One day from dyspnea to death--unsuccessful application of extracorporeal membrane oxygenation in toxoplasma myocarditis following bone marrow transplantation.
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Adult↗
Biomedical subjects
T Winkler
Publications and source records attributed to T Winkler.
Continuous EEG monitoring in patients with traumatic brain injury reveals a high incidence of epileptiform activity.
BACKGROUND: EEG is the only available method for real time monitoring of the brain and is therefore of great interest in the neurointensive care. The present study describes our experiences from implying continuous EEG monitoring as a routine method. We also present EEG patterns observed on patients with traumatic brain injury (TBI). METHODS: Seventy TBI patients requiring neurointensive care were included. Digital EEG was recorded continuously. Five minutes every hour were analysed off-line. RESULTS: Twenty-three patients (33%) developed seizures, 74+/-47 h after trauma. The seizures were brief, responding to phenytoin, or persistent, requiring propofol or barbiturate sedation. Six out of eight patients with persistent seizures had intracerebral contusions. Eighteen patients (26%) displayed focal high frequency activity that proceeded to seizures in eight cases. Twelve patients (17%) developed recurrent paroxysmal delta activity. The patients in the seizure group were significantly older (62+/-12 vs. 28+/-17 years) and more often exposed to low energy trauma (87% vs 22%) compared to the paroxysmal delta pattern group. CONCLUSION: TBI implies high risk for development of epileptiform activity, with a time lag between trauma and seizure onset. TBI patients also displayed other EEG pattern that should be investigated further in order to obtain a better understanding of posttraumatic mechanisms.
Adult↗
Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity.
BACKGROUND: The presence of "anti-DNA antibodies in abnormal titres" is a well established criterion for SLE classification, but there is no agreement on the performance of this test. OBJECTIVE: To study the correlation between clinical findings and five different solid and solution phase anti-DNA antibody assays. METHODS: 158 consecutively collected ANA positive sera were studied in a double blind fashion. Anti-DNA antibodies were determined by different solid phase assays (ssDNA-, dsDNA- specific ELISA, EliA anti-dsDNA assay, Crithidia luciliae assay), and by an experimental solution phase anti-DNA assay using biotinylated pUC18 plasmid, human, calf thymus, and E coli DNA. Antibody affinity was determined by surface plasmon resonance. Clinical data were obtained independently of the laboratory analyses and later related to the anti-dsDNA findings. RESULTS: Anti-dsDNA antibodies were most frequently detected by ELISA, but were not specific for SLE as they were present in up to 30% of other disease groups. Those detected by the Crithidia luciliae assay were predictive for SLE, while antibodies binding in solution phase ELISA using the pUC18 correlated strongly with the Crithidia luciliae assay. Surface plasmon resonance analysis showed that antibody binding to pUC18 was not due to higher relative affinity for dsDNA in general, but apparently to specificity for that plasmid DNA. Serum samples from three patients with lupus nephritis were positive in both pUC18 solution phase and Crithidia luciliae assays. CONCLUSIONS: Assay principle selection is decisive for the detection of clinically significant anti-DNA antibodies. Revision of the anti-DNA antibody criterion in the SLE classification may be needed.
Animals↗
Modeling kinetics of infused 13NN-saline in acute lung injury.
A mathematical model was developed to estimate right-to-left shunt (Fs) and the volume of distribution of 13NN in alveolar gas (VA) and shunt tissue (Vs). The data obtained from this model are complementary to, and obtained simultaneously with, pulmonary functional positron emission tomography (PET). The model describes 13NN kinetics in four compartments: central mixing volume, gas-exchanging lung, shunting compartment, and systemic recirculation. To validate the model, five normal prone (NP) and six surfactant-depleted sheep in the supine (LS) and prone (LP) positions were studied under general anesthesia. A central venous bolus of 13NN-labeled saline was injected at the onset of apnea as PET imaging and arterial 13NN sampling were initiated. The model fit the tracer kinetics well (mean r2 = 0.93). Monte Carlo simulations showed that parameters could be accurately identified in the presence of expected experimental noise. Fs derived from the model correlated well with shunt estimates derived from O2 blood concentrations and from PET images. Fs was higher for LS (54 +/- 18%) than for LP (5 +/- 4%) and NP (1 +/- 1%, P < 0.01). VA, as a fraction of PET-measured lung gas volume, was lower for LS (0.18 +/- 0.09) than for LP (0.96 +/- 0.28, P < 0.01), whereas Vs, as a fraction of PET-measured lung tissue volume, was higher for LS (0.46 +/- 0.26) than for LP (0.05 +/- 0.08, P < 0.01). The main conclusions are as follows: 1) the model accurately describes measured arterial 13NN kinetics and provides estimates of Fs, and 2) in this animal model of acute lung injury, the fraction of available gas volume participating in gas exchange is reduced in the supine position.
Algorithms↗
Topical application of TNF-alpha antiserum attenuates spinal cord trauma induced edema formation, microvascular permeability disturbances and cell injury in the rat.
The possibility that antiserum to tumour necrosis factor-alpha (TNF-alpha) is neuroprotective in spinal cord injury (SCI) was examined in a rat model. SCI was produced by making an incision into the right dorsal horn at the T10-11 segments. Top TNF-alpha antiserum at three concentrations (1:10; 1:50 and 1:100) given 30 min before or 2 min, 5 min or 10 min after trauma resulted in marked reduction in visible swelling, edema formation, and leakage of radiolabelled iodine tracer within the T9 and T12 segments at 5 h in a dose dependent manner. This neuroprotective effect was most pronounced when the antiserum at the highest dose level (1:10) was applied 10 min after SCI. The TNF-alpha antiserum also reduced the SCI induced upregulation of neuronal nitric oxide synthase (nNOS) immunoreactivity in a concentration dependent manner. Taken together, these results suggest that local application of TNF-alpha antiserum is neuroprotective in SCI and that this effect is mediated through NOS regulation.
Administration, Topical↗
An L-type calcium channel blocker, nimodipine influences trauma induced spinal cord conduction and axonal injury in the rat.
The influence of the potent L-type Ca[2+] channel antagonist Nimodipine on spinal cord evoked potentials (SCEP) and axonal injury following trauma to the spinal cord was examined in a rat model. Spinal cord injury (SCI) was produced by an incision into the right dorsal horn of the T10-11 segments under urethane anaesthesia (1.5 g/kg, i.p.). SCEPs were recorded by epidural electrodes placed over the T9 (rostral) and T12 (caudal) segments after stimulation of the right tibial and sural nerves. SCI induced a pronounced decrease of the SCEP negative amplitude in the rostral (T9) recordings immediately after trauma. Axonal injury seen as degradation of myelin basic protein (MBP) immunostaining and myelin vesiculation at the ultrastructural level was most pronounced at 5 h. Continuous administration of Nimodipine (2 microg/kg/min, i.v.) from 30 min prior to injury until sacrifice markedly attenuated the changes in SCEP amplitude and latency. Axonal damage, loss of MBP, and myelin vesiculation were much less evident in the nimodipine treated traumatised rats. These observations suggest that Ca[2+] channels play an important role in the trauma induced alterations in SCEP and axonal injury, and indicate a therapeutic value of Ca[2+] blockers in SCI.
Animals↗
[A case of symptomatic paroxysmal kinesigenic dsykinesia with primary central nervous system lymphoma].
Paroxysmal dyskinesias are rare movement disorders. In one fourth of cases, a symptomatic cause can be found, e.g., brain ischemia or inflammatory diseases. We report a unique case of secondary paroxysmal kinesigenic dyskinesia (PKD). The 37-year-old patient suffered from a primary CNS lymphoma invading the right thalamus. Consecutively, he showed dystonic-athetoid movements in the left half of the body. The involuntary movements had a duration of approximately 20 s and occurred more than 100 times per day. Carbamazepine treatment showed excellent results. This is the first reported case of a symptomatic paroxysmal dyskinesia induced by a primary CNS lymphoma.
Adult↗
Topical application of dynorphin A (1-17) antiserum attenuates trauma induced alterations in spinal cord evoked potentials, microvascular permeability disturbances, edema formation and cell injury: an experimental study in the rat using electrophysiological and morphological approaches.
Dynorphin is a neuropeptide that is present in high quantities in the dorsal horn of the spinal cord. The peptide is actively involved in pain processing pathways. However, its involvement in spinal cord injury is not well known. Alteration in dynorphin immunoreactivity occurs following a focal trauma to the rat spinal cord. Infusion of dynorphin into the intrathecal space of the cord results in ischemia, cell damage and abnormal motor function. Antibodies to dynorphin when injected into the intrathecal space of the spinal cord following trauma improve motor recovery, reduce edema and cell changes. However, influence of dynorphin on trauma induced alteration in spinal cord bioelectrical activity is still not known. Spinal cord evoked potentials (SCEP) are good indicator of spinal cord pathology following trauma. Therefore, in present investigation, influence of dynorphin antibodies on trauma induced changes in SCEP were examined in our rat model. In addition, spinal cord edema formation, microvascular permeability disturbances and cell injury were also investigated. Our results show that topical application of dynorphin antiserum (1 : 200) two min before injury markedly attenuated the SCEP changes immediately after injury. In the antiserum treated animals, a significant reduction in the microvascular permeability, edema formation and cell injury was observed in the traumatised spinal cord. These observations suggest that (i). dynorphin is involved in the altered bioelectrical activity of the spinal cord following trauma, (ii). the peptide actively participates in the pathophysiological processes of cell injury in the spinal cord trauma, and (iii). the dynorphin antiserum has potential therapeutic value for the treatment of spinal cord injuries.
Animals↗
A pTalpha-negative subpopulation of CD25+ TN thymocytes revealed by a transgenic marker.
We have recently generated 5'lambda5-huTAC mice, which express the human CD25 (huTAC) gene under the control of the 5'-flanking region of the mouse lambda5-gene. The huTAC-transgene was expressed in pre-B cells but neither in mature B cells nor in T cells of these mice. In this report we demonstrate that the transgene is also transiently expressed by adult CD25+ CD3-CD4-CD8- (triple negative, TN) thymocytes and in fetal thymocytes. The huTAC+, in contrast to the huTAC- subpopulation of the CD44+CD25+ TN cells, was unexpectedly found not to express the pTalpha-gene. Still the huTAC+CD44+CD25+ TN cells reconstituted the development of both alphabeta and gammadelta lineage cells equally efficiently as the pTalpha-expressing huTAC- fraction, demonstrating that this pTalpha-negative subpopulation contained precursors for both T-cell lineages. Single cell reverse transcription-polymerase chain reaction (RT-PCR) experiments demonstrated that also in normal mice only a fraction of CD44+CD25+ and CD44-CD25+ TN cells expressed this gene. Taken together, these data indicate that huTAC transgene expression revealed a truly pTalpha-negative fraction of the CD44+CD25+ TN cells. The observation that not all precursors in the CD25+ TN population express the pTalpha-gene has important implications for the understanding of early T-cell development and T-cell lineage commitment.
Animals↗
Antigenic targets--workshop report.
Several excellent animal models for systemic lupus erythematosus are available to study the pathogenetic mechanisms of anti-DNA antibodies, immunological mechanisms for their origin and the influence of susceptibility genes for the development of anti-DNA antibodies. Furthermore several transgenic mice have been generated to study B cell tolerance against DNA. During the meeting recent progress on animal models for systemic lupus erythematosus was discussed.
Animals↗
Towards a general procedure for sequencing single DNA molecules.
In this paper we report on the latest technical advances towards single molecule sequencing, a useful method currently developed especially for fast and easy de novo sequencing. Different approaches for complete labeling of DNA with fluorescent dyes are described. In addition, the experimental set-up for the sequencing process is shown. We demonstrate the ability to purify the buffer and enzyme solutions. Inorganic buffers were purified down to at least 20 fM of remaining fluorescent impurities. The exonuclease buffer solution could be cleaned down to 0.8 pM whereby its full activity was kept. Finally, we show a selection procedure for beads and present the data of a model experiment, in which immobilized DNA is degraded by an exonuclease within a polymethylmethacrylate (PMMA) microstructure. Furthermore, the mathematical processing of the obtained raw data is described. A first complete experimental cycle is shown, combining all preparatory steps which are necessary for single molecule sequencing in microstructures.
Biochemistry↗
Effects of inhalation of perfluorocarbon aerosol on oxygenation and pulmonary function compared to PGI2 inhalation in a sheep model of oleic acid-induced lung injury.
OBJECTIVE: To evaluate the effects of PFC aerosol compared to PGI2 aerosol and NaCl aerosol on gas exchange and lung mechanics in oleic acid-induced acute lung injury. DESIGN: A prospective, controlled, randomised, in vivo animal laboratory study. SETTING: Research laboratory at an university hospital. SUBJECTS: Twenty one (n = 21) adult sheep of either gender weighing 26.8+/-6.4 kg. INTERVENTIONS: The animals were randomised to three groups: PFC aerosol (perfluorooctane), PFC group; prostacyclin aerosol (Flolan), PGI2 group; and NaCl aerosol (0.9% sodium chloride solution), control group. After induction of anaesthesia and placement of vascular catheters, lung injury was induced with 0.12 ml x kg(-1) oleic acid. Aerosols were continuously administered for 2 h using a jet nebuliser. Gas exchange, pulmonary mechanic, and haemodynamic parameters were obtained at regular intervals. MEASUREMENTS AND MAIN RESULTS: PFC aerosol increased oxygenation (PaO2) 15 min after the initiation of treatment up to 120 min (P < 0.05). Transpulmonary shunt improved in the PFC group (P < 0.05) while it did not change in the two other groups. PFC aerosol reduced maximum airway pressure (Pmax) (median) significantly from (median) 38 mbar to 32 mbar (P < 0.05). Static compliance improved significantly in the PFC group (P < 0.05). CONCLUSION: The inhalation of a PFC aerosol led to a significant improvement in pulmonary mechanics and gas exchange, which was not observed in the other two groups. These data suggest that a small dose of perfluorocarbon will have beneficial effects on gas exchange and respiratory mechanics. Therefore, the non-invasive aerosol application technique seems to be a reasonable alternative to administer perfluorocarbons in severe lung injury.
Aerosols↗
Idiopathic neuritis--reasons for surgical treatment.
Idiopathic neuritis is a neurological condition of unknown etiology. Typical clinical findings are sudden onset of pain lasting for two-three weeks and remaining weakness in distal muscles. Non-surgical treatment is the consensus today for idiopathic neuritis. However, when exploring peripheral nerves affected by this syndrome that gave persistent paresis, we found an external fibrosis. After neurolysis motor function recovered. We suggest that with persisting motor deficits in idiopathic neuritis the affected peripheral nerves might be surgically explored at the latest one year after onset of the syndrome.
Adult↗
Pharmacokinetics and metabolism of formestane in breast cancer patients.
Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.
Aged↗
Isolation of human anti-idiotypes broadly cross reactive with anti-dsDNA antibodies from patients with Systemic lupus erythematosus.
Antibodies to double stranded (ds)DNA play a central role in clinical diagnosis and disease expression in Systemic lupus erythematosus (SLE). This paper describes the isolation of anti-idiotype reagents (anti/antidsDNA) from four SLE sera and the demonstration of broad and quantitatively similar cross reactivity to both polyclonal and monoclonal anti-dsDNA antibodies isolated from SLE patients. Seven affinity-purified polyclonal and three monoclonal human anti-dsDNA preparations reacted preferentially with anti-idiotype F(ab')(2) coated plates compared to normal immunoglobulin (Ig)G F(ab')(2) coated plates in ELISA. In contrast, autoantibodies of other specificities (anti-Ro/SSA, anti-La/SSB, and anti-U(1)RNP) reacted equally with anti/anti-dsDNA F(ab')(2) and normal IgG F(ab')(2) coated plates. Such anti-idiotypic antibodies could play a significant role in the regulation of anti-dsDNA antibody levels in SLE.
Antibodies, Anti-Idiotypic↗
Decoding "drug imprints" at the millennium: a proposal to increase accuracy and reduce costs.
The State of Washington mandated the use of imprints on all prescription drugs in 1980 and for "OTC's" in 1991. The FDA implemented federal requirements in 1995. Unfortunately, the FDA permitted the continued use of symbols, logotypes, and trademarks as code components, limiting the use of automated recognition systems. Analyses of several week-long samples of phone inquiries documented imprinting calls, the staff's ability to respond with an identification, the information sources used, and apparent reasons for any failure. In the first week we received 666 decoding requests, which when projected for the year amounted to > 25,000 calls. A review of 1999 data exceeded that number. Staff was able to reach drug identification in 93.8% of inquiries. Uninterpretable symbols and absence of code listings contributed to the 36 failures. Projecting over the US suggested as many as 1.25 million calls costing poison centers $25 million/y. A touch-tone telephone or website response system could permit automated responses. Neither solution is feasible without the elimination of symbols or logotypes when using an exclusively alpha-numeric code.
Drug Labeling↗
The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells.
The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells. It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and MO7e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571. Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases). To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H(2)O(2)) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H(2)O(2) substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H(2)O(2) or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of MO7e cells with H(2)O(2) or pervanadate increased the tyrosine kinase activity of c-ABL. Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation.
Animals↗
Functional comparison of thymic B cells and dendritic cells in vivo.
In this report we present a transgenic mouse model in which we targeted gene expression specifically to B-lymphocytes. Using the human CD19 promoter, we expressed major histocompatibility complex class II I-E molecules specifically on B cells of all tissues, but not on other cell types. If only B cells expressed I-E in a class II-deficient background, positive selection of CD4(+) T cells could not be observed. A comparison of the frequencies of I-E reactive Vbeta5(+) and Vbeta11(+) T cells shows that I-E expression on thymic B cells is sufficient to negatively select I-E reactive CD4(+) T cells partially, but not CD8(+) T cells. Thus partial negative but no positive selection events can be induced by B-lymphocytes in vivo. (Blood. 2000;95:2610-2616)
Animals↗