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Biomedical subjects

J Whelan

Publications and source records attributed to J Whelan.

At least 91 records · Page 5Linked to original sources
PubMed1996

Role of image-guided core-needle biopsy in the management of patients with lymphoma.

PURPOSE: The results of 106 radiologically guided core needle biopsies in 96 patients were analyzed retrospectively to evaluate the accuracy, safety, and role of this technique in the management of patients with lymphoma and to determine factors predictive of success. PATIENTS AND METHODS: Biopsies were performed in 51 patients with low-grade non-Hodgkin's lymphoma (NHL), 24 with high-grade NHL, 16 with previously diagnosed Hodgkin's disease (HD), and 15 with no previous history of lymphoma. Disease was infradiaphragmatic in 92 patients and supradiaphragmatic in 14. Computed tomography (CT) guidance was used in 98 biopsies and ultrasonography (US) in eight. RESULTS: The biopsy was diagnostic and yielded information on the basis of which treatment was started in 88 of 106 patients. The procedure was well tolerated and there were no major complications. Small size of the sample or inappropriate tissue sampled were the main causes of failure. The technique was equally successful in the diagnosis of HD and both high-grade and low-grade NHL as in nonlymphoproliferative disorders. The procedure was equally successful at diagnosis as at suspected recurrence or progression. In 33 of 80 cases in which the biopsy was performed at the time of recurrence or progression, the histology had changed; in 31 of 33, this influenced treatment. The technique was efficient at diagnosing transformation of follicular NHL in 16 of 18 patients, which allowed early adjustment of treatment at recurrence. CONCLUSION: At St Bartholomew's Hospital (SBH), image-guided core-needle biopsy has proven to be a quick, safe, and efficient alternative to excisional biopsy in the evaluation of lymphoproliferative disorders at presentation, recurrence, or progression. It should become the procedure of choice for histologic sampling in the absence of peripheral lymphadenopathy.

Adolescent↗
PubMed1996

Selectin synthesis and inflammation.

The selectins are a family of three cell-surface-presented glycoprotein receptors. They play a key role in the initial adhesive interaction between leukocytes and endothelial cells at sites of inflammation. The presence of selectins on the cell surface is tightly regulated and inappropriate appearance is associated with a number of inflammatory disease conditions.

Amino Acid Sequence↗
PubMed1995

Dietary n - 3 polyunsaturated fatty acids modify Syrian hamster platelet and macrophage phospholipid fatty acyl composition and eicosanoid synthesis: a controlled study.

The aim of this study was to determine the effects of varying intakes of dietary n - 3 polyunsaturated fatty acids (PUFA) on the fatty acyl composition and arachidonic acid metabolite synthesis of platelets and macrophages in Syrian hamsters consuming diets that were strictly controlled for n - 6 PUFA content. Animals consumed highly controlled diets which were not supplemented with n - 3 PUFA (control) or supplemented with 0.4%, 0.8% or 2% (w/w) n - 3 fatty acids. The content of n - 3 PUFA in cellular phospholipids increased progressively with the intake of n - 3 PUFA, while n - 6 PUFA, including arachidonic acid, decreased despite the constant intake of 18:2(n - 6); this latter effect was more substantial in macrophages than in platelets. The synthesis by stimulated macrophages of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 and 11- and 15-hydroxyeicosatetraenoic acids decreased with the intake of 0.8% n - 3 PUFA to 30-50% of the control values. Little effect of diets on platelet aggregation and eicosanoid synthesis was observed reflecting the limited effect on platelet arachidonic acid content. The synthesis of 12-hydroxyeicosapentaenoic acid by stimulated platelets increased with n - 3 PUFA consumption in a dose-dependent fashion. Circulating triacylglycerols and HDL-cholesterol were decreased only in animals consuming 2% n - 3 PUFA. The strict control of n - 6 PUFA intake allows the determination of the effects of n - 3 PUFA intake on the measured parameters without confounding effects of other dietary lipids.

Animals↗
PubMed1995

Studies on the import and processing of the alternative oxidase precursor by isolated soybean mitochondria.

Import of the synthetic precursor of the alternative oxidase from soybean was shown to be dependent on a membrane potential and ATP. The membrane potential in soybean mitochondria may be formed either by respiration through the cytochrome pathway, or through the alternative oxidase pathway with NAD(+)-linked substrates. Import of the alternative oxidase precursor in the presence of succinate as respiratory substrate was inhibited by KCN. Import in the presence of malate was insensitive to KCN and SHAM added separately, but was inhibited by KCN and SHAM added together (inhibitors of the cytochrome and alternative oxidases respectively). Import of the alternative oxidase was accompanied by processing of the precursor to a single 32 kDa product in both cotyledon and root mitochondria. This product had a different mobility than the two alternative oxidase bands detected by immunological means (34 and 36 kDa), suggesting that the enzyme had been modified in situ. When the cDNA clone of the alternative oxidase was modified by a single mutation (-2 Arg changed to -2 Gly), the processing of the precursor was inhibited.

Amino Acid Sequence↗
PubMed1995

Evidence that dietary arachidonic acid increases circulating triglycerides.

Male Syrian hamsters and male CD-1 mice were fed diets supplemented with ethyl esters of oleic, linoleic, arachidonic, and eicosapentaenoic acids (1.1-5%, w/w) for 3-4 wk. Plasma and serum triglycerides were significantly higher in the arachidonic acid-supplemented animals compared to those in the other supplementation groups. Changes in serum insulin and glucose levels did not appear to be related to the changes in circulating triglycerides observed in the arachidonic acid-supplemented group. These data indicate that dietary arachidonic acid elevates circulating triglyceride levels compared to other unsaturated fatty acids in hamsters and mice by unknown mechanisms.

Animals↗
PubMed1995

The isolation and characterisation of a gene encoding superoxide dismutase from Bradyrhizobium sp. (Parasponia) strain ANU289.

Bradyrhizobium sp. (Parasponia) strain ANU289 expresses a single Mn-SOD in both the vegetative and symbiotic states. A 500 bp sod-homologous sequence was amplified from genomic DNA of strain ANU289 using PCR. A 1.3 kb SalI fragment was subsequently cloned which contained an ORF, sodA, encoding a 23 Kd protein. This putative SOD shares considerable homology with other Mn-SODs and analysis of the sodA sequence predicts that it is expressed. A lacZ-sodA fusion complemented the SOD-deficiency of E. coli QC779 and resulted in the expression of SOD activity in both mutant and wild type E. coli. We conclude that sodA encodes the Mn-SOD of strain ANU289.

Amino Acid Sequence↗
PubMed1994

Inhibition of E-selectin gene transcription through a cAMP-dependent protein kinase pathway.

Cytokines induce the expression of E-selectin, VCAM-1, and ICAM-1 on human umbilical vein endothelial cells (HUVECs). We show that expression of these surface proteins is differently affected by cAMP. Increased cAMP levels decrease E-selectin and VCAM-1 but increase ICAM-1 expression. We demonstrate by mRNA half-life analysis and nuclear run-on assays that the cAMP repression of E-selectin occurs at the transcription level. This effect is abolished by protein kinase A inhibition, suggesting that repression is mediated by protein kinase A-driven phosphorylation. We found that a minimal E-selectin promoter sequence necessary to confer cytokine inducibility is also sufficient to mimic the cAMP effect in transfected HUVECs. Previously we characterized two regions (NF-kappa B and NF-ELAM1) of the minimal promoter that bind transcription factors necessary for E-selectin induction, Increased cAMP did not alter the binding of the complexes formed on either the NF-kappa B or NF-ELAM1 site. In contrast, in interleukin-1-treated HUVECs transactivity due to an NF-kappa B site is reduced by elevated cAMP. Increased cAMP in HUVECs appears to induce a protein kinase activity that reduces the cytokine signal for E-selectin and VCAM-1 expression. The reduction in signal may occur through an inhibitory phosphorylation of one or more of the factors responsible for regulating E-selectin expression.

Base Sequence↗
PubMed1994

ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms.

ATF3 is a member of the mammalian activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors. In this report, we demonstrate that, contrary to the implication of its name, ATF3 represses rather than activates transcription from promoters with ATF sites. We also present evidence suggesting that one possible mechanism by which ATF3 represses transcription is to stabilize inhibitory co-factors at the promoter. In addition, we describe a naturally occurring, alternatively spliced, form of ATF3: ATF3 delta Zip. ATF3 delta Zip lacks the leucine zipper domain and does not bind to DNA. In contrast to ATF3, ATF3 delta Zip stimulates transcription, presumably by sequestering inhibitory co-factors away from the promoter. It is possible that ATF3 delta Zip is a physiologically important regulator and that it, together with ATF3, regulates the expression of specific target genes.

Activating Transcription Factor 3↗
PubMed1994

Import of the mammalian cytochrome P450 (scc) precursor into plant mitochondria.

According to previous reports (Matocha M. F. and Waterman M. R. (1984) J. Biol. Chem. 259, 8672-8678 and (1986) Arch. Biochem. Biophys. 250, 456-460) import of the cytochrome P450 (scc) precursor into mitochondria is tissue-specific. The present paper shows that in vitro synthesized bovine cytochrome P450 (scc) precursor can be imported into isolated soybean cotyledon mitochondria and processed therein to the mature size product. This shows that heterologous import of the cytochrome P450 (scc) precursor is possible and that import into mitochondria of this precursor is not restricted to steroidogenic tissues.

Animals↗
PubMed1994

ATF-a0, a novel variant of the ATF/CREB transcription factor family, forms a dominant transcription inhibitor in ATF-a heterodimers.

We have isolated a cDNA encoding a variant of the transcription factor ATF-a (called ATF-a0) by screening a HeLa cDNA expression library with a regulatory element of the E-selectin promoter, NF-ELAM1/delta A. Relative to full-length ATF-a, the ATF-a0 cDNA contains a large in-frame deletion of 525 base pairs that removes the P/S/T-rich putative transactivation domain. Using reverse-transcription-polymerase chain reaction and Northern blot hybridization to characterize ATF-a0 expression, we found that putative mRNAs for ATF-a0 and ATF-a are present at varying ratios in different tissues. Full-length ATF-a is a transcriptional activator for the NF-ELAM1/delta A site of the E-selectin promoter. In contrast, we show ATF-a0 has no measurable transactivating function on this element. Moreover, we demonstrate that co-expressed ATP-a0 and ATF-a preferentially heterodimerize. In the heterodimer ATF-a0 is a dominant inhibitor that completely blocks the transactivating activity of ATF-a. Both forms of ATF-a bind the p50 subunit of NF-kappa B as shown by affinity chromatography. ATF-a0 appears to be a splice variant similar to the one found for ATF-2, its closest homologue in structure and function. Taken together, our results suggest that ATF-a0 is an important member of the ATF family with a negative regulatory role in transactivation.

Activating Transcription Factors↗
PubMed1994

Isolation of a novel soybean gene encoding a mitochondrial ATP synthase subunit.

A novel ATP synthase gene from soybean has been cloned and characterized. A subunit from the FA portion of the complex is encoded by two nuclear genes. The genomic clone(s) contain five exons encoding a protein of 179 amino acids. The amino terminal end contains many properties of a mitochondrial targeting sequence and preliminary in vitro import studies indicate that there is a cleavable precursor of approximately 30 amino acids. The predicted protein sequence shows high homology with the N-terminal sequence from an isolated subunit of ATP synthase complex from spinach (Hamsaur and Glaser (1992) Eur. J. Biochem. 205, 409-416). The subunit was tentatively identified as the equivalent of subunit d in bovine and P18 in yeast based on structural identity.

Amino Acid Sequence↗
PubMed1994

Cooperativity between two NF-kappa B complexes, mediated by high-mobility-group protein I(Y), is essential for cytokine-induced expression of the E-selectin promoter.

Cytokine-induced expression of the E-selectin gene requires the promoter binding and interaction of the transcription factors NF-kappa B and ATF. Here we have further analyzed the E-selectin promoter and revealed an additional region (nucleotides -140 to -105 [-140/-105]) which is essential in controlling promoter activation by cytokines. We identified high-mobility-group protein I(Y) [HMG-I(Y)] interacting specifically at two sites within this region. We noted that one of the HMG-I(Y)-binding sites overlaps a sequence element (-127/-118) diverging at only one position from the NF-kappa B consensus binding sequence. This led us to ask whether the -127/-118 element represents a second functional NF-kappa B-binding site within the E-selectin promoter. Using specific antisera, we show that p50, p65, and, interestingly, RelB are components of the complex interacting at this site. Mutational analysis of the -127/-118 NF-kappa B site indicates that both NF-kappa B and HMG-I(Y) binding at this site are essential for interleukin-1 induction of the promoter. We demonstrate that the binding affinity of the p50 subunit of NF-kappa B to both NF-kappa B sites within the E-selectin promoter is significantly enhanced by HMG-I(Y). In addition, an essential role for cooperative interaction between the two NF-kappa B complexes is shown by the requirement for both NF-kappa B sites to mediate E-selectin promoter activation by interleukin-1 and p50/p65 expression. We conclude that HMG-I(Y) mediates binding of a distinct NF-kappa B complex at two sites within the E-selectin promoter. Furthermore, a unique cooperativity between these NF-kappa B complexes is essential for induced E-selectin expression. These results suggest mechanisms by which NF-kappa B complexes are involved in specific gene activation.

Base Sequence↗
PubMed1994

Doxorubicin and cisplatin with granulocyte colony-stimulating factor as adjuvant chemotherapy for osteosarcoma: phase II trial of the European Osteosarcoma Intergroup.

PURPOSE: This report describes the toxicity and feasibility of administering doxorubicin (DOX) and cisplatin (CDDP) at 2-week intervals with granulocyte colony-stimulating factor (G-CSF) to patients with osteosarcoma and the compatibility of this regimen with endoprosthetic surgery performed after three cycles. PATIENTS AND METHODS: Twenty-four patients with biopsy-proven osteosarcoma were treated with three preoperative cycles of DOX 25 mg/m2/d on days 1 to 3 and CDDP 100 mg/m2 on day 1 with G-CSF 5 micrograms/kg/d on days 4 to 14. Surgery was scheduled at week 6 to be followed by three further cycles of chemotherapy at 2-week intervals. RESULTS: Two-week chemotherapy was feasible, but delays and dose reductions only allowed 74% and 78% of the intended dose-intensity of DOX and CDDP to be administered. Thrombocytopenia accounted for 50% of delays. Significant toxicity included neutropenic sepsis, severe mucositis, prolonged nausea and vomiting, and electrolyte disturbances. Twenty-one limb-salvage procedures and one amputation were performed. There were eight episodes of excessive perioperative bleeding. CONCLUSION: Intensive 2-week chemotherapy with intercurrent surgery is feasible and allows a greater dose-intensity of chemotherapy to be administered compared with the same regimen administered at 3-week intervals without G-CSF. The toxicity is considerable, but manageable.

Adolescent↗
PubMed1994

Unplanned extubation. Predictors of successful termination of mechanical ventilatory support.

BACKGROUND: Unplanned extubation (self-extubation or accidental extubation) occurs commonly in mechanically ventilated patients, and many patients do not receive mechanical ventilation indefinitely. Unfortunately, weaning parameters are often unavailable in the setting of unplanned extubation, and it would be useful to define pre-extubation respiratory and ventilatory parameters that predict which patients require reintubation. METHODS: The medical records of all patients who experienced unplanned extubation for the 2-year period of July 1989 to July 1991 were reviewed. Pre-extubation values of respiratory rate, tidal volume (VT), fraction of inspired oxygen (FIo2), PEEP, ventilatory mode, and ventilator-delivered minute volume (VVE, ventilator rate multiplied by set VT) were recorded. In addition, the following data were obtained: age, gender, respiratory failure diagnosis, duration of intubation, amount, and type of sedative agents in the 24 h before extubation. Comparisons of these values among patients who ultimately required reintubation and those who were not reintubated were made using the Mann-Whitney U two-sample test. RESULTS: During this period, there were 23 unplanned extubations involving 22 patients. Reintubation was required for 18 episodes of unplanned extubation, but was not required for 5 episodes. There were no significant differences between the two groups for any of the parameters except VVE and FIo2. The mean pre-extubation FIo2 of the reintubated group (0.49) was significantly higher than that of the patients who were not reintubated (0.35) (p = 0.021); all of the patients who remained extubated were receiving an FIo2 < or = 0.40. The VVE was also higher in the reintubated group (9.73 L/min) than in the patients who were not reintubated (1.40 L/min); all patients who remained extubated were receiving < or = 7.0 L/min of ventilator-delivered minute ventilation. CONCLUSIONS: Reintubation after unplanned extubation should not be considered mandatory. Patients who require reintubation have significantly higher preextubation FIo2 and ventilatory requirements than patients who remain extubated.

Female↗
PubMed1994

Antithetic relationship of dietary arachidonic acid and eicosapentaenoic acid on eicosanoid production in vivo.

Eicosanoids are oxidative derivatives of arachidonic acid. When produced in excessive amounts, many are proinflammatory and/or prothrombotic agents. N-3 polyunsaturated fatty acids (PUFA) have been used to attenuate tissue arachidonic acid (AA, 20:4 n-6) levels and thus modulate eicosanoid production. However, there is growing evidence that dietary arachidonic acid may also be able to modulate eicosanoid formation by enriching tissue phospholipids with AA. Therefore, the effects of dietary AA and n-3 PUFA are in diametric opposition. This study investigates the antithetic relationship of dietary AA and eicosapentaenoic acid (EPA, 20:5 n-3) on fatty acid composition of hepatic phospholipids and eicosanoid production in vivo. Forty-nine CD-1 male mice were randomly divided into four dietary groups. Identical diets were supplemented with ethyl esters (1.5% w/w) of the following fatty acids: oleic acid (OA, 18:1 n-9), AA, EPA or AA+EPA. After 4 weeks on diet, peritoneal cells were stimulated in vivo with opsonized zymosan and the peritoneal exudates were analyzed for eicosanoid production (PGE2, 6-keto-PGF1 alpha, TXB2, LTB4, LTE4, and LTE5). Hepatic phospholipids were enriched with AA when AA was included in the diet, and EPA was enriched at the expense of AA when EPA was added to the diet. However, when AA was added to the diet containing equivalent amounts of EPA (AA+EPA), any effect EPA had on modulating hepatic phospholipid fatty acid composition was almost completely eliminated. Similar effects were observed with eicosanoid production. The pooled eicosanoid production in the AA group was 41% and 300% higher compared to the OA (control) and EPA groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[Design of heterologous mitochondria: import of cattle cytochrome P-450SCC precursors in plant mitochondria].

It has been shown that pre-P-450scc of bovine adrenal cortex mitochondria synthesized in a rabbit reticulocyte lysate cell-free system, is translocated into isolated soybean cotyledon mitochondria, thereby taking the mature form size. This finding is suggestive of the occurrence of a specific receptor and maturase for pre-P-450scc in plant mitochondria. Thus, plant mitochondria can be used as recipients for the mammalian cholesterol hydroxylase system in an attempt to study the mechanism of its formation and preservation.

Adrenal Cortex↗