Gestational anaemia and severe acute maternal morbidity: a population-based study.

Anaemia is frequently diagnosed during pregnancy. However, there are few data regarding its incidence, and the association with severe maternal morbidity remains uncertain and potentially biased in high-resource countries. The purpose of this study was to explore the association between gestational anaemia and severe acute maternal morbidity during and after delivery. We performed a cohort-nested case-control analysis from the epidemiology of severe maternal mortality (EPIMOMS) prospective study conducted in six French regions (2012-2013, n = 182,309 deliveries). There were 1669 women with severe acute maternal morbidity during or after delivery, according to a standardised definition obtained by expert consensus. The control group were randomly selected among women without severe morbidity who delivered in the same health centres (n = 3234). We studied the association between gestational anaemia and severe acute maternal morbidity during or after delivery overall, by cause, and by mode of delivery, using multivariable logistic regression and multiple imputation. Gestational anaemia was significantly more frequent in women with severe acute maternal morbidity (25.3%) than in controls (16.3%), p < 0.001, and mostly mild in both groups. After adjustment for confounders, women with gestational anaemia were at increased risk of overall severe acute maternal morbidity during and after delivery (adjusted OR (95%CI) 1.8 (1.5-2.1)). This association was also found for severe postpartum haemorrhage (adjusted OR (95%CI) 1.7 (1.5-2.0)), even after omitting the transfusion criterion (adjusted OR (95%CI) 1.9 (1.6-2.3)), and for severe acute maternal morbidity secondary to causes other than haemorrhage or pregnancy-related hypertensive disorders (adjusted OR (95%CI) 2.7 (1.9-4.0)). These results highlight the importance of optimising the diagnosis and management of anaemia during pregnancy.

Visceral leishmaniasis in a lung transplant recipient: usefulness of highly sensitive real-time polymerase chain reaction for preemptive diagnosis.

We report the case of a lung transplant recipient in whom the diagnosis of visceral leishmaniasis (VL) was made by detection of parasites in a peripheral blood smear when the parasite load already reached 8.9 × 103 parasites/mL. We demonstrated that the VL diagnosis could have been done months before the development of symptoms by the use of Leishmania-specific real-time polymerase chain reaction (PCR), suggesting the role of preemptive PCR-based diagnosis in transplant recipients at risk for VL.

Linkage analysis of the murine interferon-alpha locus on chromosome 4.

Southern blot analysis with a murine interferon-alpha2 (MuIFN-alpha2) cDNA probe revealed restriction fragment polymorphism of EcoRI- and HindIII-digested C57BL/6 and BALB/cDNA. The inheritance pattern of this polymorphism was examined using DNA from each of the seven recombinant inbred strains derived from C57BL/6 and BALB/c; the strain distribution pattern suggests linkage of INF-alpha genes to two histocompatibility loci on chromosome 4. Southern blot analysis of DNA from six bilinear congenic strains carrying different fragments of the BALB/c chromosome 4 on a C57BL/6 background showed linkage of IFN-alpha genes to the histocompatibility locus H-15. It can therefore be concluded that the IFN-alpha gene cluster is situated on chromosome 4 near the H-15 locus, between loci Mup-1 and b.

Mouse leukemia: depression of serum interferon production.

Production of circulating interferon is significantly impaired in AKR/J mice after development of lymphoblastic leukemia and in Balb/c mice with clinical signs of Friend erythroblastic leukemia. This alteration has been observed with three interferon inducers, each one known to elicit an interferon response in different cells.

Depression of circulating interferon response in Balb-c mice after urethan treatment.

Urethan, when given to female Balb/c mice, impaired the capacity of these animals to produce circulating interferon. The effect appeared rapidly after a single injection of either 1 or 1.5 milligrams of urethan per gram of body weight and was of short duration. The possibility that this inhibition of the production of interferon plays a role in the enhancement of viral leukemia by urethan should now be considered.

Delayed-type hypersensitivity to sheep red blood cells: inhibition of sensitization by interferon.

Interferon, when given or induced 24 hours before contact of mice with sheep red blood cells, prevented sensitization, and no delayed-type hypersensitivity reaction could be elicited 4 days later, after challenge with the antigen, as shown by the absence of footpad swelling in treated animals.

Strain dependence of the antiproliferative action of interferon on murine erythroid precursors.

Electrophoretically pure mouse interferon inhibits erythropoietin-dependent proliferation of committed erythroid precursors (CFU-E) obtained either from adult mouse bone marrow or from 14-day fetal mouse livers. The degree of inhibition is significantly influenced by the genotype of the cell donor; about ten times as much interferon is required to inhibit proliferation of CFU-E from C57BL/6 than is needed for comparable inhibition of CFU-E from BALB/c or Swiss mice. These strain-dependent results point to the existence of genes that influence the degree of the inhibitory effect of interferon on cell multiplication.

Interferon-gamma.

During the past year, the most striking progress in our understanding of interferon-gamma has been made in the elucidation of the three-dimensional structure of the molecule and in the analysis of the molecular structure and the functional domains of the interferon-gamma receptor. A greater insight into the molecular mechanisms of gene activation by interferon-gamma has been gained, and the immunoregulatory role of interferon-gamma has been better defined in studies dealing with its effects on B-cell function and with its production by the various T-cell subsets. Finally, the effects of interferon-gamma on intracellular parasites is an important aspect of interferon-gamma activity that is giving rise to several clinical trials.

Circulating Interferon Production in the Mouse : Origin and nature of cells involved and influence of animal genotype.

A radiobiological study of circulating interferon production in the mouse was undertaken in the hope of elucidating the site(s) of circulating interferon production. After total body X-irradiation of the animals, different radiosensitivities of circulating interferon production were observed with different viral inducers. Myxovirus-induced circulating interferon production was especially radiosensitive. Moreover, a study of interferon production in syngeneic and xenogeneic radiochimeras demonstrated that cells producing NDV (Newcastle disease virus)-induced circulating interferon were derived from hematopoietic stem cells. In addition, treatment of mice with antilymphocyte serum significantly reduced NDV- and Sendai virus-induced circulating interferon, as opposed to other inducers. Taken together, these results strongly suggest that the lymphocyte is the major source of myxovirus-induced circulating interferon. A survey of interferon production in 12 inbred mouse strains, using NDV as inducer, revealed the existence of low and high producers. A Mendelian analysis carried out with low producing Balb/c and high producing C57BL indicated that the difference between low and high interferon producers was caused by a single, autosomal, codominant factor.

Development of methods for somatic cell gene therapy directed against viral diseases, using retroviral vectors carrying the murine or human interferon-beta coding sequence: establishment of the antiviral state in human cells.

We are developing methods for somatic cell gene therapy directed against chronic and fatal virus infections, such as acquired immunodeficiency (AIDS), by transforming cells with a constitutively expressed interferon (IFN) coding sequence. Previous work from our laboratory has shown that stable antiviral expression (SAVE) can be obtained in murine BALB/c 3T3 cells and human U937 cells transformed with plasmids carrying either the murine or the human IFN-beta coding sequence placed under the expression control of a 0.6-kb Xho II-Nru I promoter region of the murine H-2Kb major histocompatibility complex (MHC) gene (Macé et al., 1991; Seif et al., 1991). In the present paper, we report the construction of murine (Mu) and human (Hu) IFN-beta-expressing retroviral vectors (pMPZen-MuIFN beta, pHMB-KbMuIFN beta) and the problems encountered. Because of the murine origin of commonly used packaging cells and the species specificity of IFN, it was evident that placing the murine IFN-beta sequence under constitutive expression control could result in the production of Mu IFN in the murine packaging system, and thereby lead to decreased vector production and also to enhanced resistance of target cells. Using a packaging cell line that releases a beta-galactosidase-expressing vector, we show that, as expected, Mu IFN-alpha/beta decreases vector production of murine packaging cells and also inhibits the transformation of target NIH-3T3 cells with this vector, but the presence of anti-Mu IFN antibodies rescues the viral titer of the packaging cells and restores the sensitivity of target cells to virus transformation. However, the same antibody treatment is unable to rescue the viral titer of psi-2 packaging cells producing autocrine Mu IFN-beta encoded by the pMPZen-MuIFN beta and pHMB-KbMuIFN beta vectors. Because of the species specificity of IFN, this problem is circumvented with the pMFG-HuIFN beta vector carrying the human IFN-beta sequence. In spite of the production of Hu IFN, murine psi-CRIP packaging cells are able to release retroviral vectors expressing Hu IFN-beta, and these amphotropic vectors can transform human MRC-5 cells and confer to these cells an enhanced resistance to vesicular stomatitis virus (VSV) infection.

Effect of intravenous diazepam on renal function.

The effect of intravenous diazepam on glomerular filtration rate (inulin clearance) and effective renal plasma flow (PAH clearance) was investigated in 6 children and 12 anesthetized rabbits. A transient decrease in inulin and PAH clearances was observed in 6 children given 4 mg of diazepam intravenously, without measurable change in blood pressure. A similar renal effect was observed in anesthetized rabbits, together with a transient drop in systemic arterial pressure. Continuous infusion of diazepam (5 mg/kg/hr) did not affect renal function in rabbits. We suggest that this effect of diazepam should be borne in mind when the drug is administered to patients undergoing renal clearance studies or to patients with preexistent renal insufficiency.

Structure and expression of a new murine interferon-alpha gene: MuIFN-alpha I9.

A new murine alpha interferon gene, MuIFN-alpha I9, isolated from a BALB/c genomic clone, was characterized. It encodes a mature polypeptide of 167 amino acids (aa), presenting from 77 to 86% homology with the seven other MuIFN-alpha I aa sequences previously described. When compared to the latter, pre-IFN-alpha I9 has 13 distinctive aa, and, remarkably, ten of these occur in pairs. The coding region, fused to the SV40 early promoter and introduced into COS monkey cells, directed the transient secretion of an acid-stable functional IFN of 18-21 kDa. The production in this system reached levels of 300 000 units per 0.15 ml. A comparison of the aa sequence of different murine, rat, bovine, and human alpha and beta IFNs revealed certain common features allowing us to propose a putative secondary structure of the IFN proteins. A detailed analysis of results previously published by us and by others showed that the MuIFN-alpha I9 gene is, together with a least twelve other MuIFN-alpha I genes, located on chromosome 4.

Mapping of murine interferon-alpha genes to chromosome 4.

A cDNA library was constructed from polysomal poly(A)+RNA from Newcastle disease virus (NDV)-induced mouse C243 cells, and screened with a human interferon-alpha (HuIFN-alpha) cDNA probe. A cDNA clone for one of the murine interferon-alpha (MuIFN-alpha) genes was isolated, and sequencing analysis revealed that it was a partial copy which is almost identical to the published sequence for the MuIFN-alpha 2 gene. This partial cDNA clone represents a virus-induced message as seen by Northern blot analysis of RNA from NDV-induced C243 cells, and Southern blot analysis of DNA from BALB/c mouse revealed the presence of a multiple IFN-alpha gene family. The MuIFN-alpha genes were mapped to chromosome 4 by Southern blot analysis of hamster/mouse somatic cell hybrid DNAs.

Urinary tract infection in high-risk newborn infants.

The prevalence of neonatal urinary tract infection (UTI) was studied in 1,762 high-risk neonates. Symptomatic bacteriuria was found in 1.9% and asymptomatic bacteriuria in 0.5% of these neonates. Male preponderance was 5:1. Clinical manifestations were extremely variable--vomiting, weight loss, and diarrhea being the prominent symptoms. Bacteremia was associated with UTI in six infants. The organisms identified in the urine obtained by suprapubic aspiration were Escherichia coli, Klebsiella, and Proteus. A mixed infection was found in four patients. Roentgenographic examination of the urinary tract showed abnormalities in 44% of the symptomatic patients. It is conclued that symptomatic high-risk newborn infants should be screened for bacteriuria, and that radiological investigations be preformed in those with proven infection.

Renal function in obstructive nephropathy: long-term effect of reconstructive surgery.

Renal function was studied in 24 children with chronic hydronephrosis and renal insufficiency. The follow-up period after reconstructive surgery was 1 to 12 years. Glomerular filtration rate (GFR) was assessed by the clearance of endogenous creatinine or inulin. Effective renal plasma flow was assessed by the clearance of PAH. Reconstructive surgery was performed during the first year of life in 12 out of 24 patients, between one and two years of life in 6 patients, and after two years of life in 6 patients. Three different patterns of evolution could be observed after relief of obstruction: (1) An improvement or a normalization of renal function only occurred in patients operated upon before one year of life. (2) A stabilization of renal function without normalization was observed in patients operated upon between one and two years of life. (3) A progressive deterioration of renal function towards terminal renal failure was observed in five out of six patients operated upon after two years of age. This deterioration could not be explained by recurrence of detectable urinary tract infection or urinary stasis. The changes in GRF in four patients with a solitary kidney followed the same pattern. We conclude that it is essential to correct severe chronic hydronephrosis associated with renal insufficiency before one year of age if a lasting improvement of renal function is to be expected.

Corticoresistant nephrotic syndrome associated with T-cell deficiency in two sisters.

The coexistence in two sisters, born to related parents, of a corticoresistant nephrotic syndrome, lymphopenia, an immune deficit, short stature, and photophobia is described. The immune deficit is mainly cellular; studies of lymphocyte markers demonstrate a pronounced deficiency of T lymphocytes and Fc-mu receptor-bearing cells. It is suggested that a thorough examination of number and function of T cells should be performed in patients with a familial corticoresistant nephrotic syndrome and recurrent infectious episodes before considering immunosuppressive treatment.

Type I interferons.

Type I interferons (IFNs) constitute a family of structurally related proteins that are all derived from the same ancestral gene and act on a common cell-surface receptor. Contrary to many other cytokines, the production of type I IFNs is not a specialized function, and all cells in the organism can produce them, usually as a result of induction by viruses, via the formation of double-stranded RNA. Type I IFNs are indeed responsible for the first line of defense during virus infection and act through the induction of a great number of proteins. Of these, at least thirty have been characterized, and there are probably many more. In addition to their direct antiviral effect, type I IFNs exert a wide variety of other activities, such as for example the induction of various cytokines and the stimulation of different effector cells of the immune system. Due to these pleiotropic effects, recombinant interferons are used in the clinic to treat a variety of diseases, among which cancer, viral hepatitis and multiple sclerosis.

Urinary oxalate and urate to creatinine ratios in a healthy pediatric population.

The purpose of the study was to determine reference percentiles for the urinary (U) oxalate (Ox) and urate (Ura) to creatinine (Cr) concentration ratios in the second morning urine of healthy infants, children, and adolescents. The urinary oxalate and urate to creatinine ratios were determined in the spontaneously voided second morning urine sample. To test reproducibility, two urine samples were analyzed on 2 consecutive weeks in 63% of the subjects. Three hundred eighty-four healthy children (181 girls, 203 boys), aged 1 month to 17 years, from nurseries, kindergartens, and schools of Lausanne, Switzerland, were studied. The 5th and 95th percentiles were determined from the total number of urine samples (627) after confirmation that there was no order effect between repeated measurements and there were no significant sex differences. A nonlinear regression analysis in terms of age was used to smooth the calculated percentiles. In this manner, curves were obtained from which the reference values can be read at any given age. The 95th percentiles decreased with age: for UOx/Cr from 0.175 mg/mg (0.22 mol/mol) at 1 to 6 months to 0.048 mg/mg (0.06 mol/mol) from 7 years and beyond; and UUra/Cr from 2.378 mg/mg (1.6 mol/mol) at 1 to 6 months to 0.594 mg/mg (0.4 mol/mol) in adolescence. We provide 5th and 95th percentile curves for the UOx/Cr and UUra/Cr ratios determined from the second morning urine samples in a large cohort of healthy infants, children, and adolescents. Values were determined by standard analytical chemical techniques and were analyzed by powerful statistical methods. The calculated 95th percentile for the UOx/Cr values fell rather rapidly and reached normal adult values by the age of 7 years, whereas for UUra/Cr, the 95th percentile decreased slowly and stabilized in adolescence.

Immunoregulatory action of type I interferon in the mouse.

The effect of type I interferon production on immunity to the interferon-inducing virus was examined using the Newcastle disease virus [NDV]-mouse model and comparing If-1h and If-1l animals. The degree of cell-mediated immunity, as measured by delayed hypersensitivity [DH] to NDV, was influenced by the levels of interferon produced. Anti-interferon globulin given immediately after immunization decreased sensitization to NDV, whereas additional, exogenous, interferon, given to low interferon producers, stimulated sensitization to NDV. The alleles at the If-1 locus influenced the extent of DH to NDV, in that If-1h mice developed much stronger DH than did If-1l mice. However, results from recombinant inbred strains, F2 and backcross generations showed that for interferon production to stimulate DH to NDV, other genes, present in the C57BL/6 background but as yet not characterized, are required. Thus DH to NDV is determined on the one hand by the alleles at If-1, influencing interferon production, and on the other hand by a combination of several genes affecting the interaction of interferon with cells of the immune system.

Electrophoretically pure mouse interferon exerts multiple biological effects.

Electrophoretically pure (EP) mouse interferon (IF), was examined for a number of biological effects of previously ascribed to crude or partially purified interferon preparations. The following effects were observed: inhibition of antibody formation in vitro; inhibition or enhancement of sensitization to sheep erythrocytes in the mouse, depending on time of administration of IF, and dosage of antigen; inhibition of the expression of delayed type hypersensitivity in vivo; enhancement of natural killer cell activity in vitro and in vivo; inhibition of mouse tumor cells multiplication in vitro; inhibition of the growth of a transplantable tumor in mice. EP mouse IF had a very pronounced priming effect but had no blocking activity.