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Biomedical subjects

A Noble

Publications and source records attributed to A Noble.

At least 19 recordsLinked to original sources
PubMed2006

Preferences for aspects of a dermatology consultation.

BACKGROUND: General practitioners with special interests (GPSIs) are increasingly being used to provide dermatology services in the U.K. Little is known about U.K. dermatology patient attitudes to proposed variations in secondary care service delivery or the values they attach to aspects of the care they receive. OBJECTIVES: To quantify preferences for different attributes of care within dermatology secondary care services. METHODS: Attributes of care that are important to dermatology patients were derived using in-depth qualitative interviews with 19 patients at different points in the care pathway. A discrete choice experiment using 'best-worst scaling' was sent by post to 119 patients referred to secondary care dermatology services and suitable for GPSI care who had agreed to participate in research. RESULTS: Four attributes were derived from the qualitative work: waiting, expertise, thorough care and convenience. For the discrete choice experiment, 99 patients returned questionnaires, 93 of which contained sufficient data for analysis. All attributes were found to be quantitatively important. The attribute of greatest importance was expertise of the doctor, while waiting time was of least importance. Respondents were willing to wait longer than the current 3 months maximum to receive care that was thorough, 2.1 months to see a team led by an expert and 1.3 months to attend a consultation that is easy to get to. CONCLUSIONS: Although the need to reduce outpatient waiting times is a key policy driver behind the expansion of GPSI services, this does not appear to be the most important issue for patients. The thoroughness with which the consultation is provided and the expertise of the clinician seen are higher priorities.

Attitude to Health↗
PubMed2004

Resolution of allergic airways inflammation but persistence of airway smooth muscle proliferation after repeated allergen exposures.

BACKGROUND: Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. OBJECTIVE: We investigated the long-term effects of repeated allergen exposure. METHODS: Brown-Norway (BN) rats sensitized to ovalbumin (OVA) were exposed to OVA or saline aerosol every third day on six occasions and studied 24 h, 7 days and 35 days after the final exposure. We measured airway inflammation, ASM cell proliferation (by incorporation of bromodeoxyuridine; BrdU) and bronchial responsiveness to acetylcholine. RESULTS: At 24 h, in OVA-exposed rats, we detected elevated OVA-specific serum IgE, increased numbers of macrophages, eosinophils, lymphocytes and neutrophils in the bronchoalveolar lavage (BAL) fluid and increased numbers of MBP+ (major basic protein) eosinophils and CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU and with bronchial hyper-responsiveness (BHR). At 7 days, BHR was detected in OVA-exposed rats, coincident with increased numbers of macrophages and lymphocytes in BAL fluid together with increased numbers of CD2+ T cells within the bronchial submucosa. This coincided with increased numbers of ASM cells expressing BrdU. By day 35, the number of ASM cells expressing BrdU remained elevated in the absence of cellular infiltration and BHR. CONCLUSION: Repeated OVA-challenge results in persistent ASM cell proliferation in the absence of bronchial inflammation and BHR, which lasts for at least 1 week following cessation of exposure.

Allergens↗
PubMed2001

Early Th1/Th2 cell polarization in the absence of IL-4 and IL-12: T cell receptor signaling regulates the response to cytokines in CD4 and CD8 T cells.

Differentiation of developing T cells into the type 1 (IFN-gamma-producing) or type 2 (IL-4-producing) subsets is a central theme of immune regulation. The balance of IL-4 and IL-12 present during T cell activation has been considered the major influence on type 1 versus type 2 development. Here we show that CD4 T cells can become biased towards type 1 or type 2 phenotypes during their initial activation in the absence of IL-4 or IL-12. This type of regulation is dependent on the balance of MAPkinase, protein kinase C, and calcineurin signaling after TCR engagement. Later maturation of Th1 or Th2 effectors is dependent on IL-12 or IL-4. However Tc1 CD8 effector development is independent of IL-12, and Tc2 cell generation requires both appropriate TCR signals and IL-4 early in effector development. Using an altered peptide ligand to stimulate TCR transgenic T cells, we show that altered signaling regulates the numbers of CD8 cells capable of developing into Tc2 effectors, and also their responsiveness to IL-4. Together, the results support a two-stage model of differentiation in which intermediate cells biased towards the type 1 or type 2 pathways after activation, are subsequently matured in response to IL-12 or IL-4, respectively.

Animals↗
PubMed2001

Different forms of heroin and their relationship to cook-up techniques: data on, and explanation of, use of lemon juice and other acids.

Recent reports of the use of lemon juice in the preparation of heroin for injection have failed to recognize the importance of the different forms of heroin (in the form of the salt or the base) and the impact of this on the chemical manipulation required before injection. One hundred and four opiate addicts in London were interviewed about the forms of heroin (white, brown, etc) and their relationship to cook-up techniques (use of heat and acid). White heroin was typically prepared with water and heat; brown heroin was prepared with acid (citric acid or Vitamin C (ascorbic acid) or lemon juice) and heat; pharmaceutical heroin was prepared with water only (i.e. neither acid nor heat). On the last occasion of heroin use, brown heroin had been the form most commonly used, with over 90% of the sample using citric acid or vitamin C. Lemon juice was rarely used, and heat was almost universally applied in conjunction with lemon juice.

Adult↗
PubMed2001

Activation-induced cell death of human T-cell subsets is mediated by Fas and granzyme B but is independent of TNF-alpha.

Human primary effector T cells were analyzed for their susceptibility to anti-CD3-induced activation-induced cell death (AICD). Th1 and Tc1 cells were more susceptible to AICD than their type 2 counterparts. Type 1 and type 2 subsets were also found to be differentially susceptible to CD95-mediated apoptosis, although cell-surface expression of CD95 and CD95L was at similar levels on all subsets. A role for CD95 in AICD was confirmed by the addition of anti-CD95L antibodies that partially abrogated AICD. Residual apoptosis could not be accounted for by TNF-alpha/TNFR interactions because although type 1 cells secreted more TNF-alpha than type 2 cells, the addition of TNFR:Fc fusion protein did not inhibit AICD. Instead, a reduction in AICD was observed in the presence of EGTA or concanamycin A. The inhibition of apoptosis by a granzyme B inhibitor z-AAD-CMK in Tc1 cells further indicated an involvement of the granule exocytosis mechanism in AICD.

Adult↗
PubMed2000

Peer-initiated overdose resuscitation: fellow drug users could be mobilised to implement resuscitation.

Research interviews about overdose experiences were conducted with 115 patients attending a methadone maintenance clinic in south London, UK. While almost half (49.6%) reported having experienced overdose personally (on an average of four occasions each), almost all (97.4%) reported that they had witnessed overdoses (on an average of six occasions each). This represents a total of 706 overdoses witnessed, of which 106 had resulted in fatalities. The vast majority of patients (86/97) reported that they had taken actions when they had witnessed overdoses with those acting taking an average of nearly threee different actions on the last occasion on which they had seen someone overdosing. Most respondents reported that they would be willing to act, even if they did not know the overdose victim personally and that they had not been deterred from acting by the previous response from the emergency services. Fear of punishment was not a strong deterrent from acting certainly not for this sample, with many participants also expressing an interest in expanding their repertoire of overdose interventions, for example through training in resuscitation techniques and by keeping naloxone at home for use in overdose emergency.

Journal Article↗
PubMed2000

The balance of protein kinase C and calcium signaling directs T cell subset development.

Development of naive T cells into type 1 (Th1, Tc1) or type 2 (Th2, Tc2) effector cells is thought to be under the control of cytokines. In this study, we show that when both IL-12 and IL-4 are present, murine and human T cell differentiation is regulated by the balance of protein kinase C (PKC) and calcium signaling within T cells. Although both biochemical signals were required for T cell activation via the TCR, altering the balance between them redirected type 1 cells to type 2 and vice versa. Stimulation of calcium signaling or inhibition of PKC favored type 1 differentiation, whereas stimulation of PKC or inhibition of calcineurin resulted in type 2 effectors. Altered peptide ligands induced distinct balances of PKC/calcium signaling and altered Tc1/Tc2 development in TCR-transgenic CD8 T cells. The data suggest novel strategies for manipulation of the immune response in vivo.

Animals↗
PubMed2000

Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes.

It has recently become clear that distinct subsets of CD8 T cells, analogous to their CD4 counterparts, exist in rodents and humans. To examine functional differences between human CD8 T-cell subsets, we generated Tc1, Tc2, and Tc0 T-cell clones from the peripheral blood of healthy individuals. The majority of CD8 T-cell clones generated displayed a classic Tc1 phenotype, but 10% to 20% secreted interleukin (IL)-4 in addition to interferon-gamma (Tc0 phenotype). Generation of Tc2 clones was dependent on the use of anti-CD3 and anti-CD28 as the primary stimulus. The cytokine profiles of established clones remained susceptible to modification by the addition of IL-12 and IL-4. In addition, IL-12 enhanced and IL-4 inhibited the growth of Tc1 but not Tc2/0 CD8 T-cell clones. Significant functional differences were observed between the subsets. Tc2/0 clones expressed CD30 and CD40 ligand at a much higher level than Tc1 clones. Both Tc1 and Tc2/0 clones showed comparable cytotoxicity and produced similar levels of perforin and Fas L. However, Tc2 clones were much more resistant to activation-induced cell death and less susceptible to apoptosis by direct Fas ligation. Moreover, Tc1 and Tc2 clones had opposing effects on the development of CD4 effectors, promoting type 1 and type 2 responses, respectively. These data provide evidence for profound differences between human CD8 T-cell subsets that may be important in their functions as cytotoxic or immunoregulatory cells. (Blood. 2000;95:231-240)

Antigens, CD↗
PubMed2000

Identifying substance abusing delivering women: consequences for child maltreatment reports.

OBJECTIVE: The major objective was to determine how and the extent to which SB2669, which requires the identification of substance abusing delivering women, affected the number of children reported for abuse or neglect in several California counties. METHOD: A monthly time-series model from April 1988 to December 1995 was constructed. The idea underlying the model was that month-to-month changes in the number of child maltreatment reports was a response to the presence of SB2669 in addition to various demographic, social, and economic factors. By separately estimating each county's number of reports, it was assumed that SB2669 did not necessarily affect each county's reports by the same amount, perhaps partially because of different counties' implementation strategies or general policies. Our sampling size consisted of seven high prevalence counties. RESULTS: The results suggest that the effects of SB2669 on the number of child maltreatment reports are mixed. On an aggregate level, all else constant, and at least for a few years after the passage of SB2669, SB2669 is associated with a decrease in child maltreatment reports in two of the participating counties. This decrease may be due to conscientious implementation of the legislation in these counties. This mixed finding is expected mainly because SB2669, although mandated, was never enforced. Moreover, from the process component of the study we learned that the implementation practices of this legislation vary substantially between and even within counties' hospitals. CONCLUSIONS/FUTURE DIRECTIONS: A decrease in maltreatment reports in the presence of SB2669 is not necessarily the most desirable outcome in the light of what we know about the relationship between substance abuse and child maltreatment. Law makers need to rethink the purpose of the law and provide the necessary language, tools and training to ensure that the goals of identifying substance abusing mothers and their families are met. Provisions also need to be made that somehow enforce this legislation. These provisions could lessen county-level and hospital-level variability in implementing the law.

Child↗
PubMed2000

Review article: molecular signals and genetic reprogramming in peripheral T-cell differentiation.

Rearrangement of gene segments occurs in T lymphocytes during thymic development as the T-cell receptor (TCR) is first expressed, allowing T cells to become central regulators of antigen specificity in the acquired immune system. However, further development of T cells occurs after population of peripheral lymphoid tissues, which can result in T-cell expansion and differentiation into effectors of various immune function, or progression to memory T cells, anergic cells or death by apoptosis. This review focuses on more recent developments concerning the choices that peripheral T cells make between first encountering antigen through TCR recognition and death. These decisions are associated with a process of genetic reprogramming that alters the behaviour of cells so that immune responses are appropriately regulated.

Cell Differentiation↗
PubMed1999

CD8(+) T cell subsets and chronic obstructive pulmonary disease.

COPD is a debilitating and progressive condition in which the airways become irreversibly obstructed and the lungs progressively damaged. Unlike asthma, we know little about the cells that initiate and drive this process. Research has shown that CD8(+) T cells are overrepresented in the lungs of patients with COPD and that they are inversely related to lung function. However, not all CD8(+) T cells are alike and subsets that make IFN-gamma but not IL-4 (Tc1), IL-4 but not IFN-gamma (Tc2) as well as those that make both (Tc0) have been described. This article focuses on the characteristics of CD8(+) T cell subsets and considers their potential contribution to chronic obstructive pulmonary disease (COPD). Kemeny DM, Vyas B, Vukmanovic-Stejic M, Thomas M, Noble A, Loh LC, O'Connor BJ. CD8(+) T cell subsets and chronic obstructive pulmonary disease.

CD4-Positive T-Lymphocytes↗
PubMed1998

Suppression of immune responses by CD8 cells. I. Superantigen-activated CD8 cells induce unidirectional Fas-mediated apoptosis of antigen-activated CD4 cells.

Stimulation of mature CD4 cells through the TCR induces cellular activation and expansion that are often followed by clonal elimination by a form of apoptosis termed activation-induced cell death. This process of CD4 cell apoptosis is generally thought to reflect clonal suicide and to be independent of other cell types. Here we show that during the response to the superantigen Staphylococcal enterotoxin A, activated CD8 cells, but not activated CD4 cells, suppress the CD4 proliferative response. Suppression by CD8 cells reflects their ability to induce CD4 cell apoptosis via ligation of Fas. Moreover, although activated CD8 cells that express Fas ligand and Fas eliminate CD4 cells through a Fas-dependent mechanism, they are themselves resistant to Fas-dependent apoptosis. These findings indicate a fundamental difference between the two major T cell subsets with regard to sensitivity to Fas-dependent apoptosis, expression of Fas ligand, and mediation of suppressive activity following immunization with superantigen.

Animals↗
PubMed1998

Suppression of immune responses by CD8 cells. II. Qa-1 on activated B cells stimulates CD8 cell suppression of T helper 2 responses.

We have investigated the role of MHC class I products and CD8 T cells in regulating Ab responses using beta2-microglobulin deficient (beta2m-/-) mice. Beta2m-/- mice produced stronger IgM and IgG responses than did control beta2m+/+ mice to both cellular and viral Ags. These Ab responses could be suppressed by infusion of activated B cells from beta2m+/+ mice. Further investigation showed that the beta2m-associated molecule on activated B cells that induced CD8 suppression was Qa-1 and that the Th2 component of CD4 cells was most affected by CD8-suppressive activity. Our findings suggest a novel pathway of Th inhibition in which B cell presentation of Qa-1-associated peptides stimulates CD8 suppressive activity.

Animals↗
PubMed1998

Snyder v. American Association of Blood Banks: a re-examination of liability for medical practice guideline promulgators.

Medical practice guidelines are playing an increasingly important role in both the medical and the legal context. As tools for the health practitioner, it is thought that medical practice guidelines may contribute to an increase in the quality of patient care and cost-effectiveness. In the legal setting, guidelines may improve the functioning of the medical malpractice system by creating more rational, predictable standards of care. The development and promulgation of medical practice guidelines, while increasing, are still evolving. A number of concerns, especially in the areas of physician autonomy, physician control, and ethics, as well as efficacy, need to be resolved. The use of such guidelines as the legal standard of care in malpractice cases evokes similar concerns, along with fears that the use of guidelines at trial may either lower the standard of care, or, conversely, raise the standard of care to levels that are difficult to meet. Adding to this controversy is the recent case of Snyder v. American Association of Blood Banks (1996), in which the New Jersey Supreme Court upheld a jury finding that the American Association of Blood Banks (AABB) was liable to a plaintiff who contracted AIDS from an HIV-tainted transfusion, for negligent failure to adopt guidelines requiring blood testing for surrogate markers. This opinion is significant as the first to find a duty of care running from a medical guideline promulgator to a third person, the injured patient. The opinion is examined in depth and within the context of other relevant case law. The impact the opinion will have is difficult to gauge. The somewhat unique facts of the case, as well as the court's unusually stinging critique of the defendant, AABB, and its motivations informing its response to the concerns about blood contamination, may limit its value as precedent. However, precedent does exist in analogous non-medical cases for promulgator liability. The pros and cons of promulgator liability are weighed. While closer regulation of guideline development and promulgation or promulgator immunity may be warranted, it is premature to consider either seriously until the impact of the Snyder opinion can be appreciated.

Blood Banks↗
PubMed1998

Pharmacokinetic-pharmacodynamic relationships between pirarubicin exposure and hematotoxicity: clinical application using only one blood sample.

The objective of the present study was to evaluate the relationship between the pharmacokinetic parameters of pirarubicin and of its metabolite doxorubicin measured in plasma and whole blood, and the hematologic toxicity of this drug, in order to evaluate the predictability of changes in white blood cells (WBC) by single measurement of drug concentrations. This pharmacokinetic-pharmacodynamic relationship was studied in a total of 45 patients with different tumor types treated by combined chemotherapy containing pirarubicin, administered as short infusion (10+/-2 min) at doses ranging from 50 to 90 mg. In 45 courses performed in 24 patients, we established the relationship between the half-product of pirarubicin level in whole blood at the end of the infusion and the duration of this infusion, which represents an estimate of the area under the time x concentration curve (AUC(PIRA,wb,ei) = C(PIRA,wb,ei) x duration of infusion/2), the age of the patients and the relative fall in WBC counts. These results allowed us to establish a predictive formula in order to anticipate the number of WBC that the patient will obtain about 12 days after treatment, at the nadir of the counting. WBCnadir = 0.032404 x Age + 2.005 + WBCinitial x e(-0.009316 x AUC(PIRA,wb,ei) + 4.202265), WBC being expressed as x 10(3) cells/microl and AUC(PIRA,wb,ei) in ng/ml x h. In a second step, the validation of the prediction was carried out in 43 courses from 21 patients treated in the same conditions, for which WBC(predicted nadir) was compared by linear regression to WBCcounted. We obtained a highly significant correlation: r = 0.656; p<0.0001). Therefore, we show in this paper that the hematological toxicity, especially the WBC nadir count, can be predicted from single-sample blood HPLC analysis. This rapid and easy prediction of leukopenia can help the clinician in anticipating important hematological toxicities and in deciding to start early prophylactic treatment with hematopoietic growth factors.

Adult↗