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Cysteine-rich repeats (CRs) of the type described in Chordin constitute conserved domains present in an expanding family of secreted molecules. These motifs were shown to mediate directly the antagonism of BMP signaling by Chordin and play a major role during development. Here we report the cloning and expression pattern of neuralin-1, a new member of the chordin family. The mouse cDNA was cloned by homology with a human genomic sequence encoding putative CRs. In the human genome, neuralin-1 transcripts are encoded by 8 exons that span a region of at least 80 kilobases located on chromosome Xq22.1-23. Neuralin-1 is a 333 amino acid protein containing three CRs, two of them highly similar to the Chordin CRs that bind BMP. Like chordin, neuralin-1 is able to induce secondary axes after mRNA injection in Xenopus embryos. Interestingly, during late gastrulation, neuralin-1 and chordin present distinct and complementary expression patterns in the mouse: neuralin-1 expression starts in the neural plate at mid-gastrulation, whereas chordin expression at that stage is restricted to the node and midline mesendoderm. Later on, neuralin-1 expression becomes restricted to discrete regions of the central nervous system and to derivatives of the neural crest cells. During organogenesis, neuralin-1 presents a broad expression pattern in many tissues such as dorsal root ganglia, gut, condensing cartilages of the skeleton and developing hair follicles.

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BACKGROUND: Mycobacterium szulgai is an uncommon atypical mycobacterium human pathogen. CASE REPORT: The clinical manifestations and radiographic findings in a 31-year-old woman were strongly suggestive of pulmonary tuberculosis. The mode of transmission could not be determined. Mycobacterium szulgai was identified. The patient was treated with antituberculosis antibiotics and the clinical course was favorable. DISCUSSION: Mycobacterium szulgai is an atypical mycobacterrium difficult to identify. Its epidemiological features are unknown. This potential pulmonary pathogen is rarely described in the literature. Most cases have involved pulmonary, bone and joint or skin infections in immunodepressed patients. M. szulgai is relatively susceptible to classic antituberculosis antibiotics although standard regimens have not been established. Our patient required intensive care for mechanical ventilation.

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Formation of tubular structures from an epithelial tissue is a process common to many morphogenetic events during organogenesis. We report here new data concerning the expression pattern of the vHNF1/HNF1beta gene during this process in the mouse. vHNF1 (variant Hepatocyte Nuclear Factor 1) is a member of the HNF1 homeoprotein family. Its expression domain includes organs such as the liver, the kidney, the lung and the pancreas, but is restricted to the epithelial cells of these organs. To follow vHNF1 expression during organogenesis, we have introduced a NLS-lacZ gene under the control of vHNF1 regulatory regions by homologous recombination. Detection of the beta-galactosidase activity in heterozygous mice demonstrates that this gene is expressed in numerous tubular epitheliums as soon as they appear and all along development.

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vHNF1/HNF1beta, a member of the divergent HNF1/vHNF1 homeoprotein family, is expressed in polarized epithelia of several adult organs and may participate in controlling the transcription of specific genes. In addition to this late requirement, vHNF1 may play earlier roles during development, as it is first expressed in the visceral endoderm at the onset of gastrulation. In order to shed light on its function during embryogenesis, we have inactivated the murine gene by homologous recombination. The homozygous mutation results in embryonic lethality by day 7.5 of development and vHNF1(-)(/)(-) embryos display a disorganized visceral endoderm and a significantly reduced size. Studies of ES cell differentiation and aggregation with tetraploid morulae establish that vHNF1 expression is essential for visceral endoderm differentiation, both in vitro and in vivo. Analysis of differentiation markers confirms that vHNF1 is part of a genetic network that directs the expression of HNF4 and downstream endodermal genes. Furthermore, the complementation of the mutant embryos with wild-type visceral endoderm rescues the day 7.5 lethality and reveals an additional phenotype linked to vHNF1 later expression. The examination of chimeric embryos suggests that vHNF1 expression might be cell-autonomously required in the gut for the proper morphogenesis of the embryo.

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Munster (Mu) is a homeobox-containing gene of the Paired-class which is specifically expressed in the developing Bolwig organs, the Drosophila larval eyes. This expression is first detected during early germ band retraction stage (stage 12 from 7 h 20 at 25 degrees C) and persists until the end of embryogenesis. Mu homeodomain is most similar to that of Aristaless and D-Goosecoid. Strikingly, the Munster gene maps within 6 kb of D-goosecoid, in the same genomic region as aristaless, suggesting that these genes are part of a homeobox gene cluster.

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STUDY OBJECTIVES: To develop a simplified prognostic prediction rule for patients admitted to ICUs for severe community-acquired pneumonia (CAP). SETTING: Six ICUs in the north of France. PATIENTS: Five hundred five patients admitted to ICUs over a 9-year period (from 1987 to 1995) for severe CAP. INTERVENTIONS: Retrospective prognosis analysis and multivariate analysis using a credit scoring technique. MEASUREMENTS: The primary outcome measure was ICU mortality. RESULTS: Among the 505 patients, 472 were eligible for the prognosis study. The ICU mortality rate was 22.9%. Multivariate analysis identified, on the basis of the patient's medical history and initial examination on ICU admission, six independent predictors of mortality: age > or = 40 years, anticipated death within 5 years, nonaspiration pneumonia, chest radiograph involvement > 1 lobe, acute respiratory failure requiring mechanical ventilation, and septic shock. An initial risk score based on these factors classified patients into three risk classes of increasing mortality: 4% in class I, 25% in class II, and 60% in class III. Multivariate analysis of events occurring during ICU stay identified three independent predictors of mortality: hospital-acquired lower respiratory tract superinfections, nonspecific CAP-related complications, and sepsis-related complications. An adjustment risk score based on these factors was essential to accurately predict the final outcome of patients in the initial risk class II. CONCLUSIONS: As an aid to clinicians in stratifying the prognosis of patients with severe CAP, the simplified prediction rule used in this study could be useful for therapeutic decisions and appropriate care.

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OBJECTIVES: To compare epidemiological data, etiology, and prognosis of severe community-acquired pneumonia (CAP) in the intensive care unit (ICU) according to age (< or > or = 65 years) and to determine prognostic factors of CAP in older people. DESIGN: A retrospective (1987-1992) and prospective (1993-95) multicenter study. SETTING: Six ICUs in the north of France. PATIENTS: Five hundred five patients admitted to an ICU for severe CAP. MEASUREMENTS: Patient characteristics were compared with regard to age. Prognosis of CAP in older patients was studied by stepwise discriminant analysis. RESULTS: Two hundred seventy-eight patients (55%) were aged 65 years or older. Comparison of epidemiological data between older and younger patients revealed a higher prevalence of women (38% vs 29%), more severe underlying comorbidities (anticipated death within 5 years: 59% vs 26%), and more frequent chronic respiratory insufficiency (48% vs 33%) in the older patients. In this study group, 224 organisms were isolated from 172 patients (62%); those identified most frequently were Gram-negative bacilli (34%), S. pneumoniae (32%), and Staphylococcus sp. (19%). Compared with younger patients, no significant differences in bacteriological data were observed. However, crude and attributable mortality rates were significantly higher in the older patients (33% vs 21% and 30% vs 19%, respectively). Prognosis analysis identified four independent predictors of mortality in the older patients: initial septic shock (relative risk (RR) = 3), sepsis-related complications (RR = 4.3), hospital-acquired lower respiratory tract superinfections (RR = 2), and nonspecific pneumonia-related complications (RR = 2.8). CONCLUSION: The bacterial etiology provides some approaches to empirical therapy for older patients with severe community-acquired pneumonia. In addition, the inappropriateness of withholding intensive care for reasons of age alone is emphasized.

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Over a 9-yr period, among 505 patients exhibiting severe community-acquired pneumonia and admitted into a total of six medical ICUs in the north of France, we collected 116 patients (23%) meeting the usual criteria for aspiration pneumonia. Main medical grounds of ICU admission were respiratory distress in 54 patients and neurological disturbances in 62 patients. The main underlying risk factor for aspiration pneumonia was drug overdose (39%). Mechanical ventilation was required for 73 patients. Initial shock was present in 15 patients. Pulmonary involvement was bilateral in 27 patients. There were 94 aerobic organisms isolated from 70 patients (60%), the most frequent being gram-negative bacilli (n = 38), Staphyloccus spp. (n = 27) and Streptococcus pneumoniae (n = 22). Overall mortality was 22%, but only 11 (11%) deaths were directly or indirectly related to aspiration pneumonia. Stepwise multivariate analysis identified four independent predictors of mortality: ineffective initial antimicrobial therapy (p = 0.0001), positive initial blood culture (p = 0.0001), hospital-acquired lower respiratory tract superinfections (p = 0.0054), and use of inotropic support (p = 0.0078). The importance of prevention of hospital-acquired superinfections and permanent optimization of our antimicrobial strategies warranting efficacy of the initial antimicrobial therapy is underlined.

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OBJECTIVE: To determine predictors of intensive care unit (ICU) mortality in patients with community-acquired pneumonia (CAP), to develop a pneumonia-specific prognostic index, and to evaluate this index prospectively. DESIGN: Combined retrospective and prospective clinical study over two periods: January 1987-December 1992 and January 1993-December 1994. SETTING: Four medical ICUs in the north of France. PATIENTS: Derivation cohort: 335 patients admitted to one ICU were retrospectively studied to determine prognosis factors and to develop a pneumonia-specific prognostic index. Validation cohort: 125 consecutive patients, admitted to four ICUs, were prospectively enrolled to evaluate this index. RESULTS: In the derivation cohort, 16 predictors of mortality were identified and assigned a value directly proportional to their magnitude in the mortality model: aspiration pneumonia (-0.37), grading of sepsis > or = 11 (-0.2), antimicrobial combination (-0.01), Glasgow score > 12+mechanical ventilation (MV) (+0.09), serum creatinine > or = 15 mg/l (+0.22), chest involvement shown by X-ray > or = 3 lobes (+0.28), shock (+0.29), bacteremia (+0.29), initial MV (+0.29), underlying ultimately or rapidly fatal illness (+0.31), Simplified Acute Physiology Score > or = 12 (+0.49), neutrophil count < or = 3500/ mm3 (+0.52), acute organ system failure score > or = 2 (+0.64), delayed MV (+0.67), immunosuppression (+1.38), and ineffective initial antimicrobial therapy (+1.5). An index was obtained by adding each patient's points. According to a receiver operating characteristic curve, the cut-off value of this index was 2.5. In the validation cohort, an index of > or = 2.5 could predict death with a positive predictive value of 0.92, sensitivity 0.61, and specificity 0.98. CONCLUSION: This index, which performs well in classifying patients at high-risk of death, may help physicians in initial patient care (appropriateness of the initial antimicrobial therapy) and guide future clinical research (analysis and design of therapeutic trials).

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We have cloned a Drosophila homologue (D-gsc) of the vertebrate homeobox gene goosecoid (gsc). In the Gsc proteins, the pressure for conservation has been imposed on the homeodomain, the functional domain of the protein: sequence homology is limited to the homeodomain (78% identity) and to a short stretch of 7 aminoacids also found in other homeoproteins such as Engrailed. Despite this weak homology, D-gsc is able to mimic gsc function in a Xenopus assay, as shown by its ability to rescue the axis development of a UV-irradiated embryo. Moreover, our data suggest that the position of insect and vertebrate gsc homologues within a regulatory network has also been conserved: D-gsc expression is controlled by decapentaplegic, orthodenticle, sloppy-paired and tailless whose homologues control gsc expression (for BMP4 and Otx-2), or are expressed at the right time and the right place (for XFKH1/Pintallavis and Tlx) to be interacting with gsc during vertebrate development. However, the pattern of D-gsc expression in ectodermal cells of the nervous system and foregut cannot easily be reconciled with that of vertebrate gsc mesodermal expression, suggesting that its precise developmental function might have diverged. Still, this comparison of domains of expression and functions among Gsc proteins could shed light on a common origin of gut formation and/or on basic cellular processes. The identification of gsc target genes and/or other genes involved in similar developmental processes will allow the definition of the precise phylogenetic relationship among Gsc proteins.

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The phosphoenolpyruvate carboxykinase (PEPCK) gene is regulated at the transcriptional level by a variety of effectors in a tissue-specific fashion. In order to study the parameters involved in the tissue-specific hormonal regulation of the PEPCK gene, we have used a transient expression test in well-differentiated rat hepatoma cells as well as in dedifferentiated variants. In this test, the PEPCK promoter is induced by glucocorticoids in well-differentiated FGC4 cells, but not in H5 dedifferentiated variants, in spite of the presence in H5 cells of the glucocorticoid receptor. Study of the PEPCK promoter using electrophoretic mobility shift assays reveals binding sites for the liver-enriched transcription factors HNF1, vHNF1, HNF3, HNF4, and CAAT/enhancer binding protein members. Overexpression of the liver-enriched transcription factors absent in the dedifferentiated variants, such as HNF1 and HNF4, is not sufficient to restore glucocorticoid response of the PEPCK promoter in the variants. Moreover, systematic analysis of the PEPCK promoter reveals that the presence of a region covering a cAMP-responsive element (CRE1 at -80) and a CAAT box is necessary for full response of the PEPCK promoter to glucocorticoids in well-differentiated rat hepatoma cells. In a cotransfection test, overexpression of the regulatory subunit of protein kinase A (PKA), causing sequestering of PKA, abolishes the glucocorticoid response of the promoter in well-differentiated cells. On the other hand, in dedifferentiated variants, overexpression of the catalytic subunit of PKA restores the response to glucocorticoids. The action of PKA on the glucocorticoid response requires the presence of the CRE1 element and is promoter specific because it does not concern nonhepatic promoters such as the long terminal repeats of the mouse mammary tumor virus. These results suggest that the full response of the PEPCK promoter to glucocorticoids requires activation of another signal transduction pathway, the cAMP-mediated pathway.

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