Evaluation of unenhanced post-mortem computed tomography to detect chest injuries in violent death.

PURPOSE: The aim of this study was to assess the performances of unenhanced post-mortem computed tomography (CT) to detect thoracic injuries in violent death. MATERIALS AND METHODS: Retrospectively, we conducted a review of unenhanced CT scans of 67 victims of violent deaths with thoracic injuries and compared CT findings with the results of clinical autopsy. Our gold standard was a comparison of CT scans with autopsy discussed in a monthly forensic radiology multidisciplinary team meeting (MDTM). The data were collected by organ system: heart, pericardium, aorta, lungs, pleura, bone, and diaphragm and performance indices (sensitivity, specificity, accuracy) were calculated. RESULTS: Pleural (59/67) and bone (55/67) injuries detected on CT were also found at autopsy and confirmed by the MDTM (sensitivity and specificity 100%). Seventeen out of 67 diaphragmatic lesions were visible on CT. Eighteen out of 67 were confirmed during MDTM after autopsy, yielding overall sensitivity of 94% and specificity of 98%. Forty out of 67 lung contusions were found on CT with two false positives and one false negative yielding 95% sensitivity for CT with a specificity of 96%, and accuracy of 95%. Fourteen out of 67 aortic injuries were found on CT compared to 19 confirmed during MDTM (sensitivity 74%, specificity 85%, accuracy 82%). In terms of pericardial lesions, 19/67 were found on CT and 20 on autopsy and confirmed during MDTM (sensitivity 80%, specificity 94%, accuracy 85%). Ten out of 10/67 cardiac lesions were visible on CT imaging and 15 found on autopsy and confirmed during MDTM (sensitivity 57%, specificity 94%, accuracy 81%). CONCLUSION: Unenhanced post-mortem CT performs well to detect pleural, pulmonary, bone and diaphragmatic injuries but less well to identify cardiac and aortic injuries, for which the use of indirect signs is essential.

Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis.

ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12(-/-)) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12(-/-) mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression.

Unusual skeletal muscle metastasis from gastric adenocarcinoma.

Patients with gastric adenocarcinoma frequently develop hepatic metastases or peritoneal carcinosis but involvement of the skeletal muscle is extremely rare. We report the case of a 71-year-old man with a painful soft tissue mass in the right shoulder. Two years previously, the patient had been treated for a locally advanced gastric carcinoma (surgery plus chemoradiotherapy). Surgical exploration with biopsy showed skeletal muscle metastasis from the gastric adenocarcinoma in the deltoid muscle. Chemoradiotherapy resulted in complete regression of symptoms from the metastatic lesion. The patient is alive and free of recurrence in the deltoid muscle after a follow-up of 13 months. Based on this case study, the difficulty of diagnosing skeletal muscle metastases, the prognosis and treatment options are discussed.

Reduction of brain metastases in plasminogen activator inhibitor-1-deficient mice with transgenic ocular tumors.

Plasminogen activator inhibitor-1 is known to play a paradoxical positive role in tumor angiogenesis, but its contribution to metastatic spread remains unclear. We studied the impact of plasminogen activator inhibitor (PAI)-1 deficiency in a transgenic mouse model of ocular tumors originating from retinal epithelial cells and leading to brain metastasis (TRP-1/SV40 Tag mice). PAI-1 deficiency did not affect primary tumor growth or vascularization, but was associated with a smaller number of brain metastases. Brain metastases were found to be differentially distributed between the two genotypes. PAI-1-deficient mice displayed mostly secondary foci expanding from local optic nerve infiltration, whereas wild-type animals displayed more disseminated nodules in the scissura and meningeal spaces. SuperArray GEarray analyses aimed at detecting molecules potentially compensating for PAI-1 deficiency demonstrated an increase in fibroblast growth factor-1 (FGF-1) gene expression in primary tumors, which was confirmed by reverse transcription-polymerase chain reaction and western blotting. Our data provide the first evidence of a key role for PAI-1 in a spontaneous model of metastasis and suggest that angiogenic factors, such as FGF-1, may be important for primary tumor growth and may compensate for the absence of PAI-1. They identify PAI-1 and FGF-1 as important targets for combined antitumor strategies.

Membrane associated proteases and their inhibitors in tumour angiogenesis.

Cell surface proteolysis is an important mechanism for generating biologically active proteins that mediate a range of cellular functions and contribute to biological processes such as angiogenesis. Although most studies have focused on the plasminogen system and matrix metalloproteinases (MMPs), recently there has been an increase in the identification of membrane associated proteases, including serine proteases, ADAMs, and membrane-type MMPs (MT-MMPs). Normally, protease activity is tightly controlled by tissue inhibitors of MMPs (TIMPs) and plasminogen activator inhibitors (PAIs). The balance between active proteases and inhibitors is thought to determine the occurrence of proteolysis in vivo. High concentrations of proteolytic system components correlate with poor prognosis in many cancers. Paradoxically, high (not low) PAI-1 or TIMP concentrations predict poor survival in patients with various cancers. Recent observations indicate a much more complex role for protease inhibitors in tumour progression and angiogenesis than initially expected. As knowledge in the field of protease biology has improved, the unforeseen complexities of cell associated enzymes and their interaction with physiological inhibitors have emerged, often revealing unexpected mechanisms of action.

Role of plasminogen activator-plasmin system in tumor angiogenesis.

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

QT interval lengthening in premature infants treated with doxapram.

OBJECTIVE: Doxapram, routinely used in premature infants treated for apnea of prematurity unresponsive to methylxanthines, has been related to cardiac conduction disorders. This study was designed to evaluate doxapram cardiac and general tolerance and its relationship to drug plasma concentrations in very premature infants. METHODS: Forty infants (mean +/- SEM, 28.9 +/- 0.3 weeks of gestation) who were given intravenous doxapram, 0.5 to 1 mg/kg per hour, at 15.9 +/- 2.4 days of life were evaluated prospectively. Electrocardiograms were monitored before and during the first 3 days of treatment. QT interval corrected for heart rate (QTc) longer than 440 ms was regarded as clinically pertinent, given that it is considered a significant risk of conduction disorder leading to torsades de pointes and sudden death. Other side effects were recorded. Toxic plasma concentration of doxapram and ketodoxapram was set at >4 mg/L. RESULTS: A statistically significant but moderate lengthening of QTc interval has been observed from 394 +/- 4 ms before doxapram to 409 +/- 4 ms at 48 and 72 hours of treatment (P =.0065). For 6 patients, QTc interval became longer than 440 ms without any other rhythm or conduction disorder. Digestive disorders were observed in 20 infants but 9 presented with concomitant septicemia. No relationship was found between presence or absence of adverse effects and drug plasma concentrations. CONCLUSION: Our study enlightened the lengthening effect of doxapram on QTc interval in premature infants with a risk of exceeding the 440 ms threshold that is considered life-threatening. This finding emphasizes the need for electrocardiogram follow-up when using doxapram in neonates.

[Neonatal renal vein thrombosis in a heterozygous carrier of both factor V Leiden and prothrombin mutations]. / Thrombose veineuse rénale néonatale et double hétérozygotie pour le facteur V Leiden et la prothrombine.

UNLABELLED: We report a case of renal vein thrombosis, treated with heparin and thrombolytic therapy, in a patient who was heterozygous for both factor V Leiden and prothrombin mutations. CASE REPORT: A full-term infant was treated with heparin and fibrinolytics at the fourth day of life because of renal vein thrombosis, inferior vena cava thrombosis and adrenal hemorrhage. After four days of treatment, the repermeabilization was complete but a renal atrophy developed. The investigation for congenital coagulation disorders revealed a heterozygous mutation for both factor V Leiden and prothrombin. CONCLUSION: Search for inborn blood coagulation disorders should be systematic in the newborn infant with venous thrombosis because of the risk of recurrence, even in the presence of a known acquired risk factor. The thrombolytic treatment improves the prognosis.

An analytical study, anti-inflammatory and analgesic effects of Harpagophytum procumbens and Harpagophytum zeyheri.

The iridoids of Harpagophytum procumbens and Harpagophytum zeyheri were studied by CLHP. Harpagoside is the main iridoid for both drugs whereas 8-p-coumaroylharpagide is a representative iridoid of Harpagophytum zeyheri only. The ratio harpagoside/8-p-coumaroylharpagide can be used to distinguish chemically both species. For commercial dried aqueous extracts this ratio is intermediate because they are probably prepared from a mixture of H. procumbens and H. zeyheri drugs. The aqueous extracts of both drugs show similar analgesic and anti-inflammatory properties. Harpagophytum procumbens and Harpagophytum zeyheri should be accepted as sources for the drug Harpagophyti radix.

[Relationship between perceived health status and career choice in a sample of wage-earners]. / Relations entre les caractéristiques de la santé perçue et le choix de la profession dans un échantillon de salariés.

Many factors were related with subjective health status (SHS), but few studies have focused on identifying some intrinsic personal factors like the choice of job and perceived working situations. The present paper examines the relationships among such factors in a large French sample. Data were collected from 21,378 subjects who were randomly selected from the lists of male and female wage earners who were followed up by 380 occupational physicians and who were born in 1938, 1943, 1948 or 1953. SHS was evaluated using the French version of the Nottingham Health Profile (NHP). Socio-demographic and job characteristics were assessed by means of closed questions during the annual medical examination. Results showed that low subjective health status was related to sex, age and perceived working situation: for each of the six areas of the NHP (pain, physical mobility, energy, sleep, social isolation, emotional reactions) there was a lower SHS for women and a decrease with age for both sexes. The poorer the perceived working situations the worse was the SHS. Using general linear models it appeared that independently of these factors and the socio-economical category dichotomized in upper classes versus lower classes, those who had claimed to have not chosen their job had a lower SHS, whatever the area of SHS. Awaiting the second survey in 1995, it is difficult to explain these results from this cross sectional analysis: is the choice of job a possible risk factor or an artefact due to some unmeasured confounding factors like motivation or job satisfaction.

Thrombomodulin is synthesized by osteoblasts, stimulated by 1,25-(OH)2D3 and activates protein C at their cell membrane.

We have previously shown that protein S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts. Because protein S is a cofactor of protein C in inhibiting factor Va and VIIIa, we have looked for the presence of the proteins related to the anticoagulant protein C system in human MG 63 osteosarcoma cells and in human adult osteoblast-like cells. Using immunoblotting, we have shown that protein C, factor V, and C4b binding protein are not secreted by these cells. We have shown by enzyme-linked immunoassay, immunocytochemistry, and immunoprecipitation of labeled proteins that thrombomodulin, a transmembrane glycoprotein involved with thrombin in the activation of protein C, is present at the cell surface of osteoblasts. Moreover, using a protein C activation system where thrombin and protein C are added to the cells, we have shown that protein C could be activated at the osteoblast cell surface. This activation of exogenous protein C, reflecting the activity of thrombomodulin, as well as the expression of the thrombomodulin antigen, is regulated by some bone resorption-enhancing factors. 1,25-dihydroxyvitamin D3 and retinoic acid increase thrombomodulin expression and activity in a dose-dependent manner whereas tumor necrosis factor alpha and interleukin 1 decrease these parameters. Because thrombomodulin is known to inhibit single-chain urokinase-type plasminogen activator, a molecule present in the osteoblast microenvironment, these findings suggest that thrombomodulin could play a role in the regulation of bone resorption by modulating the plasmin system.

Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts.

Protein-S is a vitamin K (Vit K)-dependent protein synthesized by hepatocytes, megakaryocytes, and endothelial cells and plays an important role in the regulation of hemostasis. Two cases of free protein-S congenital deficiency were recently reported to be associated with osteopenia. We hypothesized that this osteopenia could be the result of a bone deficit of protein-S synthesized by bone cells. Using enzyme-linked immunoassay, immunocytochemistry, immunoblotting, and immunoprecipitation after labeling with [35S]methionine, we have shown that this protein is secreted by three human osteosarcoma cell lines and by human adult osteoblast-like cells. In addition, protein-S was present in protein extracts of human bone matrix. Protein-S secreted by MG 63 cells increased linearly from 1-7 days of culture, was biologically active, and was regulated by warfarin, as previously described for the other cell types secreting protein-S. Vit K had no direct effect on protein-S secretion or activity, but could overcome the effects of warfarin. In conclusion, in addition to osteocalcin and matrix gamma-carboxyglutamic acid (Gla) protein, osteoblasts secrete another Vit K-dependent protein, which is a constituent of the bone matrix. Our data suggest that osteopenia occurring in patients with congenital protein-S deficiency might be related to a deficiency of protein-S secretion by the osteoblasts. This finding raises the intriguing possibility that protein-S might play a role in bone turnover and bone mass.

Immunological screening of SPARC/Osteonectin in nonmineralized tissues.

SPARC/Osteonectin is a major bone-related protein that is also present in nonmineralized tissues and in platelets. As compared to bone SPARC/Osteonectin, SPARC/Osteonectin from platelets presents a slightly lower electrophoretic mobility in SDS-PAGE and a 100-fold decreased affinity for a unique monoclonal antibody, Mab2 (Malaval et al. 1991). To check the tissular diversity of SPARC/Osteonectin, protein extracts from bovine bone, nonmineralized tissues, and platelets were screened by immunoblotting and immunoradiometric assay, with Mab2 and three other monoclonal antibodies recognizing distinct epitopes. The SPARC/Osteonectin secreted by a human osteosarcoma cell line (MG63) was also tested. In all the nonmineralized tissues tested (gut, bone marrow, tendon, mesentery, artera, lens, skin, liver, and cornea), SPARC/Osteonectin presents the same immunoreactivity and electrophoretic mobility as in bone. The heavier molecular weight and Mab2-negative form present in platelets seems to be unique to this cell type. Osteosarcoma cell extracts and conditioned media give the same results as bone extracts, indicating that the low molecular weight and Mab2-positive form of SPARC/Osteonectin present in most tissues does not result from proteolytic cleavage in the matrix, but is secreted as such. Bone and platelet SPARC/Osteonectin present different patterns of sensitivity to glycosidases, suggestive of a difference in N-glycosylation. However, these treatments do not affect the decreased affinity of Mab2 for platelet SPARC/Osteonectin, which is not likely to be related to difference in N-glycosylation.

Excitotoxin lesions of the zona incerta/lateral tegmentum continuum: effects on male sexual behavior in rats.

In male rats, ibotenic acid and N-methyl-D-aspartic acid were used to destroy neuronal perikarya intrinsic to an anterior-posterior continuum including the caudal zona incerta and lateral tegmentum. Some lesions virtually eliminated male sexual behavior - an effect most closely associated with damage to the lateral hypothalamus and zona incerta. Many lesioned males who copulated to ejaculation with normally active females showed little or no mating with receptive, but relatively inactive, females. Although it is possible to identify a critical region within the subthalamus whose destruction eliminates male sexual behaviour, sexually-relevant neuronal cell bodies appear to be distributed throughout the lateral hypothalamic/incertal/tegmental continuum.

Differential susceptibility to a trematode parasite among genotypes of the Mytilus edulis/galloprovincialis complex.

We show that parasitism by the trematode Prosorhynchus squamatus in parental and introgressed Mytilus edulis/galloprovincialis (Bivalvia) mussels occurs in individuals with a predominantly M. edulis genome. This result suggests that the restricted specificity of P. squamatus is dependent on genetic factor(s) present in M. edulis. Because of its strong pathogenic effects (i.e. total castration and possible death), this parasite may be a source of intense selection against M. edulis genomes when they are present in a site. As a consequence, it may favour the geographic extension of the M. galloprovincialis genome. Previous studies have indicated that, in hybrid zones, recombinant genotypes are more susceptible to parasitic infections than either parental genotype. We demonstrate that this is not the case for the M. edulis/M. galloprovincialis system, and that the parental genotype alone determines susceptibility.