.The rats were sacrificed in 24 h after injury and their brain was resected.Nissl staining,immunohistochemical staining and Western blot assay for NF-?B,COX-2 and Caspase-3 was used to observe the changes of positive cell numbers and protein levels in the hippocampal neurons.Results The numbers of immunoreactive neurons to NF-?B(24.0?2.5),COX-2(35.9?2.7) and Caspase-3(25.1?2.7) were significantly increased in the hippocampus at 24 h after TBI when compared with the positive neuron numbers of NF-?B(1.9?0.9),COX-2(1.5?0.7) and Caspase-3(1.8?0.8) in sham group.After the treatment of PROG,the positive cell number of NF-?B(14.2?1.8),COX-2(16.6?2.7),Caspase-3(11.2?2.4) was reduced obviously as compared with the TBI group(P