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Jacques Lacroix

Publications and source records attributed to Jacques Lacroix.

At least 19 recordsLinked to original sources
PubMed2006

N-Phenyl-N'-(2-chloroethyl)ureas (CEU) as potential antineoplastic agents. Part 2: role of omega-hydroxyl group in the covalent binding to beta-tubulin.

Tubulin is the target of many anticancer drugs, including N-phenyl-N'-(2-chloroethyl)urea (CEU). Unlike most anti-beta-tubulin agents, CEUs are protein monoalkylating agents binding through their N'-(2-chloroethyl)urea moiety to an amino acid nearby the colchicine-binding site on beta-tubulin isoform-2. Following the previously synthesized and attractive N-(3-omega-hydroxyalkylphenyl)-N'-(2-chloroethyl)urea that exhibited growth inhibitory activity at the nanomolar level, we investigated the importance of lower alkyl and alkoxy groups to evaluate the effect of hydroxylated group and chain length on both cell growth inhibition and the mechanism of action of CEU. Here, we describe the preparation of two new series of CEU and show that the most potent CEU derivatives beside the omega-hydroxylated 1f were 2f and 3e, respectively. We have confirmed that the pentyl substituted CEUs 1f, 2f, and 3e are still covalently binding to beta-tubulin and still arrest cell division in G(2)/M phase.

Antineoplastic Agents↗
PubMed2006

Acceptable respiratory physiologic limits for children during weaning from mechanical ventilation.

OBJECTIVE: The aim of this survey was to characterize the physiological limits considered appropriate during weaning from mechanical ventilation in children. DESIGN: Two hundred twenty-two (222) intensivists from 63 pediatric intensive care units (PICUs) were asked to provide the limits they considered acceptable for respiratory rate (RR), tidal volume (V(T)) and end-tidal CO(2) (PetCO(2)) during weaning from mechanical ventilation of a 3-month-old, a 2-year-old and a 10-year-old patient. SETTING: Pediatric intensivists working in Canada, France, Switzerland and Belgium. PATIENTS: None. INTERVENTIONS: None. RESULTS: Ninety-seven intensivists (43%) from 49 PICUs responded to the survey. The median minimal RR (25th;75th percentile) was: 20 breaths per minute (bpm) (15;25) for the 3-month-old, 15 bpm (10;15) for the 2-year-old and 10 bpm (10;15) for the 10-year-old patient. The median maximal RR was 50 bpm (40;60) for the 3-month-old, 40 bpm (30;40) for the 2-year-old and 30 bpm (30;40) for the 10-year-old child. The median minimal V(T) was 5 ml/kg (4;6) for the 3-month-old and 2-year-old patients and 5 ml/kg (5;6) for the 10-year-old. The median maximal PetCO(2) was 55 mmHg (50;60) for the 3-month-old, 50 mmHg (45;50) for the 2-year-old and 50 mmHg (50;55) for the 10-year-old. CONCLUSION: This survey indicated that acceptable weaning limits are broad, as stated by the responders. We need to organize and consolidate our thinking on weaning children from mechanical ventilation before guidelines can be established.

Attitude of Health Personnel↗
PubMed2006

In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450.

Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Acute transfusion reactions in the pediatric intensive care unit.

BACKGROUND: Acute transfusion reactions (ATRs) are probably underdiagnosed in critically ill children because associated symptoms can frequently be attributed to the patient's underlying disease. This study was undertaken to determine the incidence, type, imputability, and severity of ATRs observed in a tertiary care pediatric intensive care unit (PICU). STUDY DESIGN AND METHODS: All transfusions of labile blood product administered to consecutive patients admitted to our PICU, between February 2002 and February 2004, were prospectively recorded. For each transfusion, the bedside nurse recorded the patient's status before, during, and up to 4 hours after the transfusion, as well as the presence of any new sign or symptom suggesting an ATR. Three independent experts retrospectively reviewed all transfusion event reports and hospital charts. The presence, type, imputability, and severity of ATRs were adjudicated by consensus of two of three experts (Delphi method), with predefined criteria. RESULTS: A total of 2509 transfusions were administered to 305 patients during the study. Forty transfusion events (1.6%) were confirmed to be ATRs by expert consensus: 24 febrile nonhemolytic, 6 minor allergic, 4 isolated hypotension, 3 bacterial contamination, 1 major allergic (anaphylactic shock), 1 TRALI, and 1 hemolytic reaction. Imputability of ATRs was probable or possible in 35 cases (88%). ATRs led to an immediate vital threat in 15 percent of cases. CONCLUSION: Improved surveillance of transfusions given to PICU patients and better knowledge of these reactions by health care professionals should improve the safety of transfusions in the PICU.

Acute Disease↗
PubMed2006

The moral experience of parents regarding life-support decisions for their critically-ill children: a preliminary study in France.

The common paediatric critical care practice in France is for physicians (rather than parents) to maintain the ultimate responsibility for lifesupport decisions in children. Some French literature asserts that it is inappropriate for parents to bear such responsibilities because they do not have the required knowledge and should be protected from feeling culpable for such decisions. The aim of this grounded theory preliminary study was to examine the moral experience of parents of critically-ill children that required life-support decisions in France. A convenience purposive sample of seven parents was recruited in Paris. Five principal themes emerged as significant from these interviews: (1) a need for more information; (2) physicians should be responsible for life-support decisions; (3) the child's concerns and wishes need to be better heard; (4) maternal guilt; and (5) physicians require better training in parent communication. These findings raise important issues for clinical practice and further research in France.

Adaptation, Psychological↗
PubMed2006

Diaphragm electrical activity during expiration in mechanically ventilated infants.

The presence of diaphragm electrical activity (EAdi) during expiration is believed to be involved in the maintenance of end-expiratory lung volume (EELV) and has never been studied in intubated and mechanically ventilated infants. The aim of this study was to quantify the amplitude of diaphragm electrical activity present during expiration in mechanically ventilated infants and to measure the impact of removing positive end-expiratory pressure (PEEP) on this activity. We studied the EAdi in 16 ready-to-be weaned intubated infants who were breathing on their prescribed ventilator and PEEP settings. In all 16 patients, 5 min of data were collected on the prescribed ventilator settings. In a subset of eight patients, the PEEP was briefly reduced to zero PEEP (ZEEP). EAdi was recorded with miniaturized sensors placed on a conventional nasogastric feeding tube. Airway pressure (Paw) was also measured. For each spontaneous breath, we identified the neural inspiration and neural expiration. Neural expiration was divided into quartiles (Q1, Q2, Q3, and Q4), and the amplitude of EAdi calculated for each Q1-Q4 represented 95 +/- 29%, 31 +/- 15%, 15 +/- 8%, and 12 +/- 7%, respectively, of the inspiratory EAdi amplitude. EAdi for Q3-Q4 significantly increased during ZEEP, and decreased after reapplication of PEEP. These findings confirm that the diaphragm remains partially active during expiration in intubated and mechanically ventilated infants and that removal of PEEP affects this tonic activity. This could have potential implications on the management of PEEP in intubated infants.

Diaphragm↗
PubMed2005

Noninvasive therapy with helium-oxygen for severe bronchiolitis.

OBJECTIVE: To determine whether noninvasive therapy using a helium-oxygen mixture reduces the use of positive-pressure ventilation in the treatment of respiratory failure caused by severe bronchiolitis. STUDY DESIGN: This was a multicenter, randomized, double-blind, placebo-controlled trial that recruited infants in 4 pediatric intensive care units (PICUs). A total of 39 nonintubated infants with severe bronchiolitis caused by respiratory syncytial virus (RSV) were randomly assigned within 8 hours of PICU admission to receive a helium-oxygen mixture (helium group) or an air-oxygen mixture (control group) through an inflatable head hood. The primary study outcome was the requirement for positive pressure mechanical ventilation. Results were compared using Fisher's exact test. RESULTS: No differences were noted between the control and helium groups with respect to age (1.0 vs 1.1 months), prematurity, or family history of asthma or smoking. Positive pressure ventilation was judged necessary for 4 of the 21 (19.0%) infants in the control group and in 4 of the 18 (22.2%) in the helium group (relative risk = 1.17; 95% confidence interval = 0.34 to 4.01). CONCLUSIONS: This study did not detect any differences between the patients in the helium group and the control group with respect to the rate of positive-pressure ventilation.

Bronchiolitis, Viral↗
PubMed2005

Determinants of red blood cell transfusions in a pediatric critical care unit: a prospective, descriptive epidemiological study.

OBJECTIVE: To determine the incidence and to characterize the determinants of red blood cell transfusions in critically ill children. DESIGN: Prospective, descriptive epidemiologic study. SETTING: A single-center, multidisciplinary, tertiary care level, university-affiliated, pediatric intensive care unit (PICU). PATIENTS: Critically ill children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,047 consecutive admissions over a 1-yr period, 985 were retained for study. At least one transfusion was given in 139 cases (14%). Incidence rate of transfusion was 304 transfusions/1,000 cases. Possible determinants of red blood cell transfusions were identified and prospectively monitored during PICU stay until a first transfusion event (transfused cases) or up until the time of death or discharge from PICU (nontransfused cases). Four significant determinants of a first red blood cell transfusion event were retained in the multivariate analysis (odds ratio, 95% confidence interval, p): a hemoglobin level <9.5 g/dL during PICU stay (13.26, 8.04-21.88, p < .001), an admission diagnosis of cardiac disease (8.07, 5.14-14.65, p < .001), an admission Pediatric Risk of Mortality score >10 (4.83, 2.33-10.04, p < .001), and the presence of multiple organ dysfunction syndrome during the stay (2.06, 1.18-3.57, p = .01). CONCLUSION: A significant proportion of critically ill children receive at least one red blood cell transfusion during their PICU stay. Presence of anemia, cardiac disease, severe critical illness, and multiple organ dysfunction syndrome are the most significant determinants of red blood cell transfusions in PICU.

Adolescent↗
PubMed2005

Severity of illness and organ dysfunction scoring in children.

OBJECTIVE: To describe predictive and descriptive general scores that can be used to estimate the severity of illness in critically ill children. DESIGN: Review of the medical literature. SETTING: Pediatric intensive care units (PICUs). PATIENTS: Critically ill children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two predictive scores are frequently used in PICUs: the Pediatric Risk of Mortality III score and the Pediatric Index of Mortality 2. The data considered in these scores are collected at baseline. Predictive scores can be used to compare expected and observed mortality in PICUs or to estimate the balance in the baseline severity of illness of patients included in the different arms of a randomized clinical trial. Only one descriptive score is validated to estimate the severity of cases of multiple organ dysfunction syndrome in PICUs, namely, the Pediatric Logistic Organ Dysfunction score. The data required to calculate this score are collected from baseline to discharge from the PICU or up to 2 hrs before death in the PICU. The Pediatric Logistic Organ Dysfunction score can be used to describe the clinical outcome of patients during their stay in a PICU. CONCLUSION: Pediatric Risk of Mortality III, Pediatric Index of Mortality 2, and Pediatric Logistic Organ Dysfunction scores are the best available tools to estimate the severity of illness in critically ill children.

Child↗
PubMed2004

Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children.

The interaction between sepsis and multiple organ dysfunction syndrome is poorly defined in children. We analyzed by Cox regression models the cumulative influence of organ dysfunctions, using the pediatric logistic organ dysfunction (PELOD) score, and septic state (systemic inflammatory response syndrome or sepsis, severe sepsis, and septic shock) on mortality of critically ill children. We included 593 children (mortality rate: 8.6%) from three pediatric intensive care units; 514 patients had at least a systemic inflammatory response syndrome and 269 had two or more organ dysfunctions. Hazard ratio of death significantly increased with the severity of organ dysfunction, as estimated by the PELOD score, and the worst diagnostic category of septic state. Each increase of one unit in the PELOD score multiplied the hazard ratio by 1.096 (p < 0.0001); hazard ratio of diagnostic category was 9.039 (p = 0.031) for systemic inflammatory response syndrome or sepsis, 18.797 (p = 0.007) for severe sepsis and 32.572 (p < 0.001) for septic shock. Cumulative hazard ratio of death = (hazard ratio of PELOD score) x (hazard ratio of diagnostic category). We conclude that there is a cumulative accrual of the risk of death both with an increasing severity of organ dysfunction and an increasing severity of the diagnostic category of septic state.

Child↗
PubMed2004

Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis.

A meta-analysis was performed to evaluate the accuracy of determination of procalcitonin (PCT) and C-reactive protein (CRP) levels for the diagnosis of bacterial infection. The analysis included published studies that evaluated these markers for the diagnosis of bacterial infections in hospitalized patients. PCT level was more sensitive (88% [95% confidence interval [CI], 80%-93%] vs. 75% [95% CI, 62%-84%]) and more specific (81% [95% CI, 67%-90%] vs. 67% [95% CI, 56%-77%]) than CRP level for differentiating bacterial from noninfective causes of inflammation. The Q value for PCT markers was higher (0.82 vs. 0.73). The sensitivity for differentiating bacterial from viral infections was also higher for PCT markers (92% [95% CI, 86%-95%] vs. 86% [95% CI, 65%-95%]); the specificities were comparable (73% [95% CI, 42%-91%] vs. 70% [95% CI, 19%-96%]). The Q value was higher for PCT markers (0.89 vs. 0.83). PCT markers also had a higher positive likelihood ratio and lower negative likelihood ratio than did CRP markers in both groups. On the basis of this analysis, the diagnostic accuracy of PCT markers was higher than that of CRP markers among patients hospitalized for suspected bacterial infections.

Bacterial Infections↗
PubMed2004

Antiangiogenic and antitumoral activity of phenyl-3-(2-chloroethyl)ureas: a class of soft alkylating agents disrupting microtubules that are unaffected by cell adhesion-mediated drug resistance.

The development of new anticancer agents with lower toxicity, higher therapeutic index, and weaker tendency to induce resistant phenotypes in tumor cells is a continuous challenge for the scientific community. Toward that end, we showed previously that a new class of soft alkylating agents designed as phenyl-3-(2-chloroethyl)ureas (CEUs) inhibits tumor cell growth in vitro and that their efficiency is not altered by clinically relevant mechanisms of resistance such as overexpression of multidrug resistance proteins, increase in intracellular concentration of glutathione and/or glutathione S-transferase activity, alteration of topoisomerase II, and increased DNA repair. Mechanistic studies have showed recently that the cytotoxic activity of several CEUs was mainly related to the disruption of microtubules. Here, we present results supporting our assumption that 4-tert-butyl-[3-(2-chloroethyl)ureido]phenyl (tBCEU) (and its bioisosteric derivative 4-iodo-[3-(2-chloroethyl)ureido]phenyl (ICEU) are potent antimicrotubule agents both in vitro and in vivo. They covalently bind to beta-tubulin, leading to a microtubule depolymerization phenotype, consequently disrupting the actin cytoskeleton and altering the nuclear morphology. Accordingly, tBCEU and ICEU also inhibited the migration and proliferation of endothelial and tumor cells in vitro in a dose-dependent manner. It is noteworthy that ICEU efficiently blocked angiogenesis and tumor growth in three distinct animal models: (a) the Matrigel plug angiogenesis assay; (b) the CT-26 tumor growth assay in mice; and (c) the chick chorioallantoic membrane tumor assay. In addition, we present evidence that CEU cytotoxicity is unaffected by additional resistance mechanisms impeding tumor response to DNA alkylating agents such as cisplatin, namely the cell adhesion mediated-drug resistance mechanism, which failed to influence the cytocidal activity of CEUs. On the basis of the apparent innocuousness of CEUs, on their ability to circumvent many classical and recently described tumor cell resistance mechanisms, and on their specific biodistribution to organs of the gastrointestinal tract, our results suggest that CEUs represent a promising new class of anticancer agents.

Actins↗
PubMed2004

Prolonged neural expiratory time induced by mechanical ventilation in infants.

Mechanical ventilation may interfere with the spontaneous breathing pattern in infants because they have strong reflexes that play a large role in the control of breathing. This study aimed to answer the following questions: does a ventilator-assisted breath 1) reduce neural inspiratory time, 2) reduce the amplitude of the diaphragm electrical activity, and 3) prolong neural expiration, within the delivered breath? In 14 infants recovering from acute respiratory failure (mean age and weight were 2.3 +/- 1.3 mo and 3.95 +/- 0.82 kg, respectively), we measured 1) the electrical activity of the diaphragm with a multiple-array esophageal electrode, and 2) airway opening pressure, while patients breathed on synchronized intermittent mandatory ventilation (mean rate, 11.2 +/- 6.5 breaths/min). We compared neural inspiratory and expiratory times for the mandatory breaths and for the spontaneous breaths immediately preceding and following the mandatory breath. Although neural inspiratory time was not different between mandatory and spontaneous breaths, neural expiratory time was significantly increased (p < 0.001) for the mandatory breaths (953 +/- 449 ms) compared with the premandatory and postmandatory spontaneous breaths (607 +/- 268 ms and 560 +/- 227 ms, respectively). Delivery of the mandatory breath resulted in a reduction in neural respiratory frequency by 28.6 +/- 6.4% from the spontaneous premandatory frequency. The magnitude of inspiratory electrical activity of the diaphragm was similar for all three breath conditions. For the mandatory breaths, ventilatory assist persisted for 507 +/- 169 ms after the end of neural inspiratory time. Infant-ventilator asynchrony (both inspiratory and expiratory asynchrony) was present in every mandatory breath and constituted 53.4 +/- 26.2% of the total breath duration.

Child, Preschool↗
PubMed2004

Transfusion in pediatrics.

In reviewing the literature, the authors noted an important variation in stated and observed transfusion practice patterns among pediatric critical care practitioners, and in published guidelines on RBC transfusion. They also noted a paucity of clinical evidence with respect to RBC transfusion to critically ill children. There has been only one large randomized trial in adults, and the authors do not believe that the results from this trial should be generalized to critically ill children because of the many differences in children and their adaptive responses, and differences in disease processes. More research about anemia and RBC transfusion to critically ill children must be performed. The TRIPICU study is testing the safety of giving more or less RBC transfusion to stable critically ill children. Other studies must be done on the epidemiology and determinants of RBC transfusion in PICUs, on prevention of transfusion, and on alternatives to RBC transfusion (eg, erythropoietin).

Anemia↗