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Biomedical subjects

C Waters

Publications and source records attributed to C Waters.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effects of selegiline dosing on motor fluctuations in Parkinson's disease.

To examine selegiline's dosing effects, we studied 16 Parkinson disease patients with motor fluctuations in a double-blind, crossover trial of selegiline at 0, 5, and 10 mg daily. Patients' motor diaries, disability scores, and walking speed were marginally improved, with no advantage of 10 mg over 5 mg found. We conclude that in patients with motor fluctuations, selegiline provides modest symptomatic effects, with daily dosing of 5 mg being indistinguishable from 10 mg.

Aged↗
PubMed1993

Discrimination between closely related Pacific oyster species (Crassostrea) via mitochondrial DNA sequences coding for large subunit rRNA.

Mitochondrial DNA sequence variation was characterized for the large subunit rRNA-coding gene (16SrDNA) in two closely related Pacific oyster species (Crassostrea gigas and C. sikamea) and an out group, the Olympia oyster (Ostrea lurida). Although each species was shown to have a single, fixed haplotype for the DNA sequence under study, 7 nucleotide differences were found between C. gigas and C. sikamea, and these two species differed from the O. lurida haplotype at 62 and 60 nucleotide sites, respectively. Nucleotide differences for the two Crassostrea species showed a notable transition bias (85.7%) in contrast to the marginal transversion bias (54.5%) in nucleotide differences between Crassostrea haplotypes and the more distantly related O. lurida. Conservation of primary sequence in all three oyster species as well as other published 16SrDNA sequences was noted for regions with apparent functional significance. We developed DNA sequence-specific discrimination techniques and employed sequence-specific PCR primers, dot-blot hybridization, and restriction digests as alternate techniques for rapid diagnosis of Crassostrea oyster larvae.

Animals↗
PubMed1992

Panic disorder and chest pain in the coronary care unit.

Consecutive admissions to a university hospital coronary intensive care unit were prospectively evaluated using a modified version of the Structured Clinical Interview for DSM-III-R by interviewers blind to the patient's cardiac status. Panic disorder was present in almost one-third of the patients. Four (21%) of the 19 patients with panic disorder also had positive cardiac findings, including 2 who had myocardial infarctions. Of the 27 patients with negative cardiac findings, 15 (55.5%) had panic disorder. Whereas panic disorder and coronary heart disease may coexist in patients with acute chest pain, there appears to be a very high prevalence of panic disorder among patients in whom cardiac disease has been excluded.

Adult↗
PubMed1992

The role of magnetic resonance imaging in acute transverse myelitis.

Eighteen adult patients presenting with acute transverse myelitis (ATM) were evaluated using magnetic resonance imaging. Only 7 had abnormal scans showing an area of increased signal intensity within the cord solely on T2 weighted images; T1 weighted images were normal. The MRI abnormality did not correlate with the cause of the transverse myelitis, the extent of maximum neurological deficit, or the prognosis. A scan performed more than 5 days after the onset of disease was most likely to be positive. Even though the prognostic value of MRI in ATM may be limited, it remains a valuable technique for ruling out other causes of noncompressive spinal cord lesions, such as hemorrhage, vascular malformation, or tumor.

Adolescent↗
PubMed1992

Inhibition of HIV-1 RNA production by the diphtheria toxin-related IL-2 fusion proteins DAB486IL-2 and DAB389IL-2.

Productive infection of cells by human immunodeficiency virus type 1 (HIV-1) is associated with the activation state of the cell and its obligatory expression of the interleukin-2 receptor (IL-2R), the latter providing a new target for antiviral therapy. A quantitative RNA-RNA hybridization assay is employed to detect production of HIV-1 RNA and to show that two IL-2 diphtheria toxin-related fusion proteins (DAB486IL-2 and its more potent, truncated form DAB389IL-2) inhibit HIV-1 RNA production in infected cells. A mutant form of DAB486IL-2 containing a single point mutation that inactivates the adenosine diphosphate ribosyltransferase activity of the toxin does not inhibit HIV RNA production, even though the molecule binds to the IL-2R. The active fusion proteins inhibit viral RNA replication in cells infected with HIV-1 clinical isolates as well as with a ZDV-resistant strain of HIV-1. These results indicate that IL-2 receptor-targeted fusion proteins can be utilized to inhibit HIV-1 replication effectively in infected human lymphocytes.

Antiviral Agents↗
PubMed1991

Multiple autophosphorylation site mutations of the epidermal growth factor receptor. Analysis of kinase activity and endocytosis.

We have utilized site-directed mutants to study the role of autophosphorylation of the epidermal growth factor (EGF) receptor in the regulation of receptor kinase activity and ligand-induced endocytosis. A single mutation of the major autophosphorylation site, Y1173, and a double mutation of two autophosphorylation sites, Y1173 and Y1148, did not inhibit kinase activity in vivo, using PLC gamma 1 as a specific substrate for the EGF receptor kinase. The simultaneous mutation of three major autophosphorylation sites (Y1173, Y1148, Y1068), however, caused more than a 50% decrease in EGF-induced tyrosine phosphorylation of PLC gamma 1. The triple mutation also resulted in a substantial inhibition of the EGF-receptor endocytic system. We have used three types of experiments to analyze internalization, recycling, and degradation of EGF in cells with these mutants or the wild-type receptor. Using a simple mathematical model we have shown that the internalization rate constant is 2-fold lower in cells expressing the triple mutation receptor (F3 cells) than in cells expressing wild-type EGF receptor (wild-type cells). However, the rate constant for recycling was similar in both cell types. The EGF degradation rate constant was also lower in F3 cells. EGF-induced EGF receptor degradation was slower in F3 cells (t1/2 = 4 h) than in wild-type cells (t1/2 = 1 h). Therefore, our results suggest that multiple autophosphorylations of the carboxyl terminus of the EGF receptor are required for EGF receptor kinase activation, and for the internalization and intracellular processing of the EGF.receptor complex.

Animals↗
PubMed1990

Adrenal to caudate transplantation--postmortem study.

A patient with Parkinson's disease who had undergone bilateral adrenal to caudate implantation by stereotactic technique came to autopsy. The implantation was shown to have produced minimal trauma and to have been well placed. Minimal surviving adrenal medullary tissue remained in the implanted coil, and no outgrowth of tissue into the striatum occurred.

Adrenal Medulla↗
PubMed1990

In vitro activity of tosufloxacin (A-60969) and clarithromycin (A-56268, TE-031) against resistant Haemophilus influenzae, Streptococcus pneumoniae and Branhamella catarrhalis isolates.

The activity of tosufloxacin (A-60969), a new oral quinolone, and clarithromycin (A-56268, TE-031), a new oral macrolide, was compared in vitro to that of other oral quinolones and beta-lactam antimicrobial agents against clinical isolates of ampicillin and/or chloramphenicol resistant Haemophilus influenzae, penicillin resistant Streptococcus pneumoniae and beta-lactamase producing Branhamella catarrhalis. Results were compared to those for sensitive isolates. Tosufloxacin was the most active compound against Haemophilus influenzae and was more active than ciprofloxacin or ofloxacin against all strains of Streptococcus pneumoniae. Tosufloxacin was also more active than any of the beta-lactam drugs tested against penicillin resistant or relatively penicillin resistant isolates. Clarithromycin was the most active compound tested against both penicillin sensitive and penicillin resistant Streptococcus pneumoniae, and was as active as ciprofloxacin against Branhamella catarrhalis. In view of the favourable in vitro activity against common bacterial respiratory pathogens, tosufloxacin should be considered for clinical trials in adults with respiratory tract infections, while clarithromycin might be useful in treatment of infection with these organisms in all age groups.

4-Quinolones↗
PubMed1990

Pharmacokinetics of the recombinant fusion protein DAB486IL-2 in animal models.

The kinetics of the in vitro cytotoxicity of DAB486IL-2, a genetically engineered fusion protein containing a portion of diphtheria toxin and human interleukin-2, were examined in the C91/PL cell line, which constitutively expresses IL-2 receptors. Maximal inhibition of protein synthesis was observed by 4-6 h after DAB486IL-2 addition at a concentration of 300 ng/ml. The tissue distribution, urinary excretion, and plasma pharmacokinetics of DAB486IL-2 in the rat and its plasma pharmacokinetics in the monkey were also examined. In rats the primary site of distribution of [35S]-DAB486IL-2 outside the vasculature appears to be the liver, followed by the kidney, spleen, and lung. Persistence of radioactive material in the liver and urinary excretion of metabolic degradation products suggest that labeled protein is metabolized by hepatic tissue. Following i.v. bolus administration of DAB486IL-2, the initial serum half-life for both the rat and the monkey was approximately 5 min. The overall clearance rate of drug for the two species differed, with DAB486IL-2 being cleared from circulation 2-3 times more rapidly in the monkey. Presence of high levels of neutralizing antibodies to diphtheria toxin in the rat significantly influenced the clearance of bioactive DAB486IL-2. However, the question as to whether the presence of in vitro biological activity for the molecule is masked by the presence of antibodies cannot be clearly answered.

Animals↗
PubMed1990

Differential expression of immediate early genes in the hippocampus and spinal cord.

We have demonstrated that immediate early genes can be differentially activated within the central nervous system. We examined the effects of tetanic stimulation in the hippocampus and of noxious sensory stimulation of the spinal cord on the expression of eight immediate early genes. Induction of long-term potentiation (LTP) in the dentate gyrus resulted in an increase in mRNA and protein for NGFI-A (also termed Zif/268, Egr-1, or Krox 24), and less consistently for jun-B mRNA. No increase was seen for c-fos, NGFI-B, c-jun, jun-D, SRF, or PC4 mRNAs. Blockade of the NMDA receptor prevented the induction of both LTP and NGFI-A mRNA in the dentate gyrus. However, commissural stimulation, which prevented the induction of LTP, resulted in bilateral activation of all the genes examined, including NGFI-A. No change was seen in animals trained in a water maze. These results suggest that no simple relationship exists between LTP, spatial learning, and immediate early gene induction. Stimulation of sensory fibers resulted in an increase in mRNA for NGFI-A, c-fos, SRF, NGFI-B, and c-jun in spinal cord neurons. Blockade of the NMDA receptor had no effect on immediate early gene induction in the spinal cord.

Animals↗
PubMed1990

In vitro activities of tosufloxacin, temafloxacin, and A-56620 against pathogens of diarrhea.

Tosufloxacin (A-60969 HCl), a new quinolone with broad activity against gram-positive and anaerobic organisms, was compared in vitro with other quinolones against bacterial pathogens of diarrhea. Tosufloxacin was the most active agent against Salmonella spp., Shigella spp., Campylobacter spp., Aeromonas hydrophila, and Vibrio spp. Temafloxacin (A-62254) also demonstrated good activity against these organisms.

Anti-Bacterial Agents↗
PubMed1990

Oral ciprofloxacin versus ceftriaxone for the treatment of urethritis from resistant Neisseria gonorrhoeae in Zambia.

Neisseria gonorrhoeae strains resistant to treatment with penicillin, tetracycline, and/or spectinomycin are increasing in prevalence in many parts of the world. In Zambia, 52% of N. gonorrhoeae isolates produced beta-lactamase in 1986. Few oral regimens have proven effective for treatment of resistant N. gonorrhoeae. We conducted a prospective, double-blind, randomized clinical trial of 250 mg of ciprofloxacin given orally versus 250 mg of ceftriaxone given intramuscularly for treatment of uncomplicated gonococcal urethritis in adult males. Two hundred men were enrolled and treated. The two groups were comparable in age (27.5 years), prevalence of latent syphilis (14 and 10%), and human immunodeficiency virus infection (32 and 38%). Of 165 patients with cultures positive for N. gonorrhoeae who returned for follow-up, ciprofloxacin cured 83 of 83 (100%), including 26 with penicillinase-producing N. gonorrhoeae (PPNG) and 21 with N. gonorrhoeae with chromosomally mediated resistance to multiple antibiotics (CMRNG), and ceftriaxone cured 81 of 82 (98.7%), including 30 with PPNG and 19 with CMRNG. Both treatment regimens were well tolerated. Chlamydia trachomatis in urethral exudate was found by direct fluorescent-antibody microscopic examination or by culture in 10 (5%) participants. All N. gonorrhoeae isolates were inhibited by ceftriaxone at 0.06 micrograms/ml, except one which was inhibited at 0.125 micrograms/ml, while ciprofloxacin inhibited all isolates at 0.03 micrograms/ml. Ciprofloxacin is a safe and effective therapy for uncomplicated gonococcal urethritis, including that caused by PPNG and CMRNG in human immunodeficiency virus-infected men.

Adult↗
PubMed1989

Oestrogen potentiates topoisomerase-II-mediated cytotoxicity in an activated subpopulation of human breast cancer cells: implications for cytotoxic drug resistance in solid tumours.

Primary resistance to chemotherapeutic agents is a major problem in the management of advanced cancer. By using oestrogen to modulate the topoisomerase II content of T-47D human breast cancer cells, we show here that cell subpopulations resistant to the topoisomerase-II-interactive drug VPI6 (etoposide) can be identified and quantified using single-cell analytical techniques. Immunohistochemical studies reveal topoisomerase II to be present in approximately 10% of control cells compared with 30% of oestrogen-stimulated cells, and this difference is reflected in the proportions of cells exhibiting VPI6-induced cell-cycle delay. This moderate increase in overall cell sensitivity is accompanied by massive enhancement of clonogenic cell kill, suggesting that oestrogen enhances VPI6 cytotoxicity by recruiting a clonogenic cell subpopulation characterized by increased topoisomerase II content. Flow cytometry confirms that the increase in topoisomerase II is localized to an activated G1-phase cell subset. We conclude that (i) single-cell analysis of cellular topoisomerase II content is predictive of VPI6 chemosensitivity; (ii) the existence of resistant tumour-cell subpopulations does not necessarily indicate the presence of phenotypically divergent subclones; and (iii) rational strategies for eliminating tumour resistance may be based on biological manipulation of specific cytotoxic drug targets.

Breast Neoplasms↗
PubMed1989

Sequential effects of interleukin 2-diphtheria toxin fusion protein on T-cell activation.

The interleukin 2-diphtheria toxin-related fusion protein (IL-2-toxin) rapidly inhibits protein synthesis in IL-2 receptor (IL-2R)-bearing phytohemagglutinin-activated T cells but transiently stimulates DNA synthesis. At 7 hr after interaction with IL-2R+ phytohemagglutinin-activated T cells, IL-2-toxin-treated cells bear augmented steady-state levels of c-myc, interferon gamma, and IL-2R mRNA; these effects are indistinguishable from those produced by recombinant IL-2. Amplification of IL-2 sequences by the polymerase chain reaction reveals an increased level of IL-2 mRNA in cell cultures treated with recombinant IL-2, IL-2-toxin, and cycloheximide. These results suggest that IL-2-toxin can affect de novo IL-2 gene transcription/mRNA stabilization through independent mechanisms exerted by both the IL-2R binding domain and ADP-ribosyltransferase activity of the fusion protein. After 20 hr of culture, IL-2R mRNA was markedly decreased in both IL-2-toxin- and cycloheximide-treated phytohemagglutinin-activated T cells. Although interaction of IL-2-toxin with IL-2R+ T cells initially mimics the stimulatory effects of IL-2 upon c-myc, interferon gamma, IL-2R, and IL-2 gene expression, the consequences of inhibition of protein synthesis mediated by the ADP-ribosyltransferase activity of the toxin dominate after 7 hr and are indistinguishable from those effects mediated by cycloheximide.

Base Sequence↗
PubMed1988

Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein.

The IL-2 toxin-mediated inhibition of protein synthesis in high affinity IL-2-R-positive murine and human T cell lines has been examined. Both excess free IL-2 and mAb to the Tac epitope of the p55 subunit of IL-2-R are shown to block the action of IL-2 toxin; whereas, agents that interact with other receptors or antigens on the T cell surface have no effect. We show that IL-2 toxin, like diphtheria toxin, must pass through an acidic vesicle in order to intoxicate target T cells. Finally, we demonstrate that the IL-2 toxin-mediated inhibition of protein synthesis in both human and murine T cells that bear the high affinity IL-2-R is due to the classic diphtheria toxin fragment A-catalyzed ADP ribosylation of elongation factor 2.

ADP Ribose Transferases↗