Biomedical subjects

S A Johnson

Publications and source records attributed to S A Johnson.

At least 55 records · Page 3Linked to original sources

PubMed1999

Synergistic interactions between ampakines and antipsychotic drugs.

Tests were made for interactions between antipsychotic drugs and compounds that enhance synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors ("ampakines"). Typical and atypical antipsychotic drugs decreased methamphetamine-induced hyperactivity in rats; the effects of near or even subthreshold doses of the antipsychotics were greatly enhanced by the ampakines. Interactions between the ampakine CX516 and low doses of different antipsychotics were generally additive and often synergistic. The ampakine did not exacerbate neuroleptic-induced catalepsy, indicating that the interaction between the different pharmacological classes was selective. These results suggest that positive modulators of cortical glutamatergic systems may be useful adjuncts in treating schizophrenia.

Animals↗

PubMed1998

Time-course of hypericin phototoxicity and effect on mitochondrial energies in EMT6 mouse mammary carcinoma cells.

Photoactivated hypericin produces singlet oxygen and superoxide anion radical; however, the intracellular events contributing to toxicity are unknown. Clonogenic assays of oxygen-dependent hypericin phototoxicity to EMT6 cells have previously shown that 0.5 microM hypericin + 1.5 J cm(-2) fluorescent light is non-toxic and that 1.0 microM hypericin + 1.5 J cm(-2) fluorescent light produces LD40 toxicity. Intracellular events leading to toxicity were revealed at these doses. Lactate dehydrogenase leakage was elevated for both 0.5 microM and 1.0 microM hypericin + light immediately following irradiation. While values eventually returned to control levels for 0.5 microM hypericin + light, leakage increased over time for 1.0 microM hypericin indicating reversible and irreversible toxicity, respectively. Increases in lipid and protein oxidation were measured immediately following irradiation; however, these parameters return to control levels within 0.5 h for both doses. Both total cellular ATP levels and cellular respiration were depressed by approximately 50% of control values for 1.0 microM hypericin + light. These values were unchanged for 0.5 microM hypericin + light. Along with previously reported data demonstrating that light-activated hypericin can inhibit mitochondial succinoxidase in beef heart mitochondria in vitro, these data support oxidative stress-initiated mitochondrial damage as a key target in hypericin phototoxicity.

Adenosine Triphosphate↗

PubMed1998

Antioxidant enzyme response to hypericin in EMT6 mouse mammary carcinoma cells.

Antioxidant enzyme activities were measured following exposure to hypericin +/- irradiation in EMT6 cells. CuZnSOD and catalase activities peaked within 0.5 h following irradiation for nontoxic 0.5 microM hypericin and toxic 1.0 microM hypericin. Catalase remained elevated up to 3 h for 1.0 microM hypericin + light. MnSOD activity was elevated immediately following irradiation for both doses. These levels returned to control by 1 h for 0.5 microM hypericin, but were depressed after 1 h for 1.0 microM hypericin. This suggests that mitochondria impairment may be a critical factor in hypericin phototoxicity. Glutathione reductase was inhibited immediately following irradiation with 1.0 microM hypericin, suggesting that an altered status of the glutathione pool contributed to cytotoxicity. Glutathione peroxidase activities were elevated following irradiation but returned to control levels within 0.5 h for both doses, implicating hydroperoxide formation as an early event in hypericin phototoxicity. Inhibition by hypericin in the dark was demonstrated for purified CuZnSOD, Se-dependent glutathione peroxidase, glutathione S-transferase, and glutathione reductase activities in vitro. Irradiation did not potentiate hypericin-mediated glutathione reductase inhibition and decrease inhibition for the other enzymes. Collectively, these data demonstrate an antioxidant enzyme response to hypericin photoactivation and confirm a role for oxygen in hypericin phototoxicity.

Animals↗

PubMed1998

The fallacy of evaluating biomaterial wear-rates with water as lubricant: a hip simulator study of alumina-PTFE nd CoCr-PTFE combinations.

Controversy surrounds wear data from hip-simulator studies, whether from the choice of lubricants or other parameters such as the particular biomaterial combinations used, and whether any such interactions could bias the resulting wear predictions. To investigate these phenomena, we studied the wear performance of CoCr and alumina femoral heads, in water and serum-based lubricants, using as our standard the polytetrafluoroethylene wear data derived clinically by Charnley. To model Charnley's clinical experience, PTFE acetabular cups were used in sets of three each with each size of femoral head for 22.25, 28, and 42-mm diameters in a nine-channel hip simulator. From the serum-based tests, the CoCr-PTFE wear data were consistently linear with duration of test, exhibited very large wear rates of 3,000-8,400 mm3/10(6), cycles had a precision within +/- 4% for each set of three cups, and copious amounts of small particulate were clearly seen circulating. The wear data clearly demonstrated Charnley's thesis that volume of wear increased with regard to size of femoral head. From the water-based tests, the CoCr-PTFE wear data were nonlinear with duration of test, had much reduced wear rates compared to the serum tests, lost the clinical relationship with ball size, and precision deteriorated to +/- 27% for each set. The wear debris appeared as 1-2 cm long ribbons which floated to the surface. For the alumina-PTFE combination in serum, the wear data appeared identical in performance to the CoCr-PTFE data in serum. Thus, the PTFE wear rates were not sensitive to the choice of femoral-head material. The most surprising outcome in this study was the zero-wear performance of the ceramic-PTFE combination in water. This contrasted remarkably with the large wear rates established for the same combinations run in serum. The zero-wear performance of the ceramic-PTFE combination in water was unexpected, but a similar phenomenon was noted in published simulator tests of ceramic-UHMWPE run in water. It now seems likely that such data may reflect the capricious behavior of water lubrication rather than any other variables under evaluation. The water-based experiments clearly favored the ceramic's superior tribological performance and placed metal bearings at a decided disadvantage. Therefore, for an in vitro simulation of materials wear-ranking of clinical relevance, it may be advisable to use a serum-based lubricant.

Alloys↗

PubMed1998

Anthracyclines in haematology: pharmacokinetics and clinical studies.

The activity of anthracyclines in the treatment of a wide spectrum of haematological malignancies has long been established. Differences in the pharmacokinetic and pharmacodynamic properties of these drugs have resulted in the selection of individual compounds for particular indications while the recent reformulation of anthracyclines in liposomal preparations seems likely to significantly alter their range of activity and toxicity. The problems related to cumulative cardiotoxicity secondary to anthracycline exposure can be ameliorated by the use of dexrazoxane and a number of agents may prove to have a role in altering their cellular resistance to their cytotoxic actions.

Acute Disease↗

PubMed1998

Phase I/II evaluation of pentostatin (2'-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia.

The purpose of this study was to determine the efficacy and toxicity of pentostatin (2'-deoxycoformycin) administered in a five day schedule every 28 days to patients with B-cell chronic lymphocytic leukaemia (B-CLL) relapsed from or refractory to at least one line of prior chemotherapy. The initial dose level of 2 mg/m2/day was adjusted up or down by 0.5 mg/m2 in subsequent cycles on the basis of haematological and non-haematological toxicities. The five day schedule was selected because published pharmacokinetic studies had indicated that although pentostatin had an elimination half-life of approximately six hours and could inhibit plasma adenosine deaminase activity for 24 hours, recovery of enzyme activity rapidly took place and accumulation of dATP which has a toxic effect on non-replicating lymphoid cells could be increased by repeated dosing. Twenty-nine patients were entered into the study and dose-escalation was possible in nine, while dose reductions were required for five patients. Of the 24 patients evaluable for response, complete responses were achieved in two and partial responses in five for an overall response rate of 29.2%. Toxicity consisted of myelosuppression, infection, nausea and vomiting and hepatotoxicity but was experienced at acceptable levels considering the heavily pre-treated nature of the patient population. Pentostatin in this schedule has salvage activity in previously treated or resistant patients with B-CLL.

Adult↗

PubMed1998

In vitro chemosensitivity of chronic lymphocytic leukaemia to purine analogues--correlation with clinical course.

Samples from 51 chronic lymphocytic leukaemia (CLL) patients (42 typical, nine atypical) were assessed for in vitro response to fludarabine and cladribine (2-CdA) using the flow cytometric terminal deoxynucleotidyl transferase (TdT) assay. No difference was demonstrated between the in vitro response of typical and atypical CLL and previous treatment did not result in a more apoptosis resistant phenotype. The assay could not distinguish those patients who required subsequent treatment from those whose disease remained stable, and universal cross-resistance/sensitivity to the two purine analogues was demonstrated. The assay's potential for use in the rapid assessment of in vivo response to purine analogue therapy in CLL was limited; correctly predicting the clinical outcome of 10/12 patients to treatment but failing to predict progression in two p53 deficient patients. The level of bcl-2 in the clonal lymphocytes did not influence the in vitro, spontaneous or drug-induced, apoptosis.

Antineoplastic Agents↗

PubMed1998

Seroconversion of type B to O erythrocytes using recombinant Glycine max alpha-D-galactosidase.

Recombinant alpha-D-galactosidase (rGal) from soybean (Glycine max) hydrolyzed the immunodominant alpha-D-galactose residue from the B epitope of red blood cells. This converted type B erythrocytes to type O which are "universally" transfusable. Type B red blood cells were obtained from four different donors and enzymatically converted. Cell function parameters, including red cell indices, pH, methemoglobin, carboxyhemoglobin, osmotic fragility, hemolysis, 2,3-diphosphoglycerate, cholinesterase, ATP, and antigen typing of treated cells were compared to controls. These pilot studies indicate that rGal could have potential biotechnical application in the production of universally transfusable red blood cells.

2,3-Diphosphoglycerate↗

PubMed1998

Single soleus muscle fiber function after hindlimb unweighting in adult and aged rats.

This investigation compared how hindlimb unweighting (HU) affected the contractile function of single soleus muscle fibers from 12- and 30-mo-old Fischer 344 Brown Norway F1 Hybrid rats. After 1 wk of HU, functional properties of single permeabilized fibers were studied, and, subsequently, the fiber type was established by myosin heavy chain (MHC) analysis. After HU, the relative mass of soleus declined by 12 and 19% and the relative mass of the gastrocnemius declined by 15 and 13% in 12- and 30-mo-old animals, respectively. In 12-mo-old animals, the peak active force (5.0 +/- 0.2 x10(-4) vs. 3.8 +/- 0.2 x10(-4) N) and the peak specific tension (92 +/- 4 vs. 78 +/- 3 kN/m2) were significantly reduced in the MHC type I fibers by 24 and 15%, respectively. In 30-mo-old animals, the peak active force declined by 40% (4.7 +/- 0.2 x10(-4) vs. 2.8 +/- 0. 3 x10(-4) N) and the peak specific tension declined by 30% (79 +/- 5 vs. 55 +/- 4 kN/m2). The maximal unloaded shortening velocity of the MHC type I fibers increased in 12-mo-old animals (from 1.65 +/- 0.12 to 2.59 +/- 0.26 fiber lengths/s) and in 30-mo-old animals (from 0.90 +/- 0. 09 to 1.50 +/- 0.10 fiber lengths/s) after HU. Collectively, these data suggest that the effects of HU on single soleus skeletal muscle fiber function occur in both age groups; however, the single MHC type I fibers from the older animals show greater changes than do single MHC type I fibers from younger animals.

Aging↗

PubMed1997

Long-term follow-up of cardioverter-defibrillator implanted under conscious sedation in prepectoral subfascial position.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) with intravenous electrode systems and downsized generators can be implanted by use of operative techniques similar to those employed for the insertion of permanent pacemakers. However, the safety, efficacy, and long-term follow-up of simplified implantation procedures remain to be evaluated. This report is a prospective long-term evaluation of nonselected patients receiving ICDs in the prepectoral subfascial position under conscious sedation. METHODS AND RESULTS: Clinical characteristics of the 231 consecutive patients included a mean age of 63 years, a male-to-female ratio of 6.4, a left ventricular ejection fraction of 0.34, a mild-to-moderate heart failure in 91%, coronary artery disease in 84%, and a history of aborted sudden cardiac death or refractory ventricular tachyarrhythmias. Insertion of transvenous leads and prepectoral subfascial ICD implantation were performed in electrophysiology laboratories under local anesthesia and conscious sedation with intravenous midazolam and propofol. Successful implantation in all patients (operation time, 80 +/- 32 minutes, mean +/- SD) irrespective of body size and skin thickness was free of major complications, including need for emergency intubation. After surgery, 1 pocket hematoma, 1 seroma, and 1 pneumothorax required treatment. There was no operative or first-month mortality. During long-term follow-up averaging 453 +/- 296 days, six leads required repositioning, but pocket erosions or infections did not occur. First-year total survival was 97%. CONCLUSIONS: Implantation under conscious sedation of ICDs in the prepectoral subfascial position is a safe and effective procedure with low operative and postoperative morbidity and favorable long-term outcome.

Adolescent↗

PubMed1997

Excisional wound healing following the use of IRM as a root-end filling material.

Intermediate Restorative Material (IRM) has been advocated as a root-end filling material based primarily on reports of clinical success and various leakage studies. The objectives of this study were to determine the excisional wound healing responses of the periradicular tissues to IRM root-end filling material and to compare this with the wound healing responses to amalgam and orthograde gutta-percha root-end filling materials. Mandibular premolars in dogs were obturated, root-ends resected, and the healing responses associated with root-end fillings of IRM, amalgam, and orthograde gutta-percha were evaluated microscopically and radiographically at postsurgical intervals of 10 and 45 days. The excisional wound healing responses associated with IRM root-end fillings were normal at both postsurgical intervals. There was no evidence of inhibition of dentoalveolar or osseous wound healing associated with IRM, amalgam, or orthograde gutta-percha. Statistical analysis showed no difference in wound healing between the 3 root-end filling materials.

Alveolar Process↗

PubMed1997

Anthracyclines in haematology: preclinical studies, toxicity and delivery systems.

The anthracyclines are widely used in the treatment of haematological and non-haematological malignancy and there is now more than 30 years' clinical experience with these agents but despite this, their mechanism of action is incompletely understood. The anthracyclines have been shown to intercalate with DNA and indirectly inhibit the activity of the enzyme topoisomerase II, resulting in DNA strand breaks. More recently, workers have focused on induction of apoptosis and have shown that daunorubicin stimulates production of the apoptotic mediator, ceramide and that the activity of doxorubicin can be blocked by inhibitors of CD95 (fas). One of the major problems with anthracycline therapy is the development of resistance which may be mediated by p-glycoprotein or by other mechanisms. Much recent research has concentrated on methods to modulate the drug-resistant phenotype and these include development of new analogues and use of specific reversal agents. The toxicity profile of the anthracyclines includes bone marrow suppression, severe local reaction following extravasation, radiation recall, alopecia, gastrointestinal and hepatic effects, development of secondary malignancies and significant cardiac toxicity. The risk factors for the development of anthracycline-related cardiac toxicity are well documented and several methods have been exploited in attempts at prevention. Finally, a number of drug delivery systems have been developed in order to improve therapeutic response and reduce toxicity to normal tissues, including the use of liposomal preparations.

Anthracyclines↗

PubMed1997

Predictors of success and major complications for primary percutaneous transluminal coronary angioplasty in acute myocardial infarction. An analysis of the 1990 to 1994 Society for Cardiac Angiography and Interventions registries.

OBJECTIVES: The purpose of this study was to determine predictors of successful coronary angioplasty for acute myocardial infarction (MI) and associated predictors of the major complications of in-hospital mortality and emergency coronary artery bypass graft surgery. BACKGROUND: Primary angioplasty is being increasingly used to treat acute MI, but factors affecting the success and major complications have not been well studied. Forty laboratories have been contributing clinical and procedural data to the Society of Cardiac Angiography and Interventions (SCA&I) on primary angioplasty for acute MI. METHODS: Univariable and stepwise multivariable logistic regression analysis of clinical and procedural variables was used to calculate predictors of success and major complications. RESULTS: There were 4,366 primary angioplasty procedures reported from 1990 through 1994, with an overall success rate of 91.5%, an in-hospital mortality rate of 2.5% and a rate of emergency surgery of 4.3%. Higher laboratory primary angioplasty volume and lower age were predictive of success. An intraaortic balloon pump in place, cardiogenic shock and a moribund condition had negative predictive effects. Unsuccessful angioplasty, cardiogenic shock or a moribund state were predictive of in-hospital death. Unsuccessful angioplasty, the absence of a history of hypertension and the absence of congestive heart failure were predictive of emergency surgery. CONCLUSIONS: The rates of success and major complications in the SCA&I Registry are similar to other series. Predictors of success and major complications can be assessed and may be useful for risk stratifying candidates for primary angioplasty in acute MI.

Aged↗

PubMed1997

Early evaluation of liposomal daunorubicin (DaunoXome, Nexstar) in the treatment of relapsed and refractory lymphoma.

We have treated 19 patients with relapsed or refractory lymphoma with liposomally encapsulated daunorubicin (DaunoXome) at two dose schedules; 40 mg/m2 repeated every 14 days and 120 mg/m2 repeated every 21 days. Non-haematological toxicity was mild, in particular, no patient treated with the higher dose schedule showed clinical deterioration in cardiac function. At the lower dose (10 patients) no objective responses were seen but at the higher dose (9 patients) one complete response and two partial responses were achieved. Liposomal daunorubicin at 120 mg/m2 appears to have some activity against refractory lymphoma and we suggest that further studies with this agent are required.

Adult↗

PubMed1997

G-CSF after peripheral blood stem cell transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital: results of a randomized BNLI trial.

We have undertaken a prospective randomized study in 90 patients with relapsed or resistant lymphomas to assess the value of G-CSF (lenograstim) in the acceleration of myeloid recovery after peripheral blood stem cell transplantation (PBSCT). A common regimen of cyclophosphamide 1.5 g/m2 on day 1 and lenograstim 263 microg s.c. on days 2-10 with two aphereses on days 10 and 11 was used for stem cell mobilization. 77% of patients achieved an adequate PBSC collection in two harvests (> 2 x 10(8) MNC/kg or > 2 x 10(6) CD34+ cells/kg). 65 patients went on to receive high-dose BEAM chemotherapy and engraftment data was available for 62. 34 patients had been randomized to receive lenograstim 263 microg/d s.c. and 28 to no growth factor. The median time to ANC > 0.5 x 10(9)/l was 9 d in the lenograstim arm versus 12.5 d in the no-lenograstim arm (P=0.0001). This was associated with a median duration of time in hospital post PBSCT of 13 d in the lenograstim arm versus 15.5 d in the no-lenograstim arm (P=0.0002). Median days to platelet independence, platelet transfusions, incidence of infection and red cell transfusion were the same in both arms. These data indicate that lenograstim significantly accelerated myeloid recovery after PBSCT and shortened the duration of hospital stay.

Adult↗

PubMed1997

A prospective randomized study of three types of platelet concentrates in patients with haematological malignancy: corrected platelet count increments and frequency of nonhaemolytic febrile transfusion reactions.

We prospectively randomized 51 patients with haematological malignancy requiring platelet concentrates (PCs) to receive either single donor platelet-pheresis products (SD-PC), PCs made from pooled buffy coats (BC-PC) or pooled units of platelets made by the platelet-rich plasma method (PRP-PC). The leucocyte content of each type of PC was 0.33 (0.03-13.5), 5.68 (0.19-99.0) and 365 (65-910) x 10(6); median (range), respectively; P < 0.0001. All red cell transfusions were leucodepleted by filtration. Statistical comparison of the probability of the occurrence of a nonhaemolytic febrile transfusion reaction (NHFTR) following transfusion of PCs in patients in each group showed a significant decrease for the SD-PC and BC-PC groups (0.031 and 0.038, respectively) when compared with PRP-PC (0.171); P = 0.0001. The actual corrected platelet count increments (CCI) at 1-6 and 18-24 h post-transfusion for all three types of PC did not differ significantly. We conclude that transfusion of PRP-PC is associated with a significant increase in NHFTR.

Adult↗

PubMed1997

Cloning, sequence, and expression of a blood group B active recombinant alpha-D-galactosidase from pinto bean (Phaseolus vulgaris).

A cDNA encoding pinto bean alpha-D-galactosidase [E.C. 3.2.1.22] was obtained by amplification of cDNA using highly conserved sequences found in eucaryotic alpha-D-galactosidases. Subsequently a full length Phaseolus cDNA clone was obtained that is 1537 nt long and contains untranslated 5' and 3' sequences. The nucleotide sequence of the cDNA has a high degree of homology with other eucaryotic alpha-D-galactosidase genes. The recombinant alpha-D-galactosidase (rGal) was expressed in Escherichia coli and purified by ion exchange and affinity chromatography. Purified rGal was homogeneous by SDS-PAGE and had relative masses of 40.1 and 45.4 kDa under nonreducing and reducing conditions, respectively. The N-terminal sequence of the expressed protein contained the sequence GNGLGQTPPMG corresponding to that deduced from the cDNA sequence. The native molecular weight for rGal was determined to be 32.18 kDa by Sephacryl S-200 chromatography. The specific activity of the rGal was 349 mu moles of PNP-alpha-D-galactopyranoside hydrolyzed per mg of pure rGal per min. rGal was highly specific for alpha-D-galactosyl residues and degraded B oligosaccharide. No detectable hemagglutinin or protease activity was present in the preparations. Furthermore, rGal was active against the blood group B antigen on native human erythrocytes in cell suspension assays. The only detectable RBC phenotypic change was loss of the B and P1 epitopes. Recombinant Phaseolus vulgaris alpha-D-galactosidase may have useful biotechnical applications in the potential mass production of enzymatically converted, universally transfusable type O RBCs. alpha-D-galactosidase [E.C. 3.2.1.22] has been purified from a variety of procaryotic and eucaryotic species. Most alpha-D-galactosidases have similar low molecular weight substrate specificities, but activity against high molecular weight substrates is variable. Terminal alpha-D-galactoside residues are present in glycoproteins and glycolipids. Some alpha-D-galactosidases have activity against alpha-D-galactosyl residues on cell membrane glycoconjugates. Glycosidases with this property are useful for carbohydrate structural studies and biotechnical applications. Enzymes free of other glycosidase activities with activity near neutral pH are particularly useful for membrane modification studies on native cells. Complex sugar chains in glycolipids and glycoproteins have often been implicated in the growth and development of eucaryotes. In particular, complex sugar chains play an important role in the recognition of self in the immune system. Some alpha-D-galactosidases can modify certain carbohydrate membrane epitopes, thereby modulating the immune response. For example, the blood group B epitope expressed on erythrocytes contains a terminal alpha-D-galactosyl residue. Individuals lacking this antigen produce naturally occurring complement fixing antibodies to the B epitope. Hydrolysis of this terminal saccharide destroys the antigenic activity of the B determinant producing H antigen (blood type O) on erythrocytes. Only rare individuals produce clinically significant antibodies to the H antigen, and therefore, type O red blood cells are "universally" compatible and in great demand. Dhar purified alpha-D-galactosidase isozymes from Phaseolus vulgaris and characterized their activity. To our knowledge, our laboratory, in a brief report, is the first to describe the cloning of the gene and the use of recombinant enzyme for seroconverting blood type B to O cells. This paper describes the cloning, sequence, expression, purification, and characterization of recombinant alpha-D-galactosidase. Activity of the recombinant enzyme on the native human erythrocyte blood group B epitope is shown.

ABO Blood-Group System↗

PubMed1997

Immunoprophylaxis of group B respiratory syncytial virus infection in cotton rats.

Two antigenic groups of respiratory syncytial virus (RSV) have been identified: A (RSV/A) and B (RSV/B). Topical administration of human IgG screened for high titers of antibody to RSV/A (RSVIg) is protective against RSV/A infection in the cotton rat model. The study attempted to determine if topical RSVIg would also be protective against RSV/B. Cotton rats were pretreated intranasally with RSVIg or with monospecific antiserum obtained from animals previously infected with RSV/A or RSV/B (day 0), challenged intranasally with RSV/A or RSV/B (day 1), and sacrificed for virus titration (day 5). Cotton rat antiserum to RSV/B protected against RSV/A and RSV/B, while antiserum to RSV/A protected only against RSV/A. RSVIg, although prepared on the basis of activity against RSV/A, was also protective against RSV/B.

Animals↗