Early discharge of patients with pulmonary embolism: a two-phase observational study.

The aim of the present study was to assess whether patients with pulmonary embolism (PE) could be managed as outpatients after early discharge from hospital using low molecular weight heparin instead of remaining as in-patients until effective oral anticoagulation was achieved. Phase 1 of the study identified criteria for the safe discharge of selected patients; phase 2 treated a cohort of low-risk patients with PE as outpatients with tinzaparin using existing deep venous thrombosis services. In phase 1, 127 (56.4%) of 225 patients were considered unsuitable for outpatient management. Reasons included: admission for another medical reason; additional monitoring or requirement for oxygen; bleeding disorders; previous PE/further PE while on warfarin; co-existing major deep venous thrombosis; likelihood of poor compliance; significant immobility; and pregnancy. In phase 2, 157 patients with PE received outpatient anticoagulation therapy. There were no deaths, bleeding or recurrent thromboembolic events during acute treatment with low molecular weight heparin. The median (range) length of hospital stay was 1.0 (1-4) day, with a median saving of 5.0 (1-42) bed-days per patient. Patients were highly satisfied with outpatient management; 144 (96.6%) indicated that they would prefer treatment as outpatients for a subsequent pulmonary embolism. Early discharge and outpatient management of pulmonary embolism appears safe and acceptable in selected low-risk patients, and can be implemented using existing outpatient deep venous thrombosis services.

The outcome of ambulatory DVT management using a multidisciplinary approach.

Low molecular weight heparins (LMWHs) have been demonstrated to be at least as safe and effective as unfractionated heparin (UFH) in the initial management of deep vein thrombosis (DVT). However, the effectiveness of using LMWH in the ambulatory management of DVT in a 'real-life' setting has yet to be evaluated. This multicentre retrospective study involving 697 patients considers the outcome data of patients under- going ambulatory DVT treatment with tinzaparin (Innohep(R), Leo Pharmaceuticals, Risborough, Buckinghamshire, UK). During the 6 months following presentation, 17 (2.5%) patients had confirmed thromboembolic complications, of which 14 occurred subsequent to the initial LMWH treatment phase ('late'). There were no deaths in this group. Bleeding complications were reported in 23 (3.4%) patients, with 13 of these being classified as 'late'. Of these, two events were considered major resulting in hospitalization and death. Hospitalization for all causes was 6.8% (45 patients) with 32 patients being admitted for thromboembolic or bleeding complications. Overall mortality was 6.7%. These results compare favourably with published clinical trial data. This study demonstrates that ambulatory treatment of proven DVT with LMWH is both safe and effective.

Effects of phytic acid and xanthotoxin on growth and detoxification in caterpillars.

Phytic acid is abundant in the fruits and seeds of many plants and is found in foliage to a lesser extent. Among its several properties, phytic acid is a potent chelator of essential minerals and proteins; thus, the possibility exists that heme-based enzymes such as cytochrome P450 monooxygenases in herbivores are detrimentally affected by phytic acid via chelation of dietary iron. Mortality, growth performance, and P450-mediated metabolism of xanthotoxin, a plant allelochemical, were examined in the presence of phytic acid in three lepidopteran species: a polyphagous seed-feeding species (Heliothis virescens), a polyphagous foliage-feeding species (Trichoplusia ni), and a species oligophagous on immature reproductive structures of two genera of Apiaceae (Depressaria pastinacella). While first instar H. virescens experienced no increase in mortality after 120 hours on a diet containing 1% phytic acid compared to a control diet, both T. ni and D. pastinacella experienced virtually complete mortality over the same time period. Ultimate instars of all three species experienced reductions in relative growth rates (RGR) and relative consumption rates (RCR) in the presence of phytic acid, although the only species to experience reduced digestive efficiency (ECI) was H. virescens. Cytochrome P450-mediated metabolism of xanthotoxin was reduced 60% in the presence of phytic acid in D. pastinacella, although metabolism remained unaffected in the two noctuids. These studies suggest a defensive function of phytic acid in addition to its primary functions of phosphorus storage, energy storage, and cell wall precursor source.

Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18.

The goal of these experiments was to evaluate the potential of the fibroblast growth factor family members FGF-5 and FGF-18 to rescue photoreceptors from cell death in retinal degenerative disease. Two strains of transgenic rats, expressing either a P23H or an S334ter rhodopsin mutation, were used as model systems. The neurotrophic growth factors were delivered by subretinal injection of adeno-associated virus vectors, driving expression of the genes with a constitutive CMV promoter. Morphological and functional analyses were performed to determine whether FGF-5 or FGF-18 overexpression could ameliorate cell death in the retina. Immunocytochemistry was used to determine the cellular sites of expression of the factors and to test for up-regulation of FGF receptors due to injection. Significant rescue from photoreceptor cell death was found after injections of vectors expressing either FGF-5 or FGF-18 in the animal models. Increased survival of photoreceptors did not produce a significant increase in electroretinographic responses, however, reflecting either trauma due to the surgery or a suppression of signaling due to expression of proteins. Three weeks after injections, both growth factors were localized to the inner and outer segments of photoreceptors, and the receptors FGFR1 and FGFR2 were also found to be up-regulated in these regions. No visible pathological changes were seen in the FGF-5- or FGF-18-treated eyes. These results indicate that the delivery of either FGF-5 or FGF-18 with adeno-associated virus protects photoreceptors from apoptosis in transgenic rat models of retinitis pigmentosa and that the rescue is probably mediated by conventional receptor tyrosine kinase pathways in photoreceptors.

Characterization of rhodopsin mis-sorting and constitutive activation in a transgenic rat model of retinitis pigmentosa.

PURPOSE: To determine the extent to which rhodopsin mis-sorting and constitutive activation of the phototransduction cascade contribute to retinal degeneration in a transgenic rat model of retinitis pigmentosa. METHODS: Retinas from transgenic rats expressing truncated rhodopsin (Ser334ter) were examined by light and electron microscopic immunocytochemistry at several time points. Retinal degeneration in transgenic rats raised in darkness was evaluated by quantification of outer nuclear layer thickness and by electroretinography. RESULTS: Mutant rhodopsin was found at inappropriately high levels in the plasma membrane and cytoplasm of Ser334ter rat photoreceptors. When the cell death rate was high this mis-sorting was severe, but mis-sorting attenuated greatly at later stages of degeneration, as the cell death rate decreased. The distributions of two other outer segment proteins (the cGMP-gated channel and peripherin) were examined and found to be sorted normally within the photoreceptors of these rats. Raising Ser334ter transgenic rats in darkness resulted in minimal rescue from retinal degeneration. CONCLUSIONS: Because dark rearing Ser334ter rats results in little rescue, it is concluded that constitutive activation of the phototransduction cascade does not contribute significantly to photoreceptor cell death in this rat model. The nature of the rhodopsin sorting defect and the correlation between the severity of mis-sorting and rate of cell death indicate that truncated rhodopsin may cause apoptosis by interfering with normal cellular machinery in the post-Golgi transport pathway or in the plasma membrane.

Development of inhibitory mechanisms in the kitten's visual cortex.

The objective of this study was to evaluate the maturity of three inhibitory mechanisms (end-inhibition, side-inhibition, and cross-orientation inhibition) in the striate cortex of kittens at 4 weeks postnatal. To accomplish this, we made extracellular recordings from area 17 neurons while presenting visual stimuli consisting of sinusoidal luminance gratings or composites of gratings. We then compared data from kittens relating to various characteristics of each inhibitory mechanism with data from adults. We find that end-inhibition, side-inhibition, and cross-orientation inhibition are all present in kittens, and all show signs of maturity by 4 weeks postnatal. We conclude that the development of these inhibitory mechanisms occurs relatively early, and may coincide with the development of excitatory properties.

Autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma and CNS involvement: those transplanted with active CNS disease have a poor outcome--a report by the European Bone Marrow Transplant Lymphoma Registry.

PURPOSE: CNS involvement of non-Hodgkin's lymphoma (NHL) has always been considered a poor prognostic factor in relation to survival with conventional therapy. However, its effect on the outcome of autologous bone marrow transplantation (ABMT) has not been assessed. We examined this using data from the European Bone Marrow Transplant (EBMT) Lymphoma Registry. PATIENTS AND METHODS: One thousand four hundred sixty-four patients with NHL have been reported to the EBMT registry, of whom 62 had CNS involvement. Patients were divided into those who were clear of CNS disease at the time of ABMT and those who were not. Response, complications, and outcome to ABMT were analyzed, as were details of CNS diagnosis, treatment, and prophylaxis. RESULTS: Status at transplant was the only factor that significantly affected outcome of ABMT on univariate analysis (P = .03). The progression-free survival (PFS) rate of the group that had no CNS involvement at ABMT was 42% at 5 years, compared with 27% in a group of stage IV NHL patients without CNS disease (matched for status at transplant and histology). There were four of 45 (8.9%) toxic deaths. The PFS rate of the group that had CNS involvement at ABMT was 9% at a median follow-up time of 71 months, which was significantly different (P = .001) from that of the other group. There were five of 17 (29.4%) toxic deaths (P = .043). Patients who had CNS involvement at diagnosis, as compared with relapse, and those treated with both intrathecal chemotherapy and irradiation had a better outcome. CONCLUSION: The presence of CNS disease before ABMT but not present at transplant does not adversely affect the outcome of ABMT. In contrast, patients with CNS involvement at the time of ABMT have a poor prognosis, although a small number survive in complete remission (CR).

A hydrogen-donating monohydroxamate scavenges ferryl myoglobin radicals.

The addition of 25 microM hydrogen peroxide to 20 microM metmyoglobin produces ferryl (FeIV = O) myoglobin. Optical spectroscopy shows that the ferryl species reaches a maximum concentration (60-70% of total haem) after 10 minutes and decays slowly (hours). Low temperature EPR spectroscopy of the high spin metmyoglobin (g = 6) signal is consistent with these findings. At this low peroxide concentration there is no evidence for iron release from the haem. At least two free radicals are detectable by EPR immediately after H2O2 addition, but decay completely after ten minutes. However, a longer-lived radical is observed at lower concentrations that is still present after 90 minutes. The monohydroxamate N-methylbutyro-hydroxamic acid (NMBH) increases the rate of decay of the fenyl species. In the presence of NMBH, none of the protein-bound free radicals are detectable; instead nitroxide radicals produced by oxidation of the hydroxamate group are observed. Similar results are observed with the trihydroxamate, desferrioxamine. "Ferryl myoglobin" is still able to initiate lipid peroxidation even after the short-lived protein free radicals are no longer detectable (E.S.R. Newman, C.A. Rice-Evans and M.J. Davies (1991) Biochemical and Biophysical Research Communications 179, 1414-1419). It is suggested that the longer-lived protein radicals described here may be partly responsible for this effect. The mechanism of inhibition of initiation of lipid peroxidation by hydroxyamate drugs, such as NMBH, may therefore be due to reduction of the protein-derived radicals, rather than reduction of ferryl haem.

The efficacy of monohydroxamates as free radical scavenging agents compared with di- and trihydroxamates.

Desferrioxamine, the therapeutic iron chelator, is limited in its usage by its short half-life in plasma and lack of oral activity, its side-effects and its slow penetration into cells. Several studies have emerged recently demonstrating the ability of this trihydroxamate compound to act as a radical scavenger, in addition to and independently of its iron-chelating properties. These include the interaction of desferrioxamine with the superoxide radical and ferryl myoglobin radical, as well as its action as a chain-breaking antioxidant in peroxidizing erythrocyte membranes. We have synthesized recently a series of monohydroxamate compounds and investigated their efficacy as radical scavenging antioxidants in comparison with desferrioxamine and rhodotorulic acid, a naturally occurring dihydroxamate compound. The results show that the relative rates of reaction of these hydroxamate derivatives with ferryl myoglobin are N-methyl-N-hexanoyl hydroxylamine > N-methyl-N-benzoyl hydroxylamine > N-methyl-N-acetyl hydroxylamine > desferrioxamine > rhodotorulic acid > N-methyl-N-butyryl hydroxylamine.

Selective toxicity of purine nucleosides to human leukaemic cells.

The in vitro cytotoxicity of various purine nucleosides and purine enzyme inhibitors, alone or in combination, and of the alkylating agent mafosfamide (Asta Z7557), incubated for 4 and 24 h have been studied in 17 leukaemic cell lines and normal bone marrow (BM). The purine nucleosides and their analogues included: 2'chlorodeoxyadenosine (CdA), 2'deoxyadenosine (AdR), 3'deoxyadenosine (3'AdR) (cordycepin), adenosine (AR), adenine arabinoside (Ara-A), deoxyguanosine (GdR) and guanine arabinoside (Ara-G). Purine enzyme inhibitors included 2-deoxycoformycin (dCF) and 8-aminoguanosine (8-AG). Cytotoxicity was based on inhibition of (i) incorporation of 3H-leucine into cell proteins and (ii) colony forming units--granulocytic/monocytic (CFU-GM) and for mixed cell colonies (CFU-GEMM). Marked and selective inhibition of T-cell growth was shown by the combinations dCF with either AdR or Ara-A, 8-AG and GdR and by CdA or Ara-G alone; these compounds even at high concentrations produced only partial inhibition of the growth of normal bone marrow CFU-GM and CFU-GEMM except for CdA which completely inhibited the formation of CFU-GEMM colonies. The combination dCF + cordycepin and alkylating agent mafosfamide were, however, toxic to all the cell lines at the concentrations employed, as well as to CFU-GM and CFU-GEMM. The high therapeutic index of some of the purine nucleosides with a relatively short exposure time makes them candidates for selective in vitro removal of residual neoplastic cells in autologous bone marrow transplantation (ABMT) for T-ALL.

Medical record quality in ambulatory care settings.

How can we respond to those who question the value of professional certification? Much research is needed to assess and document the benefits of accreditation and registration. This study lays important groundwork by examining the relationship between the quality of ambulatory care medical record systems and the use of credentialed medical record personnel.

Erythema nodosum progressing to pyoderma gangrenosum as a complication of Crohn's disease.

Erythema nodosum occurs more frequently than pyoderma gangrenosum in Crohn's disease. We report the occurrence of both lesions in a woman with Crohn's disease and the transformation of one to the other. Pyoderma gangrenosum has been described at the site of previous trauma in Crohn's disease and at the site of other skin conditions in other circumstances, but, to the best of our knowledge, actual progression from erythema nodosum to pyoderma gangrenosum has been reported on only one previous occasion in Crohn's disease.

Susceptibility of feline spinal cord energy metabolism to severe incomplete ischemia.

Feline spinal cords were subjected to 10 to 30 minutes of severe incomplete ischemia (average reduction in blood flow of 92%) with and without 90 minutes of recirculation, and the L-2 segment was analyzed for high-energy phosphates and certain glycolytic metabolites. Spinal cord tissue lactic acid levels were stepwise elevated, and adenosine triphosphate (ATP), phosphocreatine (P-creatine), and glucose were progressively consumed by increasing durations of ischemia. However, upon restoration of blood flow, there was extensive recovery of energy metabolites and normalized lactic acid, demonstrating resumption of mitochondrial oxidative metabolism. These data indicate that the spinal cord can tolerate at least 30 minutes of severely reduced blood flow before recovery of energy metabolism is significantly impaired upon restitution of blood flow.

Microvascular perfusion and metabolism in injured spinal cord after methylprednisolone treatment.

The purpose of this study was to determine the effect of treatment with the synthetic glucocorticoid, methylprednisolone, on the microvasulature and metabolism of the traumatized spinal cord. Spinal cords of cats were compressed with a 170-gm weight for 5 minutes and were treated with either high-dose methylprednisolone (HDMP, 15 mg/kg/24 hrs) or megadose methylprednisolone (MDMP,60 mg/kg/24 hrs). Animals were sacrificed at 2, 8, or 24 hours following injury. Treatment with HDMP resulted in substantial preservation of injured spinal cord microvascular perfusion at 8 hours as compared with injured untreated cats. Compression trauma caused a partial derangement of energy metabolism and a shift toward anaerobic glycolysis in both treated and untreated groups for the entire 24-hour postinjury period. Tissue levels of adenosine triphosphate, phosphocreatine, and total adenylates in the HDMP-treated cats sacrificed at 8 hours after trauma were significantly elevated over untreated controls, but those in the 2- and 24-hour groups were not. Concentration of energy intermediates in MDMP-treated cat were either equal to or below those of injured untreated animals al all three postinjury time period. The postinjury metabolite pattern and concentrations seen in this study possibly result from differing levels of blood flow and neuronal activity in the injured untreated, HDMP-, and MDMP-treated spinal cords. Better tissue perfusion in the HDMP-treated cats might be expected to result in an improved tissue energy state in these animals. However, intensive high-dose glucocorticoid treatment has been demonstrated to augment spinal cord monosynaptic and polysynaptic reflex transmission and primary afferent excitability. Furthermore, acute single intravenous dose studies have shown this direct neuronal action to be dose-related. Thus, additional high-energy phosphate molecules that may be reformed as a result of HDMP treatment were perhaps used as the energy source for any increased neuronal activity caused by steroid administration. The beneficial effects of glucocorticoid treatment in experimental spinal cord trauma might derive from preserved cellular structural integrity. This could result in increased levels of neuronal activity, energy utilization, and production in treated as compared with untreated tissue.