Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7). CONCLUSIONS: Anti-spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP

A treecode to simulate dust-plasma interactions

The interaction of a small object with surrounding plasma is an area of plasma-physics research with a multitude of applications. This paper introduces the plasma octree code pot , a microscopic simulator of a spheroidal dust grain in a plasma. pot uses the Barnes-Hut treecode algorithm to perform N -body simulations of electrons and ions in the vicinity of a chargeable spheroid, employing also the Boris particle-motion integrator and Hutchinson's reinjection algorithm from SCEPTIC; a description of the implementation of all three algorithms is provided. We present results from pot simulations of the charging of spheres in magnetized plasmas, and of spheroids in unmagnetized plasmas. The results call into question the validity of using the Boltzmann relation in hybrid PIC codes

Measurement of overall insecticidal effects in experimental hut trials

BACKGROUND: The 'overall insecticidal effect' is a key measure used to evaluate public health pesticides for indoor use in experimental hut trials. It depends on the proportion of mosquitoes that are killed out of those that enter the treated hut, intrinsic mortality in the control hut, and the ratio of mosquitoes entering the treatment hut to those entering the control hut. This paper critically examines the way the effect is defined, and discusses how it can be used to infer effectiveness of intervention programmes. FINDINGS: The overall insecticidal effect, as defined by the World Health Organization in 2006, can be negative when deterrence from entering the treated hut is high, even if all mosquitoes that enter are killed, wrongly suggesting that the insecticide enhances mosquito survival. Also in the absence of deterrence, even if the insecticide kills all mosquitoes in the treatment hut, the insecticidal effect is less than 100%, unless intrinsic mortality is nil. A proposed alternative definition for the measurement of the overall insecticidal effect has the desirable range of 0 to 1 (100%), provided mortality among non-repelled mosquitoes in the treated hut is less than the corresponding mortality in the control hut. This definition can be built upon to formulate the coverage-dependent insecticidal effectiveness of an intervention programme. Coverage-dependent population protection against feeding can be formulated similarly. CONCLUSIONS: This paper shows that the 2006 recommended quantity for measuring the overall insecticidal effect is problematic, and proposes an alternative quantity with more desirable propertie

Inhibition of Tendon Cell Proliferation and Matrix Glycosaminoglycan Synthesis by Non-Steroidal Anti-Inflammatory Drugs in vitro

The purpose of this study was to investigate the effects of some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) on human tendon. Explants of human digital flexor and patella tendons were cultured in medium containing pharmacological concentrations of NSAIDs. Cell proliferation was measured by incorporation of 3H-thymidine and glycosaminoglycan synthesis was measured by incorporation of 35S-Sulphate. Diclofenac and aceclofenac had no significant effect either on tendon cell proliferation or glycosaminoglycan synthesis. Indomethacin and naproxen inhibited cell proliferation in patella tendons and inhibited glycosaminoglycan synthesis in both digital flexor and patella tendons. If applicable to the in vivo situation, these NSAIDs should be used with caution in the treatment of pain after tendon injury and surgery

A multi-treatment experimental system to examine photosynthetic differentiation in the maize leaf

BACKGROUND: The establishment of C(4 )photosynthesis in maize is associated with differential accumulation of gene transcripts and proteins between bundle sheath and mesophyll photosynthetic cell types. We have physically separated photosynthetic cell types in the leaf blade to characterize differences in gene expression by microarray analysis. Additional control treatments were used to account for transcriptional changes induced by cell preparation treatments. To analyse these data, we have developed a statistical model to compare gene expression values derived from multiple, partially confounded, treatment groups. RESULTS: Differential gene expression in the leaves of wild-type maize seedlings was characterized using the latest release of a maize long-oligonucleotide microarray produced by the Maize Array Project consortium. The complete data set is available through the project web site. Data is also available at the NCBI GEO website, series record GSE3890. Data was analysed with and without consideration of cell preparation associated stress. CONCLUSION: Empirical comparison of the two analyses suggested that consideration of stress helped to reduce the false identification of stress responsive transcripts as cell-type enriched. Using our model including a stress term, we identified 8% of features as differentially expressed between bundle sheath and mesophyll cell types under control of false discovery rate of 5%. An estimate of the overall proportion of differentially accumulating transcripts (1-π(0)) suggested that as many as 18% of the genes may be differentially expressed between B and M. The analytical model presented here is generally applicable to gene expression data and demonstrates the use of statistical elimination of confounding effects such as stress in the context of microarray analysis. We discuss the implications of the high degree of differential transcript accumulation observed with regard to both the establishment and engineering of the C(4 )syndrome

Koala cathelicidin PhciCath5 has antimicrobial activity, including against Chlamydia pecorum.

Devastating fires in Australia over 2019-20 decimated native fauna and flora, including koalas. The resulting population bottleneck, combined with significant loss of habitat, increases the vulnerability of remaining koala populations to threats which include disease. Chlamydia is one disease which causes significant morbidity and mortality in koalas. The predominant pathogenic species, Chlamydia pecorum, causes severe ocular, urogenital and reproductive tract disease. In marsupials, including the koala, gene expansions of an antimicrobial peptide family known as cathelicidins have enabled protection of immunologically naïve pouch young during early development. We propose that koala cathelicidins are active against Chlamydia and other bacteria and fungi. Here we describe ten koala cathelicidins, five of which contained full length coding sequences that were widely expressed in tissues throughout the body. Focusing on these five, we investigate their antimicrobial activity against two koala C. pecorum isolates from distinct serovars; MarsBar and IPTaLE, as well as other bacteria and fungi. One cathelicidin, PhciCath5, inactivated C. pecorum IPTaLE and MarsBar elementary bodies and significantly reduced the number of inclusions compared to the control (p<0.0001). Despite evidence of cathelicidin expression within tissues known to be infected by Chlamydia, natural PhciCath5 concentrations may be inadequate in vivo to prevent or control C. pecorum infections in koalas. PhciCath5 also displayed antimicrobial activity against fungi and Gram negative and positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Electrostatic interactions likely drive PhciCath5 adherence to the pathogen cell membrane, followed by membrane permeabilisation leading to cell death. Activity against E. coli was reduced in the presence of 10% serum and 20% whole blood. Future modification of the PhciCath5 peptide to enhance activity, including in the presence of serum/blood, may provide a novel solution to Chlamydia infection in koalas and other species

New evidence on the management of Lewy body dementia

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordNote that the article title of the accepted author manuscript is different to that of the final published version.Dementia with Lewy bodies and Parkinson’s disease dementia, jointly known as Lewy body dementia (LBD), are common neurodegenerative conditions. Patients with LBD present with a wide range of cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms. The expression of these varies between individual patients, and over time. Treatments may benefit one symptom, but at the expense of worsening another, making management difficult. Often symptoms are managed in isolation and by different specialists, which undermines high quality care. Clinical trials and meta-analyses now provide an improved evidence base for the treatment of cognitive, neuropsychiatric and motor symptoms in LBD, in addition to which expert consensus opinion supports the application of treatments from related conditions such as Parkinson’s disease (PD) for the management of, for example, autonomic symptoms. There remain however clear evidence gaps and there is a high need for future clinical trials focused on specific symptoms in LBD.National Institute for Health Research (NIHR

Sustained attention in mild cognitive impairment with Lewy bodies and Alzheimer\u27s disease

\ua9 The Author(s), 2023. Published by Cambridge University Press on behalf of International Neuropsychological Society. Objective: Attentional impairments are common in dementia with Lewy bodies and its prodromal stage of mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). People with MCI may be capable of compensating for subtle attentional deficits in most circumstances, and so these may present as occasional lapses of attention. We aimed to assess the utility of a continuous performance task (CPT), which requires sustained attention for several minutes, for measuring attentional performance in MCI-LB in comparison to Alzheimer\u27s disease (MCI-AD), and any performance deficits which emerged with sustained effort. Method: We included longitudinal data on a CPT sustained attention task for 89 participants with MCI-LB or MCI-AD and 31 healthy controls, estimating ex-Gaussian response time parameters, omission and commission errors. Performance trajectories were estimated both cross-sectionally (intra-task progress from start to end) and longitudinally (change in performance over years). Results: While response times in successful trials were broadly similar, with slight slowing associated with clinical parkinsonism, those with MCI-LB made considerably more errors. Omission errors were more common throughout the task in MCI-LB than MCI-AD (OR 2.3, 95% CI: 1.1-4.7), while commission errors became more common after several minutes of sustained attention. Within MCI-LB, omission errors were more common in those with clinical parkinsonism (OR 1.9, 95% CI: 1.3-2.9) or cognitive fluctuations (OR 4.3, 95% CI: 2.2-8.8). Conclusions: Sustained attention deficits in MCI-LB may emerge in the form of attentional lapses leading to omissions, and a breakdown in inhibitory control leading to commission errors