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Biomedical subjects

D McDermott

Publications and source records attributed to D McDermott.

At least 19 recordsLinked to original sources
PubMed2003

A phase I-II study of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME) for B cell non-Hodgkin's lymphoma prior to and after high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT).

This phase I-II study describes the safety of rituximab, ifosfamide, mitoxantrone and etoposide (R-IME) as an induction regimen prior to high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT), and rituximab given post-HDC-ASCT for B cell non-Hodgkins's lymphoma. This study also measured the effect on disease burden and stem cell contamination. Patients with relapsed, refractory or poor risk B cell lymphomas were eligible. Patients were treated with two cycles of R-IME; all non-progressing patients under-went a third cycle and peripheral blood stem cell (PBSC) collection. Patients underwent HDC-ASCT and those patients in remission after HDC-ASCT were treated with four additional doses of rituximab. Tumor cell contamination was measured at baseline and in the PBSC. Serial immunoglobulin levels were measured. Patients were followed for time to treatment failure (TTF) and overall survival (OS). Thirty-two patients were enrolled. Thirty patients had at least stable disease after two cycles of R-IME. Twenty-nine underwent stem cell collection. The response rate to R-IME induction was 77% (20/26) with 35% (9/26) complete response(CR). Stem cell mobilization was successful in 93% (27/29) of patients. The response rate to R-IME induction and HDC-ASCT was 95% with a confirmed CR of 68%. Median follow-up was 28 months; the median TTFand OS have not been reached. There was a significant decline in stem cell tumor cell contamination and a significant decline in IgG without an increase in infections. Forty-three per cent of patients had transient neutropenia after post-transplant rituximab. R-IME is an effective cytoreductive and mobilization regimen. There appears to be a reduction in the number of lymphoma cells in the stem cell product and the toxicity is manageable.

Adult↗
PubMed2001

Risk of endometrial carcinoma associated with BRCA mutation.

OBJECTIVE: Inherited mutations in the BRCA1 or BRCA2 genes are associated with a greatly increased lifetime risk of breast and ovarian cancers and a modestly increased risk of several other cancer types. Several case reports of endometrial carcinoma in women with a BRCA mutation have led to speculation regarding the effect of these genes on the risk of endometrial cancer. The purpose of this study was to test the hypothesis that germline mutation of a BRCA gene is associated with an increased risk of endometrial carcinoma. METHODS: A retrospective cohort of 199 consecutive Ashkenazi Jewish patients with endometrial carcinoma was identified from a 12-year period at this institution. All were genotyped for the three BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) that exist in this population, and the case frequency was compared to the known population frequency of these mutations. Additionally, endometrial carcinomas occurring in patients with BRCA mutations were assessed for somatic loss of the wild-type BRCA allele. RESULTS: Germline BRCA mutations were identified in 3 (1 in BRCA1 and two in BRCA2) of 199 (1.5%) patients, compared to a frequency of 2.0% in this population generally. A relative risk of endometrial carcinoma associated with BRCA mutation, as estimated by the odds ratio, was calculated as 0.75 (95% CI = 0.24--2.34; P = 0.6). Loss of the wild-type BRCA allele was observed in two of three tumors associated with a BRCA mutation. CONCLUSIONS: For individuals with a germline BRCA mutation, the lifetime risk of endometrial carcinoma is not increased.

Aged↗
PubMed2001

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer: sequential phase I/II studies.

Two cycles of high-dose chemotherapy with stem cell support (HDC) may increase the total dose delivered and dose intensity. A brief induction phase and different non-cross-resistant agents for each HDC cycle were used to avoid drug resistance. Twenty-six women with metastatic BC had induction and stem cell mobilization with two cycles of doxorubicin/G-CSF given every 14 days. Patients with stable disease or better after induction received HD CTCb followed by HD melphalan and dose-escalated paclitaxel. At 475 mg/m(2) of paclitaxel by 24-h infusion, dose-limiting transient peripheral sensory neuropathy was encountered. No toxic deaths occurred. Complete and near complete response after completion of therapy was achieved in 22 (85%) of 26 patients. The median EFS was 38 months. The median OS has not yet been reached. At a median follow-up of 33 (25-43) months, actuarial EFS and OS were 54% (95% confidence interval (CI), 39-69%) and 69% (95% CI, 56-79%), respectively. This double transplant approach lasts only 14 weeks and is feasible, safe, and tolerable. Whilst selection biases may in part contribute to favorable EFS and OS, a randomized comparison of standard therapy vs double transplant in both metastatic and locally advanced breast cancer is warranted.

Adult↗
PubMed2001

Rituximab and ifosfamide, mitoxantrone, etoposide (RIME) with Neupogen support for B-cell non-Hodgkin's lymphoma prior to high-dose chemotherapy with autologous haematopoietic transplant.

A phase I/II study was performed to analyse the ability of ifosfamide-based chemotherapy with rituximab to produce a turmour-free graft as well as the safety of retuximab prior to stem cell harvest and post high-dose chemotherapy. Twenty-two patients with B-cell non-Hodgkin's lymphoma were enrolled either having aggressive large-cell disease in relapse or at high/high-intermediate risk of relapse, or refractory lymphoma or mantle cell lymphoma, or indolent lymphoma. Chemotherapy consisted of ifosfamide 2 g/m2, days 1-3 with mesna, etoposide 100 mg/m2, days 1-3, and mitoxantrone 8 mg/m2 day 1, with figrastim. Rituximab was given at 375 mg/m2 for 4 doses. An encouraging overall response rate of 90%, including 11 CRs was achieved. CD34+ cells were successfully mobilized in 18 or 19 patients analysed so far with a median number of 3.4 x 10(6) cells/kg. The combination of ifosfamide-based chemotherapy with rituximab significantly reduced the number of contaminating B-cells in the stem cell product and so far there has only been a single relapse post high-dose chemotherapy with autologous haematopoietic transplant. The RIME regimen was generally well tolerated with minimal non-haematological toxicity and most of the treatment was done completely on an outpatient basis. Haematological toxicity was manageable with filgrastim, there were some infectious complications.

Adult↗
PubMed2000

Immune reconstitution following high-dose chemotherapy with stem cell rescue in patients with advanced breast cancer.

The present study examines the nature of humoral and cellular immune reconstitution in 28 patients with advanced breast cancer following high-dose chemotherapy with stem cell rescue. Patients underwent testing of T, B, NK and dendritic cell function at serial time points until 1 year post transplant or until the time of disease progression. Abnormalities in T cell phenotype and function were observed following high-dose chemotherapy that persisted for at least 6-12 months. The vast majority of patients experienced an inversion of the CD4/CD8 ratio and demonstrated an anergic response to candida antigen. Mean T cell proliferation in response to PHA and to co-culture with allogeneic monocytes was significantly compromised. In contrast, mean IgG and IgA levels were normal 6 months post transplant and NK cell yields and function were transiently elevated following high-dose chemotherapy. Dendritic cells generated from peripheral blood progenitors displayed a characteristic phenotype and were potent inducers of allogeneic T cell proliferation in the post-transplant period. The study demonstrates that patients undergoing autologous transplantation for breast cancer experience a prolonged period of T cell dysfunction. In contrast, B, NK, and DC recover more rapidly. These findings carry significant implications for the design of post-transplant immunotherapy.

Adult↗
PubMed1999

Outpatient coronary stenting: femoral approach with vascular sealing.

Miniaturized devices and pressures for increased patient convenience and lowered cost have shortened length of stay for coronary interventions. A cohort of 60 patients was recruited to assess the feasibility of outpatient stenting with vascular sealing. Patients with stable and unstable angina or myocardial infarction > 24 hours were considered for this strategy. Mean time to hemostasis, ambulation and discharge were 6.1, 256 and 296 minutes, respectively, for the 6F group, and 11.0, 351 and 489 minutes for the 7 to 8F group. No acute procedural complications occurred, and there were no ischemic complications at 24 hours or 1 month. There was 1 pseudoaneurysm requiring surgical correction, but no other access site requiring treatment. The cost saved using the 6F approach is estimated at $478 and using the 8F approach, $437. Outpatient stenting using vascular sealing is feasible and safe, and may lead to significant nationwide cost reductions in the range of $40,000,000 yearly.

Ambulatory Care↗
PubMed1999

Outpatient coronary stenting using the femoral approach with vascular sealing.

PURPOSE: We report here the use of vascular sealing devices in conjunction with the use of small transfemoral guiding catheters to decrease time to ambulation, decrease cost associated with hospitalization and achieve early discharge. METHODS: Fifty patients were enrolled in this pilot project from two busy interventional practices between May 1997 and February 1999. Patients with stable or unstable angina or positive ETT and with recent myocardial infarction greater than 24 hours from the time of the procedure were included. Excluded patients included those who had received glycoprotein IIb/IIIa platelet inhibitors and those with intra-procedure access site complications. RESULTS: Of the 50 patients originally recruited, 49 underwent vascular sealing for hemostasis and 45 were discharged on the same day, as planned. Early home telephone follow-up was available on 41 of the 45 same-day discharge patients, of whom 30 noted no complaints. One patient, who had been re-accessed in the right femoral artery after a previous intervention, developed a pseudoaneurysm requiring surgical repair. One-month follow-up was available on all patients. No patient suffered a late ischemic event or access site complication requiring treatment. There were no instances of stent loss, acute closure or subacute thrombosis. CONCLUSION: Though limited by small numbers, this pilot study shows that selected patients undergoing coronary stenting via the femoral approach can be safely treated on an outpatient basis using vascular sealing devices. Cost savings may be significant using this strategy.

Ambulatory Surgical Procedures↗
PubMed1995

How one chapter successfully created a nursing research committee.

Establishing a chapter nursing research committee can be a difficult task. Many perioperative nurses have not been exposed to research in their basic nursing programs or received graduate preparation in nursing research. This lack of exposure may result in disinterest in nursing research topics. This article explains how AORN of Pittsburgh established a successful nursing research committee. The committee's process of development and its achievements can be used as a guide for other local chapters that may be struggling with similar issues.

Education, Nursing, Continuing↗
PubMed1995

Computer-based medical clerking.

All admissions to hospital begin with medical clerking. Thus, it is an essential element of any electronic patient record system. This paper describes some initial experiments to develop a computer-based clerking tool with which doctors can record their clinical observations. The clerking tool uses a structured data entry technique which is based upon an underlying semantic network of clinical terminology. This enables data to be captured and stored in a semantically structured manner, facilitating its use in computer-based record systems and also for audit, management, and decision support purposes. The prototype tool is described, and the evaluation and preliminary results obtained are reported. Initial results indicate that structured data entry is feasible for hospital-based clerking.

Admitting Department, Hospital↗
PubMed1995

A clerking tool for the patient record system.

1. BACKGROUND. The goal of the PEN&PAD (Elderly Care) project is to develop a patient record system to assist the many different professionals that care for patients in a hospital setting. At the core of the project is the use of structured data which can be reused in a variety of ways--both within the system for further manipulation and display, and externally for auditing and statistical purposes. To accommodate these needs, a compositional method of data entry called Structured Data Entry (SDE) was used in this application. SDE was developed in an earlier project PEN&PAD (GP)(1). Our application utilizes a network representation of the medical semantics that can be queried to obtain what is sensible to "say" about a particular concept. This functionality is contained within a separate application known as the Terminology Server (TeS), which has been developed within the GALEN project (2). The client application (the patient record system) requests information from the TeS which can then be used to produce compositional data entry forms that require the user to choose values for given attributes (e.g., if information pertaining to chest pain were being recorded, the attribute 'location' and a choice of possible values i.e., 'left' 'right' and 'bilateral' might appear on the form). Given the importance of capturing clinical information in a highly structured format, SDE is a valuable tool. However, its long term success depends on a very comprehensive model of the medical terminology corpus. This component is currently being studied by the GALEN team. 2. CURRENT WORK. We are developing a clerking tool to be used to create records for the newly admitted patient. The clinician seeks to identify a patient's problems based on physical examination and information obtained through conversation with the patient. Patients are usually admitted with a presenting complaint and obtaining more information about this complaint is an important part of the clerking process. While the physician may be able to use the clerking data to consider possible diagnoses right away, he/she often needs to review relevant body systems before a diagnosis is made. In traditional paper based clerking systems, notes are highly formalized but still subject to variation between clinicians. A typical clerking records information such as: 1) history of the presenting complaint; 2) previous medical history; 3) review of body systems; 4) medication; 5) social history; and 6) investigations. We have attempted to retain this clerking outline as much as possible, focusing primarily on the presenting complaint and review of body systems sections. To begin the clerking process, the user chooses a presenting complaint (from the list provided) to launch the 'clerking' window. Access buttons for the different clerking sections are positioned above a data entry window. This window contains a form for collecting information on the presenting complaint. The form is divided into sections to allow the user to record the absence or presence of an associated symptoms and other details. Free text comments can be added to the window, and a data display area shows information entered so far. The user can query the body system database by choosing a system from a menu. At this point the presenting complaint window is replaced by one on the body system in question. The user is free to switch back and forth between the presenting complaint and body system screens. On returning to a previously visited window, the user may pick up where he/she left off when exiting the window. Once the clerking is completed, the information is entered as a unit into the patient record with the date and clinicians name attached. Thereafter, the file becomes read-only. We are currently putting a prototype clerking system through field trials with clinicians from of a local hospital. In our demonstration, we hope to elaborate on these trials and their outcomes.

Admitting Department, Hospital↗
PubMed1994

Differential expression of members of the N-formylpeptide receptor gene cluster in human phagocytes.

The human genes for two N-formylpeptide phagocyte chemoattractant receptors (gene symbols FPR1 and FPRL1) cross-hybridize with each other and with FPRL2, a human gene of unknown expression and function. The FPR1 product is approximately 1000-fold more sensitive than the FPRL1 product to N-formylpeptides. We now report cloning of the first cDNA for FPRL2 and the first description of the RNA distribution in normal human phagocytes for all three genes. FPR1 and FPRL1 are expressed in neutrophils and monocytes. In contrast, FPRL2 RNA is detectable in monocytes but not in neutrophils, and its product could not be activated by N-formylpeptides. Thus, the regulation of FPRL2 gene expression in vivo differs from FPR1 and FPRL1.

Animals↗
PubMed1993

Sequence and organization of the human N-formyl peptide receptor-encoding gene.

The human FPR1 gene encodes the N-formyl peptide receptor, a G protein-coupled receptor (GPCR) that mediates the activation of mature myeloid cells by bacterial N-formyl oligopeptides. To investigate the molecular basis for myeloid-specific production of this receptor, we have cloned and sequenced FPR1. The gene is organized into three exons and two introns that span 6 kb. The coding block lacks introns. Yet, the transcription start point (tsp) is separated from the start codon by 4902 bp consisting of three exons and two large introns. Two mRNAs are produced by alternative splicing of exon 2 in HL-60 neutrophils and normal blood monocytes. The region 5' to the tsp contains three pyrimidine-rich segments, a feature that has been observed in other myeloid-specific genes. One complete Alu repeat is found in each intron and in the 3'-flanking region 317 bp downstream of the polyadenylation signal. Thus, FPR1 is a small myeloid-specific gene that is expressed as two alternatively spliced mRNAs encoding the same protein.

Amino Acid Sequence↗
PubMed1993

Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor.

The chemokine beta family is comprised of at least six distinct cytokines that regulate trafficking of phagocytes and lymphocytes in mammalian species; at least one of these, macrophage inflammatory protein 1 alpha (MIP-1 alpha), also regulates the growth of hematopoietic stem cells. We now show that MIP-1 alpha and the related beta chemokine, RANTES, induce transient alterations in intracellular Ca2+ concentration in polymorphonuclear leukocytes that can be reciprocally and specifically desensitized, suggesting a common receptor. Moreover, we have now cloned both the cDNA and the gene for this receptor, functionally expressed the receptor in Xenopus oocytes, and mapped the gene to human chromosome 3p21. Transcripts for the receptor were found in mature and immature myeloid cells as well as B cells. The receptor is a member of the G protein-coupled receptor superfamily. It has approximately 33% amino acid identity with receptors for the alpha chemokine, interleukin 8, and may be the human homologue of the product of US28, an open reading frame of human cytomegalovirus.

Amino Acid Sequence↗
PubMed1992

A structural homologue of the N-formyl peptide receptor. Characterization and chromosome mapping of a peptide chemoattractant receptor family.

Phagocytic cells of many higher species express calcium mobilizing G protein-coupled receptors for bacterial N-formyl peptides which mediate chemotaxis, degranulation, and the respiratory burst. cDNA encoding an N-formyl peptide receptor (FPR) has been reported. We now report the isolation of a closely related cDNA, 2.6 kilobase pairs in length, which we have designated as the FPRL1 receptor cDNA (FPRL1 = formyl peptide receptor like-1). FPR and the FPRL1 receptor derive from small, single-copy genes, both of which are located on human chromosome 19. The gene loci are designated FPR1 and FPRL1, respectively. Both FPR and FPRL1 cDNA cross-hybridize under high stringency conditions with a third gene, designated as FPRL2, which does not appear to be expressed in neutrophils. In contrast, transcripts for both the FPRL1 receptor and FPR are detected only in differentiated myeloid cells; the distribution of N-formyl peptide binding sites is also restricted to mature myeloid cells. FPRL1 cDNA encodes a 351-amino acid polypeptide whose sequence is 69% identical to that of FPR. G protein-coupled receptors that exhibit this degree of structural similarity typically possess a conserved ligand specificity. However, the FPRL1 receptor does not bind prototype N-formyl peptide ligands when expressed in heterologous cell types. These results suggest that FPR1 may be the only gene that is expressed by neutrophils that encodes a receptor capable of binding prototype N-formyl peptides. Moreover, discovery of the FPRL1 receptor indicates the existence of another as yet unidentified peptide that may recruit neutrophils to sites of inflammation.

Amino Acid Sequence↗
PubMed1992

The guanine nucleotide-binding protein Gs activates a novel calcium transporter in Xenopus oocytes.

Calcium influx is an important aspect of receptor-mediated signal transduction, yet limited information is available regarding the pathways of calcium influx into nonexcitable cells. We show that treatment of oocytes from Xenopus laevis with cholera toxin, a potent activator of the guanine nucleotide-binding protein Gs, specifically stimulates a sustained inward whole cell flux of calcium through a novel membrane transporter. The calcium is distributed into a mobilizable pool. The flux is voltage-independent and is completely and specifically blocked by microinjection of oocytes with an antiserum directed against Gs alpha. The flux is not activated by treatment of the cells with forskolin or 8-bromo-cyclic adenosine monophosphate indicating that the effect of Gs alpha on the transporter occurs independently of adenylylcyclase activation. Transporter activity is insensitive to benzyl amiloride, does not require a sodium gradient, and is not stimulated by external calcium, indicating that it is not a sodium-calcium exchanger. The Gs-activated flux is dramatically potentiated by lanthanum ion and other trivalent cations but not by any of six divalent cations that were tested; all other known calcium channels and exchangers are, in contrast, potently blocked by lanthanum. The divalent cation cadmium inhibited transporter activity in a concentration-dependent manner. This novel calcium transporter may be important for receptor-mediated calcium influx in the oocyte and perhaps other cell types.

Animals↗
PubMed1992

A participative approach to organisation restructuring: a case study from the Silver Chain Nursing Association (Inc).

This case study examines the review of the corporate structure of the Silver Chain Nursing Association. The design and conduct of the review process and the issues are discussed in the context of recent research and the published experiences of other organisations undergoing similar changes. The review was pro-active in that the restructuring was carried out in anticipation of changes in the external environment (eg: increased service demand and decreased funding) and issues in the internal environment (eg: decreased flexibility of labour and a dilution of the service ethos). The significant feature of the review design was allowing employees to have an opportunity to define the issues requiring change; generate and evaluate opportunities for improvement; and recommend a new organisation structure. It is concluded that in a properly designed and managed process and provided with adequate information, employees are quite capable of making objective and well informed contributions about how their organisations can best operate. Participation appears to have facilitated better quality decisions and timely, acceptable implementation plans.

Community Health Nursing↗
PubMed1991

Functional expression of the human formyl peptide receptor in Xenopus oocytes requires a complementary human factor.

Human phagocytic cells express receptors for bacterial N-formyl peptides (formyl peptide receptor or FPR) which mediate chemotaxis, degranulation, and the respiratory burst. Although cDNA encoding a human phagocyte formyl peptide-binding protein has been reported recently (Boulay, F., Tardif, M., Brouchon, L., and Vignais, P. (1990) Biochem. Biophys. Res. Commun. 168, 1103-1109), functional coupling to signal transduction processes was not demonstrated. We describe corresponding full-length cDNA clones and prove that they encode the calcium-mobilizing human formyl peptide receptor by demonstrating functional reconstitution in the Xenopus oocyte. We further demonstrate that in contrast to all other cloned guanine nucleotide-binding regulatory protein (G-protein) coupled receptors expressed in this system, microinjection of FPR transcripts is not sufficient to confer ligand responsiveness to the oocyte: co-injection of phagocyte RNA encoding a complementary human factor that is not the alpha subunit of the heterotrimeric G-proteins Gi1, Gi2 or Gi3 is also required. Whereas a 1.4-kilobase FPR transcript is expressed exclusively in differentiated phagocytic cells, the complementary factor activity localizes to a 3.5-kilobase RNA fraction and is expressed in both differentiated and undifferentiated myeloid cells as well as in liver. The deduced human FPR protein possesses seven hydrophobic putative membrane spanning segments, three sites for N-linked glycosylation, and a short 18-amino acid predicted third cytoplasmic loop. Surprisingly, the human FPR possesses only 28% amino acid identity with the rabbit FPR reported recently by Thomas and co-workers (Thomas, K. M., Pyun, H. Y., and Navarro, J. (1990) J. Biol. Chem. 265, 20061-20065). Moreover, the rabbit FPR does not require a complementary factor for calcium mobilization in the oocyte. Structural alignment reveals at most 20% amino acid identity of the human FPR with other G-protein coupled receptors, indicating a common ancestral gene. Functional reconstitution of the recombinant FPR will now permit precise delineation of its functional and regulatory domains. Moreover, discovery of a complementary factor for oocyte expression of the human FPR establishes a novel approach to the qualification by ligand screening of cDNA encoding other suspected G-protein coupled receptors.

Amino Acid Sequence↗