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Biomedical subjects

B Davis

Publications and source records attributed to B Davis.

At least 73 records · Page 4Linked to original sources
PubMed1999

A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer.

This ongoing study evaluates the efficacy of oral 9-nitrocamptothecin (9NC), or RFS-2000, in the treatment of advanced pancreatic cancer. Patients received 9NC orally for 5 days/week; 8 weeks of therapy is required to achieve minimum effective dose. Starting dose was 1.5 mg/m2/day, with adjustments made as necessary. Patients were analyzed for changes in tumor size by CT scan, changes in serum CA 19-9 tumor marker levels, quality of life, and survival. 107 consecutive patients with advanced adenocarcinoma of the pancreas were enrolled before November 3, 1997. Of this group, 47 patients did not receive the minimum 2 courses of treatment necessary to induce response, leaving 60 evaluable patients. Primary dose-limiting toxicities were myelosuppression and interstitial cystitis. No deaths were attributed to 9NC. Median survival was 6.5 months for the 107 total patients and 8.7 months for the 60 evaluable patients, with one patient surviving at 44+ months. Of the 60 evaluable patients, 31.7% were responders (median survival 18.6 months; range 6.5-44.7+ months), 31.7% were stable (median survival 9.7 months), and 36.6% were non-responders (median survival 6.8 months). Fifty-seven previously untreated patients had a median survival of 7.3 months compared to 4.7 months for the 50 previously treated patients. Thirty-three patients who failed gemcitabine therapy prior to 9NC treatment had a median survival of 4.7 months. 9NC is safe and efficacious as first-line therapy for the treatment of advanced pancreatic cancer. It also shows some modest success as second-line therapy in treating gemcitabine failures.

Adult↗
PubMed1999

Hoechst 33342 induces apoptosis in HL-60 cells and inhibits topoisomerase I in vivo.

CONTEXT: Bisbenzimides (Hoechst 33342 and Hoechst 33258) are cell-permeable, adenine-thymine-specific dyes that bind to the minor groove of DNA and stain DNA. Hoechst 33342 induces apoptosis in BC3H-1 myocytes and hepatoma cells. OBJECTIVE: To determine if Hoechst 33342 or Hoechst 33258 induces apoptosis in human promyelocytic leukemia cells (HL-60) and inhibits topoisomerase I activity. DESIGN: A variety of methods were used to detect apoptosis: cell viability (trypan blue exclusion), nuclear fluorescence staining (Hoechst 33342 or Hoechst 33258 stained for 10 minutes), flow cytometric quantitation of annexin binding to phosphatidylserine, and DNA fragmentation (agarose gel electrophoresis). Topoisomerase I activity was determined by a plasmid unwinding assay. SETTING: A large teaching hospital and research laboratories. PATIENTS: None. INTERVENTION: None. MAIN OUTCOME MEASUREMENTS: Apoptosis is characterized by decreased cell viability, condensation of nuclear chromatin, increased phosphatidylserine translocation, and DNA fragmentation into oligonucleosomes composed of multiples of 180 to 200 base pairs. Inhibition of endogenous nuclear topoisomerase I is detected by the absence of plasmid unwinding from a tightly coiled to relaxed form. RESULTS: Hoechst 33342, but not Hoechst 33258, induced apoptosis in the HL-60 cells in a time- and dose-dependent manner. Endogenous nuclear topoisomerase I activity in HL-60 cells was inhibited by treatment with Hoechst 33342 but not Hoechst 33258. CONCLUSION: Hoechst 33342-induced HL-60 cell apoptosis may be related to the dye's inhibition of topoisomerase I activity.

Apoptosis↗
PubMed1998

Role of calpain in spinal cord injury: effects of calpain and free radical inhibitors.

The demonstration of increased calpain activity, immunostaining, and expression at the gene (mRNA) and protein levels concomitant with ultrastructural degeneration and loss of axon and myelin proteins in lesioned cord have implicated a pivotal role for calpain in tissue destruction in spinal cord injury (SCI). Calpain, stimulated by free radicals, also mediates apoptotic cell death. These findings suggested that the use of calpain and lipid peroxidation drugs as therapeutic agents would protect cells and maintain the axon-myelin structural unit by preventing protein degradation. In order to examine this hypothesis, we treated SCI animals with calpain inhibitors (calpeptin) and/or methlprednisolone (MP), and antiinflammatory and free-radical inhibitor. SCI (40 g/cm) was induced by weight-drop, and 1 mg calpeptin or 165 mg MP/kg were given intravenously (i.v.) for 24 hours. Untreated injured animals receiving vehicle served as controls. Lesion 68-kDa and 200-kDa neurofilament proteins (NFPs) were analyzed by sodium dodecylsulfate polyarcylamide gel electrophoresis (SDS-PAGE) and chemiluminescence, and the extent of protein loss was quantitated. Loss of protein in the lesion of untreated cord amounted to 47% compared to sham control, while that for calpeptin- or MP-treated rats was 25-30%. Combination treatment with calpeptin and MP was slightly more effective in preventing NFP degradation, compared to either when used alone. Apopotic cell death in SCI as characterized by internucleosomal DNA fragmentation was also reduced following treatment with the inhibitors. The inhibition of cytoskeletal protein degradation suggests that calpain and free-radical inhibitors may rescue cells and preserve and maintain membrane structure by preventing protein breakdown, preserving motor function, and being neuroprotective.

Animals↗
PubMed1998

Solution structure of the C-terminal SH2 domain of the p85 alpha regulatory subunit of phosphoinositide 3-kinase.

Heterodimeric class IA phosphoinositide 3-kinase (PI 3-kinase) plays a crucial role in a variety of cellular signalling events downstream of a number of cell-surface receptor tyrosine kinases. Activation of the enzyme is effected in part by the binding of two Src homology-2 domains (SH2) of the 85 kDa regulatory subunit to specific phosphotyrosine-containing peptide motifs within activated cytoplasmic receptor domains. The solution structure of the uncomplexed C-terminal SH2 (C-SH2) domain of the p85 alpha subunit of PI 3-kinase has been determined by means of multinuclear, double and triple-resonance NMR experiments and restrained molecular-dynamics simulated-annealing calculations. The solution structure clearly indicates that the uncomplexed C-SH2 domain conforms to the consensus polypeptide fold exhibited by other SH2 domains, with an additional short helical element at the N terminus. In particular, the C-SH2 structure is very similar to both the p85 alpha N-terminal SH2 domain (N-SH2) and the Src SH2 domain with a root mean square difference (rmsd) for 44 C alpha atoms of 1.09 and 0.89 A, respectively. The canonical BC, EF and BG loops are less well-defined by the experimental restraints and show greater variability in the ensemble of C-SH2 conformers. The lower level of definition in these regions may reflect the presence of conformational disorder, an interpretation supported by the absence or broadening of backbone and side-chain NMR resonances for some of these residues. NMR experiments were performed, where C-SH2 was titrated with phosphotyrosine-containing peptides corresponding to p85 alpha recognition sites in the cytoplasmic domain of the platelet-derived growth-factor receptor. The ligand-induced chemical-shift perturbations indicate the amino-acid residues in C-SH2 involved in peptide recognition follow the pattern predicted from homologous complexes. A series of C-SH2 mutants was generated and tested for phosphotyrosine peptide binding by surface plasmon resonance. Mutation of the invariant Arg36 (beta B5) to Met completely abolishes phosphopeptide binding. Mutation of each of Ser38, Ser39 or Lys40 in the BC loop to Ala reduces the affinity of C-SH2 for a cognate phosphopeptide, as does mutation of His93 (BG5) to Asn. These effects are consistent with the involvement of the BC loop and BG loops regions in ligation of phosphopeptide ligands. Mutation of Cys57 (beta D5) in C-SH2 to Ile, the corresponding residue type in the p85 alpha N-SH2 domain, results in a change in peptide binding selectivity of C-SH2 towards that demonstrated by p85 alpha N-SH2. This pattern of p85 alpha phosphopeptide binding specificity is interpreted in terms of a model of the p85 alpha/PDGF-receptor interaction.

Amino Acid Sequence↗
PubMed1998

Increased density of glutamate/N-methyl-D-aspartate receptors in putamen from schizophrenic patients.

Saturable radioligand binding of [3H]L-689,560 to the glycine site of the N-methyl-D-aspartate (NMDA) glutamate receptor complex was employed to determine the density of this receptor in putamen, caudate and nucleus accumbens taken post mortem from schizophrenic patients and matched controls. Receptor density was found to be significantly increased in putamen of schizophrenics (P=0.012), although no significant change was found in the other two areas studied. Further experiments following 21 days administration of haloperidol to rats provided no evidence that the increase was related to prior drug treatment.

Animals↗
PubMed1998

Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients.

Fifty-one transfusion-dependent iron-loaded adult patients (38 with thalassemia major) were treated with the orally active iron chelator deferiprone (1,2 dimethyl-3-hydroxypyrid-4-one, L1) at a dose of 75 mg/kg/d (range, 50 to 79). Twenty patients discontinued the drug and five died after a mean of 18.7 months (range, 4 to 35). Of the 20, 5 had arthropathy, 5 had gastrointestinal symptoms, 4 had a rising serum ferritin, 3 had agranulocytosis or neutropenia, 1 had tachycardia, 1 had renal failure, and 1 went abroad. Twenty-six patients continued deferiprone for a mean of 39.4 months (range, 12 to 49). Among these patients, there was no overall significant change in serum ferritin (initial mean, 2,937 microg/L; range, 980 to 5,970; final mean, 2,323 microg/L; range, 825 to 5,970) or in urine iron excretion (initial mean, 31.2 mg/24 h; range, 16.3 to 58. 2; final mean, 32.1 mg/24 h; range, 9.4 to 75.8), implying no overall change in iron stores. When the patients who had received deferiprone for longer than 3 years were considered separately, there was also no significant change in serum ferritin or urinary iron excretion. The initial serum ferritin levels in the 26 patients who continued deferiprone treatment were significantly lower than in those who discontinued the drug (P < .01). The liver iron content in 17 patients who had received deferiprone for 24 to 48 months ranged from 5.9 to 41.2 mg/g dry weight, 50% having levels above 15.0 mg, a level associated with a high risk of cardiac disease due to iron overload. In this study the drug caused fewer side effects and was more effective at maintaining iron status among patients previously well chelated and with lower initial serum ferritin levels.

Adult↗
PubMed1998

Interactional processes in families with depressed and non-depressed adolescents: reinforcement of depressive behavior.

Problem-solving interactions were observed in 86 families of depressed adolescents and 408 families of non-depressed adolescents. Sequential analyses indicated that mothers of depressed adolescents were more likely than mothers of non-depressed adolescents to increase facilitative behavior in response to adolescent depressive behavior. Additionally, fathers of depressed adolescents were more likely than their counterparts in families of non-depressed adolescents to decrease aggressive behavior subsequent to adolescent depressive behavior. These analyses suggest that parents of depressed adolescents may be inadvertently reinforcing depressive behavior. Decreases in adolescent depressive symptomatology from year 1 to year 2 were not accompanied by changes in family interaction patterns.

Adolescent↗
PubMed1998

The incidence of ophthalmologic interventions in children with birth weights less than 1251 grams. Results through 5 1/2 years. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

OBJECTIVE: This study aimed to report the frequency of ophthalmologic surgical and medical therapies provided to children with birth weights less than 1251 g who had all stages of retinopathy of prematurity (ROP). In addition, this study aimed to report the initial age at which such procedures are provided and to report the frequency of cerebrospinal fluid shunts. DESIGN: Observational case series with prospective data collection. PARTICIPANTS: Children from the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) with birth weights less than 1251 g served as subjects. Group A included 257 children from all 23 CRYO-ROP study centers who had threshold ROP, who had participated in the randomized trial of cryotherapy, and who had survived to age 1 year. Group B included 1208 children from 5 of the 23 study centers who had varying severity of ROP (69 had threshold ROP) and who had participated in a 5 1/2-year study of the natural history of ROP. MAIN OUTCOME MEASURES: Investigators documented medical and surgical ophthalmologic interventions through age 5 1/2 years as well as cerebrospinal fluid shunting surgery for hydrocephalus through age 2 years. RESULTS: Group A was composed of 257 children with threshold ROP who underwent 226 ocular interventions in addition to cryotherapy (0.9 intervention per child). The most common treatments performed on the randomized cohort of children were vitrectomy (26% of patients), lensectomy (18%), amblyopia therapy (20%), and strabismus surgery (10%). Cataract surgery not associated with vitrectomy was performed infrequently (2%) and was performed equally often in treated and control eyes. Amblyopia therapy was prescribed as often for treated as for control eyes. Cerebrospinal fluid shunts were placed in 11% of these children. Group B was composed of 1208 natural history patients who underwent 239 ophthalmologic interventions (0.4 intervention per child). Strabismus surgery was the most commonly performed procedure for the natural history cohort of children (6% of the children). Amblyopia therapy was prescribed for 7% of the natural history patients. Cerebrospinal fluid shunts were required by 3% of the natural history infants, more often in children with more severe ROP. CONCLUSIONS: These premature infants underwent a large number of ophthalmologic treatments during the first 5 1/2 years of life. The long-term costs of both extreme prematurity and ROP include not only the initial ablative therapy for ROP and societal loss due to blindness that still occurs in some cases, but also the ongoing costs of caring for eye problems.

Amblyopia↗
PubMed1998

NMR analysis of the N-terminal SRCR domain of human CD5: engineering of a glycoprotein for superior characteristics in NMR experiments.

CD5 is a type-I transmembrane glycoprotein found on thymocytes, T-cells and a subset of B-cells. The extracellular region consists of three domains belonging to the scavenger receptor cysteine-rich (SRCR) superfamily for which the three-dimensional polypeptide fold is as yet unknown. Glycosylated CD5 domain 1 (CD5d1) has been obtained by expression by secretion from both Chinese hamster ovary (CHO) cells and Pichia pastoris. Recombinant CD5d1 expressed in this manner was shown to be correctly folded by binding to anti-CD5 L17F12/Leu1 monoclonal antibody. Preliminary nuclear magnetic resonance (NMR) spectra obtained for CD5d1 (residues 1-118) had spectral dispersion typical of a folded protein, but otherwise of such poor quality that NMR structural studies were not feasible. The analysis of glycoproteins by NMR is frustrated by sample heterogeneity and poor spectral quality associated with glycan resonance overlap and the potential for increased line-widths due to the large hydrodynamic volume. In order to pursue NMR structural studies of CD5d1 it was necessary to optimize the quality of NMR spectra of CD5d1. A range of constructs of varying length and carbohydrate content were expressed in CHO cells and in P. pastoris. In addition the P. pastoris CD5d1 proved susceptible to N-glycan cleavage with endoglycosidase H. The protein products were characterised using size exclusion chromatography, NMR measurement of translational self-diffusion coefficients and two-dimensional 1H nuclear Overhauser effect spectroscopy experiments. Removal of an eight residue O-glycosylated C-terminal peptide, in particular, resulted in significant improvements in the quality of the CD5d1 NMR data, while retaining native protein structure. Two-dimensional heteronuclear NMR spectroscopy of nitrogen-15 isotope labelled deglycosylated CD5d1 (residues 1-110) prepared from P. pastoris suggests that this protein product is now amenable to solution structure determination.

Amino Acid Sequence↗
PubMed1998

A lasting public health response to an outbreak of HIV infection in a Scottish prison?

Between April and June 1993, 8 cases of acute clinical hepatitis B infection and 2 seroconversions to HIV infection were detected among drug injecting inmates of HM Prison Glenochil in Scotland. To prevent the further spread of infection, an initiative which involved counselling and voluntary attributable HIV testing was conducted over a 10-day period commencing at the end of June. A team of 18 counsellors and phlebotomists was brought together rapidly as part of a unique organizational exercise in the field of public health. Fourteen cases of HIV infection were identified of which 13 were almost certainly infected in Glenochil. Following the exercise, a range of harm reduction measures for injecting prisoners was introduced; these included the availability of hepatitis B vaccine, provision of bleach tablets which could be used to clean injecting equipment, a methadone detoxification programme, increased training for prison officers and improved access to drug and harm minimization counselling for inmates. By mid-1996 all these measures had been sustained and several could be found in many other prisons throughout Scotland. Follow-up investigations showed no evidence of epidemic spread of HIV during the 12 months after the initiative. While the frequency of injecting and needle/syringe sharing may have decreased over the last 3 years, these activities are still being reported and it is highly likely that transmissions of bloodborne infections, in particular hepatitis C, continue to occur. The surveillance and prevention of infections associated with injecting drug use in the prison setting remain a high public health priority.

Disease Outbreaks↗
PubMed1998

Sensory deprivation and chronic pain: a review of the literature.

AIMS AND OBJECTIVES: The aim of this paper is to explore the literature into the use of 'Snoezelen' (Sensory Stimulation) for the management of chronic pain. Within the literature there are a number of research studies which have investigated the concept of sensory deprivation and these are considered. The studies indicate the potential of sensory input as a field of research in particular relation to the care of patients within hospital settings where they are removed from their 'normal' level of sensory input and could subsequently experience sensory deprivation. The relationship between sensory restriction and chronic pain is emphasized. This links with investigations of sensory stimulation (Snoezelen) as a potential strategy for the management of chronic pain. CONCLUSIONS: In conclusion, it is suggested that sensory deprivation cannot exist and the term 'sensory restriction' would be more appropriate. It is proposed that there is a need to develop a tool to assist carers in identifying the existence of sensory restriction in their specific client groups to provide a basis for intervention.

Adult↗