Czech doctors threatened with prosecution.
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Czechoslovakia↗
Biomedical subjects
J Cook
Publications and source records attributed to J Cook.
Determination of a cyclic guanine monophosphate phosphodiesterase inhibitor (SCH 51866) in rat serum using capillary zone electrophoresis.
A capillary zone electrophoretic (CZE) assay was developed for the determination of cis-5,6a,7,8,9,9a-hexahydro-2-[4-(trifluoromethyl)phenylmethyl]-5-methyl - cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one, SCH 51866 (I), a cyclic guanine monophosphate phosphodiesterase inhibitor, in rat serum using acetonitrile deproteination as a clean-up step before injection. The calibration curve was linear over a serum concentration range of 0.5 to 10 micrograms/ml serum with a correlation coefficient (r) > 0.99. The limit of quantitation (LOQ) was established at 0.5 micrograms/ml. Fifty microliters of serum were used for analysis, which allowed serial bleeding (8 samples) from a single rat to characterize the pharmacokinetic profile of I after either oral or intravenous drug administration. In traditional pharmacokinetic and toxicokinetic studies in rodents, one animal provides only one serum sample since 1 to 2 ml of sample volume is required for chromatographic analysis, resulting in the use of a large number of animals per study. This assay yields a significant reduction in the use of animals, hence providing a large reduction in resources and time in drug discovery and development.
3',5'-Cyclic-GMP Phosphodiesterases↗
Saporin toxins directed to basic fibroblast growth factor receptors effectively target human ovarian teratocarcinoma in an animal model.
BACKGROUND: The antitumor activity of the chemical conjugate and recombinant forms of the mitotoxin basic fibroblast growth factor (bFGF) saporin (SAP) and the bFGF receptor-directed immunotoxin 11A8-SAP against human ovarian teratocarcinoma PA-1 was examined in athymic nude mice. Alternative administration schedules to prolong therapeutic efficacy were explored. METHODS: Intravenous dosing (0.01-125 micrograms/kg) of chemical conjugate and recombinant bFGF-SAP or 11A8-SAP beginning 5 days after subcutaneous implantation of PA-1 cells was administered by i) weekly injection for 4 weeks, ii) continuous infusion for one week, or iii) daily injection five times a week for 4 weeks. RESULTS: Weekly injections (31.25 micrograms/kg) of chemical conjugate bFGF-SAP or 11A8-SAP, the latter of which is 25% the molarity of the former, resulted in mean tumor volumes that were, respectively, 35% or 52% of controls (day 30) and 52% or 76% of controls (day 60). Chemical conjugate or recombinant bFGF-SAP administered weekly resulted in mean tumor volumes that were, respectively, 51% or 77% (0.5 microgram/kg) and 42% or 31% (50 micrograms/kg) of controls (day 30). A mean tumor volume of 35% of controls (day 30) and of 49% of controls (day 60) were observed in animals treated by constant infusion of chemical conjugate bFGF-SAP (125 micrograms/kg, total dose). Alternatively, tumors of animals receiving daily injections (125 micrograms/kg, total dose) exhibited a mean volume of 21% of controls (day 30) and prolonged growth inhibition as demonstrated by a mean tumor volume of 22% of controls (day 60). CONCLUSIONS: These studies suggest a therapeutic potential for bFGF-receptor-directed saporin toxins in the treatment of ovarian teratocarcinoma and the importance of frequency of administration in achieving optimal tumor responses.
Animals↗
Recombinant antibodies containing an engineered B-cell epitope capable of eliciting conformation-specific antibody responses.
The immunogenicity of a soluble, non-self protein or peptide can be greatly enhanced by injecting this antigen coupled to an antibody specific for class II MHC molecules in the recipient. This adjuvant-independent immunization strategy is known as immunotargeting. We have investigated the ability of a mouse anti-class II MHC antibody to provide the three-dimensional framework for the reconstitution of a heterologous conformational B-cell epitope, specifically the A loop epitope from the influenza virus hemagglutinin (HA). From a panel of three anti-class II MHC immunoglobulin (Ig)-A loop constructs, we found that one of these, an insertion into the FR3 region of the Ig molecule, retained its specificity for mouse I-Ak. Although mouse monoclonal antibodies specific for the A loop region in the HA molecule were unable to react with the Ig-A loop variants, we did find that the heavy chain CDR3 insertion construct was able to elicit an A loop-specific, HA-reactive antibody response when used as an immunogen in rabbits. These results demonstrate the potential for the Ig molecule to function successfully as a structural framework for the reconstitution and presentation of heterologous conformational B-cell epitopes.
Amino Acid Sequence↗
A comparison of peripheral blood stem cell apheresis using the Fenwal CS3000 Plus and COBE Spectra.
We have compared the leukapheresis products collected on the Fenwal CS3000 Plus and COBE Spectra in a well-controlled patient population. While statistically significant differences were found, i.e. in product hematocrit, volume, number of granulocytes and platelets collected, these are not felt to be physiologically important. Similar efficiency in collecting mononuclear cells and colony forming unit assay results indicate that each instrument is capable of harvesting hematopoietic progenitor cells from peripheral blood.
Adult↗
The pumping and left ventricular unloading capabilities of the ventricular synchronous skeletal-muscle ventricle.
The pumping and left ventricular unloading capabilities of the left ventricular, ventricular synchronous skeletal-muscle ventricle were determined in nine anesthetized dogs ranging in weight from 20.7 to 31.8 kg. The ventricular synchronous skeletal-muscle ventricle consists of the left rectus abdominis muscle wrapped around a 4-mil-thick polyethylene pouch (wrapped volume 80 to 100 ml) connected to the left ventricular apex with no valve and to the aorta via a prosthetic heart valve. The rectus muscle is timed to contract tetanically and relax during left ventricular ejection. This arrangement provides a high precontraction pressure for the rectus muscle and a high muscle capillary blood flow during skeletal muscle relaxation. The timing signal for initiation of the train of stimulating pulses (40/sec) was derived from the ventricular electrogram. The delay for the stimulus train determines the preload for the rectus muscle and along with the stimulus train duration determines ventricular synchronous skeletal-muscle ventricle stroke volume, which was measured by electric impedance. With unconditioned rectus muscles (70 to 120 gm) and with a pumping ratio of 1:3, ventricular synchronous skeletal-muscle ventricle stroke volume average 26.1 ml, which provided an average output of 876 ml/min. The normalized ventricular synchronous skeletal-muscle ventricle output was 35.6 ml/min per kilogram of body weight. In a typical resting dog (and man), the normalized cardiac output is 70 ml/min per kilogram. Therefore the ventricular synchronous skeletal-muscle ventricle is capable of pumping 52% of the cardiac output (with a pumping ratio of 1:3). The optimum train delay from the apex of the ventricular electrogram ranged from 10 to 100 msec. The left ventricular ejection period averaged 309 msec, and this determines the time available for the rectus muscle to contract and relax. Evidence for unloading the left ventricle is shown by the reduced left ventricular diastolic pressure and stroke volume for the postassisted beats.
Animals↗
Costs and effects of enalapril therapy in patients with symptomatic heart failure: an economic analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial.
The clinical results of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial have been published previously, but no evaluation of cost-effectiveness based on the primary data has been reported. The authors used a decision analytic model based on primary data from SOLVD to estimate years of survival (overall, by New York Heart Association Class, and quality-adjusted) and to estimate costs of nonfatal hospitalizations, ambulatory care, therapy with enalapril, and deaths. Clinical and resource utilization data were derived from participants in SOLVD, and cost data were derived from the United States. Therapy with enalapril during the approximate 48-month follow-up period in SOLVD resulted in a gain of 0.16 year of life and savings of dollars 718. During the patient's lifetime, a survival benefit of 0.40 year, a cost per year of life saved of dollars 80, and a cost per quality-adjusted life year of dollars 115 with the use of enalapril were projected. The results indicated a net savings and gain in life expectancy during the SOLVD treatment trial. The lifetime projection suggests that therapy with angiotensin-converting enzyme inhibitors, such as enalapril, is extremely attractive when compared with many commonly used interventions in patients with cardiovascular disease or heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Characterization of reactions after exclusive transfusion of white cell-reduced cellular blood components.
BACKGROUND: Potential adverse effects of white cells (WBCs) within transfused cellular blood components include febrile nonhemolytic transfusion reactions (FNHTRs), alloimmunization, transmission of infectious diseases, transfusion-related acute lung injury, and immunomodulation. Although exclusive use of WBC-reduced components to prevent alloimmunization and cytomegalovirus transmission has been studied, the use of these components to avert FNHTR has not been examined. STUDY DESIGN AND METHODS: Transfusion reactions (FNHTRs, allergic reactions, and others) were characterized in recipients of 12,277 WBC-reduced single-donor apheresis platelets (SDAPs) and/or red cells (RBCs). Medical and laboratory evaluations for possible infectious and immunologic (alloimmunization) causes of each reaction were undertaken, and the benefit of further modification of components for the prevention of subsequent reactions was also evaluated. RESULTS: Transfusion reactions occurred after 481 (3.92%) of 12,277 transfusions. Allergic reactions occurred more commonly after transfusion of SDAPs (3.69%) than of RBCs (0.51%). Conversely, FNHTRs occurred more commonly after transfusion of RBCs (2.15%) than of SDAPs (1.58%). HLA antibodies were present in a posttransfusion sample from 27 (10.6%) of 255 patients; bacterial contamination was a possible cause of only 2 (0.42%) of 481 reactions. In patients with recurrent FNHTRs, further WBC reduction in components did not wholly prevent further FNHTRs. CONCLUSION: The incidence of FNHTRs and alloimmunization after exclusive transfusion of WBC-reduced RBCs and SDAPs was low. Further WBC reduction in components transfused to patients with a history of recurrent FNHTRs does not completely prevent subsequent reactions.
Antibodies↗
States look to press on with health system reform.
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Health Care Reform↗
Recombinant soluble human thrombomodulin: a randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model.
UNLABELLED: Thrombomodulin is an endothelial surface receptor that binds thrombin and accelerates the activation of protein C. We compared the effects of a recombinant thrombomodulin analog (TME), recombinant hirudin (r-HIR), heparin sodium (HEP), and normal saline (Control) on thrombus formation, activated partial thromboplastin time (APTT), thrombin time (TT), platelet aggregation and tail transection bleeding time (BT) in a rat model of vena cava thrombosis. RESULTS: TME, r-HIR and HEP prevented venous thrombosis in this model in a dose-dependent manner. At the dose required to reduce vena cava thrombosis by 50% (ED50), TME did not prolong the APTT or TT as did HEP and r-HIR. Platelet aggregation in response to thrombin was not effected by TME but was inhibited by both r-HIR and HEP. BT did not differentiate the agents tested. CONCLUSION: TME inhibited venous thrombosis in a rat vena cava model with less effect on hemostatic variables than HEP or r-HIR.
Animals↗
Transcription of message for tumor necrosis factor-alpha by lacrimal gland is regulated by corneal wounding.
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Animals↗
Expression of 5-lipoxygenase in lymphoblastoid B and T cells.
The expression of arachidonate 5-lipoxygenase (5-LOX, arachidonate: oxygen 5-oxidoreductase; EC 1.13.11.34) and the 5-lipoxygenase activating protein (FLAP) genes in lymphoblastoid B and T cell lines was studied at the transcriptional level by reverse transcription-PCR analysis. Two B cell lines, CESS and SKW 6.4, were found to express both 5-LOX and FLAP mRNA. One T cell line, MOLT 4, expressed only FLAP mRNA. Upon stimulation of intact cells by calcium ionophore, B lymphoblastoid cells produced 5, 12 and 15 hydroxyeicosatetraenoic acids as well as leukotriene B4.
5-Lipoxygenase-Activating Proteins↗
A teaching rotation for residents.
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Education, Medical, Undergraduate↗
Unifying the poverty line: a critique of maintaining lower poverty standards for the elderly.
Since 1982, the elderly poverty rate reported by the U.S. Census Bureau has fallen below the rate for the nonelderly population. This is cited as evidence of the success of U.S. social policies to benefit the elderly. But lower elderly poverty rates are an artifact of the fact that a lower, more stringent poverty line is applied to the elderly living in one- and two-person households, who constitute 85% of elderly persons. If the same poverty standard is applied to the elderly as to the nonelderly, the poverty rates are the same or slightly higher. The poverty line was originally based on the cost of an adequate diet. The lower standard for the elderly was based on the fact that the elderly consume fewer calories than nonelderly adults. This article shows there is no justification for this lower standard, and recommends its elimination. The overall nutrient requirements of the elderly are not lower, and the elderly spend a higher proportion of their budgets on food and on other necessities (shelter, health care) than the nonelderly. Alternative units of analysis examined under different income-pooling assumptions also show that poverty rates are not lower among the elderly than the nonelderly.
Adult↗
Stroke volume with dynamic cardiomyoplasty during ventricular fibrillation in the acute dog.
The objective of this study was to determine the pumping capability of dynamic cardiomyoplasty during induced ventricular fibrillation. In this acute study of 6 dogs, the pumping capability of the unconditioned left latissimus dorsi (LD) muscle (141 to 292 gm), wrapped around both ventricles, was investigated during induced ventricular fibrillation. Left-ventricular and femoral artery pressure, the ECG and aortic root flow velocity were monitored. Prior to inducing ventricular fibrillation, the ability of the unconditioned LD muscle to augment stroke volume (SV), was quantified as the area under the aortic flow-velocity record. The ventricles were then fibrillated and, after 10 sec, rhythmic 250 msec trains (1/sec) of stimuli (40/sec) were delivered to the thoracodorsal nerve to contract the LD muscle tetanically. In no case could dynamic cardiomyoplasty produce the same SV as when the ventricles were beating normally. In one animal, the SV attained two percent of the normal SV by 5 contractions; in another, the SV reached one percent by 25 contractions. In the remaining animals, the SV varied around 20% of the prefibrillation SV. By 90 contractions, the stroke volume was 10% of the prefibrillation value. The progressive decrease in SV was likely a consequence of LD muscle ischemia and fatigue, since the latissimus dorsi muscle provided low blood flow during the period of fibrillation.
Animals↗
[Use of health facilities by children from 0 to 5 years in Togo. Results of an epidemiological study carried out at a RHC (Atakpamé)].
Through a prospective survey coordinated by the CIE of Paris, and carried at a semi-urban regional hospital (Atakpame), the authors studied the use of health structures by inpatient and outpatient consulting children. Questionnaires were filled for the 112 children of the study. Results were as follows: There is a maladjustment between recruitment at the regional hospital and its real mission (emergency cases and special health care). Thus only 13.3% of children were seen for an emergency, and 4.5% admitted for special health case. In the majority of cases (69.4%), the health state of patients was not alarming. Improper channelling of the patients is responsible for this condition. 79.4% of children consult directly at the hospital without prior consultation at the "peripheral" health centers. The regional health center thus finds itself overburdened, whereby long waiting periods before consultation (> 300 mn for certain patients), and delay in the management of referred patients.
Child, Preschool↗
NG-nitro-L-arginine methyl ester does not affect balloon catheter-induced intimal hyperplasia in rats.
The L-arginine derived NO-cGMP pathway's role in the response of the arterial wall to balloon catheter injury was examined. Rats were given the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg/kg po twice daily) or vehicle for 6 days before and 2 weeks after balloon catheter injury. NG-nitro-L-arginine methyl ester treatment increased blood pressure and inhibited acetylcholine responses in aortic rings but did not alter the lesions produced by balloon injury. Our results suggest that the L-arginine derived NO-cGMP pathway does not play a significant role in the response of the artery wall to balloon injury in the rat.
Acetylcholine↗
Taxol in combination with doxorubicin or etoposide. Possible antagonism in vitro.
BACKGROUND: Taxol is a novel chemotherapeutic agent that promotes microtubule assembly and stabilizes tubulin polymer formation. Clinical evaluation of its antineoplastic activity as a single agent and in combination with other chemotherapeutic drugs is in progress. METHODS: To evaluate the effect of combining taxol with other commonly used antineoplastic agents, clonogenic survival of human breast cancer MCF7 cells, human lung adenocarcinoma A549 cells, and human ovarian cancer OVG1 cells were assayed after an initial exposure to taxol for 24 hours (approximately LD90 for taxol), followed by a 1-hour incubation with varying concentrations of doxorubicin or etoposide (total taxol incubation time, 25 hours). RESULTS: When corrected for taxol-induced cytotoxicity, doxorubicin and etoposide caused less cell killing in the presence of taxol compared with control incubations of doxorubicin and etoposide alone. To determine if a different schedule of drug application resulted in a similar finding, MCF7, A549, and OVG1 cells were exposed to doxorubicin for 1 hour, followed by incubation with varying concentrations of taxol for 24 hours. Less-than-additive cytotoxicity for the combination of taxol and doxorubicin was found. Flow cytometry studies in MCF7 cells showed that taxol caused a G2/M cell cycle block. Fewer cells were found to be in S-phase, which is the most doxorubicin-sensitive phase of the cell cycle. The application of doxorubicin or etoposide to MCF7 cells for 1 hour resulted in partial G1 and G2/M cell cycle blocks. Fewer cells were found to be moving through the cell cycle, which is likely required for taxol cytotoxicity. CONCLUSION: Although direct antagonism of the cytotoxicity of doxorubicin or etoposide by taxol has not been proven, there is less-than-additive in vitro cytotoxicity when taxol is combined with these chemotherapeutic agents. The clinical implications of these findings are unknown; however, these findings generate concern about the combination of these agents in clinical trials and suggest that additional studies to determine optimal scheduling are needed.
Antineoplastic Combined Chemotherapy Protocols↗