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Previous work indicates that dynamic cerebral blood flow (CBF) regulation is impaired during hypercapnia; however, less is known about the impact of resting hypercapnia on regional CBF regulation during hypovolemia. Furthermore, there is disparity within the literature on whether differences between anterior and posterior CBF regulation exist during physiological stressors. We hypothesized: (a) lower-body negative pressure (LBNP)-induced reductions in cerebral blood velocity (surrogate for CBF) would be more pronounced during hypercapnia, indicating impaired CBF regulation; and (b) the anterior and posterior cerebral circulations will exhibit similar responses to LBNP. In 12 healthy participants (6 females), heart rate (electrocardiogram), mean arterial pressure (MAP; finger photoplethosmography), partial pressure of end-tidal carbon dioxide (PETCO2), middle cerebral artery blood velocity (MCAv) and posterior cerebral artery blood velocity (PCAv; transcranial Doppler ultrasound) were measured. Cerebrovascular conductance (CVC) was calculated as MCAv or PCAv indexed to MAP. Two randomized incremental LBNP protocols were conducted (− 20, − 40, − 60 and − 80 mmHg; three-minute stages), during coached normocapnia (i.e., room air), and inspired 5% hypercapnia (~ + 7 mmHg PETCO2 in normoxia). The main findings were: (a) static CBF regulation in the MCA and PCA was similar during normocapnic and hypercapnic LBNP trials, (b) MCA and PCA CBV and CVC responded similarly to LBNP during normocapnia, but (c) PCAv and PCA CVC were reduced to a greater extent at − 60 mmHg LBNP (P = 0.029; P

This paper presents the development of a predictive model for topside annulus vent gas flow from a flexible riser and the infrastructure to feed live operational data from the offshore process, subsea and vent systems to a cloud solution. The presented data is accessed and processed through analytics prior to live presentation on a digital platform accessible to offshore and onshore subsea engineers, and to anyone inside or outside the operator's organization in need for the data and operational status. The aim is to use all available sensor data related to five operative high temperature flexible risers to reveal emerging evolvement of a failure mode previously experienced on similar risers in similar service. Carcass collapse in the seabed segment of the flexible riser is identified as the key failure mode in need for mitigation actions. The collapse is caused by excessive pressure in pipe designs with multi-layer pressure sheath, and has been observed on several occasions during startup after longer maintenance and shut down periods. As the flow rate in the risers is moderate and the performance of wells varies, it is not possible to identify the carcass collapse by pressure drop monitoring, not even with detailed analysis of pressure differences topside and subsea. Concatenating all pressure, temperature, annulus volume testing, inspection and annulus monitoring data in real time established the basis for applying machine learning techniques to identify when a carcass failure emerged. Combining data analytics with in depth understanding of the flexible pipe cross section, failure mode development and pipe dissection experiences enabled an analytics solution providing early warning of an emerging damage. As all the utilized measurement data was available, also for two previous carcass damages in identical risers, validation and confidence of the models could be established to identify these damages early. On this basis, it was concluded that the focused monitoring and digital analytics gave sufficient risk mitigation for the five remaining operating risers of the same type.

Systemic lupus erythematosus (SLE) is characterized by autoantibodies, including antibodies to the nucleosides of DNA. Guanosine is the most immunogenic nucleoside. In this study serum antiguanosine antibody levels were compared with disease activity, determined by their SLEDI score, in 86 patients with SLE. Sera from these patients were tested, by ELISA, for autoantibodies to guanosine, single-stranded DNA (ssDNA), and double-stranded DNA (dsDNA). Anti-doublestranded DNA levels were also measured by RIA. Resultant values from these assays were correlated with SLE disease activity, and compared with specific features of SLE. The strongest correlation was higher levels of antiguanosine antibodies in patients with active lupus nephritis and polyserositis compared to patients with inactive disease (P < 0.0001). Antiguanosine levels also correlated with arthritis (P < 0.006), CNS lupus (P < 0.005), and hematologic manifestations of SLE (P < 0.002). To test the validity of this association in chronic SLE, serum antiguanosine antibodies were measured in patients with SLE at various phases of disease activity. Twelve patients with SLE had serum samples drawn at active, active-improved, and inactive phases over a 3–7 y period. Differences were significant for serum antiguanosine antibodies in the active group compared to the inactive group (P < 0.05) and the active vs the active-improved group (P < 0.02), unlike those for dsDNA and ssDNA by ELISA or RIA. Antiguanosine antibodies correlated more closely with disease activity in SLE patients in this longitudinal study than either anti-dsDNA or ssDNA antibodies. Thus, antibodies to guanosine correlated as well or better with disease activity than the other anti-DNA antibodies measured and should be considered to contribute to the pathology of SLE, especially lupus nephritis.

SUMMARYT cell antigen specificity is determined by the products of the genes which encode the variable regions of their receptors. Of the T cell receptor (TCR) variable region gene products examined, only Vβ6.7a TCR-positive lymphocytes were reduced in primary Sjogren’s syndrome patients with IgG 1 hypergammaglobulinaemia compared with an age-, sex- and HLA-matched control population. The levels of Vβ6.7a T cells were also significantly reduced when these patients were compared with an age- and sex-matched but HLA-unmatched control group and non-tissue typed normal people of both sexes. Since published studies show no such abnormality in rheumatoid arthritis, systemic lupus erythematosus or other autoimmune diseases, this abnormality may reflect a pathogenic process specific to primary Sjogren’s syndrome.

OBJECTIVES: To evaluate the risk of having a child with a congenital anomaly in relation to occupational exposure to low level ionising radiation in the pre-conception period. METHODS: A case-control study based on the Canadian congenital anomalies registry used record linkage techniques to identify congenital anomalies among male and female workers in Canada9s largest electric company. Cases were defined as parents of a child with a congenital anomaly born between April 1979 and December 1986 who had a congenital anomaly diagnosed within the first year of life. Controls were an individually matched sample of parents of a liveborn child without an anomaly. Risk of congenital anomaly was assessed in relation to parental exposure to ionising radiation acquired through work within a nuclear generating station of an electric power company. Exposure was assessed according to employment, whether or not the worker was monitored for radiation exposure, and quantitative estimates of radiation dose. RESULTS: Employment within the electric power industry was not associated with an increased risk of congenital anomalies in the offspring of mothers or fathers. Risk estimates for workers monitored (those who are likely to be exposed to ionising radiation) were 1.75 (95% confidence interval (95% CI) 0.86 to 3.55) for mothers and 0.84 (95% CI 0.68 to 1.05) for fathers. Exposure for fathers before conception, defined cumulatively and for six months before conception, was not associated with increased risk of anomalies in their offspring. There were no significant increases in risk found between type of anomaly and any measure of exposure, although the statistical power in these groups was limited. The study had insufficient numbers to evaluate the effects of ionising radiation in mothers as only three mothers had recorded doses > 0 mSv. CONCLUSIONS: Overall, workers in a nuclear power industry, and specifically those exposed before conception to low levels of ionising radiation, do not appear to be at an increased risk of having a liveborn child with a congenital anomaly.

MRL-lpr/lpr mice manifest a systemic lupus-like autoimmune disease. As part of this syndrome, the mice spontaneously develop autoimmune thyroiditis, which is morphologically and biochemically similar to human autoimmune thyroiditis. In this study we investigated whether thyroid tissue obtained from sites of chronic inflammation had altered gap junctional communication. Fresh tissue sections revealed that thyroid from the nondiseased mice (MRL-(+)/+) had connexins (Cx) localized to the plasma membrane at points of thyroid cell-cell contact. In contrast, the Cx in diseased mouse (MRL-lpr/lpr) thyroid tissue were not localized to the plasma membrane, and the fluorescent intensity was reduced for Cx43 and Cx26. Northern analysis confirmed that murine thyroid tissue expressed messenger RNA for these Cx. However, the diseased tissue expressed lower levels of Cx32 and Cx26 messenger RNA. The infiltrating cells and their biologically active products present in the diseased thyroid tissue may mediate the reduced Cx expression and aberrant gap junctional assembly. We established primary thyrocyte cultures to determine whether these differences persisted when the inflammatory factors were removed. The nondiseased thyroid cells were communication competent, with fluorescent dye transfer proceeding from the injected cell to primary contacts (95%) and to second and third order neighboring cells in 75% of the trials. Thyroid cells from the diseased mice were communication incompetent, in that 80% of microinjections failed to result in dye transfer to cells in direct contact. Immunocytochemistry indicated that the functional coupling in the normal mouse thyroid cells was associated with Cx43 located in the plasma membrane as assembled gap junctional plaques. The communication-deficient diseased thyroid cells had internalized Cx43 predominantly localized to perinuclear regions of the cells. Collectively, these data document altered Cx-protein distribution in the autoimmune diseased thyroid. The diseased thyroid tissue was devoid of plasma membrane identifiable gap junctions and deficient in intercellular communication. Culturing removed the inflammatory mediators; however, the disease cells retained their communication incompetence. These results suggest that if this deficiency was initiated by components of the inflammation process, then protracted changes must have occurred so that the continued presence of these factors was no longer required to sustain this difference.

SUMMARY Serum levels of the soluble form of the low-affinity receptor for IgE (FcERII, CD23) (sCD23) are elevated in autoimmune conditions associated with hypergammaglobulinaemia and B cell hyperactivity. Very high levels of sCD23 are found in patients with B-chronic lymphatic leukaemia (B-CLL) who are, however, frequently hypogammaglobulinaemic. We therefore compared the serum levels of sCD23 in healthy controls (n= 33) with three conditions associated with hypogammaglobulinaemia (HGG) and varying B cell numbers: X-linked agammaglobulinaemia (XLA, n= 12), common variable immunodeficiency (CVI, n= 20) and B-chronic lymphatic leukaemia (n= 33). Serum levels of sCD23 showed a significant correlation with the CD19+ B cell count in both normals and patients with CVI (r= 0 65, P < 0·0001). Amongst the different clinical groups, serum levels of sCD23 were increased in the order XLA < CVI < normals < CLL (medians 2·5, 7·7, 11·1 and 540, respectively; P < 0·001 for all comparisons except CVI versus normals P < 0·03 in a one-tailed test). In the CVI group, serum sCD23 was lowest amongst four patients with low B cell numbers. There was no overlap in sCD23 between patients with XLA and this subgroup of CVI patients. Serum sCD23 is, therefore, derived predominantly from B cells, and is significantly related to the peripheral blood B cell count.

A cohort mortality study was undertaken of forestry workers at a public electrical utility who had worked for six months or more during 1950-82 and who were routinely exposed to herbicides including phenoxy acids. A total of 1222 men with 25 274 years at risk experienced 80 deaths. Ascertainment of vital state at the end of follow up was 95.5%. The male population of the province (Ontario) was used as the reference group. Overall, no excess mortality was found in this cohort relative to the reference population. A statistically significant increase in deaths occurred, however, due to suicide (SMR = 210, 95% confidence interval, 95% CI 105-376) for the cohort as a whole. No deaths were seen due to cancers such as soft tissue sarcoma and non-Hodgkin's lymphoma that have been cited by other authors as being associated with exposure to phenoxy acid herbicides. Although the cohort is not large, the absence of deaths due to these cancers is consistent with findings from other studies with sufficient numbers to allow examination of specific risks. The cohort is still young, however, and at the end of follow up most had not reached an age when increased incidence of cancer would normally be expected.

A host of immunologic abnormalities have been thoroughly described in systemic lupus erythematosus. There is an increasing body of evidence that the production of autoantibodies is the result of abnormal regulation of T cells of the early monitored response to autoantigens. Available data in the literature suggest there is a possible defect in the down-regulation of the Ras pathway in lupus T cells leading to a failure to develop anergy and abnormally prolonged expression of CD40 ligand. Treatment of MRL/lpr mice with the Ras inhibitor S-farnesylthiosalicylic acid (FTS) reduced disease symptoms in the treated mice, indicating that modulation of Ras may represent a novel therapeutic approach in SLE. In this study we are investigating the expression of CD40 ligand in CD40+ T cells from lupus and healthy subjects before and after inactivation of Ras by FTS, a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. The results of our study will help us understand if the defective functioning of Ras in lupus T cell is an intrinsic defect (by comparing the results with the ones from healthy subjects) versus an acquired one, possibly through autoantibodies. This is a continuation of a study that was previously undertaken to look at CD40 ligand expression. Methods Freshly isolated lymphocytes from SLE and healthy controls were established in culture and a portion treated with FTS and treated and untreated samples were harvested by fixation at 3 and 6 hours post initiation of treatment (FTS). The fixed lymphocytes were immunolabeled for CD40L, and dual labeled with CD3 and CD20. The secondary fluorescence was quantified by laser scanning cytometry. Results The initial study revealed that the expression of CD40L in lupus patients was modulated when Ras was inhibited by FTS treatment. The down-regulation of CD40L in SLE by FTS treatment occurred at the 4 hour harvest but was refractory at the 48 hour time point. The healthy controls showed no modulation of CD40L expression with or without FTS treatment. The current study used 3 and 6 hours ± FTS treatment and found that at 3 hours post treatment the SLE lymphocytes had down-regulated CD40L but the controls did not. At the 6 hour time point the SLE patient CD40L levels were increasing, whereas the control levels did not change. Conclusions Ras inactivation by FTS was able to markedly decrease the level of CD40L in lupus T cells but did not appear to modulate the level of CD40L in healthy subjects.