Clinically relevant bleeding in cancer patients treated for venous thromboembolism from the CATCH study.

Essentials Cancer patients receiving anticoagulants for venous thromboembolism have an elevated bleeding risk. This secondary analysis of CATCH assessed characteristics of clinically relevant bleeding (CRB). CRB occurs in 15% of cancer patients with thrombosis using therapeutic doses of anticoagulation. After multivariate analysis, risk factors for CRB were age >75 years and intracranial malignancy. SUMMARY: Background Cancer patients with acute venous thromboembolism (VTE) receiving anticoagulant treatment have an increased bleeding risk. Objectives We performed a prespecified secondary analysis of the randomized, open-label, Phase III CATCH trial (NCT01130025) to assess the rate and sites of and the risk factors for clinically relevant bleeding (CRB). Patients/Methods Patients with active cancer and acute, symptomatic VTE received either tinzaparin 175 IU kg-1 once daily or warfarin (target International Normalized Ratio [INR] of 2.0-3.0) for 6 months. Fisher's exact test was used to screen prespecified clinical risk factors; those identified as being significantly associated with an increased risk of CRB then underwent competing risk regression analysis of time to first CRB. Results Among 900 randomized patients, 138 (15.3%) had 180 CRB events. CRB occurred in 60 patients (81 events) in the tinzaparin group and in 78 patients (99 events) in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.45-0.89). Common bleeding sites were gastrointestinal (36.7%; n = 66), genitourinary (22.8%; n = 41), and nasal (10.0%; n = 18). In multivariate analysis, the risk of CRB increased with age > 75 years (HR 1.83, 95% CI 1.14-2.94) and intracranial malignancy (HR 1.97, 95% CI 1.07-3.62). In the warfarin group, 40.4% of CRB events occurred in patients with with an INR of < 3.0. A lower time in therapeutic range was associated with a higher risk of CRB. Conclusions CRB is a frequent complication in cancer patients with VTE during anticoagulant treatment, and is associated with age > 75 years and intracranial malignancy.

Lung hypoplasia--a possible teratogenic effect of valproate. Case report.

Three cases of lung hypoplasia occurring in two siblings and in an unrelated child are reported. All three cases had been exposed to valproate in utero. The two female siblings had no other malformations, whereas the third female had a number of defects consistent with the fetal valproate syndrome. Thus, none of the known major causes of lung hypoplasia was present in any of the three cases. It is discussed whether pulmonary hypoplasia may be a separate disease entity, or caused by prenatal exposure to valproate.

Development of spinal cord in the isolated CNS of a neonatal mammal (the opossum Monodelphis domestica) maintained in longterm culture.

The CNS of the newly born opossum removed in its entirety survives and maintains its electrical excitability in suitable culture media for up to ten days at 25 degrees C. The structure of the developing neonatal spinal cord has been studied in the intact animal and in the cultured CNS. The differentiation and survival of individual cells and subcellular structures were followed at the light and electron microscopic level. The expression of cell markers in neuronal and glial cells was studied immunocytochemically using commercially available antibodies. Both mono- and polyclonal antibodies raised against antigens from several other species cross-reacted with Monodelphis antigens. The spinal cord of preparations removed from three-day-old-animals showed many neuron specific enolase-positive large neurons in the ventral horn as well as vimentin- and glial fibrillary acidic protein-positive radial glial cells and numerous small diameter unmyelinated axons, abundant dendrites and synaptic structures. From post natal day 5 to post natal day 8 continued differentiation of neurons and differentiation of radial glial cells into astrocytes were apparent. Radial glial fibres and astrocytes reacted positively to antibodies against glial fibrillary acidic protein. Myelin had not appeared at 8 days. A comparison of material obtained from postnatal day 3-postnatal day 4 preparations fixed immediately after dissection and from postnatal day 3-postnatal day 4 preparations fixed after 5 days in culture showed growth with continued mitotic activity of the neuroepithelial cells and further neuronal and glial maturation in the spinal cord especially in the more rostral end. In successful experiments in vitro, the preservation of individual cells, organelles, membranes and synapses was similar in the freshly dissected and cultured preparations apart from a distinct loss of the youngest and some of the oldest neurons in the spinal cord. Also the main fibre tracts (dorsal, lateral and ventromedial funiculus) survived. Virtually all preparations that had not been damaged or injured showed these results. Possible reasons for the death or survival of individual neuronal or glial cell populations in these preparations are discussed.

An immunocytochemical study of the innervation of developing human fetal teeth using protein gene product 9.5 (PGP 9.5).

Developing teeth of 32 human fetuses (crown-rump length 11-205 mm) were examined immunohistochemically by antisera to protein gene product 9.5 (PGP 9.5) in an attempt to shed light upon the possible role of innervation in odontogenesis. As a control for the specificity of PGP 9.5 as a neuronal marker, the results were verified by immunocytochemical co-localization in peripheral nerves of neurone-specific enolase, neurofilaments and S-100 protein. The dental follicle received the first nerve fibres in the early cap stage. At this stage, fibroblasts differentiated in the presence of nerve fibres and formed the dental follicle surrounding the developing tooth. In the dental papilla, however, no fibres were demonstrated until the dentine and enamel matrices had formed, about half of the present height of the tooth germ. Most nerve fibres were localized in the basal part of the papilla until the last stage examined and usually followed the blood vessels of the papilla. Thus the effect of innervation on tooth development may be associated with the development of the dental follicle. A novel finding was that functional odontoblasts were not only positive for S-100 but also for PGP 9.5, indicating their neural crest origin.

Immunocytochemical demonstration of nerve growth factor receptor (NGF-R) in developing human fetal teeth.

Evidence is accumulating that nerve growth factor receptor (NGF-R or p75NGFR) can mediate cell growth and differentiation of non-neuronal cells. NGF-R expression was studied in developing teeth of human embryos and fetuses between the 6th and 18th weeks of gestation, using a monoclonal mouse-anti-human NGF-R antibody. In contrast to earlier findings in rodents, the NGF-R expression of the human dental papilla was found to be transient. NGF-R was present in the condensing ecto-mesenchymal cells of the dental papilla in the early cap stage tooth germ. In later developmental stages, a shift of the NGF-R expression from the papilla to the cytoplasmic membrane of the inner enamel epithelium (IEE) was demonstrated. As in rodent odontogenesis, the NGF-R immunoreactivity of the IEE remained until the odontoblasts started secretion of predentinal matrix in the late bell state. The mitotic activity in the IEE was detected by an antibody against proliferating cell nuclear antigen (PCNA) and showed that the NGF-R expression of the IEE decreased as the cell proliferation ceased. We propose that NGF-R may, be involved in differential and/or proliferative events of human odontogenesis.

Human fetuin/alpha 2 HS glycoprotein in colloid and parenchymal cells in human fetal pituitary gland.

An immunohistochemical study was undertaken, in an attempt to identify the acidic glycoprotein(s) present in colloid and in parenchymal cells in human fetal pituitary gland. As the colloid has been proposed to represent disintegrating cells, a series of antibodies against plasma glycoproteins and plasma proteins was applied; their presence intracellularly would generally be an indicator of plasma membrane leakage in dying parenchymal cells. In tissue sections from 9- to 20-week-old fetuses, the colloid showed prominent staining with an antibody to human fetuin/alpha 2 HS glycoprotein. Anti-alpha 2-HS glycoprotein labelled parenchymal cells in pars anterior and intermedia. Apart from a minor immunoreactivity for alpha 1 beta glycoprotein, no other plasma glycoprotein was seen in colloid or parenchymal cells. An antibody against bovine fetuin showed staining of the colloid and of some parenchymal cells in pars distalis and intermedia; the plasma and stroma of the pituitary gland were unstained. In contrast, the anti-human plasma protein antibodies all stained the stroma. The presence of alpha 2 HS glycoprotein in parenchymal cells and absence of other plasma glycoproteins imply integrity of the parenchymal cell plasma membrane. Thus, alpha 2 HS glycoprotein is either synthesized locally or taken up specifically in the parenchymal cells, which are proposed to participate in the formation of colloid. It is suggested that alpha 2 HS glycoprotein is part of a homeostatic system, which controls remodelling and physiological cell death during development.