Résumé L’acromégalie est le plus souvent secondaire à un adénome hypophysaire sécrétant de l’hormone de croissance (GH) entraînant une synthèse d’ Insulin-like Growth Factor type 1 (IGF-1). Les ...conséquences de l’hyperactivité de l’axe GH/IGF-1 reflètent la diversité des sites d’actions de ces hormones. Les gènes du récepteur de la GH (GHR), de l’IGF-1, du récepteur de l’IGF-1 (IGF-1R) et des protéines de transport de l’IGF-1 (IGF-BP) sont constitutivement exprimés dans le rein adulte, suggérant un rôle potentiel de l’axe somatotrope dans diverses fonctions rénales. L’expression de ces protéines est hautement organisée et diffère selon les segments anatomiques et fonctionnels du néphron évoquant des rôles différents de la GH et de l’IGF-1 dans ces différents segments. Chez l’animal, une exposition chronique à de fortes doses de GH induit une glomérulosclérose et une augmentation de l’albuminurie. L’observation de patients présentant une hypersécrétion somatotrope a permis de décrire différentes actions de l’axe GH/IGF-1 dans le rein : 1) un impact sur la filtration rénale avec une augmentation du débit de filtration glomérulaire (DFG), 2) un impact structurel ou morphologique avec une augmentation de la masse rénale et une hypertrophie glomérulaire et 3) un impact tubulaire responsable notamment d’une hyperphosphorémie, d’une hypercalciurie et d’un effet antinatriurétique. Malgré l’hyperfiltration glomérulaire observée en cas d’hypersécrétion somatotrope, la GH n’est pas un traitement efficace de l’insuffisance rénal chronique. La GH et l’IGF-1 paraissent impliqués dans la physiopathologie de la néphropathie diabétique, ce qui ouvre de nouvelles perspectives de prévention et de traitement de la néphropathie diabétique.
Our group has recently demonstrated (Gesta, S., Simon, M., Rey, A., Sibrac, D., Girard, A., Lafontan, M., Valet, P., and Saulnier-Blache, J. S. (2002) J. Lipid Res. 43, 904-910) the presence, in ...adipocyte conditioned-medium, of a soluble lysophospholipase d-activity (LPLDact) involved in synthesis of the bioactive phospholipid lysophosphatidic acid (LPA). In the present report, LPLDact was purified from 3T3F442A adipocyte-conditioned medium and identified as the type II ecto-nucleotide pyrophosphatase phosphodiesterase, autotaxin (ATX). A unique ATX cDNA was cloned from 3T3F442A adipocytes, and its recombinant expression in COS-7 cells led to extracellular release of LPLDact. ATX mRNA expression was highly up-regulated during adipocyte differentiation of 3T3F442A-preadipocytes. This up-regulation was paralleled by the ability of newly differentiated adipocytes to release LPLDact and LPA. Differentiation-dependent up-regulation of ATX expression was also observed in a primary culture of mouse preadipocytes. Treatment of 3T3F442A-preadipocytes with concentrated conditioned medium from ATX-expressing COS-7 cells led to an increase in cell number as compared with concentrated conditioned medium from ATX non-expressing COS-7 cells. The specific effect of ATX on preadipocyte proliferation was completely suppressed by co-treatment with a LPA-hydrolyzing phospholipase, phospholipase B. Finally, ATX expression was found in mature adipocytes isolated from mouse adipose tissue and was substantially increased in genetically obese-diabetic db/db mice when compared with their lean siblings. In conclusion, the present work shows that ATX is responsible for the LPLDact released by adipocytes and exerts a paracrine control on preadipocyte growth via an LPA-dependent mechanism. Up-regulations of ATX expression with adipocyte differentiation and genetic obesity suggest a possible involvement of this released protein in the development of adipose tissue and obesity-associated pathologies.
Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. The aim of this study was to assess the effect of regional anaesthesia on post ...surgery opioid induced hyperalgesia in diabetic and non-diabetic mice.
Diabetic and non-diabetic mice underwent plantar surgery. Levobupivacaine and sufentanil were used before surgery, for sciatic nerve block (regional anaesthesia) and analgesia, respectively. Diabetic and non-diabetic groups were each randomly assigned to three subgroups: control, no sufentanil and no levobupivacaine; sufentanil and no levobupivacaine; sufentanil and levobupivacaine. Three tests were used to assess pain behaviour: mechanical nociception; thermal nociception and guarding behaviours using a pain scale.
Sufentanil, alone or in combination with levobupivacaine, produced antinociceptive effects shortly after administration. Subsequently, sufentanil induced hyperalgesia in diabetic and non-diabetic mice. Opioid-induced hyperalgesia was enhanced in diabetic mice. Levobupivacaine associated to sufentanil completely prevented hyperalgesia in both groups of mice.
The results suggest that regional anaesthesia can decrease opioid-induced hyperalgesia in diabetic as well as in non-diabetic mice. These observations may be clinically relevant for the management of diabetic patients.
Kinins have been shown to influence renal hemodynamics and function. Under physiologic conditions, most kinin effects involve bradykinin B
2
receptors, but bradykinin B
1
receptors are often induced ...during inflammation. The purpose of this study was to examine
in vivo
the effects of bradykinin B
1
receptor activation on renal hemodynamics under normal and inflammatory conditions. In anesthetized rats, activation of bradykinin B
1
receptors by arterial infusion of bradykinin B
1
receptor agonist des-Arg
9
-bradykinin reduced renal plasma flow and GFR. Prior administration (18 h) of lipopolysaccharide to induce inflammation resulted in a larger bradykinin B
1
receptor-induced reduction in renal plasma flow. Values of other parameters remained unchanged, thus resulting in an increased filtration fraction. The presence and the functionality of the bradykinin B
1
receptor at the level of glomerular afferent and efferent arterioles were studied by mRNA expression analysis and intracellular calcium (Ca
2+
i
) mobilization studies. Stimulation with des-Arg
9
-bradykinin of microdissected afferent arterioles from control and lipopolysaccharide-treated rats induced Ca
2+
i
mobilization without any significant difference in amplitude between control and lipopolysaccharidetreated rats. However, des-Arg
9
-bradykinin only induced Ca
2+
i
mobilization in efferent arterioles from lipopolysaccharide-treated rats. It is suggested that activation of bradykinin B
1
receptors located along the efferent arteriole may participate in the modification of renal hemodynamics in inflammatory states.
Abstract
Background
Increased hydration is commonly recommended as a preventive measure for women with recurrent acute uncomplicated cystitis (rAUC), but supportive data are sparse. The aim of this ...study was to assess the efficacy of increased daily water intake on the frequency of rAUC in premenopausal women.
Methods
140 healthy premenopausal asymptomatic women drinking less than 1.5 L of total fluid daily (24 hours) and suffering from rAUC (33 episodes in the past year) were randomized to receive, in addition to their usual daily fluid intake, either 1.5 L water daily (water group) or no additional fluids (control group), for 12 months. Assessments of daily water and total fluid intake, urine volume and osmolality, number of urine voids, and occurrence of AUC symptoms and a reminder to notify investigators of any such symptoms were performed at baseline, 6- and 12-month clinic visits in addition to monthly telephone calls. The primary outcome was frequency of rAUC episodes (31 AUC symptom and 3103 CFU/mL of a uropathogen in voided urine) over 12 months.
Results
Between baseline and 12 month’s follow-up, the water group, compared with the control group, had statistically significant increases in mean daily water intake (1.15 vs. −0.01 L), total fluid intake (1.65 vs. 0.03 L), urine volume (1.40 vs. 0.04 L), and number of urine voids (2.2 vs. −0.2), and a decrease in urine osmolality (−408 vs. −35 mOsm/Kg). The mean number of rAUC episodes in the water group was significantly less than in the control group (1.6 vs. 3.1; odds ratio 0.52, 95% CI 0.46–0.60, P < 0.0001) (figure shows cumulative sum of AUC episodes over 12 months in both study groups). The mean number of antimicrobial regimens used to treat AUC events was 1.8 in the water group vs. 3.5 in the control group (P < 0.0001). In addition, the mean number of days to first rAUC and the mean number of days between rAUC episodes was longer in the water group compared with the control group (148 vs. 93, P = 0.0005 and 143 vs. 85, P < 0.0001, respectively).
Conclusions
Our results provide strong evidence that increased water intake is an effective antimicrobial-sparing preventive strategy for women with rAUC. Increasing daily water intake by approximately 1.5 L reduced rAUC episodes by 48% and antimicrobial regimens by 47% over 12 months.
Disclosures
M. Vecchio, Danone Research: Employee, Salary. A. Iroz, Dzanone Research: Employee, Salary. I. Tack, Danone Research: Consultant, Consulting fee and Speaker honorarium. Q. Dornic, Danone research: Employee, Salary. I. Seksek, Danone Research: Employee, Salary.
What is already known about this subject
• In burn patients it has been shown (2), that there is a correlation between the creatinine clearance (CLCR) and the clearance of inulin.
• The CLCR has ...never been studied in burn patients who have normal serum creatinine.
• The Robert, Kirkpatrick and sMDRD formulae have never been evaluated in burn patients.
What this study adds
• Despite burn patients having normal serum creatinine concentrations, the study showed that there are large variations in CLCR which cannot be detected by single serum creatinine measurements, and which have important implications for drug therapy.
• It showed that the formulae currently used to calculate creatinine clearance on the basis of serum creatinine are inadequate for use in burn patients, and they should be abandoned in favour of direct measurement from a 24 h urine collection.
Aims
The aim of this study was to evaluate whether the renal function of burn patients could be correctly assessed using a single serum creatinine measurement, within normal limits, and three prediction equations of glomerular filtration taking into account, serum creatinine, age, weight and sex.
Methods
This was a prospective study comprising 36 adult burn patients with a serum creatinine <120 µmol l−1, within the second or third week following the burn injury. Renal function was assessed using serum creatinine, 24 h urinary CLCR, and the Cockcroft–Gault, Robert, Kirkpatrick and simplified MDRD equations.
Results
Despite normal serum creatinine concentrations in all patients, a significant number had a decreased CLCR. The urinary CLCR was <80 ml−1 min‐1 1.73 m−2 in nine patients (25%), and <60 ml−1 min−1 1.73 m−2 in five patients (14%). Between the groups having a CLCR lower or greater than 80 ml−1 min−1 1.73 m−2 there were no differences in gender, burn indices, percentage of mechanically ventilated patients or length of hospital stay, but a difference in age. The highest CLCR (>140 ml−1 min−1 1.73 m−2) was found in 13 patients younger than 40 years. Regression analysis, residual and Bland–Altman plots revealed that neither the Cockcroft–Gault, Robert, Kirkpatrick nor sMDRD equations were specific enough for the assessment of renal function.
Conclusions
In burn patients with normal serum creatinine during the hypermetabolic phase, serum creatinine and creatine based predictive equations are imprecise in assessing renal function.
Abstract Objective To evaluate whether the Script Concordance Test (SCT) can discriminate between levels of experience among anesthesiology residents and attending physicians. Study type Multicenter ...(Toulouse, Nantes, Bordeaux and Limoges), prospective, observational study. Patients and methods A SCT made of 60 items was used to evaluate “junior residents” ( n = 60), “senior residents” ( n = 47) and expert anesthesiologists ( n = 10). Results There were no missing data in our study. Mean scores (±SD) were 69.9 (±6.1), 73.1 (±6.5) and 82.0 (±3.5) out of a potential score of 100 for “junior residents”, “senior residents” and expert anesthesiologists, respectively. Results were statistically different between the 3 groups ( P = 0.001) using the Kruskall-Wallis test. The Cronbach's α score was 0.63. Conclusions The SCT is a valid and useful tool for discriminating between anesthesia providers with varying levels of experience in anesthesiology. It may be a useful tool for documenting the progression of reasoning during anesthesia residency.
The identification of patients with chronic kidney disease (CKD) at risk of progressing to kidney failure (KF) is important for clinical decision-making. In this study we assesed whether urinary ...peptidome (UP) analysis may help classify patients with CKD and improve KF risk prediction.
The UP was analyzed using capillary electrophoresis coupled to mass spectrometry in a case-cohort sample of 1000 patients with CKD stage G3 to G5 from the French CKD-Renal Epidemiology and Information Network (REIN) cohort. We used unsupervised and supervised machine learning to classify patients into homogenous UP clusters and to predict 3-year KF risk with UP, respectively. The predictive performance of UP was compared with the KF risk equation (KFRE), and evaluated in an external cohort of 326 patients.
More than 1000 peptides classified patients into 3 clusters with different CKD severities and etiologies at baseline. Peptides with the highest discriminative power for clustering were fragments of proteins involved in inflammation and fibrosis, highlighting those derived from α-1-antitrypsin, a major acute phase protein with anti-inflammatory and antiapoptotic properties, as the most significant. We then identified a set of 90 urinary peptides that predicted KF with a c-index of 0.83 (95% confidence interval CI: 0.81−0.85) in the case-cohort and 0.89 (0.83−0.94) in the external cohort, which were close to that estimated with the KFRE (0.85 0.83−0.87). Combination of UP with KFRE variables did not further improve prediction.
This study shows the potential of UP analysis to uncover new pathophysiological CKD progression pathways and to predict KF risk with a performance equal to that of the KFRE.
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