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J Daley

Publications and source records attributed to J Daley.

At least 127 records · Page 7Linked to original sources
PubMed1993

Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation.

Signaling via the T-cell receptor complex is necessary but not sufficient to induce antigen-specific T lymphocytes to expand clonally. To proliferate, T cells must receive one or more costimulatory signals provided by antigen presenting cells (APCs). One such critical costimulatory signal is delivered by the CD28/CTLA-4 counterreceptor, B7, expressed on APCs. B7 costimulation induces CD28 signaling, resulting in interleukin 2 (IL-2) secretion, and T-cell proliferation. Conversely, T-cell receptor signaling in the absence of B7 costimulation results in induction of antigen-specific tolerance. Here, we show that activated human B lymphocytes express two additional CTLA-4 counterreceptors also capable of providing T-cell costimulation. At 24 hr postactivation, B cells express a CTLA-4 counterreceptor not recognized by anti-B7 or -BB-1 monoclonal antibodies (mAbs), which induces detectable IL-2 secretion and T-cell proliferation. At 48 and 72 hr postactivation, B cells express both B7 and a third CTLA-4 counterreceptor identified by the anti-BB-1 mAb. BB-1 appears to be a molecule distinct from B7 by its expression on B7- cells and its capacity to induce T cells to proliferate without significant accumulation of IL-2. As observed for B7, costimulatory signals mediated by these alternative CTLA-4/CD28 counterreceptors are likely to be essential for generation of an immune response and their absence may result in antigen-specific tolerance. We propose the following terminology for these CTLA-4 counterreceptors: (i) B7, B7-1; (ii) early CTLA-4 binding counterreceptor, B7-2; and (iii) BB-1, B7-3.

Abatacept↗
PubMed1993

Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2-4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had < or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and < or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2-4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.

Adult↗
PubMed1993

Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia.

Twenty patients with poor prognosis B-cell chronic lymphocytic leukemia (B-CLL) underwent uniform high-dose chemoradiotherapy followed by rescue with multiple monoclonal antibody-purged autologous bone marrow (BM) (12 patients) or T-cell-depleted allogeneic BM from HLA-identical siblings (8 patients) in a pilot study to assess the feasibility of BM transplantation (BMT) in this disease. All had poor prognosis disease by either staging, BM pattern, tumor doubling time criteria, or cytogenetics. All patients achieved remission criteria (defined as < or = 2 adenopathy, absence of splenomegaly, < or = 20% of the intertrabecular space involved on BM biopsy) before BMT. Despite the use of fludarabine, a median of three treatment regimens were required to achieve BMT eligibility. After BMT, all patients achieved complete hematologic engraftment. Toxicities were not significantly different between autologous versus allogeneic BMT. Two toxic deaths were observed. Of 19 evaluable patients, 17 clinical complete clinical remissions (89%) were observed, with 2 patients (1 allogeneic and 1 autologous) exhibiting persistent BM disease. Complete clinical remissions were documented at the phenotypic and molecular level for the majority of patients in whom dual fluorescence for CD5 and CD20 (15 of 15; 100%) and Ig gene rearrangements (11 of 14; 79%) were performed. Although long-term follow-up is needed to assess any potential impact on the disease-free and overall survival of these patients, this study shows the feasibility of using high-dose chemoradiotherapy and BMT in patients with poor prognosis B-CLL.

Adult↗
PubMed1993

Specificity of gap junction communication among human mammary cells and connexin transfectants in culture.

In a previous paper (Lee et al., 1992), it was shown that normal human mammary epithelial cells (NMEC) express two connexin genes, Cx26 and Cx43, whereas neither gene is transcribed in a series of mammary tumor cell lines (TMEC). In this paper it is shown that normal human mammary fibroblasts (NMF) communicate and express Cx43 mRNA and protein. Transfection of either Cx26 or Cx43 genes into a tumor line, 21MT-2, induced the expression of the corresponding mRNAs and proteins as well as communication via gap junctions (GJs), although immunofluorescence demonstrated that the majority of Cx26 and Cx43 proteins present in transfected TMEC was largely cytoplasmic. Immunoblotting demonstrated that NMEC, NMF, and transfected TMEC each displayed a unique pattern of posttranslationally modified forms of Cx43 protein. The role of different connexins in regulating gap junction intercellular communication (GJIC) was examined using a novel two-dye method to assess homologous and heterologous communication quantitatively. The recipient cell population was prestained with a permanent non-toxic lipophilic dye that binds to membranes irreversibly (PKH26, Zynaxis); and the donor population is treated with a GJ-permeable dye Calcein, a derivative of fluorescein diacetate (Molecular Probes). After mixing the two cell populations under conditions promoting GJ formation, cells were analyzed by flow cytometry to determine the percentage of cells containing both dyes. It is shown here that Cx26 and Cx43 transfectants display strong homologous communication, as do NMEC and NMF. Furthermore, NMEC mixed with NMF communicate efficiently, Cx26 transfectants communicate with NMEC but not with NMF, and Cx43 transfectants communicate with NMF. Communication between Cx26 TMEC transfectants and NMEC was asymetrical with preferential movement of calcein from TMEC to NMEC. Despite the presence of Cx43 as well as Cx26 encoded proteins in the GJs of NMEC, few Cx43 transfectants communicated with NMEC. No heterologous GJIC was observed between Cx26- and Cx43-transfected TMEC suggesting that heterotypic GJs do not form or that Cx26/Cx43 channels do not permit dye transfer.

Blotting, Western↗
PubMed1993

Oxygen tension regulates the nitric oxide pathway. Physiological role in penile erection.

Relaxation of the trabecular smooth muscle of the corpus cavernosum (the erectile tissue) of the penis is mediated by nitric oxide released by the nerves and endothelium. We have investigated the physiological role of oxygen tension in the regulation of trabecular smooth muscle tone. In human subjects, measurement of intracavernosal PO2 in blood drawn from corpus cavernosum in the flaccid state was comparable to that of venous blood (25-43 mmHg). Vasodilatation of the resistance arteries and trabecular smooth muscle relaxation by intracavernosal injection of papaverine and phentolamine caused oxygen tension to rise rapidly to arterial levels (PO2 approximately 100 mmHg). Isolated human and rabbit corpus cavernosum tissue strips in organ baths, exposed to arterial-like PO2 relaxed to the endothelium-dependent dilator acetylcholine and to electrical stimulation of the autonomic dilator nerves. These nitric oxide-mediated responses were progressively inhibited as a function of decreasing PO2 to levels measured in the flaccid penis. Reverting to normoxic conditions readily restored endothelium-dependent and neurogenic relaxation. Relaxation to exogenous nitric oxide was not impaired in low PO2. In rabbit corpus cavernosum, low PO2 reduced basal levels of cGMP and prevented cGMP accumulation induced by stimulation of dilator nerves. Furthermore, low PO2 inhibited nitric oxide synthase activity in corpus cavernosum cytosol. It is concluded that physiological concentrations of oxygen modulate penile erection by regulating nitric oxide synthesis in corpus cavernosum tissue.

Amino Acid Oxidoreductases↗
PubMed1992

Follicular dendritic cells inhibit human B-lymphocyte proliferation.

In germinal centers, B lymphocytes are intimately associated with follicular dendritic cells (FDCs). It has been hypothesized that FDCs are involved in the regulation of B-cell growth and differentiation through cell-cell interactions. In this study, highly enriched preparations of FDCs were isolated by cell sorting using the FDC restricted monoclonal antibody DRC-1. When irradiated FDCs were cultured with mitogen stimulated B cells, B cell 3H-TdR uptake was inhibited by up to 80%. This inhibitory effect was not seen when paraformaldehyde fixed FDCs were added to B-cell cultures, suggesting that the FDCs needed to be metabolically active. Moreover, supernatants from cultured FDCs were similarly able to inhibit B-cell proliferation. These results demonstrate that FDCs may downregulate the clonal expansion of B cells that occurs within lymphoid follicles as part of the normal physiologic immune response. Potentially, the loss of the inhibitory role of FDCs in vivo may be of importance in certain infectious and neoplastic processes in which germinal centers are affected.

B-Lymphocytes↗
PubMed1992

Observations on production of hemolysin, heat-labile enterotoxin and antimicrobial drug resistance among enterotoxigenic Escherichia coli from pigs.

A total of 52 isolates of Escherichia coli belonging to enterotoxigenic serotypes from piglets with diarrhea were examined for hemolysis, production of cholera-like enterotoxin (LT) and susceptibility to 10 antimicrobial drugs. A strong association between production of LT and hemolysis was seen. Ninety percent of 29 hemolylic isolates were LT+ whereas 100% of 23 nonhemolytic isolates were LT- in a commercial latex agglutination assay. Antimicrobial susceptibility tests employing disc diffusion showed that resistance to trimethoprim-sulfamethoxazole (TMS), neomycin and tetracycline was significantly less among LT+ isolates compared to LT- ones. Enrofloxacin was the only antimicrobial drug to which all the 52 isolates were susceptible.

Animals↗
PubMed1992

Pharmacotherapy of depression in the medically ill: directions for future research.

A common problem facing the psychiatric consultant and the medical practitioner is evaluating depression in patients with concurrent medical illnesses. Depression is difficult to recognize in the medically ill, often presenting with "masked" symptoms and organized into unique syndromes. A primary concern of the clinician is identifying those patients who are likely to benefit from an antidepressant trial. Although antidepressants have been shown to sometimes be of benefit in medical populations, the symptoms predicting antidepressant response remain poorly defined. Important directions for future research include 1) evaluating the safety and efficacy of newer antidepressants in the medically ill and 2) identifying those depressive syndromes that may be responsive to pharmacotherapy.

Adult↗
PubMed1992

A description and clinical assessment of the Computerized Severity Index.

Recent initiatives expanding health care data networks have increasingly emphasized severity of illness information, both to improve fairness of hospital payment and to assist in widespread assessment of hospital and physician quality. The Computerized Severity Index (CSI), one of the newest severity tools to generate interest, is disease specific and produces scores from 1 to 4 at both the disease and overall patient levels. Severity is defined as "the treatment difficulty presented to physicians due to the extent and interactions of patient's diseases." The clinical logic of the severity rating system is readily available through the "severity matrices" associated with over 820 disease groups. Questions exist about the CSI's dependence on diagnostic coding and the qualitative nature of some of the clinical criteria. More study is required to assess the utility of the CSI for various health policy purposes.

Baltimore↗
PubMed1992

A method for screening the quality of hospital care using administrative data: preliminary validation results.

Applying a computerized algorithm to administrative data to help assess the quality of hospital care is intriguing. As Iezzoni and colleagues point out, there are major differences of opinion as to the worth of such efforts. This article significantly advances the state of the art in using administrative data to screen for potential quality-of-care problems. In addition, this work on identifying complications of care goes well beyond the emphasis of many government organizations on hospital mortality rates. One question, however, not raised in the paper is: What is a practical upper limit to the sensitivity and specificity in comparing computerized screen results with the consensus judgments of a group of independent physicians? Advanced statistical techniques (such as bootstrapping) might be used to estimate the stability of consensus judgments by physician groups. When the judgments of two groups of physicians are compared with each other, the resulting sensitivity and specificity will not be .99! In addition, more training of members of the physician panels would probably have increased interrater reliability. While acknowledging this problem, the researchers' detailed analysis of the panel results is intriguing and represents a model for such studies. It is hoped that the authors will follow up on the avenues opened here. Furthermore, what degree of accuracy is necessary to identify facilities with higher-than-expected rates of complications? The authors discuss problems involved in using administrative data to target hospitals and departments for more costly in-depth reviews of quality. It is hoped that the promising findings that are reported here will be validated in other studies. Certainly their algorithms should find a ready audience in insurers and hospitals willing to try them out. Finally, should we expect additional research to lead to improvement in the authors' algorithms? I believe the algorithms will prove difficult to improve upon; but perhaps we should not worry about this. At some point, however, the cost of trying to identify and correct quality problems in "minimally outlier" hospitals will exceed the benefits, particularly given alternative uses for the funds. Might we now be close the the "flat of the curve" in the development of such systems for identification of quality problems? This issue should be discussed much further in future studies.

Abstracting and Indexing↗
PubMed1992

Signaling function of reconstituted CD16: zeta: gamma receptor complex isoforms.

Natural killer cells express an Fc receptor for IgG (CD16) in association with disulfide-linked dimers composed of two homologous subunits: the zeta chain of the T cell antigen receptor complex and the gamma chain of the mast cell/basophil Fc receptor for IgE. The ability of zeta and gamma to transduce CD16-mediated activation signals was compared by reconstituting distinct CD16 receptor isoforms composed of various combinations of zeta- and gamma-containing dimers. Stably transformed non-hematopoietic and hematopoietic cell lines were established that expressed chimeric molecules comprising the extracellular domain of CD16 joined to the transmembrane and intracellular domains of zeta or gamma. Reconstituted CD16 receptor complexes triggered Ca2+ influx, tyrosine phosphorylation, and IL-2 production in stable transformants of the Jurkat T cell line. However, cross-linking of the CD16/gamma chimera induced a specific pattern of tyrosine phosphorylation and was more efficient at signal transduction than a CD16, zeta-zeta complex, suggesting that zeta and gamma cytoplasmic domains may be coupled to distinct tyrosine kinase pathways that differentially regulate CD16-mediated activation signals. By contrast, both CD16/zeta and CD16/gamma chimeric molecules were not functional in stable transformants of the fibroblast Chinese Hamster Ovary cell line, indicating a requirement for downstream signaling components present in hematopoietic cells. Finally, the zeta transmembrane domain appears to preferentially associate with CD16 rather than the CD3:TCR complex, suggesting that a hierarchy of molecular interactions governs NK and T cell differentiation.

Animals↗
PubMed1992

Ethical issues.

The HIV virus and the associated worldwide pandemic pose enormous biomedical, clinical, and social dilemmas for health care providers, biomedical researchers, policy analysts, and the public at large 10 years after its discovery. Many of these dilemmas and challenges are captured in the difficult ethical issues the HIV epidemic has highlighted for primary care physicians. Given the vanishingly small risk to primary care providers of acquiring HIV infection in office practice and the rapidly increasing prevalence of the virus, a clear ethical obligation to care for HIV-infected patients exists for primary care physicians. Primary care providers should be sensitive to the potentially sensitive nature of patient risk status and HIV testing results and balance confidentiality in the medical record with the "need to know" the patient's clinical status by other health care professionals. Every attempt should be made by the primary care provider to encourage HIV-infected patients to act responsibly toward their intimate sexual partners and inform them of their HIV status to take appropriate precautions against acquiring the virus. Primary care providers should also model responsible shared decision making and goal setting with HIV-infected patients early in the course of the disease, laying the foundation for subsequent decision making later in the course of the illness. Finally, considerable controversy exists about the responsibilities of HIV-infected providers to inform patients of their status; professional and public policy in this area is in rapid flux. Undoubtedly, the HIV epidemic will continue to challenge us and force careful examination of many of the critical dilemmas in modern biomedical ethics.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Clonal analysis of T-cell deficiencies in autotransplant recipients.

We have used limiting dilution culture methods to determine the frequency of mitogen-responsive T cells in peripheral blood of patients after bone marrow autotransplantation, and have compared their responsiveness to that of allotransplant recipients and normal controls. Autotransplant patients were found to have low responder cell frequencies in tests for lymphokine-secreting helper function, and for IL-2 dependent proliferator and cytotoxic function. Multiple regression analysis showed that function was lower in autotransplant patients than in allorecipients, and lower in male patients for all three functional assays. Patients with clinically significant infection tended to have lower proliferative function in both transplant groups and lower cytotoxic function in the allotransplant population. Graft-versus-host disease was associated with lower T-cell function, but was present only in the allotransplant group; therefore, it cannot account for the even lower levels of function observed in the autotransplant population. Because we observe deficits in T-cell regeneration in autotransplant recipients that are even more severe than in allorecipients, we postulate that cellular immunodeficiency after bone marrow transplantation may reflect limitations in thymic-dependent repopulation rather than an effect of genetic disparity between host and donor (eg, clinical or subclinical graft-versus-host).

Adult↗
PubMed1991

Expression and tyrosine phosphorylation of the T cell receptor zeta-subunit in human thymocytes.

Recent evidence suggests that the zeta-subunit of the TCR complex plays a critical role in transducing signals initiated by the Ag receptor heterodimer. Because thymic maturation involves specific interactions between the TCR complex and thymic stromal cells, the zeta-subunit has been postulated to also play a role in this process. To assess the potential for zeta to contribute to thymocyte maturation, we have used an anti-zeta mAb (TIA-2) to quantitate its expression in mature (CD3bright) and immature (CD3dim and CD3-) populations of human thymocytes. Using both flow cytometric and immunoblotting analysis, we found that the relative expression of TCR-zeta varied directly with the surface expression of CD3. Importantly, TCR-zeta was detected in the majority of CD3- thymocytes, indicating that its expression precedes the surface appearance of CD3:TCR. In thymocytes, TCR-zeta was found to be constitutively phosphorylated on tyrosine residues. The relative expression of phospho-zeta varied directly with the maturational stage of the thymocyte, with the mature (CD3bright), single positive cells accounting for most of the phospho-zeta found in the human thymus. The expression of phospho-zeta could be significantly increased by activating thymocytes with mAb reactive with either CD3 or CD2. These results suggest that TCR-zeta is functionally linked to the major thymocyte activation receptors.

Cell Differentiation↗
PubMed1991

Practice patterns in the treatment of acutely ill hospitalized asthmatic patients at three teaching hospitals. Variability in resource utilization.

STUDY OBJECTIVE: Our objective was to determine the extent to which patterns of diagnostic and therapeutic practice differ among hospitals caring for acutely ill hospitalized asthmatic patients in a single city. DESIGN: Our study comprised a retrospective review of the records of patients admitted to the hospital for the treatment of acute asthma. SETTING: Three large teaching hospitals in Boston were the setting. PATIENTS: One hundred twenty-seven patients between 18 and 50 years of age who were admitted to the medical services specifically for the treatment of asthma were studied. INTERVENTIONS: There were no interventions. MEASUREMENTS AND MAIN RESULTS: For this group of patients with similar histories of asthma, clinical presentation, and severity of asthma, the diagnostic tests used within 12 hours of admission and the frequency and volume of diagnostic laboratory testing throughout the admission differed significantly among the three hospitals. Spirometry, the test bearing most directly on the severity of the asthmatic attack, was not used routinely as a criterion for admission or discharge at any of the hospitals. Other tests of uncertain efficacy, such as chest x-ray films, were used frequently at some of the hospitals. Patients at all three hospitals were treated similarly with intensive combined regimens of methylxanthines, sympathomimetics, and corticosteroids and had similar mean lengths of stay. The use of chest physical therapy, which has not yet been demonstrated to be effective in acute asthma, differed significantly among the three hospitals. CONCLUSIONS: We conclude that considerable variability exists in the diagnostic evaluation of acutely ill hospitalized asthmatic patients in the three hospitals; little variability exists in the pharmacologic treatment of these patients. In the absence of data on outcome regarding functional improvement and reductions in morbidity, we are unable to recommend a preferred pattern of practice from this study.

Acute Disease↗
PubMed1991

Intensity of in-hospital care for persons with AIDS.

We evaluated the intensity of medical care for 30 consecutive AIDS patients at one hospital, using methodology based on the Delay Tool of Selker et al. Of 25 AIDS patients who survived hospitalization, 15 had at least one delay day in the hospital. Major factors associated with care that could have been provided at an alternative site included difficulty with skilled nursing facility placement in 20% of the patients, difficulty coordinating out-of-hospital care in 28%, and scheduling of outpatient surgical procedures in 12%. For the 15 patients who could have received some of their care at a lower intensity setting, a median of 7 hospital days could have been potentially saved with better coordination of outpatient care and increased availability of skilled nursing facilities. The five patients who died in hospital also used large amounts of resources and had long lengths of stay. Prior studies of non-AIDS patients revealed similar results, suggesting that, for reasons of quality of care, quality of life, and economics, policy-makers must develop managed care programs, skilled nursing facilities that accept AIDS patients, inpatient psychiatry facilities, and increased hospice availability.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Reconstitution of T-cell function after CD6-depleted allogeneic bone marrow transplantation.

Patients who undergo allogeneic bone marrow transplantation (BMT) are clinically immunodeficient for a prolonged period after engraftment. In the present study, we examined immune function after BMT in a series of patients who had received HLA compatible sibling marrow grafts purged of T cells with anti-CD6 monoclonal antibody and complement. None of the patients in this analysis received immunomodulating agents and none had developed graft-versus-host disease (GVHD). Initially after BMT, natural killer (NK) cells are the predominant cell type, giving way to CD3+, CD5+ T cells after 4 to 8 weeks. Despite the return of normal numbers of T lymphocytes post-BMT phenotypic analysis reveals several long-term abnormalities, including an inverted T4:T8 ratio and a significant fraction of CD3+ T cells that do not co-express CD6. In mitogenic assays, stimulation by either nonspecific lectin (phytohemagglutinin; PHA) or antibodies to the CD2 surface structure (anti-T11(2) + anti-T11(3)) results in decreased levels of T-cell proliferation compared with controls for over 18 months post-BMT. In contrast, the ability of unstimulated peripheral blood mononuclear cells (PBMC) to respond to recombinant interleukin-2 (rIL-2) is relatively intact, most likely reflecting early functional reconstitution of the NK cell population. To further characterize the prolonged abnormalities in T-cell proliferation after PHA or CD2 stimulation, we examined more proximal events in T-cell activation such as induction of IL-2 receptor expression and stimulus-induced intracellular calcium flux. We found that the induction of IL-2 receptor (p55) after in vitro activation, although initially abnormal, recovers completely by 6 months post-BMT. We also found that, after CD2 stimulation, calcium flux in T cells was normal immediately after engraftment. In contrast, after stimulation with anti-CD3 antibodies, a large population of T cells do not develop intracellular calcium flux compared with controls. We conclude that despite the recovery of normal numbers of T lymphocytes early after engraftment of CD6-depleted marrow, these T cells exhibit several physiologic and functional abnormalities that persist for varying intervals post-BMT. At present, it is unclear which of these specific defects is most closely associated with increased susceptibility to infectious agents after BMT.

Adolescent↗