Prognostic factors for chronic post-surgical pain after lung and pleural surgery: a systematic review with meta-analysis, meta-regression and trial sequential analysis.

Chronic post-surgical pain is known to be a common complication of thoracic surgery and has been associated with a lower quality of life, increased healthcare utilisation, substantial direct and indirect costs, and increased long-term use of opioids. This systematic review with meta-analysis aimed to identify and summarise the evidence of all prognostic factors for chronic post-surgical pain after lung and pleural surgery. Electronic databases were searched for retrospective and prospective observational studies as well as randomised controlled trials that included patients undergoing lung or pleural surgery and reported on prognostic factors for chronic post-surgical pain. We included 56 studies resulting in 45 identified prognostic factors, of which 16 were pooled with a meta-analysis. Prognostic factors that increased chronic post-surgical pain risk were as follows: higher postoperative pain intensity (day 1, 0-10 score), mean difference (95%CI) 1.29 (0.62-1.95), p < 0.001; pre-operative pain, odds ratio (95%CI) 2.86 (1.94-4.21), p < 0.001; and longer surgery duration (in minutes), mean difference (95%CI) 12.07 (4.99-19.16), p < 0.001. Prognostic factors that decreased chronic post-surgical pain risk were as follows: intercostal nerve block, odds ratio (95%CI) 0.76 (0.61-0.95) p = 0.018 and video-assisted thoracic surgery, 0.54 (0.43-0.66) p < 0.001. Trial sequential analysis was used to adjust for type 1 and type 2 errors of statistical analysis and confirmed adequate power for these prognostic factors. In contrast to other studies, we found that age had no significant effect on chronic post-surgical pain and there was not enough evidence to conclude on sex. Meta-regression did not reveal significant effects of any of the study covariates on the prognostic factors with a significant effect on chronic post-surgical pain. Expressed as grading of recommendations, assessment, development and evaluations criteria, the certainty of evidence was high for pre-operative pain and video-assisted thoracic surgery, moderate for intercostal nerve block and surgery duration and low for postoperative pain intensity. We thus identified actionable factors which can be addressed to attempt to reduce the risk of chronic post-surgical pain after lung surgery.

DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis.

Low molecular weight heparins (LMWH) are the standard of care for the treatment of cancer-associated venous thromboembolism (CA-VTE). We performed a systematic review and meta-analysis to compare the effects of direct oral anticoagulants (DOAC) versus LMWH for the treatment of CA-VTE. The primary efficacy and safety outcomes were VTE recurrence and major bleeding (MB). The secondary outcomes were clinically relevant non-MB (CRNMB), all-cause mortality and the net clinical benefit. We searched MEDLINE, EMBASE, CENTRAL and Web of Science (inception-December 2019) and abstracts of relevant conferences (2000-2019) to identify randomized controlled trials comparing DOAC and LMWH for the treatment of CA-VTE. Relative risks (RR) and 95% confidence intervals were estimated (Mantel-Haenszel method, random-effects models). A non-inferiority analysis with a margin of 1.3 for the upper boundary of the RR was conducted for the primary outcomes. From 637 references, we included four publications which encompass three trials (1756 patients). Compared to LMWH, DOAC were associated with a trend for decreased VTE recurrence (RR 0.51; 95%CI 0.25-1.03; p = 0.06; I2 = 51%), whereas MB (RR 1.64; 95%CI 1.00-2.69; p = 0.05; I2 = 0%) and CRNMB (RR 1.83; 95%CI 1.04-3.20; p = 0.03; I2 = 50%) were significantly more frequent with DOAC. Conversely, all-cause mortality (RR 1.06; 95%CI 0.83-1.35; p = 0.64; I2 = 36%) and net clinical benefit (RR 0.74; 95%CI 0.38-1.42; p = 0.36; I2 = 65%) were comparable. DOAC were non-inferior to LMWH in preventing CA-VTE recurrence, but were associated with an increased risk of MB and CRNMB. Further studies are required to confirm these results and inform on the risk/benefit ratio for specific populations.

Identification and Characterization of microRNAs Associated With Human ß-Cell Loss in a Mouse Model.

Currently there is no effective approach for monitoring early ß-cell loss during islet graft rejection following human islet transplantation (HIT). Due to ethical and technical constraints, it is difficult to directly study biomarkers of islet destruction in humans. Here, we established a humanized mouse model with induced human ß-cell death using adoptive lymphocyte transfer (ALT). Human islet grafts of ALT-treated mice had perigraft lymphocyte infiltration, fewer insulin+ ß cells, and increased ß-cell apoptosis. Islet-specific miR-375 was used to validate our model, and expression of miR-375 was significantly decreased in the grafts and increased in the circulation of ALT-treated mice before hyperglycemia. A NanoString expression assay was further used to profile 800 human miRNAs in the human islet grafts, and the results were validated using quantitative real-time polymerase chain reaction. We found that miR-4454 and miR-199a-5p were decreased in the human islet grafts following ALT and increased in the circulation prior to hyperglycemia. These data demonstrate that our in vivo model of induced human ß-cell destruction is a robust method for identifying and characterizing circulating biomarkers, and suggest that miR-4454 and miR-199a-5p can serve as novel biomarkers associated with early human ß-cell loss following HIT.

MicroRNAs and the functional ß cell mass: For better or worse.

Insulin secretion from pancreatic ß cells plays a central role in the control of blood glucose levels. The amount of insulin released by ß cells is precisely adjusted to match organism requirements. A number of conditions that arise during life, including pregnancy and obesity, can result in a decreased sensitivity of insulin target tissues and a consequent rise in insulin needs. To preserve glucose homoeostasis, the augmented insulin demand requires a compensatory expansion of the pancreatic ß cell mass and an increase in its secretory activity. This compensatory process is accompanied by modifications in ß cell gene expression, although the molecular mechanisms underlying the phenomenon are still poorly understood. Emerging evidence indicates that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs. Indeed, several of these small, non-coding RNAs have either positive or negative impacts on ß cell proliferation and survival. The studies reviewed here suggest that the balance between the actions of these two groups of microRNAs, which have opposing functional effects, can determine whether ß cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet insulin demand and thus lead, as a consequence, towards diabetes manifestation. A better understanding of the mechanisms governing changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat both type 2 and gestational diabetes.

Emerging roles of non-coding RNAs in pancreatic ß-cell function and dysfunction.

Pancreatic ß-cells play a central role in glucose homeostasis by tightly regulating insulin release according to the organism's demand. Impairment of ß-cell function due to hostile environment, such as hyperglycaemia and hyperlipidaemia, or due to autoimmune destruction of ß-cells, results in diabetes onset. Both environmental factors and genetic predisposition are known to be involved in the development of the disease, but the exact mechanisms leading to ß-cell dysfunction and death remain to be characterized. Non-coding RNA molecules, such as microRNAs (miRNAs), have been suggested to be necessary for proper ß-cell development and function. The present review aims at summarizing the most recent findings about the role of non-coding RNAs in the control of ß-cell functions and their involvement in diabetes. We will also provide a perspective view of the future research directions in the field of non-coding RNAs. In particular, we will discuss the implications for diabetes research of the discovery of a new communication mechanism based on cell-to-cell miRNA transfer. Moreover, we will highlight the emerging interconnections between miRNAs and epigenetics and the possible role of long non-coding RNAs in the control of ß-cell activities.

Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.

AIMS/HYPOTHESIS: The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. MATERIALS AND METHODS: NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. RESULTS: Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. CONCLUSIONS/INTERPRETATION: The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

The clinical effect of dentifrices containing stabilized stannous fluoride on plaque formation and gingivitis--a six-month study with ad libitum brushing.

The effects of stabilized 0.454% stannous fluoride dentifrices on supragingival plaque, gingival inflammation and gingival bleeding were studied in 549 adult male and female subjects who completed a six-month, double blind clinical study. Following an oral prophylaxis, subjects were randomly assigned to brush with one of the following dentifrices: 1) 0.454% SnF2 stabilized with 2.08% sodium gluconate, 2) 0.454% SnF2 stabilized with 4.16% sodium gluconate, 3) an experimental dentifrice, or 4) 0.243% NaF control dentifrice. Follow-up examinations were conducted at 3 and 6 months. Compared to the control dentifrice at 6 months, stannous fluoride dentifrices stabilized with 2.08% or 4.16% sodium gluconate significantly reduced gingivitis by 18.8% and 18.0%, respectively. There were no statistically significant differences between the two stabilized SnF2 groups with respect to their beneficial effects on gingival health. Gingival bleeding was also reduced, relative to the control dentifrice, for both stabilized SnF2 dentifrices. However, these differences were not statistically significant at p=0.05. The stabilized SnF2 dentifrices were not significantly different from the control dentifrice in their effects on supragingival plaque. No significant differences in adverse oral soft tissue effects were observed between the test and control groups. As expected, accumulation of extrinsic tooth stain increased in the stabilized SnF2 groups. However, the difficulty in removing accumulated dental stain was similar between the control and stabilized SnF2 dentifrices. Since use of SnF2 dentifrices has been reported to produce tooth stain, gingivitis examinations were done with and without custom-made tooth covers to evaluate the potential for examiner bias. Comparable gingivitis and gingival bleeding benefits were observed when the evaluations were conducted with or without the tooth covers. Results from this study support that 0.454% stabilized stannous fluoride dentifrices can provide an important adjunct to the prevention and control of gingivitis when used in combination with regular personal oral hygiene procedures and professional care.

Plasminogen activator production by human retinal endothelial cells of nondiabetic and diabetic origin.

The authors examined the effect of insulin-like growth factor 1 (IGF 1), epidermal growth factor (EGF), and acidic fibroblast growth factor (AFGF) on the synthesis by human retinal endothelial cell (HREC) of plasminogen activators (PA; tissue-type [t-PA] and urokinase-type [u-PA]) and plasminogen activator inhibitor (PAI). Immunologic and functional assays for t-PA, u-PA, and PA1 were conducted with cell lines derived from three diabetics and three nondiabetic controls. Confluent HREC of nondiabetic origin did not respond to IGF I (100 ng/ml) with any change of t-PA antigen in the medium (10.7 +/- 1.1 ng/ml unstimulated versus 10.1 +/- 0.8 ng/ml) stimulated, P = not significant). Likewise AFGF and EGF caused no significant change of t-PA levels. Both IGF I and EGF caused a significant increase of t-PA from HREC of diabetic origin (9.6 +/- 0.8 ng/ml unstimulated versus 16.6 +/- 1.9 ng/ml IGF I-stimulated, P less than 0.001, and 14.6 +/- 2.7 ng/ml EGF-stimulated P less than 0.005). Supplementation of AFGF had no effect on HREC of diabetic origin. In confluent cultures, only small quantities of u-PA were detected. After wounding confluent cultures, u-PA activity was associated with cells migrating from the wound edges. Functional PA activity was also measured by chromogenic assay. Results further supported a predominance of t-PA activity being produced by confluent HREC in culture. These results suggest that modulation of PA production by HREC is influenced by exposure to growth factors, by the state of confluency, and the origin of the cells (diabetic vesus nondiabetic).

Insulin-like growth factor I stimulates proliferation, migration, and plasminogen activator release by human retinal pigment epithelial cells.

The migration of retinal pigment epithelial (RPE) cells from their normal anatomic position to a new position in the vitreous cavity is a critical feature of proliferative vitreous retinopathy. To determine if insulin-like growth factor I (IGF I), which is present in the vitreous fluid of diabetics, stimulates RPE cells, we examined the effects of IGF I on the proliferation, chemotaxis, and release of plasminogen activator by these cells. At the concentrations of IGF I tested, significant proliferation of RPE cells is seen. Significant chemotaxis of the RPE cells also is seen at all the concentrations of IGF I tested. The mean number of migrating cells per high-powered field in control studies was 43 +/- 13 (x +/- SEM), and for IGF I at 2.5 ng and 50 ng/ml the mean numbers of migrating cells were 96 +/- 17 and 483 +/- 62, respectively (P less than 0.001 for each comparison). The IGF I response was noted to be dose-dependent. The chemotactic response noted at 50 ng/ml of IGF I was greater than the positive chemotactic control of 10% fetal calf serum. Addition of alpha IR-3, an IGF I receptor antibody, eliminated the IGF I chemotactic response. The effect of IGF I on the secretion of plasminogen activators was assessed using an immunological assay for tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). Media conditioned by RPE cells have measureable levels of PAI and t-PA antigen. IGF I supplementation resulted in an increase of t-PA secretion and PAI secretion over basal levels. These studies support a role for IGF I in modulating RPE cell function.

Fibrinolytic capacity following stimulation with desmopressin acetate in patients with diabetes mellitus.

Tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor, (PAI), and von Willebrand factor (vWF) were measured in 30 diabetics and 17 control subjects. These studies were performed to clarify the role of obesity in causing abnormalities of the fibrinolytic system in diabetics. The t-PA antigen response measured after the infusion of desmopressin acetate (DDAVP) was similar in all groups. Peak responses to DDAVP for controls, type I diabetics, and type II diabetics were 21.2 +/- 9.5 ng/mL, 27.5 +/- 9.0 ng/mL, and 28.8 +/- 11.0 ng/mL (NS), respectively. These responses did not correlate with the body mass index (BMI) or any other of the indices examined. A significant decrease of t-PA activity as contrasted with t-PA antigen following DDAVP occurred in type II diabetics only. The decrease of t-PA activity strongly correlated with greater basal levels of plasminogen activator inhibitor in these same subjects. The plasma level of plasminogen activator inhibitor correlated with BMI but with no other index examined. In contrast to t-PA activity and PAI, vWF responses to DDAVP inversely correlated to basal vWF concentration in all groups. Basal concentrations of vWF were increased in both type I and II diabetics and showed no relationship to degree of obesity. In summary, these results suggest that type II diabetic subjects have decreased t-PA activity, which is best explained by increased levels of PAI. The increased PAI appears related to obesity and not diabetes per se.

Respiratory-mucin inhibition of the opsonophagocytic killing of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a frequent respiratory tract colonizer in diseases in which mucociliary clearance is defective. The most striking of these is cystic fibrosis. The reasons for this organism's ability to colonize the respiratory tract and to persist there are not fully understood. Earlier studies showed that P. aeruginosa adheres preferentially to tracheobronchial mucin when compared with enterobacteria. We reasoned that if adherence to respiratory mucin protected P. aeruginosa from opsonophagocytic killing, then the ability of this organism to chronically colonize the respiratory tract could be partially explained. Using an opsonophagocytic killing assay with human polymorphonuclear leukocytes, we found that respiratory mucin protected six strains of P. aeruginosa from opsonophagocytic killing but did not protect poorly adhering strains of Escherichia coli, Staphylococcus aureus, or group B streptococci. Incubating P. aeruginosa with the mucin prior to addition to the opsonic assay inhibited phagocytic killing, whereas incubation of polymorphonuclear leukocytes with mucin did not, suggesting that inhibition was not due to an effect of mucin on leukocytes per se but was a consequence of bacterial adherence to mucin. Further studies indicated no decrease in the binding of either antibody or complement component C3 to the bacterial surface in the presence of mucin. This suggests that phagocytic inhibition may be due to a defect in uptake or destruction of mucin-coated bacteria by the leukocytes. Thus, the adherence of P. aeruginosa to respiratory mucin potentially contributes to its persistence in the respiratory tract by interfering with host immune responses.

Desmopressin stimulates parallel norepinephrine and tissue plasminogen activator release in normal subjects and patients with diabetes mellitus.

Desmopressin acetate administration markedly stimulates release of tissue plasminogen activator (t-PA) from vascular endothelial cells. The mechanism for this effect is unknown. Because infusion of epinephrine has been shown to increase t-PA levels, we examined the role of endogenous catecholamine mediation of t-PA release by desmopressin. Intravenous desmopressin acetate (0.3 micrograms/kg) was infused over 30 min in 9 controls and 11 subjects with diabetes mellitus, a condition associated with abnormalities of the fibrinolytic system. Plasma was collected in the supine, overnight fasted state at 15 min intervals (0-60 min) for measurement of t-PA activity, t-PA antigen and fractionated catecholamines. t-PA activity peaked at 30-45 min and subsequently decreased. The norepinephrine levels paralleled the t-PA activity. t-PA activity increased 10-fold from 0.14 +/- .12 to 1.49 +/- 0.79 IU/ml (Mean +/- SD) and plasma norepinephrine increased 2-fold from 426 +/- 90 to 780 +/- 292 pg/ml. However, epinephrine and dopamine levels did not change significantly. The response to desmopressin of control and diabetic subjects was not shown to differ and their data were combined. We conclude that desmopressin increases plasma norepinephrine in addition to t-PA and that the parallel time course of change suggests a possible role for norepinephrine in mediating endothelial cell t-PA release.

Effects of subminimal inhibitory concentrations of antibiotics on the adherence of Pseudomonas aeruginosa to tracheobronchial mucin.

Bacterial adherence to mucins may be important in tracheobronchial infections in cystic fibrosis. Sublethal concentrations of antibiotics reduce bacterial adherence to epithelial cells and mucins. This reduction in adherence may be a component of antimicrobial effects in infections at anatomical sites where bactericidal concentrations of antibiotics are difficult to achieve. We therefore tested the effects of sublethal concentrations of an aminoglycoside, tobramycin, and a beta-lactam antibiotic, ceftazidime, on the adherence of Pseudomonas aeruginosa to tracheobronchial mucin, since mucus secretions are often colonized by P. aeruginosa in cystic fibrosis. Adherence of the mucoid strains tested was inhibited by ceftazidime, but not by tobramycin. This effect of ceftazidime may partially explain its efficacy in patients with cystic fibrosis despite variables achieved in sputum.

Pseudomonas aeruginosa adhesins for tracheobronchial mucin.

Mucins of the tracheobronchial tree are preferential sites for adherence and colonization by Pseudomonas aeruginosa. They possess specific receptors for this organism that have amino sugars as their principal constituents. Since mucins probably reflect the receptors on the cellular surfaces, we hypothesized that the bacterial adhesins previously shown to mediate the binding of P. aeruginosa to cells would also mediate bacterial binding to mucins. We therefore tested the roles of the exopolysaccharide from mucoid strains of P. aeruginosa and pili from nonmucoid strains to see whether they are indeed the adhesins for mucins. Using a microtiter plate assay of adherence to mucins, we demonstrated that the mucoid exopolysaccharide bound to mucins and enhanced the adherence of mucoid strains to this substance. Antibodies raised against the exopolysaccharide from a single mucoid strain inhibited the adherence of all mucoid strains tested. Purified pili from nonmucoid strains inhibited the binding of nonmucoid strains but not of mucoid strains. Inhibition of adherence by antibody to pili was quite specific, antibody being able to inhibit only the binding of the homologous nonmucoid strain. These data support our previous observations with tracheal cells, confirming the similarity of the adhesins for respiratory tract cells and the mucins which cover them.

[Haloperidol. Plasma monitoring and hormonal effects of treatment]. / Halopéridol. Surveillance plasmatique et incidence hormonale du traitement.

Therapeutic plasma monitoring of haloperidol, a major neuroleptic, measured by radioimmunoassay, has shown a rather good correlation between plasma level and dosage but with large interindividual variation in children as in adults; age seems not to have any effect on haloperidol metabolism. 80% of subjects present a concomitant prolactin levels variation, whereas in 20% no prolactin response is found. During acute kinetics of either a 10 mg oral haloperidol administration or a 250 mg intramuscular haloperidol decanoate injection, a parallel elevation of prolactin, cortisol, immunoreactive bêta-endorphin and bêta-lipotropin plasma levels occur, at the same time as haloperidol plasma levels. Those rise with a good equivalence between the two doses of the two forms.