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91.
E Rees G Kirov J T Walters A L Richards D Howrigan D H Kavanagh A J Pocklington M Fromer D M Ruderfer L Georgieva N Carrera P Gormley P Palta H Williams S Dwyer J S Johnson P Roussos D D Barker E Banks V Milanova S A Rose K Chambert M Mahajan E M Scolnick J L Moran M T Tsuang S J Glatt W J Chen H-G Hwu The Taiwanese Trios Exome Sequencing Consortium B M Neale A Palotie P Sklar S M Purcell S A McCarroll P Holmans M J Owen M C O'Donovan 《Translational psychiatry》2015,5(7):e607
Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P=1.5 × 10−4). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P=0.018) and de novo mutations (P=0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N=614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios. 相似文献
92.
Pulmonary immunologic features of alveolar septal amyloidosis associated with multiple myeloma 总被引:1,自引:0,他引:1
A 74-year-old man presented with interstitial pulmonary disease which was proven to be alveolar septal amyloidosis by transbronchial biopsy. Multiple myeloma was diagnosed on the basis of monoclonal IgG-lambda protein in serum, monoclonal lambda light chains in urine, a bone marrow plasmacytosis of 22 percent, and serum IgA and IgM levels less than 100 mg/dl and 50 mg/dl, respectively. Appropriate investigations failed to show additional sites of deposition of amyloid. Analysis of fluid from bronchoalveolar lavage showed an increase in total cells recovered, a lymphocytosis with a ratio of T helper over T suppressor cells greater than that in peripheral blood, the presence of an IgG-lambda paraprotein, and an IgG/albumin ratio greater than that in serum. While plasma cells could not be identified in the recovered cell population, cultured cells from bronchoalveolar lavage fluid showed increased production of IgG. These findings provide evidence of an ongoing pulmonary immune response resulting in excess IgG-lambda protein in the pulmonary compartment, a factor which may contribute to the development of amyloidosis. 相似文献
93.
The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin 总被引:4,自引:1,他引:4
The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin. 相似文献
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98.
Jon Banks Fiona M Walter Nicola Hall Katie Mills William Hamilton Katrina M Turner 《The British journal of general practice》2014,64(629):e775-e782
Background
The challenge for GPs when assessing whether to refer a patient for cancer investigation is that many cancer symptoms are also caused by benign self-limiting illness. UK National Institute for Health and Care Excellence (NICE) referral guidelines emphasise that the patient should be involved in the decision-making process and be informed of the reasons for referral. Research to date, however, has not examined the extent to which these guidelines are borne out in practice.Aim
To assess the degree to which patients are involved in the decision to be referred for investigation for symptoms associated with cancer and their understanding of the referral.Design and setting
Qualitative interview study of patients referred to secondary care for symptoms suspicious of lung and colorectal cancer. Patients were recruited from two regions of England using maximum variation sampling.Method
Transcribed interviews were analysed thematically.Results
The analysis was based on 34 patient interviews. Patients in both symptom pathways reported little involvement in the decision to be referred for investigation. This tended to be accompanied by a patient expectation for referral, however, to explain ongoing and un-resolving symptoms. It was also found that reasons for referral tended to be couched in non-specific terms rather than cancer investigation, even when the patient was on a cancer-specific pathway.Conclusion
GPs should consider a more overt discussion with patients when referring them for further investigation of symptoms suspicious of cancer. This would align clinical practice with NICE guidelines and encourage more open discussion between GPs and primary care patients around cancer. 相似文献99.
A Bahrami Y Rassi N Maleki MA Oshaghi M Mohebali MR Yagoobi-Ershadi S Rafizadeh 《亚太热带病杂志(英文版)》2014,4(2):110-114
Objective
To identify the vector(s), the parasite and the species composition of sand flies in the district during May-October 2012.Methods
For reaching our objectives we used polymerase chain reaction of kDNA, ITS1-rDNA, followed by restriction fragment length polymorphism.Results
Two species of Phlebotomus sergenti and Phlebotomus tobbi were the most prevalent among 8 species identified comprising 51.1% and 32.9% respectively. Among the 160 specimens of female sand flies tested by polymerase chain reaction of kDNA, ITS1-rDNA, followed by restriction fragment length polymorphisms, only 1 out of 80 Phlebotomus tobbi (1.25%) were positive to Leishmania infantum parasites.Conclusions
Our finding showed that Phlebotomus tobbi may play as a vector to circulate the parasite of Leishmania infantum among reservoir(s) and human. 相似文献100.