Laminin-5 gamma2-chain and collagenase-2 (MMP-8) in human peri-implant sulcular fluid

Laminin-5 (LN-5) is an important epithelial cell-derived structural and adhesive component in hemidesmosomes and basement membranes (BM). In peri-implant tissue, gingival BM underlies the junctional epithelium (JE) and reflects the peri-implant health. Matrix metalloproteinase-8 (MMP-8 or collagenase-2) is one of the key mediators of periodontal tissue destruction. Western immunoblotting with image analysis was used to quantitate the molecular forms of LN-5 gamma2-chain and MMP-8 in peri-implant sulcular fluid (PISF) from healthy and diseased implants. These observations were related to the recorded gingival (GI) and bone resorption (BR) indices of the studied sites. Altogether, 72 PISF samples from osseointegrated dental implants were examined. Significantly elevated levels of fragmented LN-5 gamma2-chain species (45 and 70 kDa) and MMP-8 immunoreactivities were observed in diseased PISF in relation to healthy PISF. The elevated levels of both LN-5 gamma2-chain 45 and 70 kDa fragments and MMP-8 in diseased PISF from peri-mucositis (BR = 0) and peri-implantitis (BR >/= 1) lesions strongly correlated with elevated GI. Low levels - almost comparable to those seen in healthy control PISF - were seen in PISF from peri-implantitis lesions (BR >/= 1) with no GI. Activation of 75 kDa neutrophil (PMN)-type proMMP-8 to 10 kDa lower-molecular-size active forms was especially detected in PISF from peri-implantitis with elevated GI. These cross-sectional findings indicate that elevated MMP-8 and LN-5 gamma2-chain fragment levels in PISF can reflect the active phase of the inflammatory peri-implant disease. Longitudinal studies are required to assess their use, either alone or in combination as molecular biochemical PISF markers, to predict the risk of progression of peri-implantitis, as well as to monitor the impact of treatment of the disease.     

Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Nocturnal Body Movements and Hypoxemia in Middle-Aged Females After Lower Abdominal Surgery Under General Anesthesia: A Study With the Static-Charge-Sensitive Bed (SCSB)

Objective. The aim of this study was to evaluate the feasibility of the static-charge-sensitive-bed (SCSB) combined with pulse oximetry (SpO₂) for postoperative monitoring and to determine variables which could be used for evaluating the quality of postoperative sleep and breathing. Methods. The frequency of body movements and the perioperative breathing abnormalities were assessed using the SCSB and pulse oximeter in 15 female ASA-class I–II patients undergoing elective lower abdominal surgery under general anesthesia. Anesthesia and control of postoperative pain followed standard practice. The patients were monitored during one preoperative and three consecutive postoperative nights. Movements were analyzed according to their duration and time interval. The effect of opioids was evaluated by measuring arterial oxyhemoglobin saturation (SpO₂) with pulse oximetry for one hour before and two hours after administration of standard doses of oxycodone. Results. The total movement time per hour increased during the first postoperative night (p = 0.003). Conversely, periodic movement activity decreased significantly during the three postoperative nights (p = 0.05, p < 0.001, p = 0.007). The mean SpO₂ decreased during the first postoperative night (95.5% vs. 94.2%, p = 0.002), but returned to the preoperative level during the following nights. No episodes of apnea with significant oxygen desaturation (a decrease in SpO₂<5%) were observed. Opioid administration was associated with decreased mean SpO₂ (94.8% vs. 93.6%, p = 0.02), but did not lead to clinically significant hypoxemia (lowest observed SpO₂ 89.8%). Conclusions. Postoperative periodic movement activity was suppressed, but sleep remained fragmented with frequent body movements. In our middle-aged non-obese females (ASA I–II), no severe postoperative hypoxemia was observed during the three-nights postoperative survey. Perioperative movement monitoring with the SCSB was a valuable tool in rejecting movement artefacts of SpO₂ and in evaluating general sleep quality.     

Subtle changes in ADMA and l-arginine concentrations in normal pregnancies are unlikely to account for pregnancy-related increased flow-mediated dilatation

BACKGROUND: Our objective was to investigate whether serum concentrations of asymmetric dimethylarginine (ADMA) or l-arginine correlate to hyperlipidemia or endothelial function in normal pregnancy compared with the non-pregnant subjects. METHODS AND RESULTS: As a part of population-based, prospective cohort Cardiovascular Risk in Young Finns study conducted in Finland we examined 57 pregnant Finnish women throughout gestation and 62 control women matched for age and smoking. Serum glucose, triglycerides (TG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C) and ADMA, symmetric dimethylarginine (SDMA) and l-arginine were determined concomitantly with endothelium-dependent brachial artery flow-mediated dilation (FMD), measured by ultrasound. All serum lipid concentrations were significantly higher in pregnant women than in non-pregnant women (P < 0.001 for each). The mean serum ADMA concentration in pregnant women was significantly lower compared with the non-pregnant controls (0.513 micromol l(-1) +/- 0.0593 versus 0.577 micromol l(-1) +/- 0.0710, P < 0.001). Lowered ADMA concentrations did not correlate statistically to FMD in these healthy pregnant women but FMD was enhanced towards the end of pregnancy. CONCLUSIONS: ADMA and l-arginine concentrations fall in normal pregnancy despite marked hypercholesterolemia. Endothelium-dependent vasodilation is enhanced in normal pregnancy but is not statistically correlated to maternal serum ADMA or l-arginine concentrations.     

G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome

BACKGROUND: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. AIM: To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. METHODS: A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. RESULTS: In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. CONCLUSIONS: The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.     

Evaluating the use of a portable ultrasound machine to quantify intima-media thickness and flow-mediated dilation: agreement between measurements from two ultrasound machines

Flow-mediated dilation (FMD) and common carotid intima-media thickness (CIMT) are intermediate endpoints for cardiovascular disease. The purpose of this study was to determine whether a portable ultrasound machine was capable of valid measurements of FMD and CIMT compared with a clinic-based machine under similar conditions. Vascular images were taken on 23 apparently healthy young adults with the portable type and clinic type instruments. The analyses revealed a high level of agreement between the two machines for measurements of mean [corrected] CIMT (mean difference [MD] = -0.025 mm, limits of agreement [LOA] = -0.080, 0.029 mm), maximum [corrected] CIMT (MD = 0.001 mm, LOA = -0.065, 0.065 mm) and FMD measures of brachial diameter (baseline MD = 0.199 mm, LOA = -0.210, 0.608 mm, maximum MD = 0.218 mm, LOA = -0.162, 0.597 mm). Reasonable agreement was found for %FMD measurements (MD = 0.27%, LOA = -4.91, 5.44%). The within-machine coefficient of variation results for mean [corrected] CIMT (5.0%), maximum [corrected] CIMT (4.3%), baseline (6.3%) and maximum (5.4%) brachial diameter and %FMD (30.1%) were comparable with normal within-subject variation. We conclude that the portable ultrasound machine can provide measurements of FMD and CIMT that are highly comparable with measurements obtained from a clinic-based machine under similar clinical conditions.