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Biomedical subjects

P Simmons

Publications and source records attributed to P Simmons.

At least 19 recordsLinked to original sources
PubMed1994

Identification of homeobox genes expressed in human haemopoietic progenitor cells.

Homeodomain (HD)-containing proteins have been shown to regulate cellular commitment and differentiation in fungal, invertebrate and vertebrate systems. Bone marrow cells synthesizing the CD34 antigen are a complex mix of early, stem and progenitor cells at various stages of commitment to the many haemopoietic lineages. Here, we report the cloning and sequencing of 31 homeobox (HB) sequences, identified using degenerate oligodeoxyribonucleotide primers, in a polymerase chain reaction with cDNA derived from a purified CD34+ population of human haemopoietic cells. Of these sequences, 16 correspond to previously identified genes, and 13 are located within the HOX A, B and C clusters. Ten of the clones most likely represent human homologues of genes identified previously in other species. Five of the clones reported here represent novel HD sequences. The identification of five new genes using a subclass-specific 5' primer, designed from the engrailed and Xanf1 sequences, suggests that there still remain several uncharacterized HB genes in the human genome. Haemopoietic cells purified on the basis of CD34 antigen synthesis are a rich source of regulatory genes consistent with their ability to differentiate into diverse haemopoietic cell types.

Amino Acid Sequence↗
PubMed1994

Trial of a topically administered local anesthetic (EMLA cream) for pain relief during central venous port accesses in children with cancer.

Procedure-related pain is a significant problem for many children receiving cytotoxic chemotherapy. In an effort to lessen this toxicity, we studied the efficacy and safety of administering topical local anesthesia using EMLA cream in 47 evaluable children with cancer undergoing implanted central venous port injections. Children (< 21 years old) scheduled to undergo repeated venous access procedures were selected for study. A placebo-controlled, randomized, double-blind, crossover study design was utilized. Statistically significant decreases in pain intensity scores (P < 0.002) were recorded by both children and investigators during the use of EMLA cream as compared with placebo. There was a good correlation between pain scores recorded by both patients and health care providers using both visual analog scales and categorized pain measurement tools. The topical application of EMLA cream 5% provides highly effective superficial anesthesia, and promises to be extremely useful for pain relief during percutaneous access procedures in cancer patients.

Administration, Cutaneous↗
PubMed1992

A human interleukin 3 analog with increased biological and binding activities.

Human interleukin 3 (IL-3) variants generated by site-directed mutagenesis were analyzed in multiple biological and binding assays to identify residues critical for IL-3 activity. Two mutants carrying substitutions in the predicted hydrophilic region within the first alpha-helix, [Ala21,Leu22]IL-3 and [Ala21,Leu22,Ala25]IL-3 showed loss of biological activity and high-affinity binding. Mutants in a second predicted hydrophilic region, [Ala44,Leu45,Ala46]IL-3 and [Ala44,Ala46]IL-3, however, showed similar biological and binding activities to wild-type IL-3. Mutations in a C-terminal hydrophilic region that overlaps the fourth predicted alpha-helix led to either loss or gain of function. IL-3 analogs [Glu104,Asp105]-, [Leu108]-, [Asn108]-, [Thr108]-, and [Ala101,Leu108]IL-3 were less active than wild-type IL-3, whereas [Ala101]IL-3 and [Val116]IL-3 were 2- to 3-fold more potent. Significantly, the double mutant [Ala101,Val116]IL-3 exhibited a 15-fold greater potency than native IL-3. Receptor binding studies showed that [Ala101,Val116]IL-3 exhibited increased binding to the high- and low-affinity receptors of monocytes. These results show the generation of an IL-3 analog with increased biological and binding activities and support a model where the C terminus of IL-3 interacts with the alpha chain of the IL-3 receptor, making this region a useful focus for the development of more potent IL-3 agonists or antagonists.

Amino Acid Sequence↗
PubMed1992

Cytomegalovirus and marrow function.

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. A proportion of patients with CMV infection also experience neutropenia. To investigate the possible role of CMV in the suppression of hematopoiesis, we have examined the effect of CMV on the growth of isolated myeloid progenitors and on the production of myeloid cells in the long-term bone marrow culture (LTMC) system. In these studies, various isolates of CMV were added either directly to cultures of progenitors or to LTMC established from normal CMV-seronegative donors. In the first system, myelosuppression is manifested by a reduction in the number of colonies that grow. In the second system, myelosuppression is manifested by a reduction in the number of myeloid cells produced and released into the culture supernatant. Analysis of the data observed indicated that myelosuppression could in some cases be attributed to direct infection of myeloid progenitors. In other cases stromal cells were infected. In the latter cases, myelosuppression was then caused by an alteration in cytokines produced by the stromal cells. These observations made in vitro raise the possibility that comparable mechanisms may be responsible for the myelosuppression observed with CMV infection in vivo. To pursue this possibility we proposed to detect the CMV genome in defined subpopulations of marrow cells isolated from infected patients. Given the technical restrictions imposed by the small sample size available from patient marrow aspirations, our initial attempts to develop on appropriate technique involved isolation of cells from CMV-seropositive normal bone marrow donors. Using the polymerase chain reaction we were able to amplify CMV DNA contained within marrow cells of some healthy CMV-seropositive marrow donors.

Bone Marrow↗
PubMed1990

Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. To study the role of CMV in the suppression of hemopoiesis that frequently accompanies infection, we investigated the effect of CMV on the growth of isolated committed myeloid progenitors and on hemopoiesis in long-term bone marrow cultures. Laboratory strain AD169 had no effect on the growth and development of progenitor cells. In contrast, 40% of clinical isolates of CMV inhibited colony formation by up to 100%. In long-term bone marrow cultures all CMV isolates resulted in myelosuppression, which in the majority of cases was associated with the infection of stromal elements. Analysis of RNA from stromal cells infected with AD169 and one clinical isolate demonstrated a specific deficiency of granulocyte colony-stimulating factor transcripts. For a small proportion of the clinical isolates tested in long-term bone marrow cultures, suppression of hemopoiesis was correlated with infection of developing granulocytes. These studies suggest that CMV can impair hemopoiesis either through infection of stromal cells and consequent perturbation of growth factor production or by direct infection of myeloid cells.

Antigens, Viral↗
PubMed1989

A technique for spot application of fibrin glue during open heart operations.

Several techniques have been described for preparing and applying fibrin glue to control surgical bleeding. However, these methods tend to be cumbersome, expensive, or messy. Furthermore, commercial kits have not been approved by the Food and Drug Administration because of the potential risk of hepatitis contamination. Therefore, we have devised a modified, simpler technique that enables the precise, pinpoint application of fibrin glue. The risk of hepatitis transmission is substantially reduced by using cryoprecipitate plasma instead of fibrinogen from pooled donors. This technique is especially well suited for anastomoses of small vessels or for sealing suture holes in nonporous grafts.

Aprotinin↗
PubMed1988

Quantitative evaluation of real-time ultrasound features of the breast.

Semi-quantitative diagnostic features were extracted by a visual analysis of the echographic images of selected cases of breast disease and the results stored in a computer database. The long term aim is to create an environment suitable for the use of multivariate statistical methods systematically to evaluate ultrasound interpretive criteria and diagnostic performance in relation to factors such as scanning instrumentation and other diagnostic techniques. Eventually it is hoped that it will be possible to generate a system for computer assisted diagnosis and training. The results of this pilot study serve to demonstrate the feasibility of the approach and a univariate analysis is used to provide a preliminary ranking of diagnostic features. Features found to be particularly valuable for distinguishing benign from malignant solid lesions were the regularity and definition of the edge of the tumour, the mobility of the tumour and measures of echo heterogeneity within and posterior to the tumour mass.

Breast↗
PubMed1987

Cellular interactions and genetic restriction.

These studies emphasize the limitations of in vitro colony assays utilizing heterogeneous cell populations for the identification of cell-cell interactions that may involve genetic restriction. Obviously, different strategies are required to determine if Class II molecules have any role, alone or in combination with other determinants, in mediating hematopoietic cell-cell interactions. In this report, we present preliminary data derived from two approaches designed to address this issue. First, clonal cell lines developed to mimic Class II expression of normal precursors have been used to study structure-function relationships of HLA-D region gene products. Second, the lymphocyte adhesion assay has been adopted to study binding of precursors to marrow stroma. We hypothesize that the strategies should make it possible to identify hematopoietic cell-cell interactions and determine to what extent Class II molecules participate in these interactions.

Animals↗
PubMed1986

Perturbed hemopoiesis and the generation of multipotential stem cell clones in src-infected bone marrow cultures is an indirect or transient effect of the oncogene.

Multipotential stem cell lines, derived specifically from long-term bone marrow cultures infected with a recombinant retrovirus carrying v-src, lack v-src. Stable consequences thus result from transient actions or indirect effects of v-src on other cells, with the latter possibility being favored by its mosaic expression in marrow cultures.

Animals↗
PubMed1985

The role of stromal cells and growth factors in haemopoiesis and modulation of their effects by the src oncogene.

In the haemopoietic system the mature blood cells have only a finite lifetime. For example, a circulating granulocyte in the peripheral blood has an approximate half-life of 7 h (Cartwright, Athens & Wintrobe, 1964; Dancey, Dubelbeiss, Harker & Finch, 1976) whilst the lifetime of an erythrocyte is approximately 120 days (Wickramasinghe & Weatherall, 1982). This constant 'death' of mature functional haemopoietic cells means that new blood cells must replace those that are removed. The process of haemopoiesis provides the mature functional blood cells to replace those lost as a consequence of performing their biological functions (e.g. lymphocytes and macrophages in the immune response) or through apparent old age and breakdown (e.g. erythrocytes that are 110-120 days old). The major questions that we are required to answer about this process are 'where do all these new cells come from?', 'what regulates their production?' and 'how is this mechanism of control lost in haemopoietic disorders such as leukaemia, hyperproliferative diseases and anaemias?'. Recent work in the field of haemopoiesis has given some clues to the answers to the questions, which provide an intriguing insight into not only haemopoiesis itself but the possible lesions associated with the various blood disorders.

Animals↗
PubMed1984

Hepatitis B core antigen synthesised in Escherichia coli: its use for antibody screening in patients attending a clinic for sexually transmitted diseases.

Hepatitis B core antigen (HBcAg) synthesised in Escherichia coli by recombinant DNA techniques was compared with HBcAg prepared from infected liver tissue. The two antigens were used in radioimmunoassays (RIA) to detect antibody to HBcAg (anti-HBc) in sera from patients attending a clinic for sexually transmitted diseases. Out of 2151 sera tested, 260 were anti-HBc positive with both HBcAg preparations but seven were positive with the liver-derived antigen alone. Reasons for these discrepant results are discussed. The slight loss of sensitivity of the anti-HBc RIA using E. coli HBcAg was not considered significant when compared with the potential advantages of a synthetic antigen. The presence of other hepatitis B markers in the 267 anti-HBc positive sera was determined: 25 contained HBsAg, 220 anti-HBs and, of the 22 that were HBsAg/anti-HBs negative, 12 contained anti-HBe. In the 10 remaining sera, anti-HBc was the only hepatitis B marker that could be found.

Escherichia coli↗
PubMed1984

Glucose production and utilization in children with glycogen storage disease type I.

Glucose turnover rates were estimated with [2H2]glucose in five children with glycogen storage disease type I (GSD I) during sequential withdrawal of an infusion of glucose to determine whether their hypoglycemia was the result of decreased glucose production or increased rates of glucose utilization. Plasma glucose concentrations were 78 +/- 5 mg/dl during infusion of glucose at 6 mg X kg-1 X min-1 and decreased to 53 +/- 3 and 45 +/- 7 mg/dl during the 3 and 1.5 mg X kg-1 X min-1 glucose infusions, respectively. Total glucose flux during the 6 mg X kg-1 X min-1 glucose infusion was 7.3 +/- 0.7 mg X kg-1 X min-1 and decreased with reduction in the rate of glucose infused. Endogenous glucose production increased with each decrease in the rate of exogenous glucose infused. Following discontinuation of glucose infusion, endogenous glucose production was 3.9 +/- 0.3 mg X kg-1 X min-1, a value that was lower (P less than 0.05) than that observed in overnight-fasted normal children (6.3 +/- 0.3 mg X kg-1 X min-1) but not statistically different from the Ra of normal children fasted for 30 h (4.1 +/- 0.5 mg X kg-1 X min-1). Thus, children with GSD have glucose production rates that are 40% lower than those of normal children fasted overnight but equal to those of normal children fasted 30 h. Rates of glucose utilization during the 6 mg X kg-1 X min-1 glucose infusion were higher (0.05 less than P less than 0.1) than those of overnight-fasted normal children, despite lower plasma glucose concentrations when expressed on a body weight basis but not when expressed on the basis of estimated brain weight.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗