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Biomedical subjects

R Gregg

Publications and source records attributed to R Gregg.

At least 19 recordsLinked to original sources
PubMed2005

The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age.

Ageing is associated with evidence of immune deficiency and dysregulation. Key changes in the immune system with ageing include a progressive reduction in naive T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. These features are associated with evidence of impaired immune responsiveness both in vitro and in vivo, termed immune senescence. CD4+ CD25+ T cells have recently been recognized as mediators of peripheral immune regulation and play a role in the control of autoimmune and pathogen-specific immune responses. The significance of CD4+ CD25+ regulatory T cells in the context of immunosenescence is not known. We have investigated the number, phenotype and function of CD4+ CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the number of CD4+ CD25+ and CD4+ CD25high T cells in healthy volunteers increases with age. In both age groups CD4+ CD25+ T cells showed a phenotype consistent with that described for regulatory T cells. Further analysis of CD4+ CD25high T cells in young and elderly donors showed equivalent expression of intracellular CTLA-4 and surface expression of activation markers. In vitro, functional titration assays of CD4+ CD25high T cells demonstrated equivalent regulatory function in both young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. These observations demonstrate an increase in peripheral blood CD4+ CD25high regulatory T cells associated with ageing. The relevance of these expanded cells in relation to the immune senescence seen in the elderly as yet remains unclear.

Adult↗
PubMed2001

Neonatal immunity develops in a transgenic TCR transfer model and reveals a requirement for elevated cell input to achieve organ-specific responses.

In recent years, it has become clear that neonatal exposure to Ag induces rather than ablates T cell immunity. Moreover, rechallenge with the Ag at adult age can trigger secondary responses that are distinct in the lymph node vs the spleen. The question addressed in this report is whether organ-specific secondary responses occur as a result of the diversity of the T cell repertoire or could they arise with homogeneous TCR-transgenic T cells. To test this premise, we used the OVA-specific DO11.10 TCR-transgenic T cells and established a neonatal T cell transfer system suitable for these investigations. In this system, neonatal T cells transferred from 1-day-old DO11.10/SCID mice into newborn (1-day-old) BALB/c mice migrate to the host's spleen and maintain stable frequency. The newborn BALB/c hosts were then given Ig-OVA, an Ig molecule carrying the OVA peptide, and challenged with the OVA peptide in CFA at the age of 7 wk; then their secondary responses were analyzed. The findings show that the lymph node T cells were deviated and produced IL-4 instead of IFN-gamma and the splenic T cells, although unable to proliferate or produce IFN-gamma, secreted a significant level of IL-2. Supply of exogenous IL-12 during Ag stimulation restores both proliferation and IFN-gamma production by the splenic T cells. This restorable form of splenic unresponsiveness referred to as IFN-gamma-dependent anergy required a transfer of a high number of neonatal DO11.10/SCID T cells to develop. Thus, the frequency of neonatal T cell precursors rather than repertoire diversity exerts control on the development of organ-specific neonatal immunity.

Amino Acid Sequence↗
PubMed2001

Phase I study of a decision aid for patients with locally advanced non-small-cell lung cancer.

PURPOSE: Many patients with locally advanced non-small-cell lung cancer (LA-NSCLC) are eligible for combined-modality therapy (CMT; chemotherapy and radiotherapy). Although CMT offers slightly higher chances of survival than radiotherapy alone (RT), it also carries a higher probability of toxicity, raising the possibility that some patients may prefer to decline CMT. We report a pilot study of a decision aid designed for patients in this setting. PATIENTS AND METHODS: The aid included a structured description of the treatment options and trade-off exercises designed to help clarify the patient's values for the relevant outcomes by determining the patient's survival advantage threshold (SAT; the increase in survival conferred by CMT over RT that the patient deemed necessary for choosing CMT). Additional outcome measures included each patient's strength of treatment preference, decisional conflict, objective understanding of survival information, and decisional role preference. RESULTS: Twenty-seven patients met the eligibility criteria for the study. Of these, seven declined the decision aid because they had a clear treatment preference. The remaining 20 participants completed the decision aid; 18 chose CMT, and two chose RT. All 20 patients wished to participate in the decision to some extent. All patients reported that using the decision support was useful to them and recommended its use for others. No patient or physician reported that the aid interfered with the physician-patient relationship. Patients' 3-year SATs and median SATs were each strongly correlated with their strengths of treatment preference (rho = 0.83, P <.001 and rho = 0.67, P =.02, respectively). For all but one patient, either their 3-year or median survival threshold was consistent with their final treatment choice. Ten patients reported a stronger treatment preference after using the decision aid. CONCLUSION: We conclude that implementing the decision-aid for patients with LA-NSCLC is feasible, that it demonstrates convergent validity, and that it is favorably evaluated by patients and their physicians. The aid seems to help patients understand the benefits and risks of treatment and to choose the treatment that is most consistent with their values. Further evaluation of the aid is warranted.

Aged↗
PubMed2001

Cancer patients' attitudes toward treatment options for advanced non-small cell lung cancer: implications for patient education and decision support.

The purpose of this study was to determine how people weigh both median survival time and 1-year survival probability when considering a choice between palliative Cisplatin-based chemotherapy with best supportive care (C+BSC) versus best supportive care alone (BSC) as treatment for advanced non-small cell lung cancer (NSCLC). Sixty people, previously treated for cancer, were interviewed as surrogate patients making a treatment decision. The interview included a structured description of the treatment options, and trade-off exercises used to clarify the participants' attitudes pertaining to the survival probabilities associated with each treatment.Participants' attitudes ranged from choosing the more toxic treatment if it offered no survival advantage to declining C+BSC no matter how large its advantage. Fifty-seven percent of participants would choose chemotherapy if the 1-year survival were 10% higher with C+BSC than with BSC alone. For 44 participants (76%), both their median survival and 1-year survival thresholds for accepting C+BSC were consistent, and for two (3%), neither threshold was consistent with their stated treatment preference. For the remaining 12 (21%), one threshold was discordant, but in all cases, this threshold was less relevant to his/her decision. Participants' thresholds could not be predicted reliably on the basis of patient age, sex, education, preferred role in treatment decision making, or previous treatment with chemotherapy. All but one participant recommended the interview as a decision-support strategy for actual patients. The findings suggest that patients with advanced NSCLC should be offered more than one treatment option, and that a systematic process for educating patients and for eliciting their preferences is desirable. The process described herein has potential for use in this clinical setting.

Aged↗
PubMed2001

Racial and ethnic disparities in infant mortality: risk in social context.

This article presents the multifaceted efforts of Syracuse Healthy Start, a federally funded initiative of the Onondaga County Health Department and over 20 partnering agencies to reduce racial and ethnic disparities in infant mortality. The analyses presented in this article demonstrate that many women--Caucasian, African American, and Hispanic--have serious risks for low birth weight and infant death. In many cases, multiple, simultaneous risks complicate a pregnant woman's situation and in other cases the longitudinal cumulative risks impact health across generations. Infant mortality decreased overall, and for both Caucasian and African American infants during the first 3 years of the project.

Black or African American↗
PubMed2001

Multi-modal antigen specific therapy for autoimmunity.

Peripheral tolerance, represents an attractive strategy to down-regulate previously activated T cells and suppress an ongoing disease. Herein, immunoglobulins (Igs) were used to deliver self and altered self peptides for efficient peptide presentation without costimulation to test for modulation of experimental allergic encephalomyelitis (EAE). Accordingly, the encephalitogenic proteolipid protein (PLP) sequence 139-151 (referred to as PLP1) and an altered form of PLP1 known as PLP-LR were genetically expressed on Igs and the resulting Ig-PLP1 and Ig-PLP-LR were tested for efficient presentation of the peptides and for amelioration of ongoing EAE. Evidence is presented indicating that Ig-PLP1 as well as Ig-PLP-LR given in saline to mice with ongoing clinical EAE suppresses subsequent relapses. However, aggregation of both chimeras allows crosslinking of Fcgamma receptors (FcgammaRs) and induction of IL-10 production by APCs but does not promote the up-regulation of costimulatory molecules. Consequently, IL-10 displays bystander suppression and synergizes with presentation without costimulation to drive effective modulation of EAE. As Ig-PLP1 is more potent than Ig-PLP-LR in the down-regulation of T cells, we conclude that peptide affinity plays a critical role in this multi-modal approach of T cell modulation.

Animals↗
PubMed2000

Differential control of neonatal tolerance by antigen dose versus extended exposure and adjuvant.

Ig-PLP1, an immunoglobulin (Ig) chimera carrying the encephalitogenic proteolipid protein (PLP) sequence 139-151 (PLP1), induces neonatal tolerance in mice and confers resistance to experimental allergic encephalomyelitis (EAE) without the need for incomplete Freund's adjuvant (IFA). The mechanism underlying such tolerance involves organ-specific T cell regulation characterized by lymph node deviation and an unusual IFNgamma-dependent splenic anergy. This form of T cell modulation may prove useful for prevention of autoimmunity. However, since the neonatal period is susceptible to regulation, further investigations are necessary to define parameters required to establish regimens suitable for optimal protection against disease. Therefore, studies were carried out to investigate the effect that IFA, the dose of Ig-PLP1, and the number of Ig-PLP1 injections might have on Ig-PLP1-mediated neonatal tolerance and protection against disease. Herein it is reported that as little as 1 microg of Ig-PLP1 supported IFNgamma-dependent splenic anergy but lymph node deviation and protection against disease strengthened as the dose of tolerogen increased. However, when a two-injection regimen was applied, resistance to disease was observed but the mechanism manifested proliferative and cytokine unresponsiveness in both lymphoid organs. Furthermore, the use of IFA along with Ig-PLP1 yielded a suppressive mechanism similar to that of the two-injection regimen. Therefore, the dose of Ig-PLP1 displays a quantitative influence, while the number of injections of Ig-PLP1 and the presence of IFA rather drive qualitative influences on such tolerance.

Adjuvants, Immunologic↗
PubMed2000

Genetics services in a social, ethical and policy context: a collaboration between consumers and providers.

We report a unique, collaborative effort by users and providers of genetic services to arrive at outlines for optimal ethics and clinical practice. Using focus groups of consumers (users) and providers (held separately), a provider-consumer project team developed 1) a consumer wish list, 2) an experientially based ethical overview of situations arising in practice, and 3) detailed suggestions for consumer-provider interactions in clinical settings. Consumers were primarily interested in accurate information, respect for persons, a smoothly functioning team, with the consumer as an equal member of the team, family integrity, and providers who knew the limits of their knowledge and were willing to refer. "Non-directive" counselling and privacy were not major issues in consumer focus groups; some thought providers should openly state their own opinions. Providers had a rather different list of priorities. Books and papers on clinical ethics usually originate from bioethicists and physicians. This pilot project is unique in including consumers and providers equally.

Community Participation↗
PubMed2000

Neonatal tolerant immunity for vaccination against autoimmunity.

Autoimmunity arises when the immune system no longer tolerates self and precipitates lymphocyte reactivity against our own antigens. Although the developing T cell repertoire is constantly purging, self-recognition events do exist when such tight control is evaded and autoreactive lymphocytes escape the thymus (the sites of T cell development) and migrate to the periphery. Upon activation these autoreactive cells may exert aggressive behavior toward one's own tissues and organs leading to autoimmune disease. Multiple sclerosis, Rheumatoid arthritis, and type I diabetes are autoimmune diseases mediated by autoreactive T cells. A logical approach to prevent such autoimmunity would be to reprogram those lymphocytes to tolerate the self antigen. Injection of antigen at the neonatal stage promotes a state of tolerance such that successive encounter with antigen does not precipitate aggressive reactions. The mechanism underlying neonatal tolerance involves priming of T cells whose effector functions do not cause inflammatory reactions upon recognition of antigen but rather induce protective immunity. This form of tolerant immunity provides an attractive strategy for vaccination against autoimmunity. Herein, it is shown that neonatal exposure to a self-peptide-immunoglobulin chimera drives a tolerant immunity toward the self-peptide and protects against the autoimmune disease, experimental allergic encephalomyelitis.

Animals↗
PubMed1999

Mice mutant for glucokinase regulatory protein exhibit decreased liver glucokinase: a sequestration mechanism in metabolic regulation.

The importance of glucokinase (GK; EC 2.7.1.12) in glucose homeostasis has been demonstrated by the association of GK mutations with diabetes mellitus in humans and by alterations in glucose metabolism in transgenic and gene knockout mice. Liver GK activity in humans and rodents is allosterically inhibited by GK regulatory protein (GKRP). To further understand the role of GKRP in GK regulation, the mouse GKRP gene was inactivated. With the knockout of the GKRP gene, there was a parallel loss of GK protein and activity in mutant mouse liver. The loss was primarily because of posttranscriptional regulation of GK, indicating a positive regulatory role for GKRP in maintaining GK levels and activity. As in rat hepatocytes, both GK and GKRP were localized in the nuclei of mouse hepatocytes cultured in low-glucose-containing medium. In the presence of fructose or high concentrations of glucose, conditions known to relieve GK inhibition by GKRP in vitro, only GK was translocated into the cytoplasm. In the GKRP-mutant hepatocytes, GK was not found in the nucleus under any tested conditions. We propose that GKRP functions as an anchor to sequester and inhibit GK in the hepatocyte nucleus, where it is protected from degradation. This ensures that glucose phosphorylation is minimal when the liver is in the fasting, glucose-producing phase. This also enables the hepatocytes to rapidly mobilize GK into the cytoplasm to phosphorylate and store or metabolize glucose after the ingestion of dietary glucose. In GKRP-mutant mice, the disruption of this regulation and the subsequent decrease in GK activity leads to altered glucose metabolism and impaired glycemic control.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with measurable, advanced NSCLC who had not received previous chemotherapy for advanced disease were considered for this study. Eligible patients who gave written informed consent initially received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3 weeks. After three patients received treatment at this dose, the dose was reduced to 500 mg/m(2) IV at the same infusion time and frequency because of toxicity seen in this study and another Canadian MTA trial in colorectal cancer. Patients received up to four cycles after complete or partial remission or six cycles after stable disease was documented. RESULTS: Thirty-three patients were accrued onto the study. All were assessable for toxicity, and 30 patients were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance status score of 0 or 1, 18 patients (55%) had adenocarcinoma, and nine patients (27%) had squamous cell carcinoma. Twenty-five patients (76%) had stage IV disease, and the remainder had stage IIIB disease at trial entry. Seven patients experienced a confirmed partial response and no complete responses were seen; thus, the overall response rate was 23.3% (95% confidence interval, 9.9% to 42.3%). The median duration of response was 3.1 months (range, 2. 3 to 13.5 months) after a median follow-up period of 7.9 months. Four (67%) of six patients with stage IIIB disease and three (12.5%) of 24 with stage IV disease responded to treatment. Four patients (13.3%) experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4 neutropenia, whereas only one patient (3%) developed grade 4 thrombocytopenia. Nonhematologic toxicity was generally mild or moderate, but 39% of patients developed a grade 3 skin rash. Most other toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and anorexia. Ten patients stopped protocol therapy because of toxicity. CONCLUSION: MTA seems to have clinically meaningful activity as a single agent against advanced NSCLC. Toxicity is generally mild and tolerable. Further study of this agent in combination with cisplatin and other active drugs is warranted in this disease.

Adult↗
PubMed1998

The effectiveness of topical diclofenac for lateral epicondylitis.

INTRODUCTION: Gastrointestinal upset and local pain commonly limit the use of oral nonsteroidal anti-inflammatory drugs and corticosteroid injection as treatments for lateral epicondylitis. Transdermal administration of an anti-inflammatory drug could avoid these adverse effects. PURPOSE: To determine the effectiveness of topical diclofenac as a treatment of lateral epicondylitis. METHODS: A convenience sample of 14 subjects meeting clinical criteria of chronic lateral epicondylitis participated in this randomized, double blind, crossover study. Each subject applied a pluronic lecithin liposomal organo-gel (PLO) over the affected lateral elbow three times daily for I week, followed by a 1-week "washout" period of no gel. A second topical PLO gel was then applied similarly for 1 week. Both gels were identical, but only one gel contained 2% diclofenac. Treatment order was randomized, and both the subject and tester were blinded. Pain and isometric wrist extension strength were measured using a visual analog pain scale (VAS) and a mounted manual muscle testing dynamometer, respectively, at the following time periods: just before application of the first gel, the last day of using the first gel, the last day of the washout week, and the last day of using the second gel. Analysis was performed using repeated measures analysis of variance. RESULTS: When subjects used diclofenac PLO, pain was significantly less than that during the pretreatment, washout, and placebo PLO periods (mean VAS: diclofenac PLO, 2.1; pretreatment, 3.5; washout, 3.4; placebo PLO, 3.6). Average wrist extension strength was significantly greater when subjects used diclofenac PLO (8.4 kg) than it was before treatment (5.9 kg). One subject developed a local rash while using diclofenac PLO. CONCLUSION: Topical 2% diclofenac in PLO appears to provide effective short-term reduction in elbow pain and wrist extensor weakness associated with chronic lateral epicondylitis.

Adult↗
PubMed1998

Teenage health and the practice nurse: choice and opportunity for both?

Teenage health issues and the means to address them have caused increasing concern over recent years. This study investigated the involvement and training of practice nurses, the topics raised during consultations with teenagers, and the comfort of the practice nurses in dealing with these topics. Data were collected using a postal questionnaire survey (response rate 80.6%). Expansion of the role of the practice nurse in teenage health may be appropriate but needs to be supported by training.

Adolescent↗
PubMed1997

Improving uptake of breast screening in multiethnic populations: a randomised controlled trial using practice reception staff to contact non-attenders.

OBJECTIVES: To determine whether a two hour training programme for general practice reception staff could improve uptake in patients who had failed to attend for breast screening, and whether women from different ethnic groups benefited equally. DESIGN: Controlled trial, randomised by general practice. SETTING: Inner London borough of Newham. SUBJECTS: 2064 women aged 50-64 years who had failed to attend for breast screening. Women came from 26 of 37 eligible practices, 31% were white, 17% were Indian, 10% Pakistani, 14% black, 6% Bangladeshi, 1% Chinese, 4% were from other ethnic groups, and in 16% the ethnic group was not reported. MAIN OUTCOME MEASURES: Attendance for breast screening in relation to ethnic group in women who had not taken up their original invitation. RESULTS: Attendance in the intervention group was significantly better than in the control group (9% v 4%). The response was best in Indian women--it was 19% in the intervention group and 5% in the control group. CONCLUSIONS: This simple, low cost intervention improved breast screening rates modestly. Improvement was greatest in Indian women--probably because many practice staff shared their cultural and linguistic background. This intervention could be effective as part of a multifaceted strategy to improve uptake in areas with low rates.

Asia↗
PubMed1997

Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant or sporadic disorder characterized by periodic, reversible attacks of muscle weakness. Mutations in the skeletal muscle dihydropyridine receptor alpha 1-subunit that functions as a calcium channel (CACNL1A3) cause hypoKPP. We studied a group of 45 hypoKPP probands and demonstrated mutations in 30 of them. When compared with patients in whom CACNL1A3 mutations were not identified, those with mutations had an earlier age of onset and more often had a family history of hypoKPP. To date, three mutations have been identified. The R1239G mutation has only been found in one family. Of the 30 probands with recognized mutations, R528H accounted for 43% and R1239H was seen in 53%. Age of onset and potassium levels during attacks were lower in patients with the R1239H mutation than those with R528H. Cardiac dysrhythmias co-segregated with hypoKPP in one small kindred with the R528H mutation. No mutations were identified in exons of the gene encoding the S4 segments of domains one and three or the cytoplasmic loop between domains two and three. In addition to the 45 hypoKPP probands, an additional 11 probands with clinical variants of hypoKPP (three thyrotoxic hypoKPP and eight Andersen syndrome patients) were examined for CACNL1A3 mutations and none were found.

Adolescent↗
PubMed1994

Gemcitabine is an active new agent in previously untreated extensive small cell lung cancer (SCLC). A study of the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: The new pyrimidine antimetabolite Gemcitabine has shown preclinical efficacy in a number of solid tumour lines and acceptable toxicity in phase I trials. As part of an ongoing effort to identify active new agents in small cell lung cancer, the NCIC Clinical Trials Group studied Gemcitabine in previously untreated patients with extensive disease. PATIENTS AND METHODS: Twenty-nine newly diagnosed patients with untreated extensive small cell lung cancer and at least one bidimensionally measurable site received Gemcitabine as a 30 minute intravenous infusion weekly x 3 every 4 weeks. The starting dose was 1000 mg/m2/week in the first 17 patients and 1250 mg/m2/week in the remainder. Patients were reevaluated for response every 4 weeks. Those failing to respond after 2 cycles of therapy were to be offered standard chemotherapy. RESULTS: Of the 29 patients entered, all were evaluable for toxicity and 26 for response. One complete and 6 partial responses were seen giving a response rate of 27% (95% CI: 11%-47%). Median response duration was 12.5 weeks and the median survival of the entire population was 12 months. Toxic effects were mild to moderate: in particular serious myelosuppression was uncommon. CONCLUSIONS: Gemcitabine is active in previously untreated small cell lung cancer in doses which produce little toxicity. Combination studies of Gemcitabine with other agents active in this disease are warranted.

Aged↗