Biomedical subjects
David Sinclair
Publications and source records attributed to David Sinclair.
Deleterious pleiotropic effects of the atypical aldehyde dehydrogenase 2 (ALDH2) allele: comment on Luo et al., 2005.
Luo [Biochem. Genet. 43:223-227] concluded, "The mutation ALDH2(() 487Lys allele is not deleterious but is of great benefit to human health." This statement is easily subject to misinterpretation and needs to be clarified. Their results actually show there is a pleiotropic effect associated with the mutation ALDH2(() 487Lys allele that is as deleterious as the risk of alcoholism for which it offers protection, and thus there is no net benefit from having the mutation. A clarification is needed because this statement and others in the paper might be used inappropriately as an endorsement of practices that are in fact worthless, because it masks the need to find what the pleiotropic effect is, and because it seems to contradict what otherwise seems to be a general rule of evolution.
Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users.
Buprenorphine (Subutex) is widely abused in Finland. A combination of buprenorphine plus naloxone (Suboxone) has been available since late 2004, permitting a comparison of the abuse of the two products among untreated intravenous (IV) users. A survey was distributed to attendees at a Helsinki needle exchange program over 2-weeks in April, 2005, At least 30% were returned anonymously. Survey variables included: years of prior IV opioid abuse, years of buprenorphine abuse, frequency, dosage, route of administration and reasons for use, concomitant IV abuse of other substances and amount paid on the street for both buprenorphine and buprenorphine+naloxone. Buprenorphine was the most frequently used IV drug for 73% of the respondents. More than 75% said they used IV buprenorphine to self-treat addiction or withdrawal. Most (68%) had tried the buprenorphine+naloxone combination IV, but 80% said they had a "bad" experience. Its street price was less than half that of buprenorphine alone. The buprenorphine+naloxone combination appears to be a feasible tool, along with easier access to addiction treatment, for decreasing IV abuse of buprenorphine.
Clinical and laboratory aspects of thyroid autoantibodies.
This review describes the aetiology of the major thyroid antigens. Iodination of thyroglobulin produces multiple antigen configurations which are functionally active but immunologically distinct. The thyroid stimulating hormone (TSH) receptor is a two-subunit glycoprotein; the extracellular A subunit is recognized by thyroid stimulating antibodies, while those antibodies recognizing the B subunit, located much nearer the cell surface, appear to function as blocking antibodies. Thyroid peroxidase (TPO), originally described as thyroid microsomal antigen, is present on the apical surface of thyroid follicular cells and is the antigen involved in cell-mediated cytotoxicity. Multiple B-cell-reactive epitopes exist, each giving rise to different antibodies. The aetiology and mechanics of the autoimmune cellular and antibody responses involves a combination of human leucocyte antigen (HLA) linkage, genetics and environmental factors to determine the initial and subsequent stages of the development of autoimmune thyroid disease. Depending on the antibody, a combination of enzyme-linked immunosorbent assay for TPO and thyroglobulin and bioassays and/or radioimmunoassay for TSH receptor antibodies are used to estimate their concentrations. The other conditions with which autoimmune thyroid diseases are associated include, for example, pernicious anaemia, connective tissue disorders, diabetes, coeliac disease, mood disorders like depression and fertility-related problems such as miscarriage, infertility, in vitro fertilization failure, pre-term delivery and postpartum thyroiditis. Often, there is no cause-and-effect relationship between them and it is debatable in some cases whether it is worthwhile monitoring patients with autoimmune thyroid disease for other conditions or vice versa. The review also itemizes the circumstances in which it might be useful to measure each antibody (i.e. the use of TPO antibodies in investigation of goitre, diagnosis of Graves' and Hashimoto's disease and the prediction of risk of developing hypothyroidism during subclinical thyroid disease; TSH receptor antibodies in maternal and neonatal hyperthyroidism and thyroglobulin antibodies in the monitoring and treatment of thyroid carcinoma). Finally, taking the current literature into account, an algorithm is recommended for the most effective use of these antibodies in the investigation of autoimmune thyroid disease.
Pneumocystis carinii pneumonia infection in a patient with known chronic mucocutaneous candidiasis.
Chronic mucocutaneous candidiasis is a disorder of the skin, nails or mucous membranes in the absence of another cause of the infection. It is also associated with autoimmune endocrinopathies in 40% of patients. It is thought to be due to a T-cell defect, although no precise mechanism has been elucidated. There have been two previous cases of Pneumocystis carinii pneumonia reported with this condition. We report a fatal case in a 34-year-old male.
In vitro allergy investigation: Does a multiple allergen testing system give useful information?
INTRODUCTION: The Hitachi CLA allergy test gives individual results on a wide range of common allergens. This study looked at the effect on patient management of the extra information gleaned from the use of this test compared to the same patient being investigated under a protocol of a total IgE and 4 allergen specific IgE tests using the Pharmacia UNICAP system. DESIGN, SETTING AND PATIENTS: Fifty-four patients who presented to our Dermatology Department with possible Type I hypersensitivity: 19 males (10 were <16 years); 36 females (12 were <16 years). Our standard investigative protocol using the Pharmacia UNICAP was applied to all samples; each was also tested using the Hitachi CLA system and the two sets of data compared. RESULTS: The CLA system identified 22/54 patients in which one or more potentially significant allergens were found that would not have been identified by our current system of total IgE plus 4 allergen specific IgE results. Multiple positive allergens were detected by the CLA system in 13/54 cases. 12/54 patients had no allergen that was positive CLA and the UNICAP. 3/54 had positive results using our Pharmacia-based protocol that were not available by use of the extended panel. 4/54 patients had profiles in which both systems offered differing clinically useful information. CONCLUSION: These data support the use of a multiple allergen testing system to identify potentially significant individual allergens, patients in whom a Type I allergic reaction is unlikely or patients with multiple positive results for whom allergen avoidance is unlikely to be effective.
Complementing the patient: a complement component deficiency in a patient with recurrent infections and glomerulonephritis.
We present a case showing the investigation of a 7-year-old girl with empyema and glomerulonephritis whose "immunological" defect was a single complement component (C2) deficiency which prevented her from activating her classical complement pathway. A defect in complement function should be suspected in any patient with severe or recurring pyogenic infections. Investigations of "? immune deficiency" should always include tests to assess the patency of the patient's complement system.
Role of the N-terminal region of Rap1p in the transcriptional activation of glycolytic genes in Saccharomyces cerevisiae.
In the yeast two-hybrid system, the N-terminal region of Rap1p was shown to interact with Gcr1p and Gcr2p. Disruption of gcr1 and/or gcr2 in the two-hybrid reporter strain demonstrated that the interaction with Gcr1p does not require Gcr2p, whereas the interaction with Gcr2p is mediated through Gcr1p. Deletion of the N-terminal region of Rap1p alone did not show a growth phenotype, but a growth defect was observed when this mutation was combined with a gcr2 deletion. The poor growth of the gcr1 null mutant was not affected further by the N-terminal deletion of Rap1p, but the growth of gcr1 strains with mutations in the DNA binding region of Gcr1p was affected by the removal of the N-terminal region of Rap1p. These results suggest that one function of the N-terminal region of Rap1p, presumably the BRCT domain, is to facilitate the binding of Gcr1p to the promoter by a protein-protein interaction.
Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
Survival of AA and ANA rats during lifelong ethanol exposure.
BACKGROUND: Study of the long-term effects of chronic alcohol consumption in human populations is confounded by genetic and environmental factors. METHODS: The study was intended to investigate the effects on morbidity and survival of lifetime forced ethanol consumption in male and female AA (Alko, Alcohol) and ANA (Alko, Non-Alcohol) rats. The ethanol-exposed rats had 12% ethanol as the only available fluid from 3 to 24 months of age. The control groups had water. Rats that died during the experiment and those that were killed at 24 months of age were all autopsied, and the pathologic findings were recorded. RESULTS: Lifelong ethanol consumption did not change the survival rate of the rats, and had no significant effect on the rates of any of the pathologic measures in either the AA or ANA line of rats, suggesting that this may not be a good animal model for studying the detrimental effects of chronic alcohol. An unexpected, highly significant finding was observed: the AA rats, bred for high voluntary ethanol drinking, lived much longer than the ANA rats, bred for ethanol avoidance. The death rate by 24 months in the AA line was less than one-third of that in the ANA line. This difference was found regardless of whether the animals were maintained on alcohol or water, and in both genders. The AA rats had significantly lower rates of kidney disease, benign tumors, and cardiovascular disease than the ANA animals. CONCLUSIONS: Lifelong ethanol consumption increased neither the mortality nor the morbidity of AA and ANA line of rats. Genes selected in the development of the high drinking AA line have additional effects producing rats that are healthier and living longer than the ANA rats possessing genes resulting in alcohol avoidance.
Spurious hyperphosphataemia caused by an IgA paraprotein: a topic revisited.
BACKGROUND: There are reports in the literature describing artefactually raised phosphate concentrations in serum samples of patients with myeloma. However, IgA paraproteins have been reported only rarely as a potential cause. METHODS: Following the detection of a grossly elevated phosphate concentration in a patient with an IgA paraprotein and another with an IgG paraprotein, we estimated phosphate concentrations in a further 73 patients with paraproteins using the Bayer ADVIA 1650 and Ortho Vitros 950 analysers. The latter method has been reported to be unaffected by pseudohyperphosphataemia. RESULTS: Deproteinization of the serum samples containing the IgA and IgG paraproteins showed that they were responsible for the interference. No significant difference in serum phosphate concentrations measured by the two analysers was noted for the larger study of serum IgG or IgM paraproteins. However, a statistically significant but clinically trivial difference in phosphate concentration was noted for serum IgA paraproteins, with the Ortho Vitros 950 giving slightly higher phosphate concentrations. Deproteinization of these samples yielded similar phosphate concentrations. Phosphate estimation in serum samples without paraproteins using both analysers yielded results that were not statistically different. CONCLUSION: On occasion, serum samples containing IgA paraproteins may give rise to erroneous phosphate concentrations when the Bayer ADVIA is used
Antibodies to thyroid peroxidase (TPOAb) in serum from patients with slightly raised thyrotropin (TSH) levels.
Assessment of thyroid antibody status can influence the decision to commence thyroxine replacement in patients with persistent marginally raised TSH concentrations. We studied 211 patients in whom we had reported a slightly raised TSH on two or more occasions. The most recent result was accompanied by a suggestion to repeat the TSH estimation and request thyroid antibodies. Although we received follow-up specimens on 59% of the audit sample, antibodies were requested on only 37%. However, a majority (62%) of those specimens showed a raised antibody concentration and this appeared to influence the decision to start thyroxine replacement. Our data suggest that it would be more effective if laboratory staff were to request thyroid antibodies on specimens from patients with persistently raised TSH concentrations and to comment further on the significance of the result.
Is DNA cut out for a long life?
Much attention has been focused on the DNA repair hypothesis of aging. Studies in mammals that seek to test the validity of this model are complicated by both the functional redundancy and the essential nature of genes involved in the repair process. Compared to mammals, the study of DNA repair and aging in yeast has considerably fewer complicating factors. In this Perspective, I discuss results presented in this month's issue of Aging Cell that address whether the types of DNA damage repaired by the base excision repair pathway cause aging in yeast.
Why do general practitioners request rheumatoid factor? A study of symptoms, requesting patterns and patient outcome.
BACKGROUND: To investigate the reasons why general practitioners (GPs) request rheumatoid factor (RF) assays, we studied 200 consecutive requests for RF from general practice in 1995. METHOD: By means of an audit questionnaire, we studied 100 negative, 50 positive and 50 borderline RF results and compared these with the presenting symptoms that prompted the request, the GPs' understanding of the significance of the result, the referral intention and behaviour of the GP, and finally, the patient outcome after 5 years. RESULTS: There was an 80% response rate. The presenting symptoms closely matched the American Rheumatism Association revised criteria for the classification of rheumatoid arthritis, indicating that the requests were made on valid clinical grounds, with polyarthralgia, morning stiffness and joint pain being the most common. Most GPs considered a negative or positive result to be meaningful, in that a positive RF meant that a referral was more likely than with a negative or borderline result, even in the presence of appropriate symptoms in all three groups. Seventeen to thirty per cent felt that the test excluded or confirmed RA. The result appeared to influence this decision to a greater extent than it should. A 5-year follow-up on these patients showed that 26/40 patients with positive RF were referred, and that 25 of them developed a rheumatic disease of some kind, with 17 patients eventually being diagnosed with RA. Only 17/80 patients with negative RF were referred, the remainder having no autoimmune problem evident after 5 years, 11 of them developing a rheumatic disease, and only three being diagnosed with RA. CONCLUSIONS: Although this is a locally based study, we believe the conclusions would be applicable to all laboratories and GPs undertaking these tests. RF requests are made on valid clinical grounds by GPs, but there may be an over-reliance on the results as regards referral behaviour. If patients were referred on clinical grounds, this would significantly lengthen consultants' waiting lists.
A comparative study of tissue transglutaminase antibodies and endomysium antibody immunofluorescence in routine clinical laboratory practice.
BACKGROUND: The demand for screening for coeliac disease has grown rapidly over the last few years. Laboratories depending on immunofluorescence assays are faced with an increasing workload using a labour-intensive test, and an alternative to this test has been sought. This study compares tissue transglutaminase (TTG) and endomysium antibodies (EMA) in a routine clinical laboratory situation. METHODS: An immunofluorescence IgA EMA test was compared with a guinea pig TTG antibody ELISA for 816 unselected requests for gut antibody screening. Discrepant results were investigated more fully using a variety of human source TTG antigen kits. RESULTS: Guinea pig TTG ELISA and EMA assays showed agreement for 93.6% of samples. Four samples were misclassified and 48 samples gave false positive TTG results. Study of 46 EMA samples (this group included 39 of the 'discrepant' negative EMA/positive guinea pig TTG group) using three different human purified and/or recombinant TTG sources showed that 42 patients had no TTG antibodies using human sources, three were misclassified and one patient had negative EMA and positive TTG results that could not be readily explained. Further study of 32 EMA positive samples showed almost complete agreement between the human source TTG kits. CONCLUSIONS: We can recommend the replacement of EMA with ELISA for TTG antibodies for the routine screening for coeliac disease, but all positive TTG antibodies should still be followed up with IgA EMA and samples should be screened for IgA deficiency.
Stridor: unusual presentation of multiple myeloma.
We present a patient with multiple myeloma whose only presenting symptom was stridor caused by a subglottic stenosis. Biopsy suggested the presence of amyloid which prompted immunological investigations that showed hypogammaglobulinaemia and the presence of Bence Jones proteinuria at 0.93 g/24 hours. Further investigation demonstrated a 15 per cent plasma cell infiltrate into the bone marrow and a lytic lesion in the mid-shaft of the right femur. Chemotherapy and localized radiotherapy were commenced. This is a most unusual presentation of multiple myeloma and shows that immunoglobulin profiles should be properly investigated in such cases.