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Biomedical subjects

H J Sutherland

Publications and source records attributed to H J Sutherland.

At least 19 recordsLinked to original sources
PubMed1992

Effect of nonmedical factors on family physicians' decisions about referral for consultation.

OBJECTIVES: To identify nonmedical factors perceived by family physicians (FPs) and consultants as important influences on decisions about referral for consultation, to determine the relative frequency with which such factors are cited and to identify those factors ranked as most important by the FPs and consultants. DESIGN: Survey with semistructured interview between July 1989 and April 1990. PARTICIPANTS: A total of 41 FPs and 20 consultants who were practising or had practised previously in Nova Scotia. INTERVENTIONS: The questionnaire comprised 10 questions: 4 were nondirective "probes" designed to elicit responses without suggesting possible answers, 2 asked the participants to rank such responses in order of importance, and 4 were "prompts" that asked for comments about a list of factors based on a review of the literature. RESULTS: A total of 4845 discrete items were mentioned as being capable of influencing FPs' decisions about referral for consultation. Aggregation of related items resulted in a list of 35 nonmedical factors, of which 11 were identified by at least half the respondents and 14 by less than half but more than 10. These 25 factors fell into three categories: patient and family factors (e.g., patient's wishes), FP and consultant factors (e.g., FP's capabilities), and other influences (e.g., style of practice). On the basis of both frequency of identification and priority scores "patient's wishes" emerged as the most important factor. Two medical factors that were consistently cited--type of problem and age of patient--were thought to interact with the other factors. CONCLUSION: Certain nonmedical considerations may substantially affect physicians' referral practices.

Data Collection↗
PubMed1992

Collection of peripheral blood mononuclear cells as a byproduct of plateletpheresis with two different blood cell separators.

Peripheral blood mononuclear cells (PBMC) were collected as a byproduct of plateletpheresis of normal blood cell donors using modifications to standard automated protocols on either the CS-3000 or Spectra blood cell separator machine. Comparison of the PBMC products obtained showed X +/- SD WBC yields of 5.3 +/- 3.4 vs. 3.8 +/- 2.0 x 10(9) with the CS-3000 and Spectra, respectively (P < .0001). The majority of the cells were lymphocytes, with 13-15% monocytes with both machines. Sixteen percent of the WBC collected with the Spectra, but only 1% of those collected with the CS-3000, were granulocytes. The CS-3000 PBMC product contained fewer RBC (0.2 +/- 0.1 x 10(11) vs. 2.4 +/- 0.6 x 10(11)) and more platelets (1.6 +/- 0.6 x 10(11) vs. 0.35 +/- 0.39 x 10(11)) in a smaller volume (40 +/- 14 ml vs. 229 +/- 37 ml) than the Spectra products. Comparison of the platelet collections harvested when PBMC were also collected to platelets harvested using standard procedures on the same machine showed no change in platelet, WBC, or RBC yields for the Spectra. A significant increase in mean WBC contamination from 40 +/- 56 x 10(7) to 112 +/- 205 x 10(7) and a small, but statistically insignificant, decrease in platelet yield from 4.1 +/- 1.2 x 10(11) to 3.9 +/- 1.8 x 10(11) was observed in the CS-3000 platelet collections when PBMC were harvested. There was no sustained change in donor lymphocyte counts and no change in acute donor side effects or time requirements when PBMC were collected.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Donors↗
PubMed1992

Is there a role for preference assessments in research on quality of life in oncology?

The development of ways to evaluate interventions that may have an impact on quality of life is a rapidly-developing area of research in clinical oncology, especially within the context of randomized controlled trials. We propose a role for assessments of preferences in such evaluations, including preference studies designed to assess attitudes toward the clinical acceptability of interventions, and preference trials designed to assess choice behaviour in relation to interventions. We suggest that such preference assessments represent a specific case of a more general issue: the need to develop an 'ethics of evidence', that is, standards for the creation, assessment and communication of evidence. We then outline a framework within which an 'ethics of evidence' might be developed, and suggest that the framework also may provide a useful model for the processes involved in the transfer of research results into clinical practice. As an illustration, we consider the problem of decision making in circumstances where the choice of therapy depends primarily on the patient's own preferences, as, for example, in the choice of mastectomy or breast-conserving treatment in early-stage breast cancer. The long-term goal is to develop criteria which might be used to foster shared rational decision making in such circumstances.

Beneficence↗
PubMed1992

Retroviral gene transfer to primitive normal and leukemic hematopoietic cells using clinically applicable procedures.

Clinical uses of gene transfer to bone marrow transplants require the establishment of a reproducible method for infecting large numbers of very primitive hematopoietic cells at high efficiency using cell-free retrovirus-containing media. In this study we report the results of experiments with preparations of a high-titer (2-5 x 10(7)/ml) helper-free recombinant neo(r) retrovirus that indicate this goal can now be achieved based on measurements of gene transfer efficiencies to cells referred to as long-term culture initiating cells (LTC-IC) because they give rise to clonogenic cells after greater than or equal to 5 wk in long-term culture (LTC). Intermittent, repeated exposure of normal human marrow mononuclear cells to virus-containing supernatant over a 3-d period of cell maintenance on an IL-3/granulocyte colony-stimulating factor (G-CSF) producing stromal layer resulted in gene transfer efficiencies to LTC-IC of 41%; a level previously obtainable only using co-cultivation infection techniques. Marrow cells enriched greater than or equal to 500-fold for LTC-IC (1-2% pure) by flow cytometry showed gene transfer efficiencies of 27% when infected in a similar fashion over a shorter period (24 h), but in the presence of added soluble IL-3 and G-CSF without stromal feeders, and this increased to 61% when Steel factor was also present during the infection period. By using a less highly enriched population of LTC-IC obtained by a bulk immunoselection technique applicable to large-scale clinical marrow harvests, gene transfer efficiencies to LTC-IC of 40% were achieved and this was increased to 60% by short-term preselection in G418. Southern analysis of DNA from the nonadherent cells produced by these LTC over a 6-wk period provided evidence of clonal evolution of LTC-IC in vitro. Leukemic chronic myelogenous leukemia LTC-IC were also infected at high efficiency using the same supernatant infection strategy with growth factor supplementation. These data demonstrate the feasibility of using cell-free virus preparations for infecting clinical marrow samples suitable for transplantation, as well as for further analysis of human marrow stem cell dynamics in vitro.

Base Sequence↗
PubMed1992

The human hematopoietic stem cell in vitro and in vivo.

A quantitative assay for a primitive human hematopoietic cell has been developed. The cell identified has been assigned the operational designation of long-term culture (LTC)-initiating cell based on its ability when cultured on supportive fibroblast monolayers to give rise to daughter cell(s) detectable by standard in vitro colony assays. Three lines of evidence support the view that the LTC-initiating cell assay may allow the relatively specific enumeration of totipotent cells with in vivo reconstituting potential. These involve the demonstration: (1) that conditions in analogous murine long-term cultures stimulate the extensive amplification (self-renewal) of some totipotent long-term repopulating cells, (2) that most of the LTC-initiating cells in normal human bone marrow are phenotypically different from most of the colony-forming cells present in the same cell suspensions in their possession of a number of characteristics specifically associated with transplantable stem cells; and (3) that cultured marrow cells from patients with chronic myeloid leukemia which, after maintenance under LTC conditions for 10 days contain some normal LTC-initiating cells but no detectable leukemic LTC-initiating cells, can after autografting reconstitute the hematopoietic system with normal cells.

Animals↗
PubMed1991

Comparison of search strategies on CD Plus/MEDLINE.

OBJECTIVE: To compare two strategies for searching MEDLINE using the CD Plus/MEDLINE program on compact disc. DESIGN: Comparison study. INTERVENTIONS: Two search strategies were designed and executed for each of two topics (patient recruitment to clinical trials and attitudes of patients, the public and health care professionals toward clinical trials). Strategy A: searches based on key words selected from the medical subject heading (MeSH) tree structure. Strategy B: searches based on MeSH terms most frequently used to index a known set of relevant articles. Defined search restrictions were then applied. The effects of the restrictions on the absolute number of citations retrieved and on the proportion of relevant citations were assessed. OUTCOME MEASURES: Number of articles retrieved, number of relevant articles, precision and recall of each search strategy and overlap between strategies. MAIN RESULTS: Strategy A produced more citations than strategy B (recruitment 147 v. 38, attitude 366 v. 57) but had more inappropriate citations (recruitment 75 v. 17, attitude 265 v. 25). Both strategies produced 73 relevant recruitment citations and 101 relevant attitude citations. In the recruitment search although the precision did not differ significantly between strategies A and B the difference in recall was significant (98.6% v. 28.8% respectively, p less than 0.0001). In the attitude search strategy A had a lower precision than strategy B (27.6% v. 56.1%, p less than 0.0001) but a much higher recall (100% v. 31.7%, p less than 0.0001). CONCLUSIONS: Strategy A would be more valuable to researchers doing extensive reviews, whereas strategy B would be useful for the busy clinician who simply wants a few appropriate references quickly and is willing to sacrifice comprehensive retrieval in the interest of efficiency.

Algorithms↗
PubMed1991

Differential regulation of primitive human hematopoietic cells in long-term cultures maintained on genetically engineered murine stromal cells.

Various growth factors are known to stimulate both early and late stages of human hematopoietic cell development in semisolid assay systems, but their role as microenvironmental regulators is poorly understood. To address this problem, we developed a novel coculture system in which highly purified primitive human hematopoietic cells were seeded onto an irradiated feeder layer of cells from a murine marrow-derived stromal cell line (M2-10B4) previously engineered by retroviral-mediated gene transfer to produce specific human factors. Effects on cells at very early, intermediate, and late stages of hematopoiesis were then evaluated by assessing the number of clonogenic cell precursors (long-term culture initiating cells [LTC-IC]), clonogenic cells, and mature granulocyte and macrophage progeny present in the cultures after 5 weeks. In the absence of any feeders, cells at all stages of hematopoiesis decreased to very low levels. In contrast, maintenance of LTC-IC was found to be supported by control murine stromal cells as effectively as by standard human marrow adherent layers. The presence of granulocyte colony-stimulating factor (G-CSF) and interleukin-3-producing M2-10B4 cells in combination was able to further enhance the maintenance and early differentiation of these cells without a decline in their proliferative potential as measured by the clonogenic output per LTC-IC. However, this effect was lost if granulocyte-macrophage CSF (GM-CSF)-producing feeders were also present. On the other hand, in the presence of GM-CSF-producing feeders, the output of mature granulocytes and macrophages increased 20-fold. These findings show that it is possible to selectively improve the maintenance of very primitive human hematopoietic cells in vitro or their output of mature progeny by appropriate manipulation of the long-term marrow culture system. Further exploitation of this approach should facilitate investigation of the mechanisms operative within the human marrow microenvironment in vivo and the design of protocols for in vitro manipulation of human marrow for future therapeutic applications.

Animals↗
PubMed1991

Communicating probabilistic information to cancer patients: is there 'noise' on the line?

The objective was to examine the way that cancer patients translate verbal descriptors of probability into numerical estimates. A list of words commonly used on consent forms to describe the likelihood for benefits or risks of therapies was provided to 100 cancer patients. Two formats, paper/pencil or computer, were used to provide the list of words. Two methods, magnitude estimation and linear analogue scaling, were used to obtain probability estimates for each word. In addition, two scenarios were developed to study 'context effects' on numerical interpretations of verbal descriptions of probability. All patients provided numerical values for the words on two occasions, separated by one week, and two interviewers collected the data. Regardless of method or format, each word elicited widely variable numerical interpretations. An ANOVA model, including patient, word, interviewer, time, method and format, indicated that patient and interviewer produced major effects on probability estimates. Agreement between methods and across time was good. Paper/pencil and computer formats yielded similar results. Context effects did not appear to influence the numerical probabilities elicited by the 2 scenarios. It was concluded that, within this group of patients, there was no consensus about numerical meaning of a given word, and that interviewers can systematically influence numerical interpretations. There appears to be a great deal of 'noise' in this particular line of communication between patients and health professionals.

Aged↗
PubMed1991

Molecular analysis of primitive hematopoietic cell proliferation control mechanisms.

Cells at two distinct early stages in the development of mature human blood cells from primitive totipotent hematopoietic stem cells can now be defined and quantitated by separate in vitro assays. Current evidence suggests that most, if not all, colony-forming cells--that is, cells that give rise to colonies of mature progeny within one to three weeks in semisolid culture systems, represent an intermediate stage of hematopoietic progenitor. These cells are not self-sustaining; if they are used to initiate hematopoiesis on competent marrow stromal layers, they rapidly disappear as they differentiate or die. However, clonogenic cells can be generated in such cultures from another cell type over a period of four to eight weeks. We have, therefore, assigned the term long-term culture initiating cell (LTC-IC) to this latter type of clonogenic precursor cell. The production and differentiation of cells in both of these compartments in LTC are dependent on, and regulated by, nonhematopoietic "stromal" cells that form a heterogeneous adherent layer in which close-range interactions with hematopoietic cells take place. The use of separate endpoints to monitor the maintenance, differentiation, and reversible activation or arrest of cycling of these cells has recently revealed different molecular mechanisms regulating their respective functions. However, an important common feature appears to be the relative local concentration of positive and negative regulators to which the target hematopoietic cell is exposed. Both gene expression and growth factor release measurements as well as results obtained using genetically engineered stroma and repeated soluble growth factor addition implicate G-CSF as an endogenous positive regulator of primitive hematopoietic cells. Similarly, gene expression, factor production, factor addition, and neutralizing antibody experiments implicate TGF-beta as an endogenous inhibitor of primitive hematopoietic cells.

Bone Marrow Cells↗
PubMed1991

Separation of functionally distinct subpopulations of primitive human hematopoietic cells using rhodamine-123.

Normal human bone marrow (BM) contains a small population of cells that can give rise to clonogenic progenitors after 5 weeks in long-term culture (LTC). We have previously shown that these LTC-initiating cells (LTC-IC) differ from the majority of directly clonogenic cells with respect to both light-scattering properties and surface antigen expression. In this paper we show that virtually all LTC-IC (94%) are among the 3%-5% of light-density marrow cells that take up relatively low amounts of rhodamine-123 (Rh-123). In contrast, only 70% of erythroid burst-forming units (BFU-E) and 40% of granulocyte-macrophage colony-forming units (CFU-GM) are recovered in the Rh-123-dull fraction. In addition, we have found that double staining of marrow with Rh-123 and phycoerythrin-labeled anti-CD34 antibodies allows the CD34+ cells to be divided into two subpopulations, of which, on average, 35% are Rh-123-dull. Isolation of these CD34+ Rh-123-dull cells thus provides a single-step enrichment of approximately 240-fold in LTC-IC by comparison to the light-density (less than 1.077 g/cm3) fraction of normal BM. This represents an overall enrichment in LTC-IC of approximately 1000-fold. As expected from the results of staining with Rh-123 only, the majority of directly clonogenic cells are present in the CD34+ Rh-123-bright fraction, where they are enriched approximately 40-fold over their concentration in the light-density fraction. These results indicate marked differences in Rh-123 uptake between subsets of primitive human hematopoietic cells currently defined by different functional assays and suggest that RH-123 staining will be useful for the further purification and analysis of these cells.

Antigens, CD34↗
PubMed1991

Human hematopoietic stem cells in long-term culture: quantitation and manipulation.

These results suggest a potentially important role for the LTC system, not only in the development of a quantitative assay for hematopoietic cells, but also clinically as a procedure for manipulating autologous marrow in culture in a variety of ways for therapeutic advantage. These include strategies for immune modulation, gene marking and gene therapy, and perhaps eventually for stem cell amplification.

Bone Marrow Transplantation↗
PubMed1990

Selective expression of CD45 isoforms on functional subpopulations of CD34+ hemopoietic cells from human bone marrow.

We have found that the small population of cells in human marrow that are characterized by their expression of CD34 can be readily subdivided into two apparently nonoverlapping subpopulations of approximate equal size, one expressing CD45RO and one CD45R. Functional studies of these subpopulations revealed that all of the primitive erythroid colony-forming cells (BFU-E) are CD34+ CD45RO+. Similarly, more primitive cells that give rise to both erythroid and granulopoietic colony-forming cells after being maintained for 5 wk on confluent irradiated long-term marrow culture feeder layers, also show this phenotype. In contrast, most granulopoietic colony-forming cells are CD34+ CD45RO- cells. The differential expression of CD45 isoforms on distinct functional subpopulations of hemopoietic cells is consistent with the concept that these molecules play an important role in the differentiation or activation of primitive, normally quiescent, hemopoietic cells. The presence of CD45RO and the lack of CD45R on human cells capable of initiating hemopoiesis in the long-term marrow culture system correspond to the reported lack of CD45R on transplantable hemopoietic stem cells in rodents and may be a useful addition to strategies for human stem cell purification, or for purging CD45R+ leukemic cells.

Antibodies, Monoclonal↗
PubMed1990

Ratings of the importance of quality of life variables: therapeutic implications for patients with metastatic breast cancer.

Metastatic breast cancer cannot be cured with currently available therapeutic agents, and the objectives of treatment must, therefore, be directed towards other goals that include the relief of symptoms and the preservation or restoration of function. The main objective of the study reported here was to examine the relative importance of 28 items concerned with general health or with disease and treatment to a group of patients with metastatic breast cancer. All items concerned aspects of quality of life whose relevance and importance to patients with metastatic breast cancer had been shown in previous work. Patients rated items according to importance using two methods, a Q sort and a linear analogue rating. General health items, notably self-care, mobility, and physical activity, appetite, sleep, and family relationships were ranked in the upper quartile of the group of items rated. By contrast, items concerned directly with the common side-effects of chemotherapy were given lower rankings. The ratings were shown to be reproducible. These results emphasize the importance of including in clinical trials of therapy that are palliative in intent, endpoints that include those aspects of quality of life that are of greatest importance to patients.

Adult↗
PubMed1990

Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers.

A major goal of current hematopoiesis research is to develop in vitro methods suitable for the measurement and characterization of stem cells with long-term in vivo repopulating potential. Previous studies from several centers have suggested the presence in normal human or murine marrow of a population of very primitive cells that are biologically, physically, and pharmacologically different from cells detectable by short-term colony assays and that can give rise to the latter in long-term cultures (LTCs) containing a competent stromal cell layer. In this report, we show that such cultures can be used to provide a quantitative assay for human "LTC-initiating cells" based on an assessment of the number of clonogenic cells present after 5-8 weeks. Production of derivative clonogenic cells is shown to be absolutely dependent on the presence of a stromal cell feeder. When this requirement is met, the clonogenic cell output (determined by assessment of 5-week-old cultures) is linearly related to the input cell number over a wide range of cell concentrations. Using limiting dilution analysis techniques, we have established the frequency of LTC-initiating cells in normal human marrow to be approximately 1 per 2 X 10(4) cells and in a highly purified CD34-positive subpopulation to be approximately 1 per 50-100 cells. The proliferative capacity exhibited by individual LTC-initiating cells cultured under apparently identical culture conditions was found to be highly variable. Values for the number of clonogenic cells per LTC-initiating cell in 5-week-old cultures ranged from 1 to 30 (the average being 4) with similar levels being detected in positive 8-week-old cultures. Some LTC-initiating cells are multipotent as evidenced by their generation of erythroid as well as granulopoietic progeny. The availability of a system for quantitative analysis of the proliferative and differentiative behavior of this newly defined compartment of primitive human hematopoietic cells should facilitate future studies of specific genetic or microenvironmental parameters involved in the regulation of these cells.

Bone Marrow Cells↗
PubMed1990

Are we getting informed consent from patients with cancer?

We developed a consent form for a hypothetical trial and asked patients to underline information that was pertinent to their decision to accept or refuse to participate in the proposed trial. We also investigated whether patients correctly interpreted statements describing the probability of certain events occurring. Of the 50 patients, 74% did not indicate that both risks and benefits were pertinent. Of the 20 patients who would not enter the trial, 70% focused on risks of therapy only. In contrast, of the 30 who agreed to enter, only 33% focused entirely on risks, while 10% did not note potential for either benefit or risk. For each of four probability statements, patients chose one of four possible interpretations, only one of which was correct. Depending on the statement, between 26 and 54% of the interpretations were incorrect. It appears that many decisions regarding trial entry may be based upon incomplete or incorrect information.

Adult↗