A Computer Prescribing Order Entry-Clinical Decision Support system designed for neonatal care: results of the 'preselected prescription' concept at the bedside.

WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

Molecular variability of group 1 and 5 grass pollen allergens between Pooideae species: implications for immunotherapy.

BACKGROUND: Differences between major allergens from distinct grass species remain to be investigated, both in terms of structure and antigenicity. METHODS: Group 1 and 5 allergens purified from five common Pooideae species were analysed by mass spectrometry (MS). Major histocompatibility complex (MHC) class II-restricted T cell epitopes were identified using predictive algorithms and human leucocyte antigen (HLA)-binding assays. CD4+ T cell reactivity and IgE binding were assessed based on the induction of CD154 expression in peripheral blood mononuclear cells and using competitive ELISA assays, respectively. RESULTS: MS analysis of group 5 pollen allergens reveals considerable intra- and inter-species variability in amino acid sequence, with 30-50 predominant isoforms found for each species. Differences in the amino acid sequence as well as N- and O-glycosylation contribute to the variability of group 1 allergens, yielding 5-10 main isoforms, depending on the species. Out of 14 MHC class II-restricted T cell epitopes identified within group 1, only one is conserved among the five grass species. Significant differences in binding affinities for HLA-DR molecules result in variable CD4+ T cell recognition of group 1 and 5 allergens purified from the various species. Up to 38% and 85% of patients exhibit seric IgE responses to species-restricted (or semi-restricted) epitopes associated with group 1 or 5 allergens, respectively. CONCLUSION: Major pollen allergens from distinct grass species bear both shared and species-restricted T and B cell immune epitopes. When compared with single extracts, a five grass pollen extract is thus more suitable for specific immunotherapy, as it contains a broader repertoire of the IgE epitopes to which patients are sensitized.

Human variable number of tandem repeat probes as a source of polymorphic markers in experimental animals.

Human VNTR (Variable Number of Tandem Repeat) markers are examined as a source of polymorphism for linkage studies in inbred strains of mice and rats. High frequencies of cross-hybridization are found under fingerprinting conditions that detect many distinct minisatellite loci in these species. Linkage studies suggest that minisatellite markers are widely distributed in the mouse genome, in contrast to humans where they are clustered, particularly in telomeric regions. Human VNTR probes can be used to screen in mouse genomic libraries to isolate mouse specific VNTR sequences. Some of these sequences reveal fingerprint patterns under stringent hybridization conditions.

In-vivo effect of somatostatin analog, lanreotide, and/or grp antagonist, bim-26226, on the growth of colon-cancer peritoneal carcinomatosis in the rat.

The effect of somatostatin analogue, lanreotide, and bombesin/GRP antagonist, BIM 26226, on the growth of colon cancer peritoneal carcinomatosis in the rat was studied. BDIX rats were i.p. injected with DHD/K12 rat colon cancer cells at day 0 and received from day 3 either lanreotide, BIM 26226, combination of treatments or peptide solvents. At sacrifice, an day 45, no significant difference between groups was observed for peritoneal tumor growth, hepatic metastases, ascite volume and labeling indices in normal colonic mucosa and tumoral tissues. Survival times were similar in other lanreotide-treated and control groups. However, BIM 26226 decreased plasma gastrin level, consistently with a physiological effect of this peptide. Ln all groups, somatostatin and bombesin receptors were found on mucosal and tumoral tissues. Interestingly, bombesin receptor number was higher in severe than in minor cancer stages, contrarily to that of somatostatin receptors. Moreover, an up-regulation of somatostatin and bombesin receptors was observed in BIM 26226- and lanreotide-treated group tumors, respectively, Despite the presence of these specific receptors, lanreotide and BIM 26226 were inactive on tumor growth in this model.

[Assessment of the discriminating power of identifiers for record linkage]. / Estimation de la valeur discriminante des traits d'identification utilisés pour le rapprochement des données d'un patient.

BACKGROUND: To reconstruct a patient's medical history, one has often to combine information from different sources, whatever the context of this reconstitution: epidemiological studies or health care. As a linkage using less informative identifiers could lead to linkage errors, it is essential to quantify the information associated to each identifier. METHODS: The aim of this study was to estimate the discriminating power of different identifiers which could be used in a record linkage process based on the means of the likelihood ratio proposed by Jaro as a probabilistic record linkage method. Six identifiers were considered: date of birth, maiden name, usual last name, first and second christian names and the gender. Two types of phonetic treatment were taken into account: the Soundex and a phonetic treatment adapted to the French language. Three situations were considered: 1) and 2) linkage of the data collected during two consecutive years in a university hospital (CHU de Dijon; 100000x100000 records) and a Paris hospital (50000x50000 records), 3) linkage of two files obtained through a healthcare network (Burgundy Perinatal Network; 200x2500 records). RESULTS: Whatever the situation, this work showed the interest of three identifiers when linking data concerning a same patient. The date of birth had the best discriminating power followed by the first and the last names. Including a poorly discriminating identifier like gender did not improve the results. Moreover, adding a second Christian name, often missing, increased linkage errors. On the contrary, it seemed that using a phonetic treatment adapted to the French language could slightly improve the results of linkage in comparison to Soundex. CONCLUSION: Whatever the method used, it seems necessary to improve the quality of identifier collection, in particular of the date of birth and of the first and last names as it could make the linkage of data obtained from different sources easier. Further research is needed to estimate the discriminating power of other identifiers (birth place and parents identifiers).

Severe respiratory disorders in term neonates.

Few prospective population-based studies of respiratory diseases have been conducted in term neonates. We aimed to describe mechanically ventilated respiratory disorders in term neonates and associated risk factors in a regional-based study of livebirths between 37 and 41 weeks. The study was prospective for epidemiological data recording, and retrospective for collecting additional data from charts of neonates with severe (mechanically ventilated) respiratory disorders. A total of 14,813 neonates with gestational age (GA) 37-38 weeks and 50,187 neonates with GA 39-41 weeks were included. The overall incidences (per thousand livebirths) of mechanically ventilated transient tachypnoea of the newborn (TTN) respiratory distress syndrome (RDS) and meconium aspiration syndrome (MAS) were 0.72 per thousand[95% CI 0.53 per thousand, 0.96 per thousand], 0.38 per thousand[95% CI 0.25 per thousand, 0.57 per thousand] and 0.61 per thousand[95% CI 0.44 per thousand, 0.84 per thousand], respectively. Increasing GA from 37 to 41 weeks was associated with a significant decrease in incidence of RDS and TTN without any significant change for MAS. Multivariable analysis was used to identify independent factors associated with severe respiratory disorders: in the 37-38 weeks group - Apgar score < or =3 at 1 min, elective caesarean section (CS), emergency CS and placental abruption; in the 39-41 weeks group - Apgar score < or =3 at 1 min, elective CS, emergency CS, meconium-stained amniotic fluid and abnormal cardiotocography. Comparing the population attributable risks, the main risk factor of severe respiratory disorders was elective CS in the 37-38 weeks group and meconium-stained amniotic fluid in the 39-41 weeks group.

Medical complications in long-term survivors with X-linked myotubular myopathy.

OBJECTIVES: X-linked myotubular myopathy (MTM1) is a rare developmental disorder of skeletal muscle characterized by the presence of central nuclei in biopsy specimens from affected male subjects. Until recently, the disorder was usually fatal within the first year of life. This study was undertaken to determine the outcome in long-term survivors (>1 year of age) with MTM1. METHODS: Clinical data were obtained on 55 male subjects from 49 independent North American families for which a mutation was identified in the X-linked myotubularin gene by direct genomic sequencing. Medical records were reviewed and families were interviewed to ascertain features at birth, length of survival, developmental milestones, and medical complications. RESULTS: Seventy-four percent (26 of 35) of the affected male subjects over the age of 1 year are living (range, 1 to 27 years); 80% remain completely or partially ventilator-dependent. In the absence of significant hypoxia, cognitive development is normal, and the muscle disorder appears nonprogressive. Several patients have had other medical problems not previously reported to be associated with MTM1. These include pyloric stenosis (4 male subjects from 3 families), spherocytosis (2 patients), gallstones (4 patients), kidney stones or nephrocalcinosis (2 patients), a vitamin K responsive bleeding diathesis (2 patients), and height >/=90% for age (40% of the patients). Six patients have had biochemical evidence of liver dysfunction, and 2 patients died after significant liver hemorrhage. CONCLUSIONS: These data suggest that the prognosis for X-linked MTM may not be as poor as previously reported. However, at least some long-term survivors appear at risk for medical complications involving other organ systems, and patients should be carefully monitored for these potentially life-threatening complications. The pleiotropic symptoms demonstrated in these patients strongly suggest that the function of the MTM1 protein is not limited to developing muscle cells.

Genetic mapping through the use of synthetic tandem repeats in the mouse genome.

Polymers of arbitrary oligonucleotides can be used to detect polymorphic loci in a wide range of vertebrate genomes. Using 60 such probes, we previously reported the selection of the most efficient STR probes for polymorphism detection in the set of genomes investigated. We now report the use of this selection for the mouse genome and its contribution to genetic mapping. Twenty-three synthetic tandem repeats (STRs) sequences were probed on a recombinant inbred panel C57B1/6 x DBA/2. The loci detected are distributed in 70 linkage groups; 42 of these groups, corresponding to about 100 different polymorphic loci, include reference markers. These linkage groups appear to be evenly distributed within all the 20 mouse chromosomes with apparently no bias of repartition towards telomeres or centromeres.

A centromere-based genetic map of the short arm of human chromosome 6.

A genetic map of the short arm of chromosomes 6 (6p) has been constructed with 20 genetic markers that define 16 loci, including a locus at the centromere. The 40 CEPH families and, for 4 loci, 13 additional Utah families were genotyped. All 16 loci form a single linkage group extending from near the telomeric region to the centromere, covering 159 cM (Haldane) on the female map and 94 cM on the male map. Sex differences in recombination frequencies are noted for the 6p map, with an excess occurring in males at the distal end. The genetic order of loci is consistent with their physical localization on 6p. Proximal to the three most distal loci on the map, markers are especially dense, providing an extended region on 6p useful for localizing genes of interest.

Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy.

A candidate gene, myotubularin, involved in the pathogenesis of X-linked myotubular myopathy (MTM1) was isolated recently. Mutations originally were identified in 12% of patients examined for 40% of the coding sequence, raising the possibility that additional genes could be responsible for a proportion of X-linked cases. We report here the identification of mutations in 26 of 41 independent male patients with muscle biopsy-proven MTM, by direct genomic sequencing of 92% of the known coding sequence of the myotubularin gene. Eighteen patients had point mutations, including one A/G transition found in four patients which alters a splice acceptor site in exon 12 and leads to a three amino acid insertion. Six patients had small deletions involving <6 bp, while two larger deletions encompassed two or six exons, respectively. No differences were noted among the types of mutations between familial and sporadic cases. However, all of the five patients with a mild phenotype had missense mutations. While 50% of the mutations were found in exons 4 and 12, and three distinct mutations were found in more than one patient, no single mutation accounted for more than 10% of the cases. The low frequency of large deletions and the varied mutations identified suggest that direct mutation screening for molecular diagnosis may require gene sequencing.

Minisatellite linkage maps in the mouse by cross-hybridization with human probes containing tandem repeats.

Tests of 29 human variable number of tandem repeat probes in inbred mouse lines showed that 80% (23/29) cross-hybridize, and 48% (14/29) produce multiple band, minisatellite polymorphisms (fingerprint patterns). Mini-satellite-type polymorphisms detected by 11 probes were characterized in eight different strains; on average, 240 polymorphic differences were detected between pairs of strains. Reproducible fingerprint patterns permit the study of the segregation of the minisatellite polymorphisms in experimentally designed crosses. As an example, we constructed primary minisatellite genetic linkage maps containing 346 polymorphic bands, distributed in 101 groups of closely linked systems, from genotypes on a recombinant inbred panel (C57BL/6J X DBA/2J); 38 of the groups were assigned by linkage to 15 autosomal chromosomes. The minisatellite genetic maps of C57BL/6J and DBA/2J can be applied in other linkage studies involving these strains.

Predictive factors in the outcome of pseudocysts complicating alcoholic chronic pancreatitis.

AIMS: To determine the clinical, biochemical, and/or morphological features which could predict the need for treatment of pseudocysts at diagnosis in a homogeneous population of patients with alcoholic chronic pancreatitis. METHODS: Between January 1983 and December 1993, all patients followed for alcoholic chronic pancreatitis complicated by pseudocysts and confirmed by computed tomography (CT) scan at diagnosis were studied retrospectively. Two groups of pseudocysts were considered according to their pattern of evolution and the therapeutic requirements. Group I included 45 pseudocysts that regressed spontaneously (25 patients) or that persisted without symptoms (20 patients). Group II included 45 pseudocysts with persisting symptoms or complications, requiring surgical or non-surgical treatment. The evolution of pseudocysts was monitored by CT scanning or abdominal ultrasound. Initial CT scans of all patients were reviewed by an experienced radiologist. For each patient with pseudocysts, the following morphological parameters were recorded: number of pseudocysts, maximal diameter, location, intrapancreatic or extrapancreatic development, complications related to the pseudocyst, pancreatic calcifications, enlargement of the main pancreatic duct, and signs of recent acute pancreatitis. Univariate analysis, and then multivariate analysis with all significant variables on univariate analysis were performed. RESULTS: On univariate analysis, location of pseudocysts in the pancreatic head and intrapancreatic development of pseudocysts were significantly more frequent in group I than in group II (78% versus 55%, p < 0.02 and 89% versus 60%, p < 0.001, respectively). The median diameter of pseudocysts was significantly smaller in group I than in group II (25 (10-110) mm and 40 (10-120) mm respectively, p < 0.001). No differences between groups I and II were found for the clinical or biochemical parameters. Multivariate analysis showed that the intrapancreatic development of pseudocysts and a diameter less than 4 cm were the only independent factors associated with a spontaneous and favourable outcome. These factors accounted for 20% of the total variance. CONCLUSIONS: Pseudocysts larger than 4 cm and extrapancreatic development can be considered independent predictive factors of persisting symptoms and/or complications in patients with pseudocysts and alcoholic chronic pancreatitis.

Comparative mapping on the mouse X chromosome defines a myotubular myopathy equivalent region.

The gene for X-linked myotubular myopathy (MTM1) has been localized to a 300-kb critical region in human Xq28 between IDS and GABRA3. As part of an effort to clone this gene, we developed a YAC contig on the mouse X Chromosome (Chr) which includes loci homologous to those within the human MTM1 critical region. The murine contig consists of 18 YACs and spans 2.5-3.0 Mb. We have aligned the human and murine physical maps by isolating conserved mouse genomic fragments, including CpG islands and trapped exons. We believe that the simultaneous isolation of genes from both mouse and human and continued comparative mapping will prove helpful in the eventual identification of MTM1 and other genes in the region.

Genetic analysis of diabetes and insulitis in an interspecific cross of the nonobese diabetic mouse with Mus spretus.

The nonobese diabetic (NOD) mouse is a widely used model for genetic studies of insulin-dependent diabetes mellitus due to the similarities between the murine and human diseases. To aid in the localization and identification of diabetes-related susceptibility genes, we have constructed an interspecific backcross between NOD and Mus spretus (SEG/Pas) mice. Although no diabetic animals were observed in the first backcross generation of (SEG/Pas x NOD) x NOD (BC1), the incidence of insulitis (lymphocyte infiltration of the islets of Langerhans) exceeded 20% after injections of cyclophosphamide, a treatment that provokes an acute form of diabetes in NOD mice. Insulitis, a prediabetic condition, is a useful phenotype in studies of diabetes susceptibility. In the second backcross (BC2) generation, 8% of the animals became diabetic and 76% were found to have insulitis. Genetic mapping studies in the BC2 families confirmed the importance of the major histocompatibility complex region on the severity of insulitis and suggested that additional susceptibility loci were linked to markers on mouse chromosomes 3, 6, and 15. Mus spretus crosses have been an important tool in recent advances in murine genetics, and our results extend their usefulness to the study of a multifactorial disease.

Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats.

The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure. Linkage studies in crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain Wistar-Kyoto have led to the localization of two genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F2 population. BP/SP-1 and BP/SP-2 were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicates that BP/SP-1 could reside on human chromosome 17q in a region that also contains the angiotensin I-converting enzyme gene (ACE). This encodes a key enzyme of the renin-angiotensin system, and is therefore a candidate gene in primary hypertension. A rat microsatellite marker of ACE was mapped to rat chromosome 10 within the region containing BP/SP-1.

Serum IgE concentration and other immune manifestations of treatment with gold salts are linked to the MHC and IL4 regions in the rat.

A subset of patients with rheumatoid arthritis occasionally develops skin reactions and glomerulonephritis and exhibits an increase in serum IgE concentration when treated with gold salts. Brown-Norway (BN) rats injected with aurothiopropanolsulfonate (ATPS) also manifest an autoimmune glomerulonephritis and increased serum IgE concentration, whereas Lewis (LEW) rats are resistant to complications. Here, we show linkage between responses to ATPS in a (BN x LEW) F2 cohort and the major histocompatibility complex (RT1) on rat chromosome 20 and between markers in the region of IL4 and other candidate genes on rat chromosome 10. Recently, human serum IgE concentration has been reported to be linked to the IL-4 region. Taken together, these findings raise the possibility that homologous genes could be implicated in ATPS manifestations in the rat and in the regulation of IgE levels in the human.

Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG.

Human homologues of mouse t-complex genes have been cloned and localized physically to chromosome 6p or 6q. TCP1, TCP10, and PLG are human homologues of genes located in the proximal portion of the t-complex on mouse chromosome 17. We present here results of genetic mapping of these human t-complex homologues previously localized to 6q25-q27, 6q21-q27, and 6q26-q27, respectively, by physical techniques. TCP1 and PLG do not recombine with each other and are separated from TCP10 by about 15 cM, while the corresponding mouse genes are no more than 4 cM apart. Genetic mapping with markers well localized cytogenetically places TCP1 and PLG proximal to TCP10 and localizes the latter to the cytogenetic band 6q27. It is likely that the organization of human t-complex homologues on 6q is similar to that of t haplotypes rather than that of wildtype murine chromosome 17.