Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis

Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Methods: We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)). Results: IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA. Conclusions: Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis

Cardiometabolic risk factors, peripheral arterial tonometry and metformin in adults with type 1 diabetes participating in the REducing with MetfOrmin Vascular Adverse Lesions trial

BACKGROUND: Peripheral arterial tonometry (PAT) provides non-invasive measures of vascular health. Beneficial effects of metformin on vascular function have been reported in youth with type 1 diabetes (T1D). In the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial in adults with T1D and high cardiovascular risk, we examined: (i) the extent to which routinely-measured cardiometabolic risk factors explain variance in baseline PAT; and (ii) the effects of metformin on PAT measures. METHODS: Cross-sectional univariable and multivariable analyses of baseline reactive hyperaemia index (RHI) and augmentation index (AI) (EndoPAT® (Itamar, Israel); and analysis of 36-months metformin versus placebo on vascular tonometry. RESULTS: In 364 adults ((mean ± SD) age 55.2 ± 8.5 years, T1D 34.0 ± 10.6 years, HbA1c 64.5 ± 9.0 mmol/mol (8.1 ± 0.8%)), RHI was 2.26 ± 0.74 and AI was 15.9 ± 19.2%. In an exhaustive search, independent associates of (i) RHI were smoking, waist circumference, systolic blood pressure and vitamin B12 (adjusted R2 = 0.11) and (ii) AI were male sex, pulse pressure, heart rate and waist circumference (adjusted R2 = 0.31). Metformin did not significantly affect RHI or AI. CONCLUSION: Cardiometabolic risk factors explained only a modest proportion of variance in PAT measures of vascular health in adults with T1D and high cardiovascular risk. PAT measures were not affected by metformin

Mechanisms of Adaptation from a Multiple to a Single Step Recovery Strategy following Repeated Exposure to Forward Loss of Balance in Older Adults

When released from an initial, static, forward lean angle and instructed to recover with a single step, some older adults are able to meet the task requirements, whereas others either stumble or fall. The purpose of the present study was to use the concept of margin of stability (MoS) to investigate balance recovery responses in the anterior-posterior direction exhibited by older single steppers, multiple steppers and those that are able to adapt from multiple to single steps following exposure to repeated forward loss of balance. One hundred and fifty-one healthy, community dwelling, older adults, aged 65–80 years, participated in the study. Participants performed four trials of the balance recovery task from each of three initial lean angles. Balance recovery responses in the anterior-posterior direction were quantified at three events; cable release (CR), toe-off (TO) and foot contact (FC), for trials performed at the intermediate lean angle. MoS was computed as the anterior-posterior distance between the forward boundary of the Base of Support (BoS) and the vertical projection of the velocity adjusted centre of mass position (XCoM). Approximately one-third of participants adapted from a multiple to a single step recovery strategy following repeated exposure to the task. MoS at FC for the single and multiple step trials in the adaptation group were intermediate between the exclusively single step group and the exclusively multiple step group, with the single step trials having a significant, 3.7 times higher MoS at FC than the multiple step trials. Consistent with differences between single and multiple steppers, adaptation from multiple to single steps was attributed to an increased BoS at FC, a reduced XCoM at FC and an increased rate of BoS displacement from TO to FC. Adaptations occurred within a single test session and suggest older adults that are close to the threshold of successful recovery can rapidly improve dynamic stability following repeated exposure to a forward loss of balance

Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

<p>Background - Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.</p> <p>Methods - We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.</p> <p>Findings - We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.</p> <p>Interpretation - Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.</p&gt

Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes

We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

Background: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. Methods: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. Discussion: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. Trial registration number: NCT02910934

Transmission Dynamics of a Virus in a Stage-Structured Insect Population

Despite the blossoming interest in host-microparasite epidemiology, and in use of viruses in the biological control of insect pests, few empirical studies have attempted to quantify transmission and mortality rates under field conditions. We report a laboratory and field study in which the transmission parameter (u) and mortality rate (a) due to nuclear polyhedrosis virus (NPV) are measured in different larval instars of the cabbage moth, Mamestra brassicae (Lepidoptera: Noctuidae). Laboratory studies of food consumption and virus susceptibility were used to produce crude estimates of relative transmission rates in successive instars. Increased in the rate of feeding outstrip increases in virus resistance with instar, so we predict that transmission rates should increase in older larvae (assuming rate of intake of virus to be proportional to rate of feeding). This prediction was tested in a field experiment in which a constant initial density of susceptible and infected (moribund) larvae were reared together on cabbage plants for 2-8 d. Estimates of the linear transmission parameter (u) did not differ between instars and gave a mean value of 2.16 x 10^-^1^2 for all instars and time points. Causes for the discrepancy between predictions based on laboratory data and field measurements are discussed. Differences were found between instars in the time from infection to death (?) (equivalent to 1/a, where @a is the rate of mortality due to viral infection). Second-instar larvae died more rapidly once infected than third instars, which, in turn, died more rapidly than fourth instars. The effect of host population stage structure on patterns of viral infection can be pronounced and if recognized, may significantly increase the accuracy and predictive value of models of host pathogen systems

Proteomics as a quality control tool of pharmaceutical probiotic bacterial lysate products

Probiotic bacteria have a wide range of applications in veterinary and human therapeutics. Inactivated probiotics are complex samples and quality control (QC) should measure as many molecular features as possible. Capillary electrophoresis coupled to mass spectrometry (CE/MS) has been used as a multidimensional and high throughput method for the identification and validation of biomarkers of disease in complex biological samples such as biofluids. In this study we evaluate the suitability of CE/MS to measure the consistency of different lots of the probiotic formulation Pro-Symbioflor which is a bacterial lysate of heat-inactivated Escherichia coli and Enterococcus faecalis. Over 5000 peptides were detected by CE/MS in 5 different lots of the bacterial lysate and in a sample of culture medium. 71 to 75% of the total peptide content was identical in all lots. This percentage increased to 87–89% when allowing the absence of a peptide in one of the 5 samples. These results, based on over 2000 peptides, suggest high similarity of the 5 different lots. Sequence analysis identified peptides of both E. coli and E. faecalis and peptides originating from the culture medium, thus confirming the presence of the strains in the formulation. Ontology analysis suggested that the majority of the peptides identified for E. coli originated from the cell membrane or the fimbrium, while peptides identified for E. faecalis were enriched for peptides originating from the cytoplasm. The bacterial lysate peptides as a whole are recognised as highly conserved molecular patterns by the innate immune system as microbe associated molecular pattern (MAMP). Sequence analysis also identified the presence of soybean, yeast and casein protein fragments that are part of the formulation of the culture medium. In conclusion CE/MS seems an appropriate QC tool to analyze complex biological products such as inactivated probiotic formulations and allows determining the similarity between lots

HLA gene expression is altered in whole blood and placenta from women who later developed preeclampsia

© The American Physiological Society.Preeclampsia is a multisystem disease that significantly contributes to maternal and fetal morbidity and mortality. In this study, we used a non-biased microarray approach to identify dysregulated genes in maternal whole blood samples which may be associated with the development of preeclampsia. Whole blood samples were obtained at 28 wk of gestation from 5 women who later developed preeclampsia (cases) and 10 matched women with normotensive pregnancies (controls). Placenta samples were obtained from an independent cohort of 19 women with preeclampsia matched with 19 women with normotensive pregnancies. We studied gene expression profiles using Illumina microarray in blood and validated changes in gene expression in whole blood and placenta tissue by qPCR. We found a transcriptional profile differentiating cases from controls; 336 genes were significantly dysregulated in blood from women who developed preeclampsia. Functional annotation of microarray results indicated that most of the genes found to be dysregulated were involved in inflammatory pathways. While general trends were preserved, only HLA-A was validated in whole blood samples from cases using qPCR (2.30-± 0.9-fold change) whereas in placental tissue HLA-DRB1 expression was found to be significantly increased in samples from women with preeclampsia (5.88-± 2.24-fold change). We have identified that HLA-A is upregulated in the circulation of women who went on to develop preeclampsia. In placenta of women with preeclampsia we identified that HLA-DRB1 is upregulated. Our data provide further evidence for involvement of the HLA gene family in the pathogenesis of preeclampsia