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Biomedical subjects

R White

Publications and source records attributed to R White.

At least 145 records · Page 8Linked to original sources
PubMed1997

Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.

PURPOSE: We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg. RESULTS: The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent. CONCLUSION: Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.

Adult↗
PubMed1997

Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study.

We estimated the remaining lifetime risks of developing Alzheimer's disease (AD) and dementia from all causes, based on data from longitudinal population studies. The risk of developing AD during one's lifetime depends on both disease incidence and life expectancy. Conventional estimates of cumulative incidence overestimate the risk when there is a substantial probability of mortality due to competing causes. A total of 2,611 cognitively intact subjects (1,061 men, 1,550 women; mean age, 66 +/- 7 years) were prospectively evaluated for the development of AD or other dementia. A modified survival analysis was used to estimate both cumulative incidence and the sex-specific remaining lifetime risk estimates for quinquennial age groups above age 65 years. Over a 20-year follow-up period, 198 subjects developed dementia (120 with AD). The remaining lifetime risk of AD or other dementia depended on sex, being higher in women, but varied little with age between 65 and 80 years. In a 65-year-old man, the remaining lifetime risk of AD was 6.3% (95% CI, 3.9 to 8.7) and the remaining lifetime risk of developing any dementing illness was 10.9% (95% CI, 8.0 to 13.8); corresponding risks for a 65-year-old woman were 12% (95% CI, 9.2 to 14.8) and 19% (95% CI, 17.2 to 22.5). The cumulative incidence between age 65 and 100 years was much higher: for AD, 25.5% in men and 28.1% in women; for dementia, 32.8% in men and 45% in women. The actual remaining lifetime risk of AD or dementia varies with age, sex, and life expectancy and is lower than the hypothetical risk estimated by a cumulative incidence in the same population.

Aged↗
PubMed1997

Evaluation of endovascular abdominal aortic aneurysm repair: anatomical classification, procedural success, clinical assessment, and data collection.

PURPOSE: To detail a methodology for evaluation of endovascular abdominal aortic aneurysm (AAA) repair that has been achieved through consensus of an international multidisciplinary team of investigators. METHODS: This schema features an anatomical classification for AAAs, a definition of procedural success, and a procedure for clinical assessment, as well as the necessary data collection forms. Patient data include demographics, procedural and clinical success, complications, and follow-up. Procedural details can be related to anatomic situations, comorbid processes, devices, and effective aneurysmal exclusion. RESULTS: These data would allow assessment of the procedures, physician learning curves, procedural indications, techniques, methodologies, the relationship of indications to success and complications, devices and subsequent graft patency, and aneurysmal exclusion. CONCLUSIONS: The use of this standardized data collection system could enable physicians and industry to better understand endovascular AAA repair and ultimately improve patient care.

Aortic Aneurysm, Abdominal↗
PubMed1997

Endograft repair of an aortic pseudoaneurysm following gunshot wound injury: impact of imaging on diagnosis and planning of intervention.

PURPOSE: To describe the endovascular treatment of a gunshot injury to the visceral aorta and the role of various imaging modalities in the staging and planning of the endograft procedure. METHODS AND RESULTS: The bullet entered the aorta posteriorly beneath the origin of the superior mesenteric artery and traversed the wall in a tangential manner entering the lumen proximal to the renal arteries. Intravascular ultrasound (IVUS) imaging and spiral computed tomography (CT) identified the injury that the initial angiograms failed to demonstrate. Combined use of IVUS and CT imaging enabled observation of the evolution of a pseudoaneurysm until an interval when endograft exclusion was possible. A stent-graft was customized based on precise IVUS and CT dimensional data and implanted successfully through an arteriotomy in the common femoral artery 3 weeks after the initial injury. Three-month follow-up imaging demonstrated continued exclusion of the pseudoaneurysm, and the patient remains well at 16 months. CONCLUSIONS: IVUS and spiral CT scans were instrumental in identifying an arteriographically undetected aortic injury. The combined imaging modalities also helped determine the timing for the endovascular procedure and provided the precise measurements for device fabrication and deployment.

Adult↗
PubMed1997

Protective effects of L-2-oxothiazolidine-4-carboxylate treatment on cyclophosphamide-induced cystitis in rats.

PURPOSE: Hemorrhagic cystitis is a therapy-limiting side effect of cyclophosphamide (CP) treatment for cancer. The purpose of this study was to investigate the potential protective effect of L-2-oxothiazolidine-4-carboxylate (OTZ; Procysteine) on CP-induced cystitis in the rat. MATERIALS AND METHODS: Thirty-six rats were divided into 6 groups: Group 1--Untreated controls, Group 2--OTZ alone (100 mg./kg., p.o.), Group 3--CP alone (68 mg./kg., i.v.), Group 4--CP + OTZ (68 mg./kg., i.v. + 100 mg.,/kg., p.o.), Group 5--CP + OTZ (68 mg./kg., i.v. + 1.0 g./kg., i.v.), and Group 6--CP + OTZ (68 mg./kg.,i.v. + 1.0 gm./kg., i.p.). OTZ was given once a day to groups 2 and 4 on the day prior to and on the day of CP administration. OTZ was given twice a day to groups 5 and 6 on the day prior to, the day of, and the day after CP administration. On the day of CP administration, CP was given 30 minutes prior to OTZ. Blood and bladder samples were taken for evaluation two days after CP administration. RESULTS: Expected depression in blood cell parameters were identified in all groups receiving CP with no differences noted between the CP-treated groups. Histologic changes (cystitis) were identified in the bladders of all CP treated groups. The lesions in the CP + OTZ groups were found to be less severe than the groups that received CP alone, with higher dosages of OTZ resulting in a significant (p < 0.05) decrease in lesion incidence and severity. CONCLUSIONS: Under the conditions of this study, L-2-oxothiazolidine-4 carboxylate caused a reduction in the incidence and severity of cyclophosphamide-induced lesions in the urinary bladder of rats. Further studies are needed to investigate optimal dosage scheme, mechanism of action, and interference with anti-tumor activity and prevention of long-term side effects of cyclophosphamide.

Animals↗
PubMed1997

Noniatrogenic pediatric vascular trauma: a ten-year experience at a level I trauma center.

We retrospectively reviewed all pediatric patients (< 18 years old) who presented to a Level I trauma center from 1984 to 1994 with noniatrogenic vascular trauma. There were 48 patients (42 male and 6 female) ages 2 to 17 years. Mechanism of injury included gunshot wounds (34) stab wounds (10), and blunt trauma (4). The lower extremities were most commonly injured (31), followed by upper extremity (17), trunk (8), and neck (4). Twenty-one (44%) patients had associated nonvascular injuries (primarily orthopedic or peripheral nerve). Eighteen (37%) patients underwent preoperative angiography for suspected extremity (15) or carotid injuries (3). Twenty-nine patients went to surgery without angiography based on severe ischemia (11) or hemorrhage (18). Arterial injuries (45) were managed by interposition reverse saphenous vein graft (16), primary repair (15), ligation (5), or other operative (5) and nonoperative treatment (4). Venous injuries (15) were treated with primary repair (8), patch (3), ligation (3), and nonoperative management (1). Fasciotomy was performed in six (12%). There were three deaths (6%), all due to aortic and/or caval injuries. Limb salvage in survivors was 100 per cent. There were no complications from angiography. Postoperative duplex scans demonstrated patency in six of the seven patients studied with venous injuries. We conclude that 1) noniatrogenic pediatric vascular trauma is uncommon, and 2) using an aggressive approach to both the diagnosis and treatment of these injuries can achieve excellent limb salvage rates with a low morbidity and mortality.

Adolescent↗
PubMed1996

Health implications for Faroe islanders of heavy metals and PCBs from pilot whales.

In the Faroe Islands marine food constitutes a considerable part of the diet. In addition to fish, both meat and blubber from pilot whales are included in the diet. Muscle tissue of pilot whales caught in the Faroe Islands contains an average mercury concentration of 3.3 micrograms/g (16 nmol/g), about half of which is methylmercury. In some years an evenly distributed annual catch of pilot whales would make the average dietary intake of mercury close to an excess of the Provisional Temporary Weekly Intake of 0.3 mg recommended by WHO. In one out of eight consecutive births, the mercury concentration in maternal hair exceeded a limit of 10 micrograms/g where a risk of neurobehavioral dysfunction in the child may occur; the maximum was 39.1 micrograms/g. Mercury concentrations in umbilical cord blood showed a similar distribution with a maximum of 351 micrograms/l. The large variation in mercury exposure is associated with differences in the frequency of whale dinners. The average PCB concentration in pilot whale blubber is very high, i.e. about 30 micrograms/g. With an estimated daily consumption of 7 g of blubber, the average daily PCB intake could therefore exceed 200 micrograms, i.e. close to the Acceptable Daily Intake. In Scandinavia, the average daily PCB intake is about 15-20 micrograms. To obtain an improved scientific basis for public health action, two major prospective studies have been initiated. A birth cohort of 1000 children has been examined at approximately 7 years of age for neurobehavioral dysfunctions associated with prenatal exposure to mercury and PCB. Preliminary analyses of the data show that several neurobehavioral tests are associated with mercury exposure parameters. With emphasis on prenatal exposures to PCB, another cohort has been generated during 1994-95, and this cohort will be followed closely during the next years.

Animals↗
PubMed1996

Suppression of a human colon cancer cell line by introduction of an exogenous NF1 gene.

Human colon carcinoma cell line HCT116 harbors an oncogenic Ki-ras gene. Introduction of an exogenous full-length NF1 gene or its GTPase-activating protein (GAP)-related domain suppressed the tumor-forming ability of this cell line in nude mice. A GAP-related domain peptide carrying a K1423E mutation, which shows greatly diminished GAP activity but a normal binding affinity for p2lras-GTP, was also tested. This construct was able to suppress tumor formation by the HCT116 cell line, thus ruling out the possibility that the observed tumor suppression is due to the GAP activity of NF1. Reduced Raf-1 kinase activity in cells which expressed these NF1 constructs suggested that neurofibromin may interfere with the interaction between Ras and Raf. Introduction of a mutationally activated Raf-1 kinase domain reversed tumor suppression by neurofibromin, implicating Raf-1 as the primary downstream transducer of the oncogenic Ras signal. An increase in apoptotic cell death, which could be delayed by activated Raf-1 kinase, was also seen in cells carrying the exogenous NF1 gene.

Animals↗
PubMed1996

Sequence, genomic structure, and chromosomal assignment of human DOC-2.

DOC-2 is a human gene originally identified as a 767-bp cDNA fragment isolated from normal ovarian epithelial cells by differential display against ovarian carcinoma cells. We have now determined the complete cDNA sequence of the 3.2-kb DOC-2 transcript and localized the gene to chromosome 5. A 12.5-kb genomic fragment at the 5'-end of DOC-2 has also been sequenced, revealing the intron-exon structure of the first eight exons (788 bases) of the DOC-2 gene. Translation of the DOC-2 cDNA predicts a hydrophobic protein of 770 amino acid residues with a molecular weight of 82.5 kDa. Comparison of the DNA and amino acid sequences of DOC-2 to publicly accessible sequence databases revealed 83% identify to p96, a murine protein of similar size, thought to be a mitogen-responsive phosphoprotein. In addition, about 45% identity was observed between the first 140 N-terminal residues of DOC-2 and the Caenorhabditas elegans M110.5 and Drosophila melanogaster Dab genes.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.

Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases the number of intestinal polyps that develop in the multiple intestinal neoplasia (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested the hypothesis that mutation of the human homologue(s) of this gene might be responsible for the more severe phenotype (hundreds of polyps) seen in a subset of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence analysis demonstrated that alterations of PLA2G2A, as well as related genes PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC subjects: those with small, intermediate, and large numbers of adenomatous colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in PLA2G2C did not correlate with an increased burden of adenomatous polyps. Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear to be responsible for phenotypic variation among subjects with AAPC.

Adenomatous Polyposis Coli↗
PubMed1996

Isolation of a gene (DLG3) encoding a second member of the discs-large family on chromosome 17q12-q21.

The discs-large family is a collection of proteins that have a common structural organization and are thought to be involved in signal transduction and mediating protein-protein interactions at the cytoplasmic surface of the cell membrane. The defining member of this group of proteins is the gene product of the Drosophila lethal (1) discs large (dlg) 1 locus, which was originally identified by the analysis of recessive lethal mutants. Germline mutations in dlg result in loss of apical-basolateral polarity, disruption of normal cell-cell adhesion, and neoplastic overgrowth of the imaginal disc epithelium. We have isolated and characterized a novel human gene, DLG3, that encodes a new member of the discs-large family of proteins. The putative DLG3 gene product has a molecular weight of 66 kDa and contains a discs-large homologous region, a src oncogene homology motif 3, and a domain with homology to guanylate kinase. The DLG3 gene is located on chromosome 17, in the same segment, 17q12-q21, as the related gene, DLG2. The products of the DLG2 and DLG3 genes show 36% identity and 58% similarity to each other, and both show nearly 60% sequence similarity to p55, an erythroid phosphoprotein that is a component of the red cell membrane. We suggest that p55, DLG2, and DLG3 are closely related members of a gene family, whose protein products have a common structural organization and probably a similar function.

Amino Acid Sequence↗
PubMed1996

In vitro propagation and production of hepatitis E virus from in vivo-infected primary macaque hepatocytes.

Hepatitis E virus (HEV) is responsible for sporadic cases as well as large epidemics of acute viral hepatitis in many developing countries. The nucleotide sequence of HEV appears to be unique among known viruses and thus may represent a prototype human pathogen in a novel class of single-stranded, positive-sense RNA viruses. To facilitate further studies of the biology of HEV, a tissue culture system using a serum-free medium formulation has been developed to propagate the virus in vitro. Hepatocytes were isolated from livers of cynomolgus macaques experimentally infected with a HEV (Burma strain) inoculum and maintained in long-term cultures. Using a highly strand-specific RT-PCR assay, both the positive-sense and the negative replicative strands of HEV RNA were detected in these hepatocytes throughout the course of the experiments. Positive-strand genomic RNA was also detected in the culture medium, suggesting the production and secretion of HEV virus particles. The virus particles were successfully concentrated 200-fold from the medium using ultrafiltration, and they could be observed by immunoelectron microscopy using anti-HEV-positive immune serum. These results demonstrate the capacity of this hepatocyte culture system to replicate HEV in vitro, thus providing an experimental means to study the replicative process of the virus.

Animals↗
PubMed1996

Cardiac assessment prior to vascular surgery: is dipyridamole-sestamibi necessary?

Dipyridamole-sestamibi (PMIBI) is recommended prior to vascular surgery in patients with > or = 1 Eagle criteria (Q waves, history of ventricular ectopy, diabetes, advanced age, and/or angina). To review our cardiac morbidity and mortality and the need for preoperative PMIBI, we reviewed 109 consecutive patients with a mean age of 59 years who underwent 145 elective major vascular procedures over a 1-year period. Seventy patients (with a mean of 0.8 Eagle criteria) underwent 92 vascular procedures without preoperative PMIBI and without coronary revascularization. Thirty-one patients (with a mean of 1.1 Eagle criteria) underwent 39 procedures without coronary revascularization following PMIBI, which showed reversible ischemia in seven and a fixed defect in 10; findings were normal in 14. Preoperative coronary bypass or angioplasty was limited to eight patients (14 procedures, mean of 1.6 Eagle criteria) who had unstable angina with (2 patients) or without (6 patients) acute myocardial infarction. There were four perioperative myocardial infarctions (2.8%), seven cardiac events overall (4.8%), and one cardiac death (0.7%). Three (43%) of the seven cardiac events occurred in patients with a normal scan or fixed defect on PMIBI imaging. In the absence of unstable angina, PMIBI had a sensitivity of only 25% and a specificity of 80% for cardiac events. We conclude that among patients without severe cardiac symptoms (1) PMIBI has a very limited ability to identify patients at risk for cardiac complications, and (2) preoperative PMIBI is neither necessary nor cost-effective.

Age Factors↗
PubMed1996

Comparison of the deployment and healing of thin-walled expanded PTFE stented grafts and covered stents.

This study evaluated the deployment and short-term healing of thin-walled expanded polytetrafluoroethylene (ePTFE) stented grafts and covered stents as endoluminal prostheses in normal canine aortas and in an abdominal aortic aneurysm (AAA) model. Stented grafts consisted of a 7 cm length of 3 mm internal diameter ePTFE graft (Impra, Inc., Tempe, Ariz.) with two P-188 Palmaz stents (Johnson & Johnson Interventional Systems, Warren, N.J.) deployed along the inner surface of the ends of the graft to secure the prosthesis to the arterial wall. Covered stents were fabricated by placing a 3.7 cm length of 3 mm internal diameter thin-walled ePTFE graft over a P-394 Palmaz stent. Four covered stents and four stented graft prostheses (two of each prototype in the normal canine aorta and AAA model) were implanted in eight animals. One prosthesis of each type in each model was removed at 30 days and one at 60 days. Prior to removal, prostheses were evaluated by CT scan, arteriography, and intravascular ultrasound imaging with values compared to those obtained when the prostheses were deployed. Gross inspection and microscopic evaluation were performed at scheduled explantation. In general, the stented grafts were more difficult to accurately deploy. Healing and maintenance of long-term patency without significant luminal obstruction or occlusion occurred in only one 30-day sample in a normal canine aorta. The 30-day stented graft specimen that had been implanted in an AAA and required the addition of a covered stent to seal a maldeployment of the distal segment was also patent. The 60-day stented graft in the normal canine aorta was occluded with narrowing of the graft between the stents. The 60-day stented graft in the AAA was patent with one central fold and thrombus occupying approximately 20% to 30% of the lumen at this site. In contrast, the covered stent devices were less difficult to accurately deploy. All of the covered stent devices were patent with well-incorporated surfaces. Deployment of covered stents was more accurate and less complicated compared to stented grafts. All patent endoluminal prostheses and stent surfaces were well incorporated into aortic tissues. Problems with graft narrowing, folding, and subsequent thrombosis occurred in the unstented segments of the stented grafts. These preliminary findings support the further development and use of completely supported (stented) devices as endoluminal prostheses.

Angioplasty, Balloon↗