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Biomedical subjects

J Brennan

Publications and source records attributed to J Brennan.

At least 55 records · Page 3Linked to original sources
PubMed1998

ICP-CBF trauma bolt, laboratory evaluation.

Thermal diffusion flowmetry is a continuous quantitative technique of measuring regional cerebral blood flow utilizing a silastic strip probe placed through a craniotomy or craniectomy in the operating room. A new bolt like application of this technology is now available for commercial use and is especially designed for bedside placement in trauma patients. This new trauma bolt is tested in juvenile pigs who are subjected to episodes of hypercapnea to increase cerebral blood flow, and records significant changes in blood flow. Another feature of the trauma bolt is a second port for the placement of an intracranial pressure (ICP) monitor. Placement of the probe and ICP monitor were easier than with the silastic probe and had relatively little complication.

Animals↗
PubMed1998

Do infants with cystic fibrosis need a protein hydrolysate formula? A prospective, randomized, comparative study.

OBJECTIVES: We compared the nutritional benefits of a protein hydrolysate and a conventional infant formula in infants newly diagnosed with cystic fibrosis (CF). STUDY DESIGN: Twenty-three infants with CF (<6 months of age) and pancreatic insufficiency were randomized to receive a hydrolysate formula (Alimentum) or a cow's milk-based formula (Similac). Each patient was monitored at 1 month and then every 3 months for 1 year. RESULTS: Eighteen patients (8 Alimentum, 10 Similac) completed the study. At entry, the age distribution and clinical characteristics of each group were comparable. Energy intake with each formula was the same at 1 and 3 months, but at 6 and 12 months the hydrolysate-fed infants had higher age-adjusted energy intake. There were no differences in fecal energy or fecal fat at entry or throughout the study. Although the hydrolysate-fed infants were slightly more malnourished at diagnosis, growth velocity and nutritional status of infants with CF in each group were the same throughout the study. CONCLUSIONS: The results of this randomized study fail to support the use of a hydrolyzed formula for the routine care of infants newly diagnosed with CF.

Cystic Fibrosis↗
PubMed1998

Occult deep venous thrombosis complicating superficial thrombophlebitis.

PURPOSE: To determine whether superficial thrombophlebitis (STP) can extend into the deep venous system (DVS) and whether this may result in pulmonary embolization. METHODS: All venous duplex ultrasound examinations performed in our vascular laboratory to rule out deep venous thrombosis from June 1, 1994, to June 24, 1996, were reviewed. RESULTS: Of 8313 limbs studied by duplex scanning in 6148 patients, 1756 limbs (21.1%) had a positive result for deep venous thrombosis. STP was demonstrated in 232 limbs (213 patients), of which 20 (8.6%) extended into the DVS. Fourteen (70%) were noted on the initial scan, and six (30%) were detected on serial follow-up scans. Eighteen (90%) originated in the proximal greater saphenous vein and extended across the saphenofemoral junction into the common femoral vein. Nine demonstrated "free-floating" thrombus with a "tongue" extending into the common femoral vein while still attached proximally to the greater saphenous vein. Extension of thrombus from the lesser saphenous vein into the popliteal vein was noted in two cases (10%). One pulmonary embolization was directly observed to occur in real time during scanning. No pulmonary embolization was seen when STP did not involve the DVS. CONCLUSIONS: STP can extend into the DVS. In this series STP of the proximal greater saphenous vein extended into the common femoral vein in 8.6% of the cases, of which 10% embolized to the lungs. When the DVS is involved, standard deep venous thrombosis treatment (heparin, warfarin, bed rest) should be instituted. We recommend duplex imaging for STP involving the greater saphenous vein in the thigh to rule out occult deep venous thrombosis. STP is not always benign and self-limiting as previously described.

Femoral Vein↗
PubMed1998

Color flow-directed Doppler studies of ovarian masses. Computer analysis.

OBJECTIVE: To determine if analyzing the entire color Doppler image (CDI) pulse wave of an ovarian mass can improve the ability to predict its histopathology. STUDY DESIGN: The CDI of 42 histopathologically diagnosed adnexal masses were retrospectively analyzed. Using an image analysis software program, the following parameters were calculated: area under the curve, compactness, Feret diameter, perimeter, shape factor and width of the waveform. Using an automated curve-fitting software program, the up and down slopes were processed separately for the optimal equation and coefficient for each slope. Two computerized neural networks were created, both consisting of an input layer, one hidden layer and an output layer of three neurons: benign, borderline and malignant. The first network contained two input neurons: pulsatility index (PI) and resistance index (RI). The second network contained 10 input neurons consistent with the shape and slope parameters calculated. The coefficient of determination (R2) was determined for each network. RESULTS: The neural network utilizing RI and PI failed to train (1,397 runs, 67,056 facts, R2 = 0.59, 0.12 and 0.43 for benign, borderline and malignant masses, respectively). The network using the 10 calculated parameters achieved an R2 of 0.96 after 685 runs and 27 facts. CONCLUSION: Analyzing the CDI studies of ovarian masses, using the entire pulse wave, improved the ability to differentiate between their benign, borderline and malignant histopathology.

Diagnosis, Differential↗
PubMed1997

Endoluminal repair of internal carotid artery aneurysm: a feasible but hazardous procedure.

PURPOSE: The aim of this study was to report the repair of an aneurysm of the internal carotid artery using the endoluminal method. METHODS: A 70-year-old male patient noted a swelling in the right side of his neck 22 years after endarterectomy of the right internal carotid artery. Duplex ultrasound confirmed the clinical diagnosis of aneurysm of the internal carotid artery. Further investigation included contrast-enhanced computed tomographic (CT) scanning and carotid angiography performed via a retrograde femoral approach. The aneurysm contained thrombus and was 3 cm in diameter and in length. It extended superiorly from a point 0.5 cm above the carotid bifurcation to a point estimated to be 2 cm from the base of the skull. Repair of the aneurysm was undertaken using the endoluminal method. A self-expanding endograft 8 mm in diameter and 4 cm in length was introduced through a 12F sheath in the common carotid artery. An on-table completion angiogram of the right-sided extracranial carotid arteries and the intracranial internal carotid artery and branches was obtained. RESULTS: The completion angiogram and postoperative CT scan confirmed exclusion of the aneurysm sac from the circulation. The patient awoke from anesthesia with complete paralysis of the left arm. Recovery of movement commenced 1 hour later. A brain CT scan demonstrated the event to be an embolic stroke. Strength had returned by 7 days. Function of the arm was good 1 month after operation, but coordination for fine movements was lacking. At the 6-month follow-up, good arm function was maintained. A duplex ultrasound scan demonstrated not only continued exclusion of the aneurysm sac but occlusion of the endograft, also. CONCLUSIONS: Endoluminal repair of aneurysms of the internal carotid artery is feasible but carries the risk of major morbidity as a result of peripheral embolization and early occlusion of the endograft.

Aged↗
PubMed1997

A prototype simulator for endovascular repair of abdominal aortic aneurysms.

A prototype simulator for training in endovascular repair of abdominal aortic aneurysms (AAA) has been developed. Employing transparent models of human AAA complete with renal, iliac and femoral arteries, this system allows accurate simulation of aortography, road-mapping, catheter guidewire manipulation and stent-graft deployment while obviating the need for ionising radiation.

Aortic Aneurysm, Abdominal↗
PubMed1997

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer.

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.

Adult↗
PubMed1997

The NK2.1 receptor is encoded by Ly-49C and its expression is regulated by MHC class I alleles.

A dual receptor system composed of activation and inhibitory receptors apparently controls NK cell-mediated lysis. In the C57BL/6 mouse, the NK1.1 molecule acts as an activation receptor whereas Ly-49A, C and G2 can inhibit NK cell lysis of target cells expressing specific MHC class I molecules. We previously reported that NK2.1 is an activation receptor sharing structural properties with members of the NKR-P1 and Ly-49 receptor families. In this study, we have shown that NK2.1 is encoded by the previously described Ly-49C gene. We also found that the expression level of NK2.1/Ly-49C is modulated by H-2-dependent factors and that this regulation differs from that previously described for Ly-49A. Flow cytometry analyses of NK-enriched spleen cells from MHC congenic strains on C57BL/10 and BALB/c backgrounds indeed revealed that the level of NK2.1/Ly-49C expression, but not the number of positive cells, is low in strains expressing H-2b and H-2k haplotypes as compared to H-2d mice. Similar analyses of splenic NK cells from two series of congenic and congenic recombinant strains on the C57BL/10 background indicate that the main regulatory element(s) are most likely the H-2Kb and H-2Dk alleles. Together with our and others previous observations, these results identify the NK2.1/Ly-49C antigen as a receptor for MHC class I molecules whose expression is regulated by host MHC genes.

Alleles↗
PubMed1997

The Ly-49 family: genes, proteins and recognition of class I MHC.

The Ly-49 family consists of at least nine members, of which Ly-49A and C have been found to be NK-cell inhibitory receptors specific for class I MHC. The functions of other Ly-49 molecules are still unclear. Further analysis of Ly-49 is complicated by the cross-reactivities of some anti-Ly-49 antibodies initially thought to be specific for individual Ly-49 molecules. Studies on the role of Ly-49 in hybrid resistance as well as on allelic exclusion are also complicated by our recent finding that a novel Ly-49CB6 gene is the likely allelic form of Ly-49CBALB as opposed to a previously reported highly related but distinct gene in B6 mice. In cell-cell binding assays, only Ly-49A and C show significant binding to class I MHC. Ly-49A and C also bind some polysaccharides, and carbohydrates on class I MHC seem to be important for its binding to Ly-49. However, this interaction involves not only the carbohydrate recognition domain of Ly-49 but also a part of the stalk region, suggesting that both carbohydrates and peptide backbone of class I MHC may be recognized by Ly-49. It is likely that additional Ly-49 molecules yet to be identified function as NK-inhibitory receptors specific for class I MHC.

Animals↗
PubMed1996

Heterogeneity among Ly-49C natural killer (NK) cells: characterization of highly related receptors with differing functions and expression patterns.

Ly-49C is a member of the polymorphic family of murine NK cell inhibitory receptors. The 5E6 antibody that defines a subset of NK cells responsible for the rejection of parental H-2d bone marrow by F1 mice has been shown previously to react with Ly-49C. Here, the 5E6 antibody was found to detect two Ly-49C-related molecules in B6 mice. Two cDNA clones were isolated from B6 NK cells, one identical to previously reported Ly-49CB6 and the other a novel cDNA. The deduced amino acid sequence of the latter differs from that of Ly-49CBALB at only 4 residues, whereas the previously reported Ly-49CB6 differs at 22 residues. Flow cytometric analyses of COS cells transfected with the two cDNAs showed that the 5E6 antibody binds to both Ly-49 molecules, while another anti-Ly-49C antibody, 4LO3311, binds to the newly described Ly-49C but not the previously reported Ly-49CB6. Two-color flow cytometric analysis detected 5E6+4LO3311- as well as 5E6+4LO3311+ subsets of NK cells from B6, but not BALB/c, mice. The level of Ly-49C expression on B6 NK cells detected by the 4LO3311 antibody was substantially lower than that on BALB/c NK cells. Binding specificity of the novel Ly-49CB6 was indistinguishable from that of Ly-49CBALB, whereas no binding was detectable with previously reported Ly-49CB6. These results demonstrate that the newly described Ly-49CB6, not the previously reported Ly-49CB6, is the probable B6 allelic form of Ly-49C. The previously reported Ly-49CB6 must be encoded by a separate gene and should be renamed Ly-49I. The implication of these results with respect to the role of Ly-49C in hybrid resistance is discussed.

Amino Acid Sequence↗
PubMed1996

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the lower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration.

Adult↗
PubMed1996

Recognition of class I major histocompatibility complex molecules by Ly-49: specificities and domain interactions.

Ly-49 is a family type II transmembrane proteins encoded by a gene cluster on murine chromosome 6. One member of this family, Ly-49A, is expressed by a natural killer (NK) cell subset, binds to class I major histocompatibility complex (MHC) molecules, and blocks the killing of target cells bearing the appropriate H-2 antigens. Here we show that another member of this family which is expressed by an NK cell subset, Ly-49C, recognizes H-2b and H-2d structures which are distinct from and overlapping with those recognized by Ly-49A. Interactions between Ly-49A and C and their class I ligands are entirely blocked by the antibodies 5E6, YE1/48, YE1/32, and A1, all of which were found to recognize epitopes contained within the carbohydrate recognition domain (CRD). However, cell-cell binding assays revealed that class I binding specificity is conferred by a combination of sequences within both the CRD and a 19-amino acid adjacent region. We also investigated the question of whether Ly-49A and C form dimers on cells which express both receptors. When coexpressed on COS cells, sequential immunoprecipitation demonstrated that these receptors pair exclusively as homodimers, with no evidence for heterodimeric structures. These observations provide insight into both the biochemical nature of the Ly-49 family as well as the receptor functions of Ly-49C on NK cells.

Amino Acid Sequence↗
PubMed1996

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

Adult↗
PubMed1996

Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.

PURPOSE AND METHODS: Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. RESULTS: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively. CONCLUSION: A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.

Adult↗
PubMed1996

Role of computed quantitation of immunohistochemical staining of Ki-67 antigen in diagnosing ampullary lesions.

OBJECTIVE: To determine the possible role of Ki-67 antigen expression by visual and computed quantitation in diagnosing ampullary lesions. STUDY DESIGN: Twenty-two cases of ampullary lesions treated at Thomas Jefferson University Hospital between 1989 and 1994 were analyzed. Four cases of adenoma, 4 of epithelial dysplasia in adenoma, 7 of well-differentiated adenocarcinoma and 7 of high grade adenocarcinoma were included. For each case three consecutive sections were obtained from the paraffin-embedded blocks. The first slide was stained with hematoxylin & eosin for visual diagnosis; the other two were immunoprocessed to evaluate the expression of Ki-67 antigen. Visual quantitation of Ki-67 was evaluated by light microscopy, and computed quantitation was performed utilizing the SAMBA 4000 cell image analysis system. RESULTS: Immunohistochemical analysis of the ampullary lesions showed a positive correlation of Ki-67 expression, both by visual and computed quantitation, with biologic grade. The cell proliferation sequence was carcinoma, adenoma with dysplasia and adenomia. CONCLUSION: Ki-67 antigen expression correlated highly with the progression of malignancy in ampullary lesions. Computed quantitation of Ki-67 was more sensitive than visual quantitation, especially in differentiating between low and high grade adenocarcinomas.

Adenocarcinoma↗
PubMed1995

Time-dependent pharmacodynamic models in cancer chemotherapy: population pharmacodynamic model for glutathione depletion following modulation by buthionine sulfoximine (BSO) in a Phase I trial of melphalan and BSO.

The development of time-dependent pharmacodynamic models in cancer chemotherapy has been extremely limited. A population approach was used to develop such a model to describe the effect of buthionine sulfoximine (BSO), via its active S-isomer (S-BSO), on glutathione (GSH) depletion in peripheral mononuclear cells. The Phase I trial utilized escalating doses of BSO, from 5 to 17 gm/m2, as a multiple infusion regimen. The population model consisted of a linear 2-compartment pharmacokinetic model coupled to an indirect response model. The indirect response model consisted of a GSH compartment with input and output rate processes that are modulated as a function of S-BSO and GSH concentrations. The model predicted the observed gradual depletion of GSH, a nadir at approximately 30 h after the last dose of BSO, and a return to baseline GSH levels. On the basis of an IC50 estimate of about 1.6 microM for inhibition of gamma-glutamylcysteine synthetase, the target enzyme of BSO, the population model predicted near identical GSH concentration time profiles over the dose range studied. Time-dependent pharmacodynamic models are seen as a powerful means to design dosing regimens and to provide a mathematical platform for mechanistic based models.

Adult↗