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21.
Rapid biomonitoring protocols, using biotic indices based on macroinvertebrate diversity to assess river ecosystem health, are widely used globally. Such quick assessment techniques are lauded for the rapid results obtained and the relatively easy protocol used to achieve an answer. However, do such quick assessments of water quality give enough information about ecosystems? Are important details being overlooked? When should a full faunal survey be used in preference? Important research programmes, including environmental impact studies, often misuse biomonitoring techniques, making influential management decisions using superficial, low-level data obtained using biomonitoring tools, inappropriate to address those management objectives. The value of using biomonitoring as a quick tool, versus a more detailed faunal assessment, is considered here. The assessment of teloganodid mayfly fauna occurring in South African rivers provides an example of the value of detailed studies versus superficial family level investigations, showing that a rapid biomonitoring approach should not be used as a shortcut when a more detailed survey is needed. Each situation should be assessed for its own merit in a given set of project circumstances. A checklist of criteria is presented, giving guidance on when rapid biomonitoring alone is valuable and when more detailed assessments would give a more relevant result. 相似文献
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Voltage-gated Ca2+ (Ca(V)) channels are central to the biology of excitable cells, and therefore regulating their activity has widespread applications. We describe genetically encoded molecules for inducibly inhibiting Ca(V) channels (GEMIICCs). GEMIICCs are derivatives of Rem, a Ras-like GTPase that constitutively inhibits Ca2+ currents (I(Ca)). C terminus-truncated Rem(1-265) lost the ability to inhibit I(Ca) owing to loss of membrane targeting. Fusing the C1 domain of protein kinase Cgamma to yellow fluorescent protein (YFP)-Rem(1-265) generated a molecule that rapidly translocated from cytosol to plasma membrane with phorbol-12,13-dibutyrate in human embryonic kidney cells. Recombinant Ca(V)2.2 and Ca(V)1.2 channels were inhibited concomitantly with C1(PKCgamma)-YFP-Rem(1-265) membrane translocation. The generality of the approach was confirmed by creating a GEMIICC using rapamycin-dependent heterodimerization of YFP-FKBP-Rem(1-265) and a constitutively membrane-targeted rapamycin-binding domain. GEMIICCs reduced I(Ca) without diminishing gating charge, thereby ruling out decreased number of surface channels and voltage-sensor immobilization as mechanisms for inhibition. We introduce small-molecule-regulated GEMIICCs as potent tools for rapidly manipulating Ca2+ signals in excitable cells. 相似文献
25.
Ana Cecilia AX De-Oliveira Renato S Carvalho Flavio HM Paixão Hellen S Tavares Luciana S Gueiros Carolina M Siqueira Francisco JR Paumgartten 《Malaria journal》2010,9(1):1-17
Background
The mechanisms by which malaria up and down-regulates CYP activities are not understood yet. It is also unclear whether CYP activities are modulated during non-lethal malaria infections. This study was undertaken to evaluate the time course of CYP alterations in lethal (Plasmodium berghei ANKA) and non-lethal (Plasmodium chabaudi chabaudi) murine malaria. Additionally, hypotheses on the association of CYP depression with enhanced nitric oxide (NO) production, and of CYP2a5 induction with endoplasmic reticulum dysfunction, enhanced haem metabolism and oxidative stress were examined as well.Methods
Female DBA-2 and C57BL/6 mice were infected with P.berghei ANKA or P. chabaudi and killed at different post-infection days. Infection was monitored by parasitaemia rates and clinical signs. NO levels were measured in the serum. Activities of CYP1a (ethoxyresorufin-O-deethylase), 2b (benzyloxyresorufin-O-debenzylase), 2a5 (coumarin-7-hydroxylase) and uridine-diphosphoglucuronyl-transferase (UGT) were determined in liver microsomes. Glutathione-S-transferase (GST) activity and concentrations of gluthatione (GSH) and thiobarbituric acid-reactive substances (TBARS) were determined in the liver. Levels of glucose-regulated protein 78 (GRP78) were evaluated by immunoblotting, while mRNAs of haemoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) were determined by quantitative RT-PCR.Results
Plasmodium berghei depressed CYP1a and 2b and induced 2a5 in DBA-2 mice. In P.berghei-infected C57BL/6 mice CYP activities remained unaltered. In both strains, GST and UGT were not affected by P.berghei. Plasmodium c. chabaudi depressed CYP1a and 2b and induced 2a5 activities on the day of peak parasitaemia or near this day. CYP2a5 induction was associated with over-expression of HO-1 and enhanced oxidative stress, but it was not associated with GRP78 induction, a marker of endoplasmic reticulum stress. Plasmodium chabaudi increased serum NO on days near the parasitaemia peak in both strains. Although not elevating serum NO, P.berghei enhanced iNOS mRNA expression in the liver.Conclusion
Down-regulation of CYP1a and 2b and induction of 2a5 occurred in lethal and non-lethal infections when parasitaemia rates were high. A contribution of NO for depression of CYP2b cannot be ruled out. Results were consistent with the view that CYP2a5 and HO-1 are concurrently up-regulated and suggested that CYP2a5 induction may occur in the absence of enhanced endoplasmic reticulum stress. 相似文献26.
27.
Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis
van der Helm-van Mil AH Verpoort KN Breedveld FC Toes RE Huizinga TW 《Arthritis research & therapy》2005,7(5):R949-R958
Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid
arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently
showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease.
These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or
anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative
RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have
a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454
incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms,
tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological
destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness,
type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between
RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion
was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction.
Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In
conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation
but differs with respect to disease course. 相似文献
28.
Sofie HM Manders Wietske Kievit Eddy Adang Herman L Brus Hein J Bernelot Moens Andre Hartkamp Lidy Hendriks Elisabeth Brouwer Henk Visser Harald E Vonkeman Jos Hendrikx Tim L Jansen Rene Westhovens Mart AFJ van de Laar Piet LCM van Riel 《Arthritis research & therapy》2015,17(1)
IntroductionFor patients with rheumatoid arthritis (RA) whose treatment with a tumour necrosis factor inhibitor (TNFi) is failing, several biological treatment options are available. Often, another TNFi or a biological with another mode of action is prescribed. The objective of this study was to compare the effectiveness and cost-effectiveness of three biologic treatments with different modes of action in patients with RA whose TNFi therapy is failing.MethodsWe conducted a pragmatic, 1-year randomised trial in a multicentre setting. Patients with active RA despite previous TNFi treatment were randomised to receive abatacept, rituximab or a different TNFi. The primary outcome (Disease Activity Score in 28 joints) and the secondary outcomes (Health Assessment Questionnaire Disability Index and 36-item Short Form Health Survey scores) were analysed using linear mixed models. Cost-effectiveness was analysed on the basis of incremental net monetary benefit, which was based on quality-adjusted life-years (calculated using EQ-5D scores), and all medication expenditures consumed in 1 year. All analyses were also corrected for possible confounders.ResultsOf 144 randomised patients, 5 were excluded and 139 started taking abatacept (43 patients), rituximab (46 patients) or a different TNFi (50 patients). There were no significant differences between the three groups with respect to multiple measures of RA outcomes. However, our analysis revealed that rituximab therapy is significantly more cost-effective than both abatacept and TNFi over a willingness-to-pay range of 0 to 80,000 euros.ConclusionsAll three treatment options were similarly effective; however, when costs were factored into the treatment decision, rituximab was the best option available to patients whose first TNFi treatment failed. However, generalization of these costs to other countries should be undertaken carefully.
Trial registration
Netherlands Trial Register number NTR1605. Registered 24 December 2008.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0630-5) contains supplementary material, which is available to authorized users. 相似文献29.
Erin N Smith Kristen Jepsen Mahdieh Khosroheidari Laura Z Rassenti Matteo D’Antonio Emanuela M Ghia Dennis A Carson Catriona HM Jamieson Thomas J Kipps Kelly A Frazer 《Genome biology》2014,15(7)
Accurate allele frequencies are important for measuring subclonal heterogeneity and clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positive rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0420-4) contains supplementary material, which is available to authorized users. 相似文献30.
Femke HM Prince Vivian P Bykerk Nancy A Shadick Bing Lu Jing Cui Michelle Frits Christine K Iannaccone Michael E Weinblatt Daniel H Solomon 《Arthritis research & therapy》2012,14(2):R68-8