What you should know about PR3-ANCA: Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Does allometry of a sexually selected ornamental trait vary with sexual selection intensity? A multi‐species test in damselflies

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Use of a crude extract or purified antigen from first‐instar cattle grubs,Hypoderma lineatum,for the detection of anti‐Hypoderma antibodies in free‐ranging cervids from southern Spain

During the 2003–2005 hunting seasons, a total of 120 Cervidae, including 39 red deer (Cervus elaphus hispanicus) and 81 fallow deer (Dama dama), were examined for subcutaneous myiasis. Animals were shot from January to June in southern Spain. Specific antibodies against Hypodermatinae (Diptera: Oestridae) were detected by indirect enzyme‐linked immunosorbent assay (iELISA) using a crude larval extract (CLE) and a purified antigen [hypodermin C (HC)] obtained from first instars of Hypoderma lineatum (De Villers) (Diptera: Oestridae). Hypoderma actaeon Brauer was the only species detected in this study, which represents the first confirmation of this species in fallow deer from Spain. The overall prevalence of animals presenting subcutaneous larvae (14.2%) was considerably lower than the prevalences determined by iELISA with CLE (43.3%) and HC (40.0%). Red deer showed a higher prevalence of Hypoderma than fallow deer. The concordance between larval examination during the hunting season and iELISA using both antigens was low, whereas the concordance between the CLE and HC ELISAs was good. Larval antigens obtained from H. lineatum constitute a good tool for the diagnosis of H. actaeon in Cervidae, especially when the hunting season does not coincide with the maximum presence of larvae on the back.     

Associations between COPD related manifestations: a cross-sectional study

Background

Cardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort.

Methods

We assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register.

Results

We studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV₁% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ≤ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively).

Conclusions

Increased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality.

Trial registration

Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.     

Translocation of Borrelia burgdorferi surface lipoprotein OspA through the outer membrane requires an unfolded conformation and can initiate at the C‐terminus

Borrelia burgdorferi surface lipoproteins are essential to the pathogenesis of Lyme borreliosis, but the mechanisms responsible for their localization are only beginning to emerge. We have previously demonstrated the critical nature of the amino‐terminal ‘tether’ domain of the mature lipoprotein for sorting a fluorescent reporter to the Borrelia cell surface. Here, we show that individual deletion of four contiguous residues within the tether of major surface lipoprotein OspA results in its inefficient translocation across the Borrelia outer membrane. Intriguingly, C‐terminal epitope tags of these N‐terminal deletion mutants were selectively surface‐exposed. Fold‐destabilizing C‐terminal point mutations and deletions did not block OspA secretion, but rather restored one of the otherwise periplasmic tether mutants to the bacterial surface. Together, these data indicate that disturbance of a confined tether feature leads to premature folding of OspA in the periplasm and thereby prevents secretion through the outer membrane. Furthermore, they suggest that OspA emerges tail‐first on the bacterial surface, yet independent of a specific C‐terminal targeting peptide sequence.     

Blood plasma levels of lipoperoxides,glutathione peroxidase,beta carotene,vitamin A and E in women with habitual abortion

The plasma levels of lipoperoxides, glutathione peroxidase (GSH-Px), reduced glutathione (GSH), beta carotene, vitamin A, E, some plasma biochemical and blood haematological parameters were investigated in 40 women with habitual abortion (HA) and controls. The levels of GSH, vitamin A, E and beta carotene were significantly lower in women with HA than in controls. However, the plasma levels of lipid peroxidation, alkaline phosphatase (ALP), glucose and blood haemoglobin were significantly higher in HA than in controls. In addition, plasma levels of GSH-Px, AST, ALT, total bilirubin, total protein, albumin, sodium, potassium, calcium and number of white blood cells, red blood cells, platelet and values of packet cell volume showed no significant differences between HA and controls. According to the results of this study, we observed that the levels of lipid peroxidation were increased and plasma levels of vitamin A, E and beta carotene were decreased in HA. The decrease of those antioxidants may play a significant role in women with habitual abortion. Copyright © 1998 John Wiley & Sons, Ltd.     

Comparison of serum copper,zinc, calcium,and magnesium levels in preeclamptic and healthy pregnant women

Deficient or excessive levels of blood trace elements can be an adverse factor in human and animal pregnancy. The aim of this study was to investigate possible differences in the levels of serum magnesium, calcium, copper, and zinc in preeclamptic and healthy pregnant women. Samples were collected from 30 preeclamptic (PE) and 30 healthy pregnant (HP) women. The serum copper concentration was significantly lower in the PE group by 68% (p<0.0001) when compared to the healthy controls. The serum zinc and calcium were 43% and 10% lower in the PE women, respectively (both with p<0.0001), whereas the magnesium concentration showed nonsignificant differences between the two groups. Measurement of these elements may be useful for the early diagnosis of a preeclamptic condition.     

Probing structurally altered and aggregated states of therapeutically relevant proteins using GroEL coupled to bio-layer interferometry

The ability of a GroEL-based bio-layer interferometry (BLI) assay to detect structurally altered and/or aggregated species of pharmaceutically relevant proteins is demonstrated. Assay development included optimizing biotinylated-GroEL immobilization to streptavidin biosensors, combined with biophysical and activity measurements showing native and biotinylated GroEL are both stable and active. First, acidic fibroblast growth factor (FGF-1) was incubated under conditions known to promote (40°C) and inhibit (heparin addition) molten globule formation. Heat exposed (40°C) FGF-1 exhibited binding to GroEL-biosensors, which was significantly diminished in the presence of heparin. Second, a polyclonal human IgG solution containing 6–8% non-native dimer showed an increase in higher molecular weight aggregates upon heating by size exclusion chromatography (SEC). The poly IgG solution displayed binding to GroEL-biosensors initially with progressively increased binding upon heating. Enriched preparations of the IgG dimers or monomers showed significant binding to GroEL-biosensors. Finally, a thermally treated IgG1 monoclonal antibody (mAb) solution also demonstrated increased GroEL-biosensor binding, but with different kinetics. The bound complexes could be partially to fully dissociated after ATP addition (i.e., specific GroEL binding) depending on the protein, environmental stress, and the assay’s experimental conditions. Transmission electron microscopy (TEM) images of GroEL-mAb complexes, released from the biosensor, also confirmed interaction of bound complexes at the GroEL binding site with heat-stressed mAb. Results indicate that the GroEL-biosensor-BLI method can detect conformationally altered and/or early aggregation states of proteins, and may potentially be useful as a rapid, stability-indicating biosensor assay for monitoring the structural integrity and physical stability of therapeutic protein candidates.     

A Monte Carlo evaluation for effects of probable dimensional uncertainties of low dose rate brachytherapy seeds on dose

The aim of this study is to determine effects of size deviations of brachytherapy seeds on two dimensional dose distributions around the seed. Although many uncertainties are well known, the uncertainties which stem from geometric features of radiation sources are weakly considered and predicted. Neither TG-43 report which is not completely in common consensus, nor individual scientific MC and experimental studies include sufficient data for geometric uncertainties. Sizes of seed and its components can vary in a manufacturing deviation. This causes geometrical uncertainties, too. In this study, three seeds which have different geometrical properties were modeled using EGSnrc-Code Packages. Seeds were designed with all their details using the geometry package. 5% deviations of seed sizes were assumed. Modified seeds were derived from original seed by changing sizes by 5%. Normalizations of doses which were calculated from three kinds of brachytherapy seed and their derivations were found to be about 3%–20%. It was shown that manufacturing differences of brachytherapy seed cause considerable changes in dose distribution.