A class of plane symmetric perfect-fluid cosmologies with a Kasner-like singularity

We prove the existence of a class of plane symmetric perfect-fluid cosmologies with a (-1/3, 2/3, 2/3) Kasner-like singularity. These solutions of the Einstein equations depend on two smooth functions of one space coordinate. They are constructed by solving a symmetric hyperbolic system of Fuchsian equations.Comment: LaTeX, 15 pages, no figures, to appear in CQG, correction to existence proo

Spontaneous purinergic neurotransmission in the mouse urinary bladder

Spontaneous purinergic neurotransmission was characterized in the mouse urinary bladder, a model for the pathological or ageing human bladder. Intracellular electrophysiological recording from smooth muscle cells of the detrusor muscle revealed spontaneous depolarizations, distinguishable from spontaneous action potentials (sAPs) by their amplitude (< 40 mV) and insensitivity to the L-type Ca(2+) channel blocker nifedipine (1 μm) (100 ± 29%). Spontaneous depolarizations were abolished by the P2X(1) receptor antagonist NF449 (10 μm) (frequency 8.5 ± 8.5% of controls), insensitive to the muscarinic acetylcholine receptor antagonist atropine (1 μm) (103.4 ± 3.0%), and became more frequent in latrotoxin (LTX; 1 nm) (438 ± 95%), suggesting that they are spontaneous excitatory junction potentials (sEJPs). Such sEJPs were correlated, in amplitude and timing, with focal Ca(2+) transients in smooth muscle cells (measured using confocal microscopy), suggesting a common origin: ATP binding to P2X(1) receptors. sAPs were abolished by NF449, insensitive to atropine (126 ± 39%) and increased in frequency by LTX (930 ± 450%) suggesting a neurogenic, purinergic origin, in common with sEJPs. By comparing the kinetics of sAPs and sEJPs, we demonstrated that sAPs occur when sufficient cation influx through P2X(1) receptors triggers L-type Ca(2+) channels; the first peak of the differentiated rising phase of depolarizations – attributed to the influx of cations through the P2X(1) receptor – is of larger amplitude for sAPs (2248 mV s(−1)) than sEJPs (439 mV s(−1)). Surprisingly, sAPs in the mouse urinary bladder, unlike those from other species, are triggered by stochastic ATP release from parasympathetic nerve terminals rather than being myogenic

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Co-morbidity and utilization of medical services by pain patients receiving opioid medications:data from an insurance claims database

We used a large medical insurance claims database to identify three groups: chronic opioid (>180 therapeutic days, N=3726); acute opioid use (<10 therapeutic days, N=37,108); and a non-opioid group (N=337,366) who filled at least one insurance claim but none for opioids. Our results showed that, although chronic opioid users represented only 0.65% of the total population, they filed 4.56% of all insurance claims, used 45% of all opioid analgesics and had much more physical and psychiatric co-morbidity than the acute opioid or non-opioid samples. Women were substantially over-represented (>63%) in the chronic pain group and used a much greater share of all medical services than males especially as they grew older. Although our data suggest that chronic pain is optimally managed in a multidisciplinary patient- and gender-specific treatment plan, this was rarely the case with internists being the primary, and often only, physician seen. Moreover, our data suggest that opioids were often used for conditions in which they are generally not indicated (e.g. arthritis and headaches) or contraindicated by co-existing physical ailments (COPD). Finally, we conclude that adherence to the WHO analgesic ladder and other pain treatment guidelines was relatively infrequent: first, opioid extended release preparations which are ideally suited for chronic pain were used only in 1 in 4 patients; and, second, the selection of a weak (propoxyphene, codeine, tramadol) or strong opioid (e.g. morphine, oxycodone, etc.) seemed to be driven by numerous factors not necessarily related to the intensity or duration of pain

Tissue targeting of anti-RNP autoimmunity: Effects of T cells and myeloid dendritic cells in a murine model

Using adoptive transfer techniques, we explored the immune cells implicated in a model of anti-RNP autoimmunity that presents either with pneumonitis or glomerulonephritis. Unfractionated splenocytes from donors without renal disease induced predominantly lung disease (8/14 (57%) lung versus 2/14 (14%) renal, p = 0.046). However, the CD4+ cells taken from these splenocytes induced renal disease more frequently than lung disease (7/10 (70%) renal versus 2/10 (20%) lung, p = 0.01). Adoptive transfer of RNP+ CD4+ T cells from short-term culture gave results similar to those with donor splenic CD4+ cells (8/11 (73%) of recipients with renal disease versus 3/11 (27%) with lung disease). Co-transfer of myeloid dendritic cells (MDCs) from the spleens of immunized mice along with CD4+ cells from immunized donors prevented the induction of renal disease (0/5 mice, p = 0.026 versus recipients of fresh CD4+ cells), though lung disease was still seen in 1/5 mice. Transfer of MDCs alone from immunized donors induced lung disease in 3/5 (60%) of recipients, with no nephritis. Co-transfer of splenocytes from mice with nephritis along with splenocytes from mice without nephritis led to renal disease in 4/5 recipients, with lung disease in 0/5 recipients. These findings indicate that RNP+ CD4+ T cells are sufficient to induce anti-RNP autoimmunity, that the tissue targeting of anti-RNP autoimmunity can be deviated to either a renal or pulmonary phenotype depending upon the presence of accessory cells including MDCs, and that dendritic cell subsets can play roles in both propagation of autoimmunity and end organ targeting