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Biomedical subjects

P Cook

Publications and source records attributed to P Cook.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cranial computed tomographic findings in tuberous sclerosis are not affected by sex.

Males with the tuberous sclerosis complex (TSC) have been shown to be more at risk of learning disorder than females. A retrospective population based study was undertaken to see if males with TSC have more cerebral lesions than females. 47 of 131 individuals with TSC identified in a prevalence study had a cranial CT scan available for review. No significant difference between the sexes was found in the number of subependymal nodules or the number, site or size of parenchymal lesions. However, males with five or fewer parenchymal lesions were at greater risk of learning disorder than females. The increased risk of learning disorder in males with tuberous sclerosis is not accounted for by an increase in number, site or size of cranial lesions as seen on CT scans. Therefore there must be an alternative mechanism to account for this difference between the sexes.

Adult↗
PubMed1996

Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells.

When isolated from cells grown under hormone-free conditions, the glucocorticoid receptor (GR) is known to exist as a large heteroprotein complex that contains, among its multiple components, the stress protein hsp90 (heat shock protein 90). To explore hsp90's role in mediating glucocorticoid hormone action, we have examined the effects of a selective hsp90-binding agent, geldanamycin (GA), or GR structure and function. Using a steroid-responsive reporter construct, we found that GA inhibited the dexamethasone-dependent transactivating activity of GR in transfected cells. At the molecular level, GA bound hsp90, but not GR, in a stable and specific manner in intact cells. GA treatment of cells did not inhibit coprecipitation of hsp90 or hsp70 with the GR but did result in a complete loss of the recently described p23 protein from GR immunoprecipitates. This drug-induced alteration in GR heteroprotein complex composition was associated with a rapid (15-30 min), noncompetitive loss of dexamethasone-binding activity. Longer exposures of cells to GA (2-8 h), resulted in a marked decline in the cellular level of GR protein. Pulse-chase data revealed that this decline resulted from a decrease in GR protein stability, not rate of synthesis. GA-induced declines in GR protein level were blocked by cotreatment of cells with lactacystin, a selective inhibitor of 20S proteasome activity, suggesting the possible involvement of the ubiquitin-proteasome pathway in mediating GA-induced decreases in GR protein abundance. Overall, these findings provide direct pharmacological evidence that hsp90 function is required to maintain both the hormone-binding activity and stability of the GR protein in intact cells and suggest that hsp90 function may provide a novel target for the modulation of steroid hormone signaling.

3T3 Cells↗
PubMed1996

Response of human multiple myeloma-derived cell lines to alkyl-lysophospholipid.

Clinical studies using high-dose chemotherapy and autologous bone marrow transplantation in multiple myeloma report improvement in tumor regression. The potential success of this approach may be compromised because of the myeloma cell burden. A promising approach is chemopurging of bone marrow with alkyl-lysophospholipids (ALP), a new class of antitumor agents. Using a limiting dilution assay, we tested ALP against several drug-resistant human myeloma cell lines: RPMI 8226/S, 8226/DOX40, 8226/LR-5, 8226/MR-20, 8226/DOX1V, and 8226/MDR10V. IC50 values were approximately 6 microg/mL, for all cell lines evaluated. ALP was effective against all cells, with mean log kills ranging from 2.48 to 4.95. Cytotoxicity was temperature-dependent. Survival curves of cell lines exposed to ALP showed a steep slope during the first 4 hours of exposure, with little additional cell kill after 24 hours. Dose-response curves after drug exposure for 4 and 24 hours reached plateaus at 75 and 25 microg/mL, respectively. Increasing concentrations of ALP caused a sustained increase in resting [Ca2+]i of sufficient magnitude to induce cell death. These results suggest that ALP is an effective cytotoxic agent even in cells known to be resistant to alkylating agents and other classes of cytotoxic drugs.

Antineoplastic Agents, Alkylating↗
PubMed1995

Replicative advantage in tissue culture of egg-adapted influenza virus over tissue-culture derived virus: implications for vaccine manufacture.

Influenza virus derived from clinical material on MDCK cells has been shown to possess haemagglutinin (HA) indistinguishable from that of the natural, uncultivated virus. In contrast, viurs derived in embryonated hens' eggs are variants with substitutions in their HA in the vicinity of the receptor binding site. We report here the superior growth of egg-adapted virus over cell-derived virus on MDCK cells in studies in which MDCK-derived virus was spiked with small amounts of egg-adapted virus and the mixture sequentially passaged on MDCK cells. Such egg-derived variants bind to and are internalized by MDCK cells with a much higher efficiency than cell-derived virus. These data imply that the natural virus, whilst able to replicate on MDCK cells, is by no means the best fit for the MDCK receptor and variants with appropriate substitutions around the receptor binding site can readily displace the natural virus. Vaccine manufacturers who are investigating the use of tissue culture for vaccine production should minimize passage levels of cell-derived virus and beware of the displacement of the original virus with variants similar to those derived in eggs, which are often antigenically distinct.

Animals↗
PubMed1995

Changes in mucociliary clearance during and after isocapnic hyperventilation in asthmatic and healthy subjects.

Hyperpnoea with dry air could lead to a reduction in depth and hyperosmolarity of the periciliary fluid layer (PFL) as a consequence of evaporative water loss. We investigated whether mucociliary clearance (MCC) is likely to be affected by dry air hyperpnoea, which also results in airway narrowing in asthmatics. MCC was measured by radioaerosol technique, for about 1 h, in 10 asthmatic and 8 healthy subjects on 3 separate days: 1) nasal resting breathing with ambient air; 2) isocapnic hyperventilation (ISH) with dry air; and 3) ISH with warm humid air. Analysis of the initial and post-intervention lung radioactivity for the whole right lung and for defined regions of interest showed that, compared to ISH with warm humid air and nasal resting breathing, MCC was reduced during and increased post-ISH with dry air in the whole right lung of both groups. The mean reduction in clearance (+/- 95% confidence interval (95% CI)) was -9.3% (-3.1 to -15.6%) and -3.6% (-2.0 to -9.1%), and the mean increase (+/- 95% CI) was 19.2% (11.8 to 26.6%) and 14.8% (7.1 to 22.5%), compared to warm humid air, in asthmatic and healthy subjects, respectively. However, regional analysis showed that the changes were present in all lung regions of the asthmatics, whilst only in the central region of the healthy subjects. The duration of the increased clearance rates post-ISH was also different in both groups. The changes in mucociliary clearance during and after isocapnic hyperventilation with dry air was probably related to the water content of the inspired air, causing transient changes in the periciliary fluid layer.

Adult↗
PubMed1995

Phorbol ester treatment of U937 cells with altered protein kinase C content and distribution induces cell death rather than differentiation.

Overexpression of protein kinase C (PKC)-zeta, an atypical PKC isoform, in U937 cells stimulates certain parameters of phenotypic maturation and increases expression of endogenous alpha and beta PKC isoforms. In response to 12-O-tetradecanoylphorbol-13-acetate (TPA), parental U937 cells displayed growth arrest and differentiated into a monocyte/macrophage-like cell line, while PKC-zeta cells underwent death. The ability of GF109203X to inhibit TPA-induced death of PKC-zeta cells suggested that activation of a conventional isoform was necessary to induce apoptosis. While exhibiting unique morphological changes, parameters indicative of a further degree of differentiation were not observed in TPA-treated PKC-zeta cells. TPA-induced down-regulation of PKC activity was similar in both cells. While modest quantitative differences in individual isoform down-regulation existed, intracellular localization of isoforms prior to activation differed significantly between U937 and PKC-zeta cells. Expression of gadd45 was induced by TPA in PKC-zeta but not parental cells and occurred as a primary response to TPA and prior to the onset of cell death. These data suggest that the decision of a cell to undergo death or differentiation in response to phorbol esters may, in part, be modulated by alterations within the PKC signal transduction pathway.

Antigens, CD↗
PubMed1994

Auto- and cross-induction within the mammalian epidermal growth factor-related peptide family.

Several polypeptide growth factors related to epidermal growth factor (EGF) have been identified recently, including transforming growth factor-alpha (TGF-alpha), amphiregulin (AR), heparin-binding EGF-like growth factor (HB-EGF), and betacellulin (BTC). These peptides all bind to the EGF receptor (EGFr). In an effort to understand redundancy within this peptide family and interactions among these related peptides, we compared the biological activities of EGF, TGF-alpha, AR, and HB-EGF in an EGF-responsive, nontransformed intestinal epithelial line (RIE-1) and also determined the effect of individual EGF-related peptides on the expression of related family members in these cells. TGF-alpha, AR, HB-EGF, and EGF were equipotent in stimulating [3H]thymidine incorporation by RIE-1 cells and bound the EGFr with equivalent affinity. Each EGF-related peptide induced the mRNA expression of the remaining family members, including BTC. HB-EGF and AR mRNAs were induced rapidly (within 30 min) and to a greater extent than TGF-alpha and BTC mRNAs, suggesting heterogeneity in the molecular mechanisms for induction. This same pattern was observed for all EGF-related peptides tested. A similar pattern of mRNA induction was observed in secondary cultures of human keratinocytes and in LIM1215 colon adenocarcinoma cells. Nuclear run-on analysis showed that induction of AR and HB-EGF is, at least in part, regulated at the level of gene transcription. Concurrent treatment with HB-EGF and cycloheximide resulted in superinduction of HB-EGF and AR, suggesting that these peptides are immediate early genes in RIE-1 cells. Our results demonstrate an equivalent biological response to EGF-related peptides in RIE-1 cells and further indicate that extensive auto-induction and cross-induction occur within the EGF-related peptide family in several EGF-responsive epithelial cell types.

Amphiregulin↗
PubMed1994

Adenosine in the termination of albuterol-induced supraventricular tachycardia.

Five percent of children in the United States have asthma. Status asthmaticus is one of the most common conditions for which children seek care in a pediatric emergency department. beta 2-Agonists such as albuterol are the mainstay of emergency therapy for such children. We present a case of a 4-year-old boy who experienced supraventricular tachycardia (SVT) following albuterol therapy. This is believed to be the first report of adenosine being successfully used to treat a child with albuterol-induced SVT. We also briefly review the recognition and management of SVT in children and the pharmacokinetics of and indications for adenosine.

Adenosine↗
PubMed1994

Mixed populations in influenza virus vaccine strains.

Human influenza viruses used for vaccine production have previously been adapted to grow in eggs. During egg adaptation, variants are selected and we have observed that more than one variant may derive in a single egg resulting in a mixed population. We have now investigated the extent of heterogeneity, due to host cell selection, of virus strains used for the manufacture of influenza vaccine for the 1991/1992 and 1992/1993 seasons. The A(H1N1) vaccine virus was homogeneous with respect to substitutions in the haemagglutinin deriving from egg adaptation. However, two A(H3N2) vaccine strains and the influenza B component, B/Yamagata/16/88, consisted of mixed populations, apparently due to their cultivation in eggs. The individual variants within B/Yamagata were isolated and found to be antigenically distinct. The ratios of these variants within different manufacturers' seed stocks varied to the extent that vaccine derived from them could be distinguished antigenically. Furthermore, derivation of high-growth reassortants from the A(H3N2) strains which involves passaging at limit dilution did not necessarily lead to a homogeneous virus population. The significance of these findings for the efficacy of vaccine is not known at present.

Base Sequence↗
PubMed1994

Outbreak of vancomycin-, ampicillin-, and aminoglycoside-resistant Enterococcus faecium bacteremia in an adult oncology unit.

An outbreak of bacteremia caused by Enterococcus faecium with high-level resistance to vancomycin (MIC of > or = 256 micrograms/ml), ampicillin (MIC of > or = 64 micrograms/ml), and gentamicin or streptomycin (MIC of > or = 2,000 micrograms/ml) occurred in an adult oncology unit from June 1991 to May 1992. Active surveillance for the presence of this organism in stool or perianal cultures was begun in September 1991. Between June 1991 and May 1992, seven patients with bacteremia and 22 noninfected carriers of the organism in stool were identified. The vanA gene, tested for by PCR and gene probe, was present in all isolates evaluated. All bacteremic patients also had resistant E. faecium present in a stool or perianal culture; the stool isolates tested were closely related to the respective blood isolates as determined by pulsed-field gel electrophoresis. Antibiotic regimens using high-dose ampicillin and an aminoglycoside were ineffective with four patients. Five patients (71%) had multiple positive blood cultures; four of these patients died. Following a multiple logistic regression analysis, it was found that bacteremic patients received a significantly greater number of total antibiotic days compared with noninfected stool carriers (P = 0.019). The emergence of E. faecium with high-level resistance to vancomycin, ampicillin, and aminoglycosides underscores the importance of performing susceptibility testing on all clinically significant isolates. In the neutropenic adult oncology patient, bacteremia with this organism is of probable gastrointestinal origin, is often persistent, and is refractory to treatment with ampicillin in combination with an aminoglycoside. Prolonged use of antibiotics may predispose patients with gastrointestinal colonization to develop bacteremia.

Adult↗
PubMed1994

Incidence and treatment of tumor lysis syndrome in patients with acute leukemia.

Tumor lysis syndrome (TLS) is a complication associated with electrolyte abnormalities that is observed in patients with acute leukemia who are receiving intense doses of chemotherapy. Forty-one patients with acute leukemia were treated with high-dose combination chemotherapy and were evaluated for TLS. A grading system developed for the evaluation of these patients was applied. Grade I tumor lysis was observed in 22 patients, grade II TLS in 2 patients and grade III in 1 patient. All patients were treated with intravenous fluids, mannitol, allopurinol and in some patients, aluminum-based antacids. Treatment for TLS prior to intensive chemotherapy reduced morbidity and mortality associated with high-dose chemotherapy for acute leukemias.

Adolescent↗
PubMed1994

Mucociliary clearance in patients with cystic fibrosis and in normal subjects.

The aim of this study was to examine baseline mucociliary clearance (MCC) in patients with cystic fibrosis (n = 30; mean +/- SEM age, 23 +/- 1 yr; FEV1, 68 +/- 5% pred; range, 14 to 126%) and a group of normal subjects (n = 12; mean age, 27 +/- 1 yr) after an aerosol deposition of 99mTc-sulphur colloid (mass median diameter, 4.8 microns; geometric standard deviation, 1.6). Dynamic geometric mean images were formed from gamma camera data, and the percent clearance of activity after 60 min (%C60) was calculated for the whole right lung. Initial deposition of the aerosol was determined in terms of the penetration index, the ratio of peripheral to central activity. For normal subjects, an increase in mean inspiratory flow rate (MIFR) (49 +/- 5 versus 21 +/- 3 L/min, p < 0.05) resulted in an increase in whole right lung MCC (%C60, 31 +/- 4 versus 18 +/- 2%; p < 0.05). When aerosol delivery was controlled (MIFR, 34 +/- 5 versus 36 +/- 5 L/min), there was excellent reproducibility between studies (whole lung %C60, 34 +/- 8 versus 31 +/- 7; NS). The measurement of MCC was highly reproducible in six patients studied on four occasions with a mean coefficient of variation of 3.3 +/- 1%. A breathing pattern to accentuate central deposition was utilized in the patient studies (MIFR, 49 +/- 4 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Status of quantitative EEG (QEEG) in clinical practice, 1994.

Clinical quantitative EEG (qEEG) is a complex specialty that may include not only standard EEG but also digital ("paperless") EEG, topographic mapping, spectral analysis, spectral coherence, long latency and event related potentials (EP), significance probability mapping (SPM), dipole source localization methodology (DLM), and discriminant function analysis. There are three basic clinical uses: non-specific detection of organicity/encephalopathy, specific categorization of disease or clinical condition, and epileptic source localization. Extreme variations exist in the competency of laboratories practicing clinical qEEG; universally agreed upon standards of practice have not been established but there are a number of efforts to do so. As expected, the clinical value of qEEG to patients varies similarly. Criticisms of qEEG have now been answered: Color displays need not be deceptive. Statistical "capitalization upon chance" can be easily avoided. By training and with newer analytic procedures, artifacts can be recognized and often removed. Data based upon spectral analysis and EP can reliably classify clinical conditions thereby demonstrating a greater sensitivity to EEG/EP data than possible by conventional visual inspection. QEEG is clearly of clinical value when performed in concert with standard EEG and analyzed by clinicians with demonstrated competency in standard EEG followed by specialized training and demonstrated competency in qEEG. QEEG is not a simple substitute for conventional EEG and cannot be seen as a substitute for clinical competence. Although continuing to develop, qEEG technology has matured sufficiently and is now well established. Concerns regarding its clinical use have primarily resulted from its misapplication and misinterpretation stemming, largely, from inadequate personnel training and expertise.

Brain Mapping↗
PubMed1994

Regional deposition of nebulized hypodense nonisotonic solutions in the human respiratory tract.

Deposition of nonisotonic therapeutic and diagnosis aerosols can cause changes in airway fluid composition and bronchoconstriction in sensitive subjects. "Hypodense" aerosols containing a relatively low concentration of droplets in the carrier air were used in the studies of regional deposition of radiolabelled nebulized solutions of hypo- and hypertonic saline, in order to investigate whether the number of droplets per volume of carrier can affect deposition. Solutions with and without 0.5% nedocromil sodium were nebulized in order to examine the effects of a potential modifier of the rates of heat and mass transfer. The deposition was quantified using penetration index (PI) calculated from images obtained by single photon emission computerized tomography (SPECT) in 11 healthy volunteers per study. There was an increase in the penetration index (10.9%, for the saline only; 15.5%, for the nedocromil study) of the hypotonic compared to the hypertonic aerosol, although the initial size distribution of both types of aerosols was very similar (mass median aerodynamic diameter (MMAD) 3.7 and 3.8 microns; geometric standard deviation (GSD) 1.8 and 1.5 for the hypo- and hypertonic aerosols, respectively). The present results confirm the effects of tonicity on deposition of aerosols found in a parallel study reported in this issue of the Journal. They also give support to the theory that, in addition to the concentration of the nebulized solutions, the number of droplets per volume of the carrier air is a factor affecting deposition of aqueous aerosols. The presence of 0.5% nedocromil sodium in the solutions did not appear to interfere with the processes of heat and water transfer in the airways.

Adult↗
PubMed1994

Allogeneic marrow transplantation for myelodysplastic syndrome complicating autologous bone marrow transplantation.

A patient with refractory relapsed Hodgkin's disease underwent an autologous bone marrow transplant in July 1987 and achieved remission of Hodgkin's disease. He had complete hematological recovery but developed pancytopenia 3 years post bone marrow transplantation with morphological evidence of myelodysplasia. High-dose cyclophosphamide, 200 mg/kg, chemotherapy followed by an allogeneic bone marrow transplant from a HLA-matched sibling was performed in April 1991 with complete hematological recovery. Allogeneic bone marrow transplantation was thus used successfully to treat a potential complication of autologous bone marrow transplantation.

Adult↗
PubMed1994

Treatment of gancyclovir resistant cytomegalovirus with foscarnet: a report of two cases occurring after bone marrow transplantation.

Cytomegalovirus (CMV) infection is common in patients who undergo allogeneic bone marrow transplantation. Gancyclovir is useful in treating CMV infections. Resistance to gancyclovir is rare and has, thus far, not been reported in the setting of BMT. Two patients with CMV infections unresponsive to gancyclovir were successfully treated with foscarnet. 10-15% of CMV infections are resistant initially or develop resistance to gancyclovir. Both patients had an adequate trial of gancyclovir and resistance developed over time. While we did not document resistance in the laboratory there was dramatic clinical improvement with foscarnet.

Adult↗