Biomedical subjects
E Williamson
Publications and source records attributed to E Williamson.
Resistance to antibiotics and biocides among non-fermenting Gram-negative bacteria.
OBJECTIVE: To investigate the antibiotic and biocide susceptibilities of clinical isolates of rarely encountered Gram-negative, non-fermenting bacteria. METHODS: Thirty Gram-negative non-fermenting bacterial strains were isolated from blood cultures of oncology patients. These were studied for their resistance to 11 antibiotics. Their susceptibilities to seven biocides used in hospitals were also examined. RESULTS: Isolates of Stenotrophomonas maltophilia and Ochrobactrum anthropi were generally resistant to at least five of the antibiotics, whereas isolates of Comamonas acidivorans, Flavobacterium oryzihabitans, Aeromonas hydrophila, Sphingobacterium spiritivorum, Acinetobacter junii and Acinetobacter lwoffi were generally sensitive to at least nine of the antibiotics. Trovafloxacin and trimethoprim-sulfamethoxazole were the most effective antibacterial agents tested, with 0% and 7%, respectively, of isolates being resistant, whereas 63% of isolates were resistant to aztreonam. Some isolates, sensitive to meropenem and/or ceftazidime in vitro, possessed very high MBC/MIC ratios for these beta-lactams. Two out of three biocides used in hospital pharmacies showed lethal activity towards all strains tested when used at less than one-third of their recommended in-use concentration. Proceine 40 failed to give a 5 log reduction in bacterial cell number for the isolates tested when used at its "in-use" concentration. A concentration of > 500 mg/L chlorhexidine was required to achieve a 5 log reduction for the same isolates. CONCLUSIONS: We have examined the antibiotic susceptibilities of non-fermenting Gram-negative bacterial strains isolated from immunocompromised patients. Despite being sensitive to certain antibiotics in vitro, some isolates were still able to cause serious bacteremia. We have also reported for the first time the susceptibilities of non-fermenting Gram-negative bacteria to common biocides used in hospital infection control, and have shown that some strains are able to persist at the "in-use" concentration of particular biocides. It is therefore important to study further this particular group of organisms, and, in particular, to examine whether there exists a link between resistance to antibiotics and resistance to biocides.
Multiprofessional learning: the attitudes of medical, nursing and pharmacy students to shared learning.
OBJECTIVES: The belief that the effectiveness of patient care will improve through collaboration and teamwork within and between health care teams is providing a focus internationally for 'shared learning' in health professional education. While it may be hard to overcome structural and organizational obstacles to implementing interprofessional learning, negative student attitudes may be most difficult to change. This study has sought to quantify the attitudes of first-year medical, nursing and pharmacy students' towards interprofessional learning, at course commencement. DESIGN: The Readiness for Interprofessional Learning Scale (RIPLS) (University of Liverpool, Department of Health Care Education), was administered to first-year medical, nursing and pharmacy students at the University of Auckland. Differences between the three groups were analysed. SETTING: The Faculty of Medical and Health Sciences, University of Auckland. RESULTS: The majority of students reported positive attitudes towards shared learning. The benefits of shared learning, including the acquisition of teamworking skills, were seen to be beneficial to patient care and likely to enhance professional working relationships. However professional groups differed: nursing and pharmacy students indicated more strongly that an outcome of learning together would be more effective teamworking. Medical students were the least sure of their professional role, and considered that they required the acquisition of more knowledge and skills than nursing or pharmacy students. CONCLUSION: Developing effective teamworking skills is an appropriate focus for first-year health professional students. The timing of learning about the roles of different professionals is yet to be resolved.
Perceptions of older Latino adults regarding physical fitness, physical activity, and exercise.
Healthy People 2000 has identified the importance of physical activity for healthy aging, but little is known about what motivates older individuals, older Latino adults, in particular, to be physically active. The purpose of this research was to examine the perceptions of older Latino adults toward physical fitness, physical activity, and exercise. This study used a qualitative focus group design. The sample of Latino adults age 60 and older resided in Northeast Massachusetts and was recruited from community settings which serve older Latino adults. Three focus groups, consisting of four to eight individuals in each group, were conducted and audiotaped. Data analysis used a combination of open, axial, and selective coding procedures. Focus group participants viewed physical fitness as being able to do anything; the mind and body working together; and feeling "light," being healthy. Support was viewed as a motivator of physical activity and exercise and included community resources, group support, cultural unity, and health provider assistance Barriers of fear and a feeling of inappropriateness were identified by focus group participants. Although the study was exploratory and the sample size small, it provides useful cultural knowledge and information for community health and gerontological nurses. Knowledge about older Latino adults' perceptions of motivators and barriers to physical activity and exercise is a necessary first step for nurses to prescribe activities that will help improve functional independence and quality of life. Nurses can serve as links for older Latino adults in accessing community resources. Sociocultural factors that influence Latino adult perceptions must be assessed if health promotion program planning is to be tailored to meet individual and group needs.
A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions.
BACKGROUND: Chemoprevention of breast cancer is an active area of investigation. Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g., troglitazone) and retinoids are able to inhibit the growth of breast cancer cells. Troglitazone mediates its action via peroxisome proliferator-activated receptor gamma (PPARgamma). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent the induction of preneoplastic lesions by 7,12-dimethylbenz[a]anthracene (DMBA) in a mouse mammary gland organ culture model. METHODS: Mammary glands of BALB/c mice were treated with DMBA (2 microg/mL) to induce preneoplastic lesions in organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha), and LG10068 (ligand for retinoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sided. RESULTS: Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) markedly inhibited the development of mammary lesions (both P values <.05); however, together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to inhibit development of these lesions, but a combination of LG10068 (at 10(-8) M) and troglitazone (at 10(-5) M or 10(-6) M) almost completely inhibited (by 85% and 100%, respectively; both P values <. 05) the development of mammary lesions. The expression of PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha was substantially reduced after treatment with the combination of retinoic acid and troglitazone. CONCLUSIONS: To our knowledge, this is the first report showing the possibility of a PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.
Novel therapeutic approach: organic arsenical melarsoprol) alone or with all-trans-retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo.
The organic arsenical known as melarsoprol (Mel-B) is used to treat African trypanosomiasis. Recently, another arsenical, As2O3 was shown to be effective in treatment of acute promyelocytic leukaemia. We have investigated the anti-tumour activities of Mel-B either with or without all-trans-retinoic acid (ATRA) using the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human prostate cancer cells both in vitro and in vivo. The antiproliferative effects of Mel-B and/or ATRA against breast and prostate cancer were tested in vitro using clonogenic assays and in vivo in triple immunodeficient mice. Furthermore, the mechanism of action of these compounds was studied by examining the cell cycle, levels of bcl-2, apoptosis and antiproliferative potency using a pulse-exposure assay. Clonogenic assays showed that the cancer cell lines were sensitive to the inhibitory effect of Mel-B (effective dose that inhibited 50% clonal growth [ED50]: 7 x 10(-9) M for MCF-7, 2 x 10(-7) M for PC-3, 3 x 10(-7) M for DU145 cells. Remarkably, the combination of Mel-B and ATRA had an enhanced antiproliferative activity against all three cancer cell lines. Furthermore, the combination of Mel-B and ATRA induced a high level of apoptosis in all three cell lines. Treatment of PC-3 and MCF-7 tumours growing in triple immunodeficient mice with Mel-B and ATRA either alone or in combination markedly retarded tumour size and weight of the tumours without major side-effects. In conclusion, our results suggest that either Mel-B alone or with ATRA may be a useful, novel therapy for breast and prostate cancers.
Perceptions of nurse practitioners regarding their role in physical activity and exercise prescription for older adults.
Health promotion related to physical activity and exercise is an integral part of the nurse practitioner (NP) role. Yet, studies suggest that only 30% of primary care clinicians provide counseling to their sedentary patients (Clinician's Handbook of Preventive Services, 1994). This percentage may be even less with clients who represent the oldest old or a minority population. Information about the extent to which NPs counsel patients about physical activity and exercise prescription has not been well documented. The purpose of this research study was to identify the NPs role in providing individualized exercise prescription and to determine what strategies NPs use in assisting older adults to initiate and maintain an exercise program. The study utilized a focus group design comprising two focus groups, ranging in size from 6 to 7. Purposive sampling was used to enlist NP focus group participants. Content analysis of each transcript revealed that NP participants in these two focus groups utilize health history taking and observation skills in determining an older adult's physical fitness, physical activity, and exercise. None of the NP participants used a formalized instrument, nor did they use specific guidelines in prescribing physical activity and exercise recommendations. Frailty and socioeconomic status were variables that NPs consider in their physical activity and exercise recommendations, whereas ethnicity, age, and gender were not. Overall, NPs reported using a very small percentage of their time to physical activity and exercise counseling in primary care visits. Given the well-documented benefits of physical activity and exercise (U.S. Department of Health and Human Services, 1996; American College of Sports Medicine, 1998), it remains a matter of serious concern that more than 60% of American adults are not regularly physically active (Office of the Surgeon General, 1996). It is imperative that policymakers include physical activity and exercise counseling as a condition for reimbursement in primary care visits.
Modulating dendritic cells to optimize mucosal immunization protocols.
Oral administration of soluble protein Ag induces tolerance, a phenomenon that has hampered mucosal vaccine design. To provoke active immunity, orally administered Ag must be fed together with a mucosal adjuvant such as cholera toxin (CT). Unfortunately, CT is not suitable for clinical use because of its associated toxicity. There is, therefore, a need to develop alternative mucosal immunization regimens. Here we have attempted to alter the intrinsically tolerogenic nature of the intestine and improve immunization potential by expanding and activating intestinal APC in vivo. Previous studies have indicated that intestinal dendritic cells (DC) present oral Ag, but do so in a tolerogenic manner. In the present study we investigated whether DC can be converted from tolerogenic into immunogenic APC by treating mice with Flt3 ligand (Flt3L), a DC growth factor, and then immunizing with CT. We observed increased local and systemic responses to CT in the presence of elevated numbers of intestinal DC. In parallel, CT induced up-regulation of CD80 and CD86 on these Flt3L-expanded DC. In an attempt to develop a toxin-free adjuvant system, we investigated whether IL-1 could be used as an alternative DC-activating stimulus. Using a combination of Flt3L and IL-1alpha, we observed a potent active response to fed soluble Ag, rather than the tolerogenic response normally observed. These data suggest that Flt3L-expanded DC are well positioned to regulate intestinal responses depending on the presence or the absence of inflammatory signals. Flt3L may therefore be a reagent useful for the design of mucosal immunization strategies.
Visualizing the T-cell response elicited by oral administration of soluble protein antigen.
Oral administration of soluble protein antigen induces tolerance, while particulate antigens encountered in the intestine provoke active immunity. Although the events that lead to these distinct outcomes are not yet fully characterized, they may reflect differences at the antigen-presenting cell (APC) level. The role of dendritic cells (DC) in regulating responses at mucosal sites has remained largely undefined because of the low frequency of DC in mucosal-associated tissues. In this study we have used the growth factor Flt3-ligand (Flt3L) to expand DC populations in vivo, in combination with an adoptive transfer system, in order to track antigen-specific T cells during oral tolerance induction. We observed rapid T-cell activation, localized particularly in the mucosal tissues, within hours after feeding the soluble protein antigen, ovalbumin (OVA). The response was enhanced in Flt3L-treated mice, indicating an important role for DC during the inductive phase of tolerance.
Unrelated donor bone marrow transplantation in adults: some current controversies.
The results of unrelated donor bone marrow transplantation are continually improving. These improved results are due to a better understanding of the complications of the procedure and the devising of strategies to avoid them. Nonetheless, many problems remain. This review will address some of the major controversies of the field including the indications for UD-BMT, infection, GVHD prophylaxis and treatment and whether UD-BMT should only be performed in specialist centres. Conclusions will be supported by evidence from the limited published literature and the authors' experience in 3 major transplant centres.
Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids.
Peroxisome proliferator activated receptor gamma (PPARgamma) plays a central role in the process of adipocyte differentiation. This receptor and its heterodimeric partner, retinoid X receptor alpha (RXRalpha), form a DNA-binding complex that regulates transcription of adipocyte-specific genes. Troglitazone, an antidiabetic drug, has recently been identified as a synthetic ligand for PPARgamma. We studied the effects of troglitazone on proliferation and differentiation of normal and malignant hematopoietic cells. Expression of PPARgamma was easily detectable by Western blot analyses in all five myeloid leukemia cell lines. Troglitazone alone (10-5 M) did not induce differentiation in any of the cell lines; however, this compound suppressed the clonal growth (10-75% of inhibition) of all five myeloid leukemia cell lines. Myelomonocytic U937 cells, which were the most responsive to the growth suppressing effects of troglitazone, were arrested in the G1 phase of the cell cycle when cultured with this compound. Simultaneous treatment of myeloid leukemia cell lines with both troglitazone and a ligand that specifically binds either RXR (LG100268), or retinoic acid receptors (RAR, ATRA, ALART1550), or both (9-cis RA) resulted in additive suppression of clonal growth. In summary, our studies showed that troglitazone when combined with a retinoid was a moderately potent inhibitor of clonogenic growth of acute myeloid leukemia cells.
Expanding dendritic cells in vivo enhances the induction of oral tolerance.
The intestine is under perpetual challenge from both pathogens and essential nutrients, yet the mucosal immune system is able to discriminate effectively between harmful and innocuous Ags. It is likely that this selective immunoregulation is dependent on the nature of the APC at sites where gut Ags are processed and presented. Dendritic cells (DC) are considered the most potent of APC and are renowned for their immunostimulatory role in the initiation of immune responses. To investigate the role of DC in regulating the homeostatic balance between mucosal immunity and tolerance, we treated mice with Flt3 ligand (Flt3L), a growth factor that expands DC in vivo, and assessed subsequent systemic immune responsiveness using mouse models of oral tolerance. Surprisingly, mice treated with Flt3L to expand DC exhibited more profound systemic tolerance after they were fed soluble Ag. Most notably, tolerance could be induced in Flt3L-treated mice using very low doses of Ag that were ineffective in control animals. These findings contrast with the generally accepted view of DC as immunostimulatory APC and furthermore suggest a pivotal role for DC during the induction of tolerance following mucosal administration of Ag.
Cutting edge: signals from the B lymphocyte antigen receptor regulate MHC class II containing late endosomes.
The B lymphocyte response to protein Ag is dependent upon the successful presentation to T cells of Ag-derived, MHC class II-restricted peptides. The B cell Ag receptor (BCR) facilitates this process by internalizing ligand and delivering it to specialized compartment(s) (MHC class II peptide-loading compartments (MIIC)) where it is processed into peptides and loaded onto MHC class II. In addition to efficiently targeting Ag, the BCR can provide tyrosine kinase-dependent signals that augment the presentation of Ag, possibly by enhancing the generation of immunogenic peptides. However, the mechanism by which this occurs is unclear. Herein, we report that the BCR signals a reorganization, fusion, and acidification of an MHC-like compartment into an invariant chain- and MHC class II-rich complex of large vesicles. This complex becomes the primary target for endocytosed receptors. These data suggest that signals generated by the BCR regulate the site of Ag processing.
Religious sanctions and rates of suicide worldwide.
In order to understand differences in suicide rates between the countries affiliated to the International Association for Suicide Prevention (IASP), the present paper investigates whether there is a relationship between the existence of religious sanctions and aggregate national suicide rates as reported to the World Health Organization. Through their participation in this study, 49 IASP national representatives reported on the existence of religious sanctions against suicide. It was discovered that countries with religious sanctions were less likely to return rates of suicide to the WHO. Comparative analysis revealed that the average reported rates for countries with sanctions are lower than those for countries without religious sanctions. The difference is particularly significant for females. Overall, then, at an aggregate level, it would appear that an inverse relationship does exist; however, while countries with religious sanctions against suicide return lower rates of suicide, as recorded by the WHO, recording and reporting procedures may be affected by the existence of sanctions, thus diminishing the reliability of reported rates. Furthermore, distinctions between rates among the different denominations seem to have been somewhat blurred, in particular between Catholics and Protestants, to the extent that in certain societies Catholics have a higher reported rate of suicide--despite the fact that, doctrinally, Catholicism is more severe in the condemnation of suicide than the majority of Protestant churches (with a few notable exceptions, such as the Orthodox Calvinists).
Euthanasia and related practices worldwide.
The present paper examines the occurrence of matters relating to the ending of life, including active euthanasia, which is, technically speaking, illegal worldwide. Interest in this most controversial area is drawn from many varied sources, from legal and medical practitioners to religious and moral ethicists. In some countries, public interest has been mobilized into organizations that attempt to influence legislation relating to euthanasia. Despite the obvious international importance of euthanasia, very little is known about the extent of its practice, whether passive or active, voluntary or involuntary. This examination is based on questionnaires completed by 49 national representatives of the International Association for Suicide Prevention (IASP), dealing with legal and religious aspects of euthanasia and physician-assisted suicide, as well as suicide. A dichotomy between the law and medical practices relating to the end of life was uncovered by the results of the survey. In 12 of the 49 countries active euthanasia is said to occur while a general acceptance of passive euthanasia was reported to be widespread. Clearly, definition is crucial in making the distinction between active and passive euthanasia; otherwise, the entire concept may become distorted, and legal acceptance may become more widespread with the effect of broadening the category of individuals to whom euthanasia becomes an available option. The "slippery slope" argument is briefly considered.
Dendroaxonal transcytosis of transferrin in cultured hippocampal and sympathetic neurons.
Previous studies using overexpressed polymeric immunoglobulin receptor in cultured neurons have suggested that these cells may use a dendroaxonal transcytotic pathway (Ikonen et al., 1993; de Hoop et al., 1995). By using a combination of semiquantitative light microscopy, video microscopy, and a biochemical assay, we show that this pathway is used by the endogenous ligand transferrin (Tf) and its receptor. Labeled Tf added to fully mature hippocampal neurons changes the intracellular distribution of its receptor from preferentially dendritic shortly after addition to dendritic and axonal at longer times. Incubation of living neurons with (caged)FITC-Tf followed by uncaging in the dendrites results in the later appearance of fluorescence in the axon of the same cell. In "chambered" sympathetic neurons in culture, 125I-Tf or iron as 55Fe-Tf added to the cell body/dendrite chamber is recovered in the axonal chamber, showing that internalized ligand from the cell body-dendrite area is released at the axonal end. Finally, we show that excitatory neurotransmitters increase Tf receptor transcytosis, whereas inhibitory neurotransmitters reduce it. The dendritic uptake, transcytotic transport, and axonal release of physiologically active Tf demonstrated here could be envisioned for other trophic factors and therefore have important consequences for neuronal anterograde target maturation. Moreover, the changes in transcytosis after neurotransmitter addition may be important in the cellular responses that follow electrical activation.
Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease.
Injection of parental spleen cells into BDF1 mice results in a graft-vs-host disease (GVHD), the nature of which is critically dependent on the parental haplotype. B6-->BDF1 mice develop a Th1-mediated immunosuppressive lethal GVHD, whereas DBA/2-->BDF1 mice develop a Th2-dependent chronic GVHD, characterized by autoantibody production and glomerulonephritis. In this study we show that neutralizing endogenous IL-12 for a brief period during the initiation of acute GVHD in B6-->BDF1 mice not only confers long term protection from the acute disease, but also permits full repopulation of the recipient with donor B6 lymphocytes. Antibody-treated animals showed normal T cell proliferation in response to Con A stimulation and remained healthy throughout the study. Splenocytes from such mice showed reduced in vitro production of IFN-gamma and enhanced production of IL-5 and IL-10, suggesting a permanent switch from a Th1 to a Th2 cytokine response, comparable to that associated with chronic GVHD in DBA/2-->BDF1 mice. In contrast to DBA/2-->BDF1 mice, however, anti-IL-12-treated B6-->BDF1 mice displayed only mild B cell hyper-responsiveness, as evidenced by a modest increase in serum IgG and IgE levels and moderate levels of anti-dsDNA Abs. Importantly, however, anti-IL-12-treated B6-->BDF1 mice showed no evidence of immune complex-mediated glomerulonephritis. These results demonstrate that neutralizing IL-12 is an effective means of preventing acute GVHD and does not result in the development of chronic GVHD, which might otherwise limit its application.
Liposomally-encapsulated ricin toxoid vaccine delivered intratracheally elicits a good immune response and protects against a lethal pulmonary dose of ricin toxin.
A small study was performed to examine whether the instillation of ricin toxoid vaccine into the lungs of Porton rats offered protection from lethal effects of subsequent intratracheal challenge with ricin toxin. Further the immune response to liposomally-encapsulated vaccine and the protection offered was compared with vaccine either adsorbed to Alhydrogel adjuvant or as a simple aqueous solution. The formaldehyde-treated ricin toxin vaccine (RTV) was administered at two dose levels, 500 and 100 micrograms kg-1 body weight to groups of rats, on two occasions by intratracheal instillation. Liposomally-encapsulated vaccine (LRTV) produced a higher titre of ricin-specific antibodies than Alhydrogel-vaccine (ARTV) and vaccine solution. When challenged with 3 LD50 of ricin by intratracheal instillation 7 weeks after the second vaccine instillation, all rats in both LRTV dose groups survived with minimal signs of incapacitation. Analysis of antibody secretion by spleen cells, 14 days post challenge, showed that the IgG isotype in the LRTV group was significantly higher than that in the ARTV and RTV groups and also that the proportion of specific IgA in lung fluid was higher in the LRTV group than in the ARTV and RTV groups. The results of this study indicate that effective vaccinations against inhaled ricin could be achieved with liposomally-encapsulated ricin toxoid, via the lung and should be investigated further.