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Biomedical subjects

C Farrell

Publications and source records attributed to C Farrell.

At least 19 recordsLinked to original sources
PubMed2000

The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation. We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator. To facilitate our understanding of the normal function of MEFV, we extended our previous studies. MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization. CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment. The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation. MEFV was also expressed in the monocytic cell lines U937 and THP-1. Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes. Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements. In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta inhibited such expression. Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide. IFN-alpha also induced MEFV expression. In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine. These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-gamma immediate early gene.

Cell Differentiation↗
PubMed1999

Conservation of sequence and structure flanking the mouse and human beta-globin loci: the beta-globin genes are embedded within an array of odorant receptor genes.

In mouse and human, the beta-globin genes reside in a linear array that is associated with a positive regulatory element located 5' to the genes known as the locus control region (LCR). The sequences of the mouse and human beta-globin LCRs are homologous, indicating conservation of an essential function in beta-globin gene regulation. We have sequenced regions flanking the beta-globin locus in both mouse and human and found that homology associated with the LCR is more extensive than previously known, making up a conserved block of approximately 40 kb. In addition, we have identified DNaseI-hypersensitive sites within the newly sequenced regions in both mouse and human, and these structural features also are conserved. Finally, we have found that both mouse and human beta-globin loci are embedded within an array of odorant receptor genes that are expressed in olfactory epithelium, and we also identify an olfactory receptor gene located 3' of the beta-globin locus in chicken. The data demonstrate an evolutionarily conserved genomic organization for the beta-globin locus and suggest a possible role for the beta-globin LCR in control of expression of these odorant receptor genes and/or the presence of mechanisms to separate regulatory signals in different tissues.

Animals↗
PubMed1999

The incidence of venous thromboembolism after total hip arthroplasty: a specific hypotensive epidural anesthesia protocol.

We retrospectively reviewed all consecutive unilateral primary total hip arthroplasty (THA) procedures performed by 3 attending surgeons on the Arthroplasty Service at our institution from January 1, 1990, to December 31, 1993. All surgery was performed under a specific hypotensive epidural anesthesia protocol. Hypotensive epidural anesthesia at our institution provides a lower level of hypotension (mean arterial pressure of 50-60 mmHg) as compared to hypotensive anesthesia used more generally around the world (mean arterial pressure >70 mmHg). For each patient, hospital and postdischarge office records for a minimum of 3 months after surgery were reviewed for the type of postoperative screening test, the incidence of deep venous thrombosis (DVT), and the incidence of symptomatic pulmonary embolism (PE). Overall, 2,592 primary unilateral THAs were performed with 78.6% (2,037 of 2,592) of patients receiving a venogram. Our protocol for thromboembolic disease prophylaxis in these patients included aspirin postoperatively as well as antithromboembolic disease stockings and early ambulation (24-48 hours postoperatively). The 555 patients who did not receive venography were managed with a different protocol that included warfarin postoperatively as well as antithromboembolic disease stockings and early ambulation. This high-risk group consisted of patients who received warfarin preoperatively (ie, cardiac valve) or patients with a history of DVT who were to receive warfarin postoperatively, regardless of venography result. Overall, DVT was diagnosed in 10.3% (210 of 2,037) of patients who had a venogram. Of these patients who had venography, 2.3% (46 of 2,037) had an isolated proximal DVT; 6.0% (123 of 2,037), a distal DVT; and 2.0% (41 of 2,037), both a proximal and a distal DVT. Of the 87 cases of proximal DVT identified, 60.9% (53 of 87) were femoral DVT; 18.4% (16 of 87), popliteal DVT; and 20.7% (18 of 87), both femoral and popliteal DVT. Of the 164 distal DVT, 68.3% (112 of 164) were major calf DVT and 31.7% (52 of 164) were minor calf DVT. The overall incidence of major venous thrombosis (sum of proximal and major calf thrombi) was 9.8% (199 of 2,037) in patients who had venography. Ventilation-perfusion scanning was used selectively in patients symptomatic for PE. Overall, symptomatic PE was diagnosed by ventilation-perfusion scan in 1.0% (26 of 2,592) of patients, with 0.58% (15 of 2,592) of patients having an in-hospital PE. Of the 15 patients who had an in-hospital PE, 11 patients had a venogram, and only 3 of 11 were positive. Late symptomatic PE was defined from discharge (mean, 7 +/- 2 days) to 3 months after discharge from the hospital and occurred in 0.42% (11 of 2,592) of patients. One of the 11 late symptomatic PEs was fatal. In the overall study, this represents 0.04% (1 of 2,592) fatal PE. Of the 11 patients with a late symptomatic PE, 10 had venograms in the hospital, and all 10 were negative for DVT. Overall, in the patients with a positive venogram, the incidence of symptomatic PE was 1.4% (3 of 210), whereas in the patients with a negative venogram, the incidence of symptomatic PE was 0.44% (8 of 1,827). At our institution, patients who undergo primary THA performed with hypotensive epidural anesthesia, postoperative aspirin, antithromboembolic disease stockings, and early ambulation have a low risk for thromboembolic disease.

Anesthesia, Epidural↗
PubMed1998

A convenient and reliable IL-2 bioassay using frozen CTLL-2 to improve the detection of helper T lymphocyte precursors.

The helper T lymphocyte precursor (HTLp) frequency detected in HLA matched sibling donors is directed against alloantigens and this frequency has been shown to correlate with the development of graft-versus-host disease in the patient after bone marrow transplantation. Using limiting dilution analysis the HTLp frequency is determined by measuring IL-2 using the IL-2-dependent murine cell line CTLL-2. An important factor associated with the successful performance of any bioassay is the reliability of the indicator cell line used. When maintained in continuous culture, however, the overall sensitivity of this cell line is highly variable. To overcome this problem, large batches of CTLL-2 were grown, frozen and tested for their ability to detect low levels of IL-2 (0.01 IU) in dose response assays. Batches meeting this criterion were stored in liquid nitrogen until required. In this study, we investigated the effect of freezing and storing large batches of this cell line, thereby assuring a plentiful supply of sensitive indicator cells.

Animals↗
PubMed1998

Minimally invasive parathyroidectomy for primary hyperparathyroidism: decreasing operative time and potential complications while improving cosmetic results.

Primarily because of the lack of highly accurate preoperative localizing studies, the standard operation for primary hyperparathyroidism (HPTH) has consisted of bilateral neck exploration with examination of all four parathyroid glands. Recent experience with the technetium-99m-Sestamibi scan at our hospital has suggested that this single test was now accurate enough to allow unilateral neck exploration. This study was designed to examine the efficacy and safety of minimally invasive parathyroid-ectomy in select patients with a single adenoma demonstrated on a preoperative sestamibi. Eighteen consecutive patients with primary HPTH in whom a sestamibi scan suggested a single adenoma underwent unilateral neck exploration through a 2.5-cm incision, which was extended as necessary. Results were compared to the preceding 25 parathyroid explorations for primary HPTH due to a single adenoma, which were nondirected and included bilateral neck exploration. All patients undergoing minimal exploration were found to have a single adenoma and demonstrated a normal serum calcium within 24 hours of surgery. Standard bilateral exploration failed to locate the adenoma in one patient requiring subsequent re-exploration. Operative time, incision length, and length of hospital stay were all significantly less for those undergoing minimal exploration (all P < 0.01). There were no complications in either group. Minimally invasive neck exploration is a safe and effective treatment for primary HPTH, is easily accomplished under local anesthesia, and is associated with significant reductions in operative time and hospital stay. Limited exploration provides a better cosmetic result while decreasing the potential complications of bilateral exploration, but is dependent upon a high-quality sestamibi scan.

Adenoma↗
PubMed1997

Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene.

We have isolated and characterized complete cDNAs for two isoforms (HSPDE4D4 and HSPDE4A5) encoded by the human PDE4D gene, one of four genes that encode cAMP-specific rolipram-inhibited 3',5'-cyclic nucleotide phosphodiesterases (type IVPDEs; PDE4 family). The HSPDE4D4 and HSPDE4D5 cDNAs encode proteins of 810 and 746 amino acids respectively. A comparison of the nucleotide sequences of these two cDNAs with those encoding the three other human PDE4D proteins (HSPDE4D1, HSPDE4D2 and HSPDE4D3) demonstrates that each corresponding mRNA transcript has a unique region of sequence at or near its 5'-end, consistent with alternative mRNA splicing. Transient expression of the five cDNAs in monkey COS-7 cells produced proteins of apparent molecular mass under denaturing conditions of 68, 68, 95, 119 and 105 kDa for isoforms HSPDE4D1-5 respectively. Immunoblotting of human cell lines and rat brain demonstrated the presence of species that co-migrated with the proteins produced in COS-7 cells. COS-cell-expressed and native HSPDE4D1 and HSPDE4D2 were found to exist only in the cytosol, whereas HSPDE4D3, HSPDE4D4 and HSPDE4D5 were found in both cytosolic and particulate fractions. The IC50 values for the selective PDE4 inhibitor rolipram for the cytosolic forms of the five enzymes were similar (0.05-0.14 microM), whereas they were 2-7-fold higher for the particulate forms of HSPDE4D3 and HSPDE4D5 (0.32 and 0.59 microM respectively), than for the corresponding cytosolic forms. Our data indicate that the N-terminal regions of the HSPDE4D3, HSPDE4D4 and HSPDE4D5 proteins, which are derived from alternatively spliced regions of their mRNAs, are important in determining their subcellular localization, activity and differential sensitivity to inhibitors.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

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Humans↗
PubMed1997

Donor helper T-cell frequencies as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings.

BACKGROUND: Despite the current level of sophistication of molecular typing for class I and class II alleles, a significant proportion (20-40%) of recipients of HLA-identical sibling marrow develop severe, acute graft-versus-host disease (GVHD) after bone marrow transplantation. It has been suggested that the frequency of patient-specific helper T lymphocyte precursors (HTLp) detected in the HLA-identical sibling donor correlates with the incidence and severity of acute GVHD after transplantation. METHODS: This study group consisted of 42 patients who all received bone marrow from HLA-identical sibling donors from January 1990 to December 1996. Using a limiting dilution analysis, donor HTLp frequencies were determined on samples collected before transplantation. The HTLp assay used the cytotoxic T-cell line, CTLL-2, which proliferates in the presence of interleukin-2. The reliability and reproducibility of this assay was established by using cryopreserved batches of CTLL-2 cells of known sensitivity. RESULTS: The recipient-directed HTLp frequencies detected in the donor before transplantation were correlated with the incidence and severity of acute GVHD experienced by the recipient after transplantation. Statistical analysis revealed an extremely significant correlation between donor precursor frequencies and the development of acute GVHD in the patient after transplantation (P<0.0001). CONCLUSIONS: This study suggests that together with molecular typing the HTLp frequency should be considered when selecting the most suitable sibling donor for bone marrow transplantation.

Adolescent↗
PubMed1997

Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 Eastern United States hereditary nonpolyposis colorectal cancer pedigrees.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early age of onset colorectal cancer (mean 45 years) as well as endometrial, urinary tract, and upper gastrointestinal adenocarcinomas. The HNPCC phenotype has been shown to segregate with germline mutations in the human homologues of the DNA mismatch repair genes MSH2, MLH1, PMS1, and PMS2. However, the majority of published DNA mismatch repair gene mutation surveys associated with HNPCC kindreds report multiple levels of preselection, including 2p and 3p chromosomal linkage analysis and the evaluation of microsatellite instability of proband colorectal cancers prior to mutation analysis. For this reason, the concise contribution of each of the known DNA mismatch repair genes to the HNPCC phenotype remains unknown. We report the results of a genomic DNA-based analysis of hMSH2 and hMLH1 germline mutations in 32 unrelated Eastern United States HNPCC kindreds. These families were selected for study on the basis of phenotype only. We identified three hMSH2 and six hMLH1 mutations in eight families, for a positive mutation rate of 25%. Two mutations were identified in one of the families. Four of the mutations detected have not been reported in the literature previously. One of the mutation-positive families is African American; the others were of European-American ancestry. These results provide a clarification of the contribution of hMSH2 and hMLH1 to the HNPCC phenotype and suggest that in the majority of Eastern United States HNPCC kindreds selected by phenotype alone, the molecular genetic basis for the disease remains unknown.

Adult↗
PubMed1997

The benefits of a partnership approach to disability management.

Taking a partnership approach to disability management and fostering a return-to-work culture can significantly reduce disability costs for employers and help disabled employees successfully return to work. Two rehabilitation case managers from ReliaStar Life Insurance Company share their perspective and experience, including three case studies that illustrate successful case management intervention and return-to-work strategies.

Cost-Benefit Analysis↗
PubMed1996

Rapid identification of a novel chondrocyte-specific gene by RNA differential display.

Differential display or RNA fingerprinting is a novel approach for the isolation of differentially expressed genes. Here we describe the application of the RNA differential display technique to the analysis of the genes expressed in chick embryonic sternal chondrocytes, fibroblasts and BrdU-treated chondrocytes, which dedifferentiate back to mesenchymal-like phenotype. Parallel display among the genetags allowed us to isolate seven clones with differential expression patterns. Nucleotide sequencing of one of these clones revealed that it is a novel developmentally regulated gene with no significant homology to those reported previously. An RT-PCR analysis, using primers derived from this novel clone, confirmed the presence of the corresponding RNA only in the untreated chondrocytes, and not in the BrdU-treated chondrocytes or fibroblasts. This confirmation of the expression pattern given by the differential display reinforces the reliability of this approach. These results indicate that the differential display analysis provides a rapid and effective way to identify novel differentially expressed genes during chondrogenesis.

Animals↗