ß-Adrenergic signaling induces Notch-mediated salivary gland progenitor cell control.

ß-Adrenergic signaling blockade is a mainstay of hypertension management. One percent of patients taking ß-blockers develop reduced salivary gland (SG) function. Here we investigate the role of SG progenitor cells in ß-blocker-induced hyposalivation, using human SG organoid cultures (SGOs). Compared with control SGs, initial low SG progenitor cell yield from patients taking ß-blockers was observed. When passaged, these SGOs recovered self-renewal and upregulated Notch pathway expression. Notch signaling was downregulated in situ in ß-adrenergic receptor-expressing luminal intercalated duct (ID) cells of patients taking ß-blockers. Control SGOs treated with ß-adrenergic agonist isoproterenol demonstrated increased proportion of luminal ID SGO cells with active Notch signaling. Control SGOs exposed to isoproterenol differentiated into more mature SGOs (mSGOs) expressing markers of acinar cells. We propose that ß-blocker-induced Notch signaling reduction in luminal ID cells hampers their ability to proliferate and differentiate into acinar cells, inducing a persistent hyposalivation in some patients taking ß-blocking medication.

Abatacept treatment reduces disease activity in early primary Sjögren's syndrome (open-label proof of concept ASAP study).

OBJECTIVE: To assess the efficacy and safety of abatacept in patients with early and active primary Sjögren's syndrome (pSS). METHODS: All 15 patients (12 women, three men) included in the open-label Active Sjögren Abatacept Pilot study met the revised American-European Consensus Group criteria for pSS and were biological disease-modifying antirheumatic drug-naive. Patients were treated with eight intravenous abatacept infusions on days 1, 15 and 29 and every 4 weeks thereafter. Follow-up was conducted at 4, 12, 24 (on treatment), 36 and 48 weeks (off treatment). Disease activity was assessed with European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI). Several other functional, laboratory and subjective variables were analysed. Generalised estimating equations were used to analyse parameters over time. RESULTS: ESSDAI, ESSPRI, rheumatoid factor and IgG levels decreased significantly during abatacept treatment and increased post-treatment. Salivary and lacrimal gland function did not change during treatment. Fatigue and health-related quality of life (HR-QoL) improved significantly during treatment. No serious side effects or infections were seen. CONCLUSIONS: In this open-label study, abatacept treatment is effective, safe and well tolerated, and results in improved disease activity, laboratory parameters, fatigue and HR-QoL in patients with early and active pSS. TRIAL REGISTRATION NUMBER: 2009-015558-40.

Blood cell dynamics during hibernation in the European Ground Squirrel.

Hibernation is a unique natural model to study large and specific modulation in numbers of leukocytes and thrombocytes, with potential relevance for medical application. Hibernating animals cycle through cold (torpor) and warm (arousal) phases. Previous research demonstrated clearance of leukocytes and thrombocytes from the circulation during torpor, but did not provide information regarding the timing during torpor or the subtype of leukocytes affected. To study the influence of torpor-bout duration on clearance of circulating cells, we measured blood cell dynamics in the European Ground Squirrel. Numbers of leukocytes and thrombocytes decreased within 24h of torpor by 90% and remained unchanged during the remainder of the torpor-bout. Differential counts demonstrated that granulocytes, lymphocytes and monocytes are all affected by torpor. Although a decreased production might explain the reduced number of thrombocytes, granulocytes and monocytes, this cannot explain the observed lymphopenia since lymphocytes have a much lower turnover rate than thrombocytes, granulocytes and monocytes. In conclusion, although underlying biochemical signaling pathways need to be unraveled, our data show that the leukocyte count drops dramatically after entrance into torpor and that euthermic cell counts are restored within 1.5h after onset of arousal, even before body temperature is fully normalized.

Bacterial population analysis of human colon and terminal ileum biopsies with 16S rRNA-based fluorescent probes: commensal bacteria live in suspension and have no direct contact with epithelial cells.

BACKGROUND: The commensal intestinal microflora has important metabolic and perhaps also immune modulatory functions. Evidence has accumulated that the microflora plays a role in the pathogenesis of inflammatory bowel disease. Therefore, there is a growing interest in the intestinal microflora and its interaction with the host. Presumably, this interaction takes place at the mucus layer. In this study, we investigated the microflora that is present at the mucus layer and addressed the following questions. Does a specific mucus-adherent microflora exist? Is there direct contact between commensal bacteria and epithelial cells? METHODS: Snap-frozen biopsies were taken of 5 colon regions and of the terminal ileum in 9 subjects with a normal colon. Fecal samples were also collected. Bacteria were detected in cryosections with fluorescent in situ hybridization (FISH) with 16S ribosomal (r)RNA-targeted probes for all bacteria and specific probes for the major representatives of anaerobic microflora (bifidobacteria, Bacteroides, clostridia, atopobia) and aerobic microflora (Enterobacteriaceae, enterococci, streptococci, lactobacilli). RESULTS: With this sensitive technique, bacteria were only observed at the luminal side of the intestinal mucus layer. Very few microcolonies were present at the mucus layer, and the composition of the bacterial microflora present in the feces was similar to that at the mucus layer of the terminal ileum and colon regions. CONCLUSIONS: We did not observe direct contact between bacteria and epithelial cells. The equal distribution of bacterial species suggests that intestinal commensal bacteria live in suspension in the lumen and that there is no specific mucus-adherent microflora.