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Biomedical subjects

J Brennan

Publications and source records attributed to J Brennan.

At least 73 records · Page 4Linked to original sources
PubMed1995

Cloning and developmental expression of Nsk2, a novel receptor tyrosine kinase implicated in skeletal myogenesis.

The protein superfamily of transmembrane receptor tyrosine kinases (RTKs) are essential components of intercellular signalling pathways necessary for normal cellular regulation. We report the cloning and developmental expression pattern of Nsk2, a novel, structurally distinct mammalian RTK characterised by a putative extracellular region bearing four immunoglobulin-like domains. The Nsk2 locus was mapped to the distal region of mouse chromosome 13 and was found to be expressed preferentially in skeletal muscle amongst adult mouse tissues. Moreover, increased steady-state levels of Nsk2 transcripts were apparent on terminal differentiation of committed skeletal myoblast cell lines in vitro and multiple isoforms of the Nsk2 RTK were identified in skeletal myotube cultures. RNA in situ hybridisation studies of mouse embryos confirmed skeletal myogenesis to be a major site of Nsk2 expression during normal embryogenesis, and identified other likely sites of Nsk2 function in ganglia of the developing peripheral nervous system and various embryonic epithelia, including those of kidney, lung and gut, during fetal development. Taken together, our data suggest normal functions for Nsk2 RTKs in distinctive aspects of skeletal muscle development, neurogenesis and mesenchymal-epithelial interactions during organ formation.

Amino Acid Sequence↗
PubMed1995

Carbohydrate recognition by a natural killer cell receptor, Ly-49C.

Ly-49 represents a family of type II transmembrane proteins containing C-type lectin domains. At least two members of the Ly-49 family, namely Ly-49A and Ly-49C, are expressed by distinct subsets of natural killer cells and bind to class I major histocompatibility complex antigens on the surface of target cells. In this report we have established that Ly-49C mediates carbohydrate recognition. The sulfated glycans fucoidan, lambda-carrageenan, and dextran sulfate were found to be potent inhibitors of Ly-49C-mediated cell adhesion, whereas other polysaccharides of similar size, charge, or sulfate content were noninhibitory. All of the polysaccharides which inhibited Ly-49C adhesion also blocked the binding of the antibody 5E6 to Ly-49C-expressing COS cells, confirming the direct protein-carbohydrate interaction. The enzymatic removal of specific carbohydrates from the target cell surface has shown that Ly-49C-mediated adhesion is not sialic acid-dependent, but is significantly decreased following fucosidase treatment. These results suggest an important role for carbohydrate recognition by natural killer cell receptors.

Animals↗
PubMed1995

Squamous cell carcinoma of the head and neck in the elderly.

OBJECTIVE: While squamous cell carcinoma of the head and neck (HNSCC) most commonly affects individuals in the fifth to seventh decades of life, it occasionally arises in older patients. Biologic and epidemiologic factors of HNSCC in elderly patients have been investigated to shed light on the process of neoplastic transformation in that population. DESIGN: The medical records of patients with new onset of HNSCC presenting between 1988 and 1993 were reviewed retrospectively. SETTING: Tertiary-care hospital-based clinic. PATIENTS: Eighty-one individuals who developed HNSCC of the upper aerodigestive tract after their 75th birthday constituted the study group. A control group consisting of 102 patients who developed HNSCC between the ages of 40 and 70 years was also analyzed. MAIN OUTCOME MEASURE: Information about each individual's tobacco and ethanol exposure, family history of cancer, history of second primary cancer, treatment provided, and current disease status were derived from the medical record. The presence or absence of p53 gene mutation was tabulated for a subset of individuals in both the elderly and the middle-aged groups. RESULTS: The elderly patients had a significantly lower degree of alcohol and tobacco exposure, but a significantly higher rate of second primary cancers, especially in sites outside the upper aerodigestive tract. There was no difference in the incidence of cancer in first-degree relatives in the two groups. These findings were interpreted in light of results from our laboratory examining the incidence of p53 gene mutation in a large number of patients with HNSCC. A significantly higher percentage of tumors from the younger group contained a p53 gene mutation. Major surgery was an integral part of the treatment plan for most of the older patient group despite their advanced age. CONCLUSIONS: These findings suggest that HNSCC arising after the seventh decade of life less frequently involves a genetic change commonly found in younger patients. Heavy carcinogen exposure and p53 gene mutations are present less often in elderly individuals, whereas this group appears to be more susceptible to multiple cancers. The precise biologic factors involved in neoplastic transformation in this older population await discovery. Since aggressive therapy can be successfully tolerated by many elderly patients, an individualized approach to treatment is advocated.

Adult↗
PubMed1995

Risk-adjusted analysis of surgeon performance: a 1-year study.

A 1-year prospective analysis was undertaken of all non-day-case general surgery in a district general hospital. Using the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) scoring system 3004 patients were assessed. From the predictions of mortality and morbidity so obtained, a quality measure, the ratio of observed to expected numbers of deaths and complications (O:E ratio) was determined for each surgeon, both overall and within specialty zones. The present study demonstrates the serious hazard in using 'raw' uncorrected mortality and morbidity statistics to compare surgeon performance. Mortality rates varied from 1.0 to 4.9 per cent whereas O:E ratios ranged from 0.83 to 1.06; morbidity rates varied from 5.3 to 12.6 per cent with O:E ratios 0.86-1.02. Great misunderstanding may result from the publication of surgeon or hospital 'league tables'. The present study demonstrates a technique that might allow surgeon performance to be monitored adequately and accurately.

Day Care, Medical↗
PubMed1995

Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Absorption and presystemic metabolism of nefazodone administered at different regions in the gastrointestinal tract of humans.

PURPOSE: The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. METHODS: NEF HCl (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. RESULTS: The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. CONCLUSIONS: NEF is absorbed throughout the length of the gastro-intestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.

Adult↗
PubMed1995

Using and archiving the labor curves.

Optimal interpretation of the events of labor requires integration of information about cervical changes, fetal descent, uterine contractions, fetal position and attitude, as well as fetal heart rate monitoring and maternal condition. The use and understanding of labor curves is a vital part of this process. The complexity and diversity of labor data lend itself to computer storage and analysis.

Cervix Uteri↗
PubMed1994

Expression of different members of the Ly-49 gene family defines distinct natural killer cell subsets and cell adhesion properties.

The murine Ly-49 antigen belongs to a family of type II transmembrane molecules containing lectin-like domains. The original member of this family, Ly-49A, has been demonstrated to be expressed by a subpopulation of natural killer (NK) cells, bind certain class I major histocompatibility complexes (MHC), and act as a negative regulator of lytic activity. The expression patterns and functional activities of the other Ly-49s, however, is unknown. We extended the study of this family by isolating cDNAs encoding two new Ly-49 molecules. The reactivity of these and previously identified Ly-49 molecules with NK antibodies was tested in a COS cell expression system. YE1/32 and YE1/48 bound Ly-49A specifically, and 5E6 reacted only with Ly-49C. Three-color flow cytometric analysis demonstrated Ly-49A and Ly-49C expression defines complex, but distinct subsets within NK1.1+ cells. Some NK1.1-CD3+ as well as NK1.1-CD3- cells expressing Ly-49A or C were also detected. Analysis of MHC congenic strains of mice demonstrated that YE1/32+ and YE1/48+ NK cells are not deleted, as has been shown with the Ly-49A mAb A1. Furthermore, COS cells transfected with Ly-49A bound H-2d and H-2k cell lines, whereas Ly-49C transfectants bound H-2d, H-2k, H-2b, and H-2s. The antibodies 5E6 and 34-1-2S (anti-class I MHC) inhibited the binding of Ly-49C to an H-2s cell line. These results imply that the NK cell antigens Ly-49A and C bind to different repertoires of class I MHC molecules.

Amino Acid Sequence↗
PubMed1994

Mutations in the conserved regions of p53 are infrequent in betel-associated oral cancers from Papua New Guinea.

Seventy-five % of the world's oral cancers arise in developing countries. In high incidence areas of Southeast Asia such as Papua New Guinea (PNG) the major region-specific risk exposure is betel quid chewing. While it has been shown that p53 gene mutations in the conserved midregion (exons 5-9) are a common feature of oral cancers in the developed world, there is no information on this type of genetic lesion in betel quid-associated oral cancers. We examined 50 oral squamous cell carcinomas, 20 from Baltimore, MD and 30 from PNG, for mutations in exons 5-9 of the p53 gene. DNA extracted from frozen biopsies was amplified by polymerase chain reaction, the purified product was sequenced directly, and mutations were confirmed by repeating the entire procedure. Mutations were found in 3 of 30 tumors from PNG (10%), whereas 9 mutations were detected among the 20 tumors (45%) from Baltimore, MD. This difference in frequency is statistically significant (P < 0.01) by chi 2 analysis. Nuclear accumulation of p53 protein, determined by immunohistochemistry with the CM-1 antiserum, was observed in the PNG cases harboring a missense mutation of the p53 gene. In agreement with the low number of PNG cancers with mutations, only 17% of the cases from PNG were immunostain positive. To explore whether less conserved regions of the gene are preferential targets for alterations in this patient group, sequence analysis in tumors from PNG was extended to outlying regions of the gene (all of exons 4 and 10, and splice sites), but mutations in only two additional tumors were identified. The presence of human papillomavirus DNA in PNG cases was examined with a polymerase chain reaction-based procedure, and viral sequences (human papillomavirus strains 11/16) were detected in two tumors. Human papillomavirus-triggered degradation of the tumor suppressor protein is thus unlikely to be a typical pathway to p53 dysfunction in tumors from PNG.

Adult↗
PubMed1994

A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells.

In early phases of human T-cell lymphotrophic virus I-induced adult T-cell leukemia (ATL), the malignant cell proliferation is associated with an autocrine process involving coordinate expression of interleukin (IL) 2 and its receptor. However, during late-phase ATL, leukemic cells no longer produce IL-2 yet continue to express high-affinity IL-2 receptors. During studies to define pathogenic mechanisms that underlie this IL-2-independent proliferation, we demonstrated that the ATL cell line HuT-102 secretes a lymphokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Conditioned medium from HuT-102, when added to the IL-2-dependent CTLL-2 line, yielded a stimulation index of 230. Since CTLL-2 was purported to be IL-2-specific, we performed a number of studies to exclude IL-2 production by HuT-102. Stimulation of CTLL-2 cells by HuT-102-conditioned medium was not meaningfully inhibited by addition of an antiserum to IL-2. Furthermore, uninduced HuT-102 cells did not express mRNA encoding IL-2 as assessed by Northern blot analysis. No biological activity on CTLL-2 cells was mediated by purified IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, or granulocyte/macrophage colony-stimulating factor, thus differentiating these factors from IL-T. Based on preliminary biochemical data, IL-T is a protein with a pI value of 4.5 and a molecular mass in SDS gels of 14 kDa. In addition to its action on CTLL-2 cells, 3200-fold-purified IL-T stimulated proliferation of the human cytokine-dependent T-cell line Kit-225. Furthermore, addition of IL-T enhanced cytotoxic activity of large granular lymphocytes (i.e., induced lymphokine-activated killer cells). Thus, IL-T is a lymphokine that plays a role in T-cell proliferation and induction of lymphokine-activated killer cells. Furthermore, IL-T may contribute to IL-2-independent proliferation of select ATL cells and lines.

Animals↗
PubMed1994

The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells.

Late-phase human T-cell lymphotropic virus I-associated adult T-cell leukemia cells express IL-2 receptors (IL-2R) but no longer produce IL-2. We have reported that the IL-2-independent adult T-cell leukemia line HuT-102 secretes a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and lymphokine-activated killer cell activity. Stimulation of proliferation of the cytokine-dependent human T-cell line Kit-225 mediated by HuT-102-conditioned medium or by 3200-fold-purified IL-T was not blocked by the addition of antibodies against IL-2 or IL-2R alpha subunit. However, IL-T-mediated stimulation of this human T-cell line was inhibited by addition of Mik-beta 1, an antibody that binds specifically to IL-2R beta subunit. In addition, the activation of large granular lymphocytes to lymphokine-activated killer cells mediated by IL-T-containing conditioned medium was not blocked by antibodies directed toward IL-2 or IL-2 alpha but was inhibited by an antibody to IL-2R beta, suggesting the requirement of this receptor subunit for IL-T action. This conclusion was confirmed using an IL-3-dependent murine myeloid precursor cell line, 32D, that expresses IL-2R alpha and IL-2R gamma, but not IL-2R beta. Neither IL-2 nor IL-T stimulated 32D cell proliferation. However, after transfection with the gene encoding human IL-2R beta, 32D beta cells proliferated on addition of either cytokine. The IL-T-mediated stimulation of 32D beta proliferation was inhibited by an anti-IL-2R beta antibody but not by an anti-IL-2 antibody. Thus, the IL-T-mediated stimulation of T-cell and lymphokine-activated killer cell activation requires the expression of the IL-2R beta subunit.

Animals↗
PubMed1994

The value of urinalysis in differentiating acute pyelonephritis from lower urinary tract infection in febrile infants.

There is an ongoing debate on the best way to screen febrile infants for urinary tract infection. We examined the urinanalysis (UA) findings on admission among infants less than 16 weeks old, with and without acute pyelonephritis (APN), as defined by the dimercaptosuccinic acid (DMSA) renal scan findings, performed during a 57-month period. Forty-nine cases with a positive DMSA scan were compared with 79 negative study cases. A negative UA for leukocytes (< 5 white blood cells/high power field) was found in 4 of 49 (8.1%) cases with APN by DMSA, and in 34 of 79 (43%) cases with a negative DMSA (odds ratio 10.88 (95% confidence interval, 2.31 to 70.3; P < 0.001)). Three of the 4 infants not suspected to have APN by their UA findings would have been admitted for a full sepsis workup based on their clinical presentation and/or their laboratory findings on admission. We conclude that a fresh UA may be a sufficient screening method for the exclusion of APN in infants assessed for fever of no obvious origin.

Acute Disease↗
PubMed1994

Predictors of coronary dissection following percutaneous transluminal coronary balloon angioplasty.

To determine predictors of acute coronary dissection after coronary angioplasty, we studied 170 consecutive patients who underwent arterial dilatations of 234 arteries. Coronary dissection occurred in 103 (44%) arteries. More dissections occurred in women [40/73 (55%) versus 63/161 (39%), p < 0.03] and in patients with long lesions [45/74 (61%) versus 56/158 (35%), p < 0.0005]. Balloon/arterial diameter ratio was higher in patients with dissection (1.1 +/- 0.2 versus 1.0 +/- 0.2, p < 0.02). Complications did not differ in patients with and without dissection except for non-Q wave myocardial infarctions which were more frequent in patients with coronary dissection [10/12 (83%) versus 2/12 (17%), p < 0.01]. Thus coronary dissection during angioplasty is relatively frequent. However, most dissections are not associated with complications. Balloon dilatation of lesions in female patients and in patients with long lesions are more likely to result in dissection.

Acute Disease↗
PubMed1994

The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development.

Members of the protein superfamily of transmembrane receptor tyrosine kinases are key components of intercellular signal transduction pathways that elicit appropriate cellular responses to environmental cues during development of multicellular organisms. In a search for additional receptor tyrosine kinases expressed during mouse embryogenesis we cloned the murine homolog of Eck, a member of the Eph subfamily, that maps to the distal region of mouse chromosome 4. Specific antisera defined Eck in murine embryonic cells as a glycoprotein of 130 kDa with an intrinsic autophosphorylation activity. Immunohistochemical staining and laser scanning microscopy revealed a dynamic and tightly regulated distribution of Eck receptor protein in the developing mouse embryo. During gastrulation, a high transient distribution of Eck was seen in mesodermal cells aggregating in the midline as notochordal plate. A similar restriction of Eck receptor protein was apparent along the rostrocaudal axis of the developing neural tube. In hindbrain neuroepithelia, Eck protein localised specifically to cells of rhombomere 4 and was also seen transiently in cells populating second and third branchial arches and neurogenic facial crest VII-VIII and IX-X. Receptor distribution also implicated Eck in development of the proximodistal axis of the limb, expression being restricted to distal regions of limb bud mesenchyme. At later stages, additional sites of Eck protein expression were seen in the cartilaginous model of the skeleton, tooth primordia, infundibular component of the pituitary and various fetal tissue epithelia. Taken together, our data suggest pleiotropic functions for the Eck receptor, initially in distinctive aspects of pattern formation and subsequently in development of several fetal tissues, and reveal possible allelism with known mouse developmental mutant loci.

Animals↗
PubMed1993

Atrial natriuretic factor and arginine vasopressin production in tumor cell lines from patients with lung cancer and their relationship to serum sodium.

Patients with lung cancer (n = 263) were studied to determine the relationship among ectopic production of atrial natriuretic factors (ANF) and arginine vasopressin (AVP), serum sodium, and patient outcome. Of 133, 21 (16%) patients with small cell lung cancer (SCLC) had hyponatremia (serum sodium, < 130 mmol/liter), compared to none of 130 (0%) patients with non-small cell lung cancer (P < 0.0001). Patients with extensive-stage SCLC and hyponatremia had shorter survival than patients with extensive stage SCLC and normal serum sodium values (P = 0.012). Of the 11 hyponatremic patients with SCLC and tumor cell lines available for study, 9 produced ANF mRNA, 7 of 11 produced AVP mRNA, and 5 of 11 produced both ANF mRNA and AVP mRNA. All 11 cell lines produced either ANF mRNA and ANF peptide or AVP mRNA and AVP peptide, or both. The quantity of AVP peptide in the tumor cell lines was more closely associated with hyponatremia in the patients (P = 0.0026, r2 = 0.28) than was the production of ANF peptide (P = 0.066, r2 = 0.12), although neither association was strong. All tumor cell lines studied from SCLC patients with hyponatremia produce ANF and/or AVP mRNA and peptides.

Arginine Vasopressin↗
PubMed1993

Clinical and angiographic determinants of initial percutaneous transluminal coronary angioplasty success.

Clinical and anatomic determinants of primary success of percutaneous transluminal coronary angioplasty were retrospectively evaluated in 299 patients. Successful angioplasty (residual stenosis < 50%) was achieved in 350 (94%) of 373 lesions. The success rate in patients chronically treated with aspirin was higher than that of patients not treated with aspirin (95% versus 86%, P < 0.03). An additional finding was that the success rate in patients referred for coronary angioplasty because of acute myocardial infarction or postinfarction angina was lower than that of those without these characteristics (89% versus 96%, P < 0.01). No other clinical features studied influenced the outcome of coronary angioplasty. The angiographic characteristics of the lesions did not differ between patients with successful or failed angioplasty except for the degree of stenosis prior to the procedure, being lower in patients with successful procedure (92.4 +/- 7.6% versus 97.3 +/- 3.1%), P < 0.002). Thus coronary angioplasty can be performed with a high rate of success. Long-term pretreatment with aspirin may have a beneficial effect.

Aged↗