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Biomedical subjects

M Howard

Publications and source records attributed to M Howard.

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

Activated B cells from patients with common variable immunodeficiency proliferate and synthesize immunoglobulin.

Most patients with common variable immunodeficiency (CVI) have normal numbers of circulating B cells but low concentrations of serum Ig. To determine if the hypogammaglobulinemia is caused by an intrinsic B cell defect, we studied B cell function of 22 CVI patients. Cultured B cells from all CVI patients underwent normal proliferation and synthesized normal quantities of IgE in the presence of anti-CD40 and IL-4. If cultured with anti-CD40 and IL-10, four patterns of Ig isotype synthesis were observed. Six CVI patients produced normal amounts of IgM, IgG, and IgA. Four patients produced normal quantities of IgM and IgG. Of the remaining 12 patients who failed to synthesize IgG and IgA, 8 produced normal and 4 synthesized decreased amounts of IgM. Analysis of the IgG subclasses produced by 10 patients with IgG-secreting B cells revealed that IgG4 was the most affected subclass, followed by IgG2; synthesis of IgG3 and IgG1 remained normal. Similarly, in the six IgA producing patients, IgA2 was more often affected than IgA1. The hierarchy of Ig isotype and subclass synthesis corresponds to Ig heavy chain constant region gene location on chromosome 14. Thus, circulating B cells of CVI patients are committed to synthesize one or more Ig isotypes or subclasses, and under proper conditions can proliferate, mature into Ig-secreting cells, and undergo class switch to IgE.

Adolescent↗
PubMed1993

[Colorectal cancer. Study of survival and surgical results].

The aim of this study was to assess the progress in the surgical treatment of colorectal carcinoma in a 15 years period at the Catholic University Clinical Hospital. The medical records of 397 patients were retrospectively analyzed. Two hundred eighty four patients (164 male) aged 24 to 90 years old, subjected to elective and curative interventions, were selected for the study and separated in two groups: 132 subjects operated between 1975 and 1984 (group A) and 152 operated between 1985 and 1989 (group B). Group B patients were older (66.7 vs 61.3 years old), had a higher proportion of Dukes A tumors (11 vs 18%) and a lower proportion of lesions localized in the rectum (37 vs 49%). Rectal operations had higher morbidity than colonic interventions (35 vs 17.5%). Operative mortality was 0.7% in group A and 0.6% in group B. Ninety one percent of patients had a mean follow up of 38 months. Five years actuarial survival was 52% in group A and 69% in group B and 58, 74 and 46% for tumors Dukes A, B and C respectively.

Actuarial Analysis↗
PubMed1993

Prospective evaluation of unrelated donor bone marrow transplantation. The International Marrow Unrelated Search and Transplant (IMUST) Study.

The International Marrow Unrelated Search and Transplant (IMUST) Study has prospectively assessed outcome of unrelated donor BMT (UD-BMT) in comparison with a matched cohort of patients treated by HLA-identical sibling BMT (ID-BMT). We report an interim analysis of the first 165 UD-BMT and 368 ID-BMT. Eighty-two percent of UD-BMT pairs were matched by serology for HLA-A, B and DR, 10% were less well matched and HLA matching data was incomplete in 8%. The Kaplan-Meier estimated probability of survival until day 400 was 0.42 (95% confidence limits 0.33-0.51) after UD-BMT and 0.62 (0.56-0.68) after ID-BMT (p = < 0.001). Probability of engraftment by day 100 was 0.90 (0.85-0.95) and 0.95-0.99) after UD-BMT and ID-BMT, respectively (p = < 0.001). Cumulative probability of acute GVHD by day 100 was 0.52 (0.45-0.60) and 0.42 (0.37-0.47) after UD-BMT and ID-BMT, respectively (p = 0.009). After UD-BMT, 52% of patients with early disease survived until day 400 (40-64%) and 27% (14-40%) with advanced disease (p = < 0.001). Multifactorial analysis of survival showed success was related to the centre's experience of UD-BMT and this effect was modified by conditioning protocol. Increased probability of survival after UD-BMT in centres with most experience of the procedure is novel finding. We conclude UD-BMT is a more difficult procedure than ID-BMT but results are acceptable in patients with early disease and when UD-BMT is carried out in experienced centres.

Acute Disease↗
PubMed1993

The Advanced Trauma Life Support Program in Manitoba: a 5-year review.

Twenty Advanced Trauma Life Support (ATLS) courses were conducted at the University of Manitoba between 1982 and 1987. There were 302 registrants, 95 of whom were from rural communities. Twelve registrants failed the course. The impact of the program was assessed by questionnaire (68.8% response overall). The response from department heads of surgery in urban hospitals was 87.5% and from surgeons in rural areas 50%. Fifty-eight percent of rural surgeons, 62.5% of urban surgeons and 75% of urban emergency-department directors claimed they could identify those who had attended an ATLS course by the increased confidence demonstrated and the use of more timely and appropriate consultation and treatment. Thirty percent of rural surgeons, 37% of urban surgeons and 42% of emergency-department directors claimed that mortality and morbidity were decreased when care was provided by ATLS-trained physicians. The remainder were undecided because of lack of information. Ninety-three percent of respondents indicated that the course increased their confidence, trauma capability and ability to communicate with consultant trauma surgeons. Fifty-two percent thought the course should be mandatory for all physicians, and 100% thought it should be mandatory for all emergency-department physicians. The data suggest that although most physicians treat fewer trauma patients 5 years after their ATLS training, the course is still highly recommended, and it has improved trauma care. Although the ATLS program was intended primarily for rural physicians, more urban-based physicians registered for it.

Education, Medical, Continuing↗
PubMed1992

Genomic structure and chromosomal mapping of the murine CD40 gene.

The B cell-associated surface molecule, CD40, is likely to play a central role in the expansion of Ag-stimulated B cells, and their interaction with activated Th cells. In our study we have isolated genomic clones of murine CD40 from a mouse liver genomic DNA library. Comparison with the murine CD40 cDNA sequence revealed the presence of nine exons that together contain the entire murine CD40 coding region, and span approximately 16.3 kb of genomic DNA. The intron/exon structure of the CD40 gene resembles that of the low affinity nerve growth factor receptor gene, a close homolog of both human and murine CD40. In both cases the functional domains of the receptor molecules are separated onto different exons throughout the genes. Southern blot analysis demonstrated that murine CD40 is a single copy gene that maps in the distal region of mouse chromosome 2.

Amino Acid Sequence↗
PubMed1992

Identification of an essential region for growth signal transduction in the cytoplasmic domain of the human interleukin-4 receptor.

Interleukin-4 (IL-4) is a pleiotropic lymphokine which plays an important role in the immune system by regulating proliferation and differentiation of a wide variety of lymphoid and myeloid cells. These biological effects are manifested via binding of IL-4 to specific membrane-associated high affinity receptors. While the IL-4 receptor (IL-4R) cDNA expresses high affinity binding sites when transfected in COS7 cells, its intracellular domain lacks consensus motifs for known signal transducing molecules such as a tyrosine kinase. In this study, we use a DNA deletion approach to explore the mechanism of signal transduction utilized by the human IL-4R cDNA expressed in a murine pro-B cell line, Ba/F3 cells. Using this system, we have identified the critical region of the cytoplasmic domain of human IL-4R for human IL-4-induced transduction of a growth signal in these cells. Our data indicate that the critical region for signal transduction is located between amino acid residues 433-473 numbering from the carboxyl terminus. This region is highly conserved between mouse and human IL-4R but lacks homology with other cytokine receptors. Our studies additionally demonstrate that the cytoplasmic domain is not essential for forming high affinity IL-4-binding sites nor for ligand internalization.

Amino Acid Sequence↗
PubMed1992

Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells.

Ly-1 B cells have the distinctive property of continuous self-replenishment and, as we have shown previously, can be further distinguished from conventional B cells on the basis of greatly elevated constitutive and inducible production of the recently described cytokine interleukin 10 (IL-10). To test the possibility that IL-10 acts as either an autocrine or paracrine growth factor for Ly-1 B cells, we treated mice continuously from birth to 8 wk of age with a monoclonal rat IgM antibody that specifically neutralizes mouse IL-10. Mice treated in this way lacked peritoneal-resident Ly-1 B cells, contained greatly reduced serum immunoglobulin M levels, and were unable to generate significant in vivo antibody responses to intraperitoneal injections of alpha 1,3-dextran or phosphorylcholine, antigens for which specific B cells reside in the Ly-1 B cell subset. In contrast, conventional splenic B cells of anti-IL-10-treated mice were normal with respect to total numbers, phenotype, and in vitro responsiveness to B cell mitogens and the thymus-dependent antigen trinitrophenyl-keyhole limpet hemocyanin (TNP-KLH). The mechanism of Ly-1 B cell depletion appeared to be related to elevation of endogenous interferon gamma (IFN-gamma) levels in anti-IL-10-treated mice, since coadministration of neutralizing anti-IFN-gamma antibodies substantially restored the number of peritoneal-resident Ly-1 B cells in these mice. These results implicate IL-10 as a regulator of Ly-1 B cell development, and identify a procedure to specifically deplete Ly-1 B cells, thereby allowing further evaluation of the role of these cells in the immune system.

Animals↗
PubMed1992

Identification and sequence analysis of the promoter for the leukocyte integrin beta-subunit (CD18): a retinoic acid-inducible gene.

Leukocyte adhesion receptors (LFA-1; Mac-1; p150,95) are a family of heterodimeric cell-surface adhesion molecules expressed exclusively in granulocytes, lymphocytes, and macrophages. Expression of these proteins is under complex regulatory control, but to date promoters for these genes have not been identified. The CD18 gene codes for the common beta-subunit of the leukocyte adhesion receptors. Transcription of CD18 is highly tissue-specific, hormonally inducible (by retinoic acid [RA]), and coordinately regulated with leukocyte integrin alpha-chains. To identify the CD18 promoter, we screened a human genomic phage library with a human CD18 cDNA probe and obtained a clone that contains an exon coding for the 5' untranslated region (UTR). Using rapid amplification of cDNA ends (RACE), RNAse protection, S1 nuclease, and primer extension assays, we demonstrated the existence of multiple transcription start sites clustered in a 45-nt region. We investigated the transcription-promoting activity of the genomic sequences 5' to the CD18 gene by performing transient expression assays with a growth hormone reporter gene in various hematopoietic cell lines. The CD18 promoter was active in Jurkat cells, a lineage that normally expresses CD18 but was considerably less active in K562, an early erythroid line that does not normally express CD18. The genomic sequences upstream of the start site cluster lack CAAT and TATA boxes, but have two Sp1 binding sites and 10 T(G/C)AC(C/A) boxes, which may represent binding sites for RA receptors (RAR). These features distinguish the CD18 promoter from the promoters of other tissue-specific, hormone-inducible genes, and may be representative of leukocyte integrin promoters in general.

Antigens, CD↗
PubMed1992

Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10.

We have previously reported (O'Garra, A. et al., Int. Immunol. 1990, 2:821) that murine B lymphomas and purified normal peritoneal B cells produce interleukin (IL) 10. We now show that this production of IL 10 B cells correlates with the presence of Ly-1 (B-1) B cells, in both normal and diseased mice. Using a semi-quantitative modification of the polymerase chain reaction, we show that IL 10 expression is detectable in peritoneal B cells but only becomes apparent in splenic B cells of aged mice of which a high proportion are Ly-1+. Furthermore, the expression of IL 10 is constitutive in splenic B cells from mice carrying the Ly-1+ BCL1 lymphoma. Since IL 10 is a potent regulator of in vitro immune function, its production by Ly-1 lineage B (B-1) cells raises the possibility that this subset of B cells may regulate their own development and/or the function of other immunocompetent cells.

Aging↗
PubMed1992

Biological properties of interleukin 10.

An enormous amount of information on interleukin 10 (IL-10) has been gathered since its original description as cytokine synthesis inhibition factor (CSIF) several years ago. In this short article, Maureen Howard and Anne O'Garra summarize what is currently known of the biological properties of IL-10 and speculate on its clinical potential.

Animals↗
PubMed1992

Local cytokine production in a murine model of Escherichia coli pyelonephritis.

Cytokines may play an important role in the regulation of host defense against local bacterial infections. We have evaluated the local production of cytokines in a BALB/c mouse model of Escherichia coli pyelonephritis. Kidneys, draining lymph nodes, and spleens, were harvested at specific time intervals after bladder inoculation with E. coli corresponding to the stages of renal infection, infiltration, and bacterial clearance seen in this model. The presence of messenger RNA for specific cytokines (interleukins 1 through 6, chemotactic factors, granulocyte and granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF alpha) and beta, IFN gamma, transforming growth factor (TGF beta), and cytokine synthesis inhibitory factor (CSIF)/IL-10) was determined by polymerase chain reaction (PCR) amplification of reverse transcribed RNA. We have demonstrated mRNA encoding IL-1, IL-6, G-CSF, GM-CSF, TNF alpha, H400 (a protein homologous to a family of chemotactic factors and identical to MIP-1 beta), and CSIF/IL-10 in the kidney at 12 h and 1, 2, and 3 d after bacterial challenge. No signal was seen in normal animals or in mice after 5 d. This pattern of cytokine expression was observed only in renal tissues suggesting a localized response. IL-6 was present in the urine at 4 h with rapid resolution to baseline levels by 24 to 48 h. In contrast, IL-6 was not usually detectable in the serum. TNF alpha was not detectable in the serum or urine during the course of the infection. By immunohistochemical staining of kidney sections we have shown that IL-6 is produced predominantly by mesangial cells rather than by the inflammatory infiltrate. This study provides additional evidence utilizing novel techniques that specific cytokines are produced locally in response to bacterial infections. The time course of production demonstrated in this model supports the important role of cytokines in natural host resistance to local infection.

Animals↗
PubMed1992

Cytokines and Ly-1 (B1) B cells.

In an attempt to elucidate the possible role of cytokines in autocrine growth of Ly-1+B cells, and the role of this subset of B cells in immune regulation, both in normal and diseased hosts, we have performed a systematic analysis of cytokine production by a series of mouse Ly-1+B lymphomas, as well as normal peritoneal Ly-1+ and conventional B cells. The lymphomas all express TGF-beta, and some express IL-3 and IL-4. We observed that both the lymphomas and the peritoneal cells produce TNF-alpha, TNF-beta and IL-6. Another cytokine, IL-10, is produced predominantly by peritoneal Ly-1+B cells from healthy mice and by Ly-1+ B lymphomas, but not by conventional B cells. As IL-10 regulates the production of monokines and a subset of T-cell derived cytokines, our results suggest a broad immunoregulatory role for Ly-1 B cells. To complement these studies we have also examined the responses of Ly-1 B cells to mitogens and cytokines previously shown to stimulate conventional B cells. In summary, Ly-1 B cells, in contrast to conventional B cells do not respond to anti-Ig antibodies, even in the presence of IL-4. They do respond to LPS, and this response is preferentially enhanced by IL-5, and marginally enhanced by IL-3. Surprisingly LPS-induced proliferation of peritoneal B cells is inhibited by IL-6 and to a greater extent by IL-10. Whether this inhibition is a result of differentiation into Ig secreting cells is currently being evaluated. We discuss our findings in terms of the potential of Ly-1 B cells to regulate their own development and the immunocompetence of other cells.

Animals↗
PubMed1992

Standing up to the big squeeze.

Consumer confidence is at its lowest ebb since 1980. Economic growth is at a standstill & unemployment & inflation are both rising. Here's a front-line report from more than three dozen operators who are fending off the recession's dual pressures of slow sales & rising costs. They are using discount pricing, partnering with vendors, setting pay for performance standards & a variety of other recession-beating practices.

Cost Control↗
PubMed1992

Delaying the Start of Intercourse Among Adolescents.

A high proportion of today's parents do not know how to help their school-age children avoid early sexual involvement. Interventions to delay the start of sexual intercourse are explored, and the goals and results of several abstinence intervention programs are described.

Journal Article↗