Tolerance-related V beta clonal deletions in normal CD4-8-, TCR-alpha/beta + and abnormal lpr and gld cell populations.

We have analyzed tolerance-related clonal deletion of Mls-and I-E-reactive thymocytes at the RNA level using a multi-V beta probe RNAse protection assay, and used this phenomenon to identify the maturation stage of the abnormally expanded CD4-8-, TCR-alpha/beta + subset in lpr and gld homozygous mice, and of the phenotypically similar minor thymocyte subset found in normal mice. Essentially complete V beta clonal deletions were detected in lpr and gld cells of all appropriate background strains. Substantial, but not complete, V beta clonal deletions were also detected in the CD4-8- TCR-alpha/beta + subset of normal mice. Since expression of CD4/CD8 is required for V beta clonal deletions to occur, we conclude that lpr and gld cells, and at least a portion of CD4-8- TCR-alpha/beta + thymocytes in normal mice, are derived by secondary loss of CD4/CD8 accessory molecules from more mature CD4+8+ precursors. One possible interpretation of these findings is that such CD4/CD8 loss may affect a class of self-reactive thymocytes that have escaped direct clonal deletion. Exportation and expansion of such cells in the periphery may be an important contributory factor in the induction of systemic autoimmunity.

Delineation of a defect in T cell receptor beta genes of NZW mice predisposed to autoimmunity.

In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined.

Harnessing genomics and biotechnology to improve global health equity.

With decisive and timely action, genome-related biotechnology can be harnessed to improve global health equity. In June 2002 in Kananaskis, Canada, leaders of the G8 industrial nations will develop an action plan to support implementation of the New African Initiative. By extending their discussion of health issues raised in the New African Initiative to include genomics, G8 leaders could signal their intention to increase global health equity by preventing a health genomics divide from developing. There are already some early and growing examples of genome-related biotechnology being applied successfully to health problems in developing countries. But how can genomics be systematically harnessed to benefit health in developing countries? We propose a five-point strategy, including research, capacity strengthening, consensus building, public engagement, and an investment fund.

Clinical ethicists' perspectives on organisational ethics in healthcare organisations.

BACKGROUND: Demand for organisational ethics capacity is growing in health organisations, particularly among managers. The role of clinical ethicists in, and perspective on, organisational ethics has not been well described or documented in the literature. OBJECTIVE: To describe clinical ethicists' perspectives on organisational ethics issues in their hospitals, their institutional role in relation to organisational ethics, and their perceived effectiveness in helping to address organisational ethics issues. DESIGN AND SETTING: Qualitative case study involving semi-structured interviews with 18 clinical ethicists across 13 health organisations in Toronto, Canada. RESULTS: From the clinical ethicists' perspective, the most pressing organisational ethics issues in their organisations are: resource allocation, staff moral distress linked to the organisation's moral climate, conflicts of interest, and clinical issues with a significant organisational dimension. Clinical ethicists were consulted in particular on issues related to staff moral distress and clinical issues with an organisational dimension. Some ethicists described being increasingly consulted on resource allocation, conflicts of interest, and other corporate decisions. Many clinical ethicists felt they lacked sufficient knowledge and understanding of organisational decision-making processes, training in organisational ethics, and access to organisational ethics tools to deal effectively with the increasing demand for organisational ethics support. CONCLUSION: Growing demand for organisational ethics expertise in healthcare institutions is reshaping the role of clinical ethicists. Effectiveness in organisational ethics entails a re-evaluation of clinical ethics training to include capacity building in organisational ethics and organisational decision-making processes as a complement to traditional clinical ethics education.

Assessment of thyrotropin-releasing hormone and thyrotropin reserve in man.

Endogenous thyrotropin-releasing hormone (TRH) reserve and pituitary thyrotropin (TSH) reserve were assessed in four normal subjects, three patients post-cryohypophysectomy, one patient with a hypothalamic lesion secondary to trauma, and four patients with Sheehan's syndrome. TSH reserve was determined by the immunoassayable TSH response to 500 mug TRH given i.v. (TRH stimulation test). TRH reserve was assessed by the rebound response in thyroidal iodine release (TIR) following withdrawal of pharmacologic doses of prednisolone (glucocorticoid withdrawal test). When compared with normals, the post-cryohypophysectomy patients demonstrated parallel impairment of TRH stimulation and glucocorticoid withdrawal testing. The patient with the hypothalamic lesion and the four patients with Sheehan's syndrome all had normal TRH stimulation tests, indicating adequate TSH reserve capacity, yet had abnormal glucocorticoid withdrawal tests, indicative of impairment in endogenous TRH reserve or neurohumoral transport. Three of the patients (hypothalamic injury and two Sheehan's) with impaired TRH reserve were euthyroid. THE FOLLOWING CONCLUSIONS WERE REACHED: (a) A combination of the TRH stimulation test and glucocorticoid withdrawal test may allow for differentiation between pituitary and suprahypophyseal disorders. (b) Certain cases of Sheehan's syndrome appear to have impaired endogenous TRH reserve or transport. (c) Euthyroidism can be maintained in spite of diminished TRH reserve.

Applying genomics-related technologies for Africa's health needs.

While the past century has seen significant improvement in life expectancies in the developed world, it has also witnessed diseases like HIV/AIDS, malaria and tuberculosis ravage populations in the developing world. In some Sub-Saharan African countries, life expectancies have plummeted to less than 40 years--nearly half of those in developed countries. Unequal access to the benefits of science and technology, including medical advances, exacerbate this disparity. In order to address the challenge of global health inequities and strengthen the role of science and technology innovation in contributing to real solutions, the Canadian Program on Genomics and Global health (CPGGH), based at the University of Toronto, has identified three guiding questions: Which genomics-related technologies are most likely to improve the health of people in developing countries?; How can developing countries harness these technologies for health development?; and What can industrialized countries do to assist developing countries?

Sex or survival: trade-offs between quality and quantity of life.

Patients with localized prostate cancer may be treated with either surgery (radical prostatectomy) or radiotherapy. Although controversial, many physicians believe that surgery offers a higher survival rate. However, the surgical treatment may also produce a higher rate of sexual impotency. Our study assessed how men value survival and sexual potency when asked to trade off one for the other. Using the treatment-choice technique, we interviewed 50 men aged 45 to 70 years without known prostate cancer. At hypothetical rates of survival (90% at 5 years for surgery) and impotency (90% for surgery and 40% for radiotherapy) representing published estimates, 32% of respondents were unwilling to trade off any survival, but 68% were willing to trade off a 10% or greater advantage in 5-year survival (by choosing radiotherapy) to maintain sexual potency. The median 5-year survival traded off was 10% (range, 0% to 80%). Willingness to trade off survival for sexual potency was significantly related to level of education, but not to age, interest in sex, frequency of sexual intercourse, or ability to achieve erection. We conclude that some men may choose treatment with lower long-term survival to increase their chance of remaining sexually potent. Because these men may be difficult to identify in clinical practice, physicians should thoroughly discuss both surgery and radiotherapy options with patients who have localized prostate cancer.

Synthesis of the isoleucyl- and valyl-tRNA synthetases and the isoleucine-valine biosynthetic enzymes in a threonine deaminase regulatory mutant of Escherichia coli K-12.

A mutation in the structural gene for threonine deaminase, ilvA538 , results in lower than normal levels of the isoleucyl, valyl- and leucyl-tRNA synthetases. Moreover, this regulatory mutation decreases the level of expression of the ilv biosynthetic operons and renders their expression non-responsive to limitations of the branched-chain amino acids. In this paper, we present in vitro evidence for the inhibition of isoleucyl- and valyl-tRNA synthetase activity by threonine deaminase and 2-ketobutyrate, the product of the threonine deaminase reaction, through the formation of a high molecular weight complex of the three molecules. Based on these results, we propose a model to explain the regulation of the isoleucyl- and valyt -tRNA synthetases in which transient inhibition of the synthetase enzyme activities by threonine deaminase and 2-ketobutyrate increases the expression of ileS and valS , the structural genes for isoleucyl- and valyt -tRNA synthetase, respectively. Further, the results suggest that the hyperattenuated expression of the ilv biosynthetic operons is due to an increased rate of complex formation of valyl and isoleucyl-tRNA synthetases and the altered form of threonine deaminase of the ilvA538 mutant strain.

A review of public policies to procure and distribute kidneys for transplantation.

The purpose of this article is to provide an up-to-date review of the current status of frequently changing public policies for the procurement and distribution of donor kidneys for transplantation. Issues in procurement involve the Uniform Anatomical Gift Act, criteria for brain death, routine inquiry/required request policies, and the use of living kidney donors. Issues in distribution involve access to the transplant waiting list and use of the new national point system to select recipients from the list. These public policies are relevant for internists, who often care for potential organ donors and patients with end-stage renal disease. The issues are also relevant for policy-minded physicians because renal transplantation is the paradigm for organ transplant policy.

Familial postpartum transient hyperthyroidism.

Postpartum painless thyroiditis with transient hyperthyroidism is being recognized with increasing frequency. Evidence tends to support an autoimmune cause. We treated a 33-year-old woman who experienced typical postpartum painless thyroiditis. Her sister had had a similar episode 13 years previously, and their mother had had postpartum hyperthyroidism 42 years earlier. We believe that this familial association provides further support for autoimmunity in postpartum thyroiditis.

What does Cruzan mean to the practicing physician?

The United States Supreme Court's recent decision in the Cruzan case declared that the states have broad powers to formulate their own rules in "right to die" cases. The Court held that competent adults have a constitutionally protected "liberty interest" that allows them to accept or refuse medical treatments. Since liberty interests are subject to rational state regulation, the narrow holding in Cruzan affirmed Missouri's authority to require a "clear and convincing" evidence standard to determine a patient's wishes before life-sustaining treatment could be withdrawn from a formerly competent adult now in a persistent vegetative state. For practicing physicians, some of the implications of Cruzan are as follows: (1) For competent adult patients, physicians should respect patient wishes regarding life-sustaining treatment. (2) Physicians also should discuss with competent patients their wishes for life-sustaining treatment at a future time, when a patient may no longer be able to participate in such decisions. (3) Physicians should record these wishes in a legally acceptable instrument that addresses two aspects of care that may arise in the future if the patient becomes incompetent. What would the patient want done? Who would the patient wish to designate as a surrogate or proxy? (4) For patients who are now incompetent, but for whom decisions must be made about life-sustaining treatment, physicians should focus on the previously expressed wishes of the patient rather than on the patient's current quality of life or on the wishes of the patient's family.

Referral for dialysis in Ontario.

BACKGROUND: Because the incidence rates of treated end-stage renal disease are much lower in Canada than in the United States, we hypothesized that decisions, made by family physicians and community internists, not to refer certain patients to nephrologists might explain this difference. OBJECTIVE: To elicit patterns of practice and attitudes from nonnephrologist physicians who care for, and possibly refer, patients with renal disease. METHODS: A mailed survey was sent to a random sample of 1924 members of the Ontario Medical Association, Sections on General and Family Practice and Internal Medicine. Of 1778 eligible respondents, responses were received from 728 physicians (40.9%). RESULTS: Patients with microscopic hematuria (79.2%), proteinuria (69.5%), and serum creatinine levels in the 120 to 150 mumol/L (1.4 to 1.7 mg/dL) range (84.3%) were generally not referred by family physicians. A hypothetical question about patient age and comorbid features revealed that physicians were less likely to refer patients as their age and comorbidity increased. In response to the question, "In the past 3 years, did you care for a patient who, after due consideration, died of renal failure without referral for dialysis," 14.2% of family physicians and 44.6% of internists said yes. Overall, 67.4% of respondents strongly or somewhat agree that rationing of dialysis is occurring now. Opinions about possible criteria for rationing of dialysis were that the majority strongly or somewhat agreed to basing a decision on the wishes of a competent patient (94.1%), short life expectancy (87.9), poor quality of life (87.0%), and age (63.6%). CONCLUSIONS: These results suggest that nonreferral for dialysis occurs in Ontario and that the act of referral, or nonreferral as the case may be, is influenced by both age and coexisting disease. The patterns of nonreferral reported raise a concern that patients who might benefit are not being referred to dialysis centers.

A new model of advance care planning: observations from people with HIV.

BACKGROUND: Although theoretical concepts from ethics and law have been applied, there is no conceptual model of advance care planning rooted in the perspective of individuals engaged in it. OBJECTIVE: To develop a conceptual model of advance care planning by examining the perspectives of individuals engaged in it. METHODS: In this qualitative research, we studied 140 individuals with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome who were engaged in advance care planning. Respondents' experience with and opinions about advance care planning were noted in interviews that were audiotaped, transcribed, and analyzed. RESULTS: The primary goal of advance care planning was to prepare for death, which entailed facing death, achieving a sense of control, and strengthening relationships. CONCLUSIONS: We have developed a conceptual model of advance care planning rooted in the perspectives of individuals engaged in it. The model has implications for theory, research, and practice regarding end-of-life care.

Pneumocystis carinii thyroiditis. Report of three cases and review of the literature.

Pneumocystis carinii infection of the thyroid gland has previously been described in only four living patients with acquired immunodeficiency syndrome, three of whom had been receiving inhaled pentamidine prophylaxis against P carinii pneumonia. We treated three additional patients with P carinii thyroid involvement, all of whom were receiving aerosolized pentamidine. Two of our patients presented with clinical features suggestive of subacute granulomatous thyroiditis. The diagnosis of P carinii in our patients, as well as in the previously described patients, was established by thyroid fine-needle aspiration and Gomori's silver methenamine stains. The recent emergence of P carinii infection of the thyroid gland is likely related to the use of inhaled pentamidine prophylaxis, which appears to predispose to the development of extrapulmonary pneumocystosis. Clinicians need to be aware of the possibility of P carinii thyroiditis and should use aspiration and Gomori's methenamine silver staining in studying patients with the acquired immunodeficiency syndrome who have a painful (or other unexplained) thyroid mass so as to be able to initiate prompt and appropriate therapy.

American Thyroid Association guidelines for detection of thyroid dysfunction.

OBJECTIVE: To define the optimal approach to identify patients with thyroid dysfunction. PARTICIPANTS: The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. EVIDENCE: Relevant published studies were identified through MEDLINE and the association membership's personal resources. CONSENSUS PROCESS: Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. CONCLUSIONS: The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the serum thyrotropin concentration, beginning at age 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing.

Reconceptualizing advance care planning from the patient's perspective.

BACKGROUND: Traditional academic assumptions about advance care planning (ACP) include the following: (1) the purpose of ACP is preparing for incapacity; (2) ACP is based on the ethical principle of autonomy and the exercise of control; (3) the focus of ACP is completing written advance directive forms; and (4) ACP occurs within the context of the physician-patient relationship. These assumptions about ACP have never been empirically validated. OBJECTIVE: To examine the traditional academic assumptions by exploring ACP from the perspective of patients actively participating in the planning process. METHODS: Forty-eight patients (30 men and 18 women with a mean age of 48.3 years) who were undergoing hemodialysis were interviewed 6 months after receiving an advance directive form. Their experience of ACP was noted in interviews that were audiotaped, transcribed, and analyzed. RESULTS: The participants said that their purpose in ACP was to prepare for death and dying, and their underlying goals included the exercise of control and an attempt to relieve burdens placed on loved ones. Advance care planning was viewed as a social process, and completing a written advance directive form was often regarded as unnecessary. Participants often involved close loved ones, but physicians infrequently. CONCLUSIONS: The traditional academic assumptions are not fully supported from the perspective of patients involved in ACP. The patients we interviewed stated that (1) the purpose of ACP is not only preparing for incapacity but also preparing for death; (2) ACP is not based solely on autonomy and the exercise of control, but also on personal relationships and relieving burdens placed on others; (3) the focus of ACP is not only on completing written advance directive forms but also on the social process; and (4) ACP does not occur solely within the context of the physician-patient relationship but also within relationships with close loved ones.

Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association.

A set of minimum clinical guidelines for use by primary care physicians in the evaluation and management of patients with thyroid nodules or thyroid cancer was developed by consensus by an 11-member Standards of Care Committee (the authors of the article) of the American Thyroid Association, New York, NY. The participants were selected by the committee chairman and by the president of the American Thyroid Association based on their clinical experience. The committee members represented different geographic areas within the United States, to reflect different practice patterns. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information. Each committee participant was initially assigned to write a section of the document and to submit it to the committee chairman, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. Several of the committee members further revised and refined the document, which was then submitted to the entire membership of the American Thyroid Association for written comments and suggestions, many of which were incorporated into a final draft document, which was reviewed and approved by the Executive Council of the American Thyroid Association.

Transient TRH deficiency after prolonged thyroid hormone therapy.

A patient who had been treated with large doses of thyroid hormone for several years developed features of secondary hypothyroidism after thyroid hormone withdrawal. These findings were low serum T4 (3.8 micrograms/dl), T3 (23 ng/dl), and a failure of serum TSH to rise after TRH injection. Serum PRL values rose normally after TRH administration, and evaluation of other pituitary hormones was normal. When retested 3 months later, at which time the serum T4 was 5.5 micrograms/dl, the patient was somewhat less hypothyroid and there was an exaggerated TSH response to exogenous TRH, indicating recovery of pituitary TSH reserve. Indirect assessment of endogenous TRH reserve capacity was consistent with impairment of endogenous TRH activity. Repeat studies performed 7 months later indicated some improvements in this indirect assessment of endogenous TRH reserve capacity but a continued exaggerated TSH response to exogenous TRH administration. Further testing at 28 months revealed a serum T4 value of 7.8 micrograms/dl and a serum T3 value of 141 ng/dl. At this time, the TSH response to TRH was normal and the patient was considered fully recovered. A causal relationship between high doses of thyroid hormone and the presumptive impairment of endogenous TRH reserve is suggested.

Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma.

The prevalence of circulating thyroid autoantibodies (TgAb or antithyroid peroxidase) was increased nearly 3-fold in patients with differentiated thyroid cancers (DTC) compared with the general population (40% vs. 14%, respectively). Serum TgAb (with or without antithyroid peroxidase) was present in 25% of DTC patients and 10% of the general population. Serial postsurgical serum TgAb and serum Tg patterns correlated with the presence or absence of disease. Measurements of serum Tg were made in 87 TgAb-positive sera by a RIA and two immunometric assay (IMA) methods to study TgAb interference. TgAb interference, defined as a significant intermethod discordance (>41.7% coefficient of variation) between the Tg RIA and Tg IMA values relative to TgAb-negative sera, was found in 69% of the TgAb-positive sera. TgAb interference was characterized by higher Tg RIA vs. IMA values and was, in general, more frequent and severe in sera containing high TgAb concentrations. However, some sera displayed marked interference when serum TgAb was low (1-2 IU/mL), whereas other sera with very high TgAb values (>1000 IU/mL) displayed no interference. An agglutination method was found to be too insensitive to detect low TgAb concentrations (1-10 IU/mL) causing interference. Exogenous Tg recovery tests were an unreliable means for detecting TgAb interference. Specifically, the exogenous Tg recovered varied with the type and amount of Tg added and the duration of incubation employed. Further, recoveries of more than 80% were found for some sera displaying gross serum RIA/IMA discordances. The measurement of serum Tg in DTC patients with circulating TgAb is currently problematic. It is important to use a Tg method that provides measurements that are concordant with tumor status. IMA methods are prone to underestimate serum when TgAb is present, increasing the risk that persistent or metastatic DTC will be missed. The RIA method used in this study provided more clinically appropriate serum Tg values in the group of TgAb-positive patients with metastatic DTC. Furthermore, as serial serum TgAb measurements paralleled serial serum Tg RIA measurements, TgAb concentrations may be an additional clinically useful tumor marker parameter for following TgAb-positive patients. Disparities between serial serum Tg and TgAb measurements might alert the physician to the possibility of TgAb interference with the serum Tg measurement and prompt a more cautious use of such data for clinical decision-making.

Trismus. An unusual sign in polymyositis.

Neuromuscular disease is an unusual cause of trismus. However, we describe two patients with severe polymyositis who had difficulty opening their mouths during the acute phase of the illness. Electromyography demonstrated involvement of the masseters, and there was no evidence of myasthenia. The mechanism appeared to be decreased elasticity of the masseter because of inflammation, edema, and perhaps contractures.