[Show abstract][Hide abstract] ABSTRACT: The earliest symptom of glomerular injury in patients with sickle cell disease (SCD) is microalbuminuria. The effect of hydroxyurea (HU) on urine albumin-to-creatinine ratio (ACR) is unclear and should be determined, because increasing numbers of patients with SCD take this drug to improve red blood cell function. In this cohort study of 58 SS-homozygous adults with SCD who initiated HU therapy, we evaluated ACR changes and relationships of these changes with demographic, clinical, and biologic parameters at HU initiation (baseline) and 6 months later (follow-up). Between baseline and follow-up, ACR declined significantly for the entire population (3.0-1.7 mg/mmol; P<0.01), but this was primarily driven by the ACR reduction in the microalbuminuria subgroup (8.1-2.3 mg/mmol; P=0.03; n=23). According to bivariate analyses on 39 patients who did not receive a blood transfusion during the study period, the baseline to follow-up ACR decline was strongly associated with decreases in levels of hemolysis markers, percentage of dense red blood cells, and systolic BP. Bivariate analysis also revealed a close association between the ACR decrease and high baseline levels of hemolysis markers and percentage of dense red blood cells. These results show that urine ACR decreased significantly after 6 months of HU and confirm a close relationship between ACR and hemolysis evolution in patients with SCD.
Full-text · Article · Nov 2015 · Journal of the American Society of Nephrology
[Show abstract][Hide abstract] ABSTRACT: The pathophysiologic mechanisms classically involved in sickle-cell nephropathy include endothelial dysfunction and vascular occlusion. Arguments demonstrating that ischemia-reperfusion injury-related kidney damage might coincide with vaso-occlusive crisis (VOC) are lacking.
In this prospective study, we sought to determine whether tubular cells and glomerular permeability might be altered during VOC. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels and albumin-excretion rates (AER) of 25 patients were evaluated prospectively during 25 VOC episodes and compared to their steady state (ST) values.
During VOC, white blood-cell counts (WBC) and C-reactive protein (CRP) were significantly higher than at ST but creatinine levels were comparable. Urine NGAL levels were significantly increased during VOC vs ST (P = 0.007) and remained significant when normalized to urine creatinine (P = 0.004), while AER did not change significantly. The higher urine NGAL concentration was not associated with subsequent (24-48 hour) acute kidney injury. Univariate analysis identified no significant correlations between urine NGAL levels and laboratory parameters during VOC.
These results demonstrated that subclinical ischemia-reperfusion tubular injury is common during VOC and highlight the importance of hydroelectrolyte monitoring and correction during VOC.
[Show abstract][Hide abstract] ABSTRACT: Abstract Background: Familial amyloid polyneuropathy (FAP) mainly targets the peripheral nervous system and heart. Early noninvasive detection of cardiac impairment is critical for therapeutic management. Aim: To assess if amino-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (cTnT) can predict echocardiographic left-ventricle (LV) impairment in FAP. Methods: Thirty-six asymptomatic carriers and patients with FAP had echocardiographic measurement of left-ventricular (LV) systolic function, hypertrophy (LVH) and estimation of filling pressure (FP). Results: Overall, median age, NT-proBNP, and LV ejection fraction were, respectively, 59 years (41-74), 323 pg/ml (58-1960), and 60% (51-66). Twelve patients had increased cTnT. Prevalence of ATTR gene mutations was 53% for Val30Met. Four individuals were asymptomatic, 6 patients had isolated neurological clinical signs, and 26 had echo-LV abnormalities. The ROC curve identified NT-proBNP patients with echo-LV abnormalities (area: 0.92; (0.83-0.99), p = 0.001) at a threshold >82 pg/ml with a sensitivity of 92%, and a specificity of 90%. Increased in NT-proBNP occurred in patients with SD and/or LVH with or without increase in FP. Elevated cTnT (>0.01ng/ml) was only observed in patients with LVH and systolic dysfunction, with or without FP. Conclusion: In FAP, NT-proBNP was associated with cardiac impairment suggesting that NT-proBNP could be used in carriers or in FAP patients with only neurologic symptoms for identifying the appropriate time to start cardiac echocardiographic assessment and follow-up. cTnT identified patients with severe cardiac disease.
Preview · Article · Aug 2013 · Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis
[Show abstract][Hide abstract] ABSTRACT: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an epithelial anion channel. Morbidity is mainly due to lung disease, which is characterized by chronic neutrophilic inflammation. Deregulation of inflammatory pathways is observed in the airways of CF patients, as evidenced by exaggerated NF-κB activity, causing an increase in the local release of pro-inflammatory cytokines such as IL-8. COMMD1, a pleiotropic protein, was recently shown to interact with CFTR and to promote CFTR cell surface expression. The effect of COMMD1 on the NF-κB pathway was assessed in CF and non-CF bronchial epithelial cells by knockdown and overexpression experiments. Results showed that (i) COMMD1 knockdown induced NF-κB-dependent transcription, (ii) COMMD1 overexpression inhibited NF-κB activity and was associated with a decrease in IL-8 transcript level and protein secretion. These data demonstrate the anti-inflammatory properties of COMMD1 in bronchial epithelial cells and open new therapeutic avenues in CF.
No preview · Article · Jul 2013 · The international journal of biochemistry & cell biology
[Show abstract][Hide abstract] ABSTRACT: Patients with Parkinson's disease frequently complain of sleep disturbances and loss of muscle atonia during rapid-eye-movement (REM) sleep is not rare. The orexin-A (hypocretin-1) hypothalamic system plays a central role in controlling REM sleep. Loss of orexin neurons results in narcolepsy-cataplexy, a condition characterized by diurnal sleepiness and REM sleep without atonia. Alterations in the orexin-A system have been also documented in Parkinson's disease, but whether these alterations have clinical consequences remains unknown.
Here, we measured orexin-A levels in ventricular cerebrospinal fluid from eight patients with Parkinson's disease (four males and four females) who underwent ventriculography during deep brain-stimulation surgery and performed full-night polysomnography before surgery.
Our results showed a positive correlation between orexin-A levels and REM sleep without muscle atonia.
Our results suggest that high levels of orexin-A in Parkinson's disease may be associated with loss of REM muscle atonia.
Full-text · Article · Jun 2013 · Nature and Science of Sleep
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The use of N-acetylcysteine (NAC) for preventing contrast induced nephropathy (CIN) is debated in the intensive care unit. NAC may alter the concentration of serum creatinine and interfere with CIN diagnosis. The effectiveness of NAC was evaluated with a special attention on its specific effect on creatinine levels compared to cystatin C.
In a first period, we prospectively enrolled patients receiving saline and low osmolality contrast media for 140 exams in 2 intensive care units with opposite policies regarding the use of NAC. Renal impairment was defined by both the classical CIN and the "sensitive" Acute Kidney Injury Network (AKIN) (taking creatinine and diuresis) definitions. In a second period, we compared the evolution of serum creatinine and cystatin C after 23 additional contrast examinations under NAC.
Seventy exams with and without NAC were compared in the first period. Risk factors for CIN were similar in the two intensive care unit populations. No difference in CIN incidence was found with and without NAC, using the CIN (10/70 vs 15/70) or the AKIN (24/70 vs 22/70) definition. Interestingly, NAC seemed to reduce renal impairment when the creatinine criterion of the AKIN definition was considered alone [9% vs 21%, P=.033]. Overall, the incidence of renal impairment was 18%, 33% and 15% using the CIN definition, the AKIN, or using AKIN with creatinine alone. Serum creatinine significantly decreased after exams with NAC while cystatin C remained stable.
The incidence of CIN does not seem to be influenced by NAC, except if small changes in creatinine only are considered.
No preview · Article · May 2013 · Journal of critical care
[Show abstract][Hide abstract] ABSTRACT: Inhibition of hepcidin expression by erythropoietic signals is of great physiological importance, however the inhibitory pathways remain poorly understood. To investigate i) the direct effect of erythropoietin (Epo) and ii) the contribution of putative mediators on hepcidin repression, healthy volunteers were injected with a single dose of Epo, either low (63 IU/kg, n=8) or high (400 IU/kg, n=6). Low-dose Epo provoked hepcidin down-modulation within 24 hours; the effect was not immediate since hepcidin circadian variations were still present following injection. High-dose Epo induced no additional effect on the hepcidin response, i.e. hepcidin diurnal fluctuations were not abolished in spite of extremely high Epo levels. We did not find significant changes in putative mediators of hepcidin repression, such as transferrin saturation, soluble transferrin receptor, or growth differentiation factor 15. Furthermore, the potential hepcidin inhibitor, soluble hemojuvelin, was found unaltered by Epo stimulation. This finding was consistent with the absence of signs of iron deficiency observed at the level of skeletal muscle tissue. Our data suggest that hepcidin repression by erythropoietic signals in humans may not be controlled directly by Epo but mediated by a still undefined factor. This article is protected by copyright. All rights reserved.
Full-text · Article · Apr 2013 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: Fetuin-A is a ubiquitous anti-inflammatory glycoprotein that counteracts proinflammatory cytokine production. Previous studies have shown that low fetuin-A concentration is associated with cardiovascular death and may play an important role in the prognosis of patients with acute coronary syndromes (ACS). The purpose of this study was to assess in large cohort of patients admitted for ACS the prognostic value of fetuin-A adjusted for C-reactive protein value (CRP) and Global Registry of Acute Coronary Events (GRACE) risk score. Plasma fetuin-A and CRP concentrations were measured on day 3 in 754 consecutive patients with ACS (mean age 66 ± 14 years, 404 with ST-segment elevation and 350 without ST-segment elevation) included in the French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI), and these data were correlated to 1-year mortality. Plasma fetuin-A and CRP concentrations at admission averaged 95 ± 27 and 12 ± 16 mg/L, respectively. Overall, 1-year cardiovascular mortality was 10% (28 in-hospital deaths and 51 deaths after discharge), 17% in patients with low fetuin-A (less than the first tertile), 18% with high CRP (higher than the third tertile), and 23% in patients with low fetuin associated with high CRP (p <0.01). In contrast, patients with neither low fetuin-A nor high CRP had a low mortality rate (5%). Multivariate analysis adjusted for GRACE risk score showed that low fetuin-A and high CRP concentration remained associated with outcomes (odds ratio 2.28, 95% confidence interval 1.20 to 4.33). In conclusion, fetuin-A combined with CRP level is associated with cardiovascular death in patients with ACS.
No preview · Article · Oct 2012 · The American journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer (PCa) is androgen sensitive in its development and progression to metastatic disease. Hedgehog (Hh) pathway activation is important in the initiation and growth of various carcinomas including PCa. We and others have observed aberrations of Hh pathway during the progression of PCa to the castration-resistant state. The involvement of androgen signalling in Hh pathway activation, however, remains largely elusive. Here we investigate the direct role of androgen signalling on Hh pathway. We examined the effect of Dihydrosterone (DHT), antiandrogen, bicalutamide, and Hh pathway inhibitor, KAAD-cyclopamine in four human prostate cell lines (two cancerous: LNCaP, VCaP, and two normal: PNT2 and PNT2-ARm which harbours a mutant version of androgen receptor (AR) that is commonly found in LNCaP). Cell proliferation as well as Hh pathway members (SHH, IHH, DHH, GLI, PTCH) mRNA expression levels were assessed. We showed that KAAD-cyclopamine decreased cell proliferation of DHT-stimulated LNCaP, VCaP and PNT2-ARm cells. SHH expression was found to be downregulated by DHT in all AR posititve cells. The negative effect of DHT on SHH expression was counteracted when cells were treated by bicalutamide. Importantly, KAAD-cyclopamine treatment seemed to inhibit AR activity. Moreover, bicalutamide as well as KAAD-cyclopamine treatments induced GLI and PTCH expression in VCaP and PNT2-ARm. Our results suggest that Hh pathway activity can be regulated by androgen signalling. Specifically, we show that the DHT-induced inhibition of Hh pathway is AR dependent. The mutual interaction between these two pathways might be important in the regulation of cell proliferation in PCa.
Full-text · Article · Sep 2012 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Prolonged running is known to induce hemolysis. It has been suggested that hemolysis may lead to a significant loss of red blood cells; however, its actual impact on the erythrocyte pool is unknown. Here, we test the hypothesis that prolonged running with high hemolytic potential decreases total red blood cell volume (RCV). Hemolysis (n = 22) and RCV (n = 19) were quantified in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon (RUN) with 9500 m of altitude gain/loss. Assessment of total hemoglobin mass (Hb(mass) ) and RCV was performed using a carbon monoxide rebreathing technique. RUN induced a marked acute-phase response and promoted hemolysis, as shown by a decrease in serum haptoglobin (P < 0.05). Elevated serum erythropoietin concentration and reticulocyte count after RUN were indicative of erythropoietic stimulation. Following RUN, runners experienced hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone. However, neither Hb(mass) nor RCV were found to be altered after RUN. Our findings indicate that mechanical/physiological stress associated with RUN promotes hemolysis but this has no impact on total erythrocyte volume. We therefore suggest that exercise 'anemia' is entirely due to plasma volume expansion and not to a concomitant decrease in RCV.
Full-text · Article · Jun 2012 · Scandinavian Journal of Medicine and Science in Sports
[Show abstract][Hide abstract] ABSTRACT: Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins. These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve-sparing surgery.
To assess correlations between Prostate CAncer gene 3 (PCA3) levels and pathological features of radical prostatectomy (RP) specimens, which define cancer aggressiveness.
After digital rectal examination (DRE), first-catch urine was collected from 160 patients with localized prostate cancer. The PCA3 score was calculated using the Gene Probe Progensa(™) assay. PCA3 scores were then correlated to the pathological features of the RP specimens.
PCA3 scores correlated significantly with tumour volume (r= 0.34, P < 0.01). A PCA3 score of >35 was an independent predictor in a multivariate analysis of a tumour volume >0.5 mL (odds ratio [OR] 2.7, P= 0.04). It was also an independent predictor of positive surgical margins (OR 2.4, P= 0.04). Receiver-operator characteristic curves indicated PCA3 as the most accurate predictor of positive margins (area under the curve [AUC] 0.62), in addition to a positive biopsy percentage (AUC 0.52). There was also a significant difference in the mean PCA3 score between Gleason score patient groups (6 vs ≥ 7) and pathological stage groups (pT0/2 vs pT3/4).
PCA3 scores correlate to numerous histoprognostic factors, specifically tumour volume and positive surgical margins. These results may have a clinical impact in the near future on the selection of patients eligible to undergo active surveillance and nerve-sparing surgery.
No preview · Article · Jan 2012 · BJU International
[Show abstract][Hide abstract] ABSTRACT: The lack of accuracy from typical prostate cancer diagnostic tools led us to investigate new biomarkers. Prostate cancer gene 3 (PCA3 or DD3) is a promising urinary biomarker of prostate cancer. This specific noncoding mRNA is highly overexpressed in more than 95% of primary prostate tumors. The feasibility of a PCA3 gene-based molecular assay based on the detection of prostate cancer cells in urine has been demonstrated, and a quantitative PCA3 urine test with the potential for general use in clinical settings was developed; the Progensa™ (Gen-Probe Inc., San Diego, CA, USA) PCA3 urine test. Current data from the literature demonstrate the superiority of the PCA3 score over prostate-specific antigen, in terms of predictive value and specificity, albeit with a slightly lower sensitivity. These results are particularly encouraging for the specific population of patients who have a first negative biopsy, as a PCA3 assay could avoid unnecessary repeated biopsies. Furthermore, limited data have investigated a correlation between PCA3 scores and tumor volumes, as well as an ability to distinguish indolent from significant cancer. In the near future, combinations of multiple biomarkers integrating PCA3 will optimize the detection and characterization of prostate cancer.
No preview · Article · Mar 2011 · Expert Review of Molecular Diagnostics