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Biomedical subjects

J C Mercier

Publications and source records attributed to J C Mercier.

At least 37 records · Page 2Linked to original sources
PubMed1998

Congenital diaphragmatic hernia. A cause of persistent pulmonary hypertension of the newborn which lacks an effective therapy.

Congenital diaphragmatic hernia (CDH) is still an unsolved problem. A disease which was, for a long time, thought to be merely a hole in the diaphragm appears today to be an intriguing malformation with a poorly understood pathogenesis and a complex pathophysiology. CDH results in various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension of the newborn. Despite antenatal ultrasound diagnosis and continuous improvement in neonatal intensive care, these features could not be overcome, and the overall mortality rate in CDH is still reaching 50%. Experimental works during the past 20 years suggest that CDH is a disease of impaired lung development associated with, but not caused by, a structural defect of the diaphragm. Furthermore, there is increasing evidence that the lung in CDH is not only small but that there are numerous disorders (e.g. surfactant deficiency, decreased anti-oxidant activity, increased vascular reactivity with decreased nitric oxide and increased endothelin 1 activity, and left heart hypoplasia) which may be associated with impaired lung development. Although antenatal diagnosis of CDH is feasible by ultrasound, there is no reliable predictor of pulmonary hypoplasia, the main prognostic factor in CDH. Whilst modern therapeutic strategies such as high-frequency oscillatory ventilation, exogenous surfactant or inhaled nitric oxide may be beneficial in selected subjects, most newborns with hypoplastic lungs will not survive despite these postnatal therapies. Perhaps these newborns would benefit from antenatal treatment directed at altering lung growth early in utero to minimize pulmonary hypoplasia. Therefore, research is needed to elucidate the aetiology and pathogenesis of CDH. Knowledge about the cellular control of proliferation, differentiation and programmed cell death (apoptosis) in the organogenesis should clarify our understanding of these processes and allow us to develop drugs that stimulate lung growth or even correct the anatomical defect. Furthermore, early and reliable assessment of prognosis for fetuses with CDH at risk of death will become increasingly important in the identification of fetuses most likely to benefit from antenatal therapies and may eventually lead to decreased mortality.

Embryonic and Fetal Development↗
PubMed1998

Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.

Dexfenfluramine and fenfluramine greatly increase the risk of developing pulmonary hypertension (PHT). The mechanism of anorexigen-associated PHT (AA-PHT) and the reason PHT occurs in a minority of people exposed are unknown. Anorexigens are weak pulmonary vasoconstrictors, but they become potent when synthesis of the endogenous vasodilator nitric oxide (NO) is suppressed. We hypothesized NO deficiency predisposes affected individuals to develop AA-PHT. A prospective, case-control, study was performed on consecutive patients with AA-PHT (n = 9). Two sex-matched control groups were selected: patients with primary PHT (P-PHT, n = 8) and normal volunteers (n = 12). Lung NO production (VNO) and systemic plasma oxidation products of NO (NOx) were measured at rest and during exercise. AA-PHT developed 17 +/- 6 mo after a short course of anorexigen (6 +/- 2 mo) and was irreversible. VNO was lower in AA-PHT than in P-PHT and correlated inversely with PVR (p < 0.05). The apparent VNO deficiency may have resulted from increased oxidative inactivation of NO in patients with AA-PHT, as their NOx levels were elevated (p < 0.05) in inverse proportion to VNO (r2 = 0. 55; p < 0.02). In susceptible persons, anorexigens can cause an irreversible syndrome of PHT, hypoxemia, and systemic vascular complications after brief exposures. These patients have a relative NO deficiency years after discontinuing the anorexigen, perhaps explaining their original susceptibility.

Adult↗
PubMed1997

[Inhaled nitric oxide: a physiologic treatment of persistent pulmonary arterial hypertension in the newborn].

Fetal pulmonary circulation is characterized by high resistance and low pulmonary blood flow. Right-to-left shunting through the foramen ovale and/or patent ductus arteriosus is necessary to perfuse the placenta and insure fetal life. At birth, pulmonary arterial blood flow increases immediately by 8- to 10-fold, and allows pulmonary gas exchange and postnatal life. In some circumstances, this adaptation to extra-uterine life is inadequate, because of persistent high pulmonary resistance (PPHN). Due to the lack of a selective pulmonary vasodilator, the treatment of this syndrome remained purely symptomatic using high oxygen levels and barotraumatic mechanical hyperventilation. When this medical treatment failed, the only alternative was extracorporeal membrane oxygenation (ECMO). The discovery of the major role of various endothelium-derived factors including nitric oxide (NO) in the control of vascular reactivity led to dramatic switches in the concepts of severe neonatal respiratory failure and the therapeutic approach of PPHN. It was shown, first in experimental animals then in a few infants with hypoxemic respiratory failure, that NO inhalation selectively vasodilated the vasoconstricted pulmonary vessels, and reversed right-to-left shunting and refractory hypoxemia. Whether inhaled NO also reduces mortality and/or morbidity in hypoxic infants remains to be proven by appropriate randomized clinical trials. However, not only PPHN is associated with pulmonary diseases of various etiologies and underlying pathophysiologic mechanisms, but also inhaled NO is used in conjunction with other validated therapeutic strategies including ante- or postnatal steroids, exogenous surfactants, and high-frequency oscillatory ventilation. Thus, the relevant primary endpoint might be not only crude survival but the most physiological and economical way of obtaining it.

Administration, Inhalation↗
PubMed1997

[Roles of vasoactive factors synthetized by endothelium in pulmonary arterial hypertension].

Pulmonary vascular endothelium synthesizes and releases two groups of vasoactive substances, namely the endothelium-derived relaxing and contracting factors. Among the former, the effects of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), and those of the so-called endothelium-derived hyperpolarizing factor (EDHF) have been extensively investigated. Among the latter, endothelin is probably one of the most potent endogenous vasoconstrictors. NO is a free radical which can be readly inactivated by hemoglobin. NO has all the characteristics of a gas, whereas its pharmacological properties are consistent with those of an endogenous nitrovasodilator. Therefore, inhalation of the gas NO is now considered as one of the most promising means to treat persistent pulmonary hypertension of the newborn. EDHF relaxes vascular smooth muscle through activation of ATP-dependent potassium channels. Both the chemical nature and the physiological role of EDHF are still unclear. The pharmacological properties of endothelin are far from being unequivocal. It is a potent vasoconstrictor, when it directly acts on vascular smooth muscle. However, it can also induce the release of NO and EDHF, hence causing vasorelaxation. These effects of endothelin are mediated by various transduction pathways. Activations of ET-B receptors located on endothelium on the one hand, and ET-A receptors located on smooth muscle on the other hand, are responsible for relaxation and constriction of vascular smooth muscle, respectively. Such highly complex cellular mechanisms highlight the need for further insight into the physiology of the cell related to the pulmonary circulation. This, in turn, will help to better define the target upon which one can try to correct the abnormal function of the cell underlying the pathophysiological processes.

Biological Factors↗
PubMed1997

Acute respiratory distress syndrome in children.

The adult (acute) respiratory distress syndrome is a significant cause of morbidity in children. The mortality rates remain elevated, greater than 50%, and even greater than 80% in patients with underlying malignancies. The therapeutic interventions remain mainly supportive. Strategies of conventional mechanical ventilation are directed toward the use of high positive end-expiratory pressures, low positive inspiratory pressure, and permissive hypercapnia. High-frequency oscillatory ventilation and tracheal insufflation are not yet used extensively, although they should contribute to less aggressive ventilation. Surfactant replacement, nitric oxide inhalation, and partial liquid ventilation seem to be promising technologies, but controlled clinical studies are necessary before their wide-spread use. Extracorporeal membrane oxygenation remains the alternative technology in case of failure of conventional support.

Animals↗
PubMed1996

Developmental regulation of murine integrin beta 1 subunit- and Hsc73-encoding genes in mammary gland: sequence of a new mouse Hsc73 cDNA.

A partial integrin beta 1 subunit-encoding cDNA (Itg beta 1) and a new heat-shock protein 70-like-encoding cDNA (Hsc73) homologous to rat Hsc73 were cloned by differential display and RT-PCR from mouse mammary gland. Their developmental regulation during pregnancy, lactation and involution is reported. The Itg beta 1 mRNA content was stable in the first half of gestation, decreased to a minimum during lactation and increased markedly in early involution. Hsc73 gene expression was high in the first half of gestation and decreased to a minimum during lactation. The possible significance of the two observed patterns of expression is discussed.

Amino Acid Sequence↗
PubMed1996

Efficient and specific ribozyme-mediated reduction of bovine alpha-lactalbumin expression in double transgenic mice.

Transgenic mice carrying a bovine alpha-lactalbumin (alpha-lac) specific ribozyme gene under the transcriptional control of the mouse mammary tumor virus long terminal repeat were generated and cross-bred with animals that highly express a bovine alpha-lac transgene (0.4 mg of alpha-lac/ml(-1) of milk). The ribozyme contains the hammerhead catalytic domain, flanked by 12-nt sequences complementary to the 3' untranslated region of bovine alpha-lac transcript. High-level expression of the ribozyme gene was detected by Northern blot analysis in the mammary gland of 7-8 day lactating transgenic mice, from 3 of 12 lines analyzed. Heterozygous expression of the ribozyme resulted in a reduction in the levels of the target mRNA to 78, 58, and 50% of that observed in the nonribozyme transgenic littermate controls for three independent lines. The ribozyme-mediated reduction in the levels of the bovine protein paralleled that observed for the mRNA, and was positively correlated with the level of expression of the ribozyme. In nonribozyme expressing transgenic mice, the level of bovine alpha-lac mRNA and protein was not affected. The specificity of this activity is demonstrated by the absence of a reduction in the levels of the endogenous murine alpha-lac mRNA or protein. These results demonstrate the feasibility of ribozyme-mediated down-regulation of highly-expressed transcripts in transgenic animals.

Animals↗
PubMed1996

Hemodynamics and oxygenation changes induced by the discontinuation of low-dose inhalational nitric oxide in newborn infants.

OBJECTIVE: To assess changes associated with nitric oxide (NO) discontinuation in neonates receiving inhalational NO therapy as a treatment for pulmonary hypertension of the neonate (PPHN). DESIGN: Prospective study. SETTING: A pediatric PICU in a university hospital. PATIENTS AND METHODS: Ten neonates were included. NO discontinuation was attempted when the oxygenation index fell below 10. The mean NO concentration was 4.9 +/- 0.8 ppm. Each infant was studied over three successive 5-min periods and was assigned to either group 1 (NO1+, NO2+, NO-) or group 2 (NO1+, NO-, NO2+). MEASUREMENTS AND RESULTS: Postductal transcutaneous PO2 (tcPO2), postductal oxygen saturation with pulse oxymetry (SpO2), systolic and diastolic blood pressure (BP), heart rate (HR), left ventricular shortening fraction (LVSF), cardiac output (CO), and ratio of pulmonary artery time to peak velocity and right ventricular ejection time (TPV/RVET) were similar during the two successive NO+ periods (group 1), thus demonstrating that the measurements were reproducible. NO removal (groups 1 and 2) did not modify systolic or diastolic BP, HR, CO, or LVSF but did induce a significant decline in SpO2, tcPO2 (- 25 +/- 5%) and TPV/RVET ratio (- 25 +/- 3%). No reinstitution reversed the effects of NO withdrawal on tcPO2, SpO2 and TPV/RVET ratio (group 2) without any changes in systemic hemodynamics. CONCLUSION: The shut-off of low-dose NO induced in each patient a decrease in oxygen delivery that may be due to increased pulmonary vascular resistances and/or redistribution of pulmonary blood flow with ventilation-perfusion mismatching. The optimum weaning-off procedure of inhalational NO remains to be determined.

Administration, Inhalation↗
PubMed1996

Thrombosis of the arterial cannula during extracorporeal membrane oxygenation in a full-term newborn infant.

The authors report a rare case of cannula thrombosis during extracorporeal membrane oxygenation (ECMO). A full-term newborn infant was successively placed on single-cannula veno-venous extracorporeal lung support and then on veno-arterial ECMO, because of persistent pulmonary hypertension. At 140 hours of ECMO, the infant displayed general cyanosis except in the right arm. Since asymmetric hypoxemia during ECMO may be related either to cannula malposition or to a tip thrombosis, a chest x-ray after contrast injection into the arterial line of the circuit was performed. It showed an opacification of the whole cannula but for the last distal centimeter, and of the vascular bed extending from the right subclavian artery. Cannula thrombosis was suspected and confirmed by removal of the arterial cannula. Demonstration of cannula thrombosis by opacification of the arterial line of the circuit indicates catheter removal.

Catheterization, Peripheral↗
PubMed1995

High-level, stage- and mammary-tissue-specific expression of a caprine kappa-casein-encoding minigene driven by a beta-casein promoter in transgenic mice.

A 5' truncated caprine (ca) kappa-casein-encoding gene (kappa Cas) was fused to the 3' end of a 3' truncated ca beta Cas. The kappa Cas form comprised the 0.8-kb 3' end of intron 2, the remaining part of the transcription unit containing codons -2 to stop 172, and 0.43 kb of the 3' flanking region. The beta Cas form comprised a 3-kb 5' flanking region and the 5' end of the transcription unit terminating 69 bp downstream from exon 2 which encodes the 15-amino-acid (aa) signal peptide and the first 2 aa of mature beta Cas. The resulting hybrid gene driven by the beta Cas promoter was expressed in all eight lines of transgenic mice investigated, although at different levels. In two lines, the yield of recombinant (re-) kappa Cas was > or = 3 mg/ml of milk. The stage- and mammary tissue-specific expression was similar to that of endogenous beta Cas. The re-kappa Cas differed from its goat milk counterpart by the occurrence of four extra aa at the N-terminal end, indicating that the signal peptidase released the beta Cas signal peptide. According to sedimentation analyses of murine milk containing > or = 3 mg re-kappa Cas/ml, the latter essentially occurred in micelles. Preliminary comparative assays of the behavior of ca alpha s1Cas-kappa Cas and alpha s1Cas-re-kappa Cas mixtures upon incremental addition of Ca2+ showed that re-kappa Cas had the capacity to protect alpha s1Cas against Ca(2+)-induced precipitation in forming stable micelles.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis.

OBJECTIVE: To examine the incidence, risk factors, and outcome of severe sepsis in intensive care unit (ICU) patients. DESIGN AND SETTING: Inception cohort study from a 2-month prospective survey of 11,828 consecutive admissions to 170 adult ICUs of public hospitals in France. PATIENTS: Patients meeting clinical criteria for severe sepsis were included and classified as having documented infection (ie, documented severe sepsis, n = 742), or a clinical diagnosis of infection without microbiological documentation (ie, culture-negative severe sepsis, n = 310). MAIN OUTCOME MEASURES: Hospital and 28-day mortality after severe sepsis. RESULTS: Clinically suspected sepsis and confirmed severe sepsis occurred in 9.0 (95% confidence interval [CI], 8.5 to 9.5) and 6.3 (95% CI, 5.8 to 6.7) of 100 ICU admissions, respectively. The 28-day mortality was 56% (95% CI, 52% to 60%) in patients with severe sepsis, and 60% (95% CI, 55% to 66%) in those with culture-negative severe sepsis. Major determinants of both early (< 3 days) and secondary deaths in the whole cohort were the Simplified Acute Physiology Score (SAPS) II and the number of acute organ system failures. Other risk factors for early death included a low arterial blood pH (< 7.33) (P < .001) and shock (P = .03), whereas secondary deaths were associated with the admission category (P < .001), a rapidly or ultimately fatal underlying disease (P < .001), a preexisting liver (P = .01) or cardiovascular (P = .002) insufficiency, hypothermia (P = .02), thrombocytopenia (P = .01), and multiple sources of infection (P = .02). In patients with documented sepsis, bacteremia was associated with early mortality (P = .03). CONCLUSIONS: Only three of four patients presenting with clinically suspected severe sepsis have documented infection. However, patients with clinically suspected sepsis but without microbiological documentation and patients with documented infection share common risk factors and are at similarly high risk of death. In addition to the severity of illness score, acute organ failures and the characteristics of underlying diseases should be accounted for in stratification of patients and outcome analyses.

Adult↗
PubMed1995

Complete sequence of the ovine beta-casein-encoding gene and interspecies comparison.

The 9149-bp transcription unit encoding ovine beta-casein (Cas) and 4636 bp of 5' flanking region were completely sequenced. The gene is composed of nine exons and its overall organization is similar to that of its counterparts from other species. Intron 4, the largest, shares three similar stretches (sizes ranging from 0.1 to 0.3 kb) with the region upstream from the transcription unit. These common sequences are part of short interspersed nuclear elements (SINE) specific to Bovidae (Bov). Intron 4 contains two 274-bp Bov-A2 SINE in opposite orientation, as well as a full-length 569-bp Bov-B SINE. This latter SINE, also present in caprine intron 4, is missing in cattle. This suggests that the amplification of Bov-SINE has continued after the divergence of cattle from sheep and goats, assuming that the presently known sequences are representative of these species.

Amino Acid Sequence↗
PubMed1995

Is there a role for inhaled nitric oxide in pediatric ARDS?

Despite advances in ventilator management and use of extracorporeal lung support, mortality related to ARDS in pediatric patients has not been reduced over the past 20 years. Progressive respiratory failure, due to evolution of the primary illness or to complications of ventilator therapy, significantly contributes to poor outcome. ARDS is characterized by severe ventilation-perfusion mismatch and by pulmonary hypertension. Because of their side effects which affect systemic hemodynamic status or worsen intrapulmonary shunting, intravenous vasodilator trials have been of limited interest. Nitric oxide (NO) has been recognized as a gas with vasodilator properties. In neonates studies have shown that inhaled NO may have an important role in the therapy of persistent pulmonary hypertension. Inhaled NO in adults with severe ARDS has been shown to reduce pulmonary hypertension without producing systemic vasodilation. This reduction of pulmonary vascular resistances may reduce pulmonary edema formation, decrease vasoconstrictor response to cardiotonic agents, and improve biventricular function. In addition, arterial oxygenation seems to be increased by improved matching of ventilation with perfusion. Improvement of oxygenation with inhaled NO suggests that use of lower tidal volumes and FIO2 may be more successful. Until now, there are no published studies regarding NO administration in ARDS affecting nonneonatal pediatric patients. However, the results obtained in adults and newborns suggest that inhaled NO may be a useful adjuvant therapy of ARDS in children, possibly in association with other therapies. Even in adults it remains unclear whether therapy with inhaled NO can reduce morbidity and mortality. Prospectives and randomized studies are essential to assess the real utility of inhaled NO in ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Echocardiographic investigation of inhaled nitric oxide in newborn babies with severe hypoxaemia.

Nitric oxide inhalation can benefit newborn babies with right-to-left extrapulmonary shunt (EPS). Using doppler ultrasound, we compared the effects of nitric oxide on systemic oxygenation and mean pulmonary-blood-flow velocity (MPBFV) in severely hypoxic babies with or without EPS. With a median (interquartile range) dose of 20 (32) parts per million, oxygenation index decreased significantly in both groups (EPS, 49 [19] vs 11 [9]; non-EPS, 40 [11] vs 20 [13]). The decrease was significantly greater in the EPS group. MPBFV increased significantly in the EPS group (18 [4] vs 29 [8] m/s) only. Nitric oxide may improve systemic oxygenation in neonates with severe hypoxaemia secondary to EPS by increasing pulmonary blood flow, and in those without EPS by improving ventilation-perfusion matching.

Administration, Inhalation↗
PubMed1994

Creation and phenotypic analysis of alpha-lactalbumin-deficient mice.

alpha-Lactalbumin is an abundant milk-specific calcium metalloprotein which has an evolutionary relationship to lysozyme. It modifies the substrate specificity of a Golgi galactosyltransferase by forming the lactose synthetase binary complex. Lactose, together with other sugars and diffusible ions, is responsible for the osmotic pressure of milk. To assess the involvement of alpha-lactalbumin in lactogenesis, alpha-lactalbumin-deficient mice were created by disrupting the gene by homologous recombination in embryonic stem cells. Homozygous mutant mice are viable and fertile but females cannot feed their offspring. They produce a highly viscous milk that pups appear to be unable to remove from the mammary gland. This milk is rich in fat and protein and is devoid of alpha-lactalbumin and lactose. The phenotype of heterozygous mice was found to be intermediate, with a 40% decrease in alpha-lactalbumin but only a 10-20% decrease in the lactose content of their milk compared with wild-type animals. These results emphasize the key function of alpha-lactalbumin in lactogenesis and open new opportunities to manipulate milk composition.

Animals↗
PubMed1994

Doppler echocardiographic assessment of pulmonary circulation in severe respiratory failure of the neonate: an aid for extracorporeal lung support indications.

Extracorporeal lung support (ECLS) for newborns with acute respiratory failure has achieved increased popularity over the last decade. However, precise criteria for its implementation remain controversial. The aim of this study was to assess the value of Doppler echocardiography (DE) in 31 neonates with PaO2 of < or = 50 mmHg, FIO2 of 1, and optimal ventilation. Treatment included mechanical ventilation, paralysis, volume loading, vasopressors, and tolazoline. Markers indicative of ECLS (failure of maximal medical therapy, assessed by AaDO2 of more than 610 mm Hg beyond 8 hours and/or an oxygenation index (OI = mean airway pressure x FIO2%/postductal PaO2) of more than 40 beyond 4 to 6 hours) were present in 23 (group 1) and absent in eight (group 2). Shunt direction and systolic pulmonary arterial pressure (sPAP) calculated from tricuspid insufficiency velocity were assessed using DE. At the time of admission, sPAP was significantly higher in group 1 (62.1 v 43.7 mm Hg). On day 1, group 1 differed from group 2 in maximum sPAP value (73.2 v 44.4 mm Hg), PaCO2 (56.1 v 40 mm Hg), right-to-left shunting (85% v 25% of the patients), and pulmonary-to-systemic-pressure systolic ratio (sPAP:sSAP) (1.29 v 0.75). Patients with an sPAP:sSAP ratio of more than 1 and patients with high sPAP associated with high PaCO2 on day 1, all later (average, 10 hours later) fulfilled ECLS criteria; this suggests that DE assessment of pulmonary circulation may yield early and predictive markers of impending ECLS indication. Further confirmation of these results would help avoid unnecessary delays in ECLS implementation in newborns with severe respiratory failure.

Echocardiography, Doppler↗