Biomedical subjects
Publications and source records attributed to D Gillis.
Rituximab is a chimeric monoclonal antibody specific for human CD20 that causes selective transient depletion of the CD20+ B-cell subpopulation. We report the first case of systemic lupus erythematosus (SLE) pneumonitis resistant to conventional treatments that responded well to rituximab and review current reports on the use of rituximab in SLE.
Radiocontrast media (RCM) is used commonly in clinical practice, and can be associated with significant adverse effects. We report a patient who experienced severe anaphylaxis after being given multiple drugs. Challenge testing established allergy to both RCM and ceftriaxone. Premedication did not prevent recurrence of anaphylaxis on repeat challenge with RCM. The haemodynamic and serum tryptase consequences of the challenges are discussed, and a summary of RCM allergy is provided.
Aspirin-sensitive asthma is a common and often underdiagnosed disease affecting up to 20% of the adult asthmatic population. It is associated with more severe asthma, requires increased use of inhaled and oral corticosteroids, more presentations to hospital and a risk of life-threatening reactions with aspirin/non-steroid anti-inflammatory drug (NSAID) ingestion. Aspirin-sensitive asthma is often accompanied by severe rhinosinusitis and recurrent nasal polyposis, causing significant impairment of patients' quality of life. The pathogenesis of aspirin-sensitive asthma is complex and involves chronic eosinophilic inflammatory changes, with evidence of increased mast cell activation. The cyclo-oxygenase pathways play a major role in the respiratory reactions that develop after aspirin ingestion. The cysteinyl-leukotrienes have also been shown to play a role in the pathogenesis of aspirin-sensitive asthma. The clinical management of aspirin-sensitive asthma is complicated by the lack of diagnostic testing, other than challenge procedures. Other aspects of management include management of the underlying asthma and avoidance of NSAID in the majority of patients. Other considerations in the management of patients with aspirin-sensitive asthma include the role of leukotriene modifying agents, aspirin desensitization, and the use of other agents, such as roxithromycin. The management of nasal polyposis in patients with aspirin-sensitive asthma often needs to be considered as a separate issue, and requires a team approach.
An examination of the prevalence and phenotype of immune disorders in different ethnic groups may provide important clues to the etiopathogenesis of these disorders. Whilst still conjectural the restricted and somewhat unique polymorphisms of the MHC (and other genetic loci involving host defences) of the Australian Aborigines may provide an explanation for their apparent heightened susceptibility to newly encountered infections and their resistance to many (auto) immune and allergic disorders. In comparison with non-Aboriginal Australians, Australian Aborigines have heightened frequencies of rheumatic fever, systemic lupus erythematosus, various infections and post-streptococcal glomerulonephritis. In contrast various autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis, CREST, biliary cirrhosis, coeliac disease, pernicious anaemia, vitiligo), B27 related arthropathies, psoriasis, lymphoproliferative disorders and atopic disorders appear infrequent or absent. Similarly various autoantibodies occur with increased or diminished frequency. With continuing racial admixture, social deprivation and deleterious lifestyles of these people it is likely that further changes in both the frequencies and phenotype of these immune disorders will occur. It is only with a full understanding of the pathogenic mechanisms involved in these immune disorders that meaningful and clinical relevant interventions will be possible.
AIM: To establish a method suitable for diagnostic genotyping of CYP2D6 alleles by DNA sequencing. METHODS: Initial PCR reactions were performed to specifically amplify exons 3, 4, 5 and 6 of the CYP2D6 gene using primers previously published. New primers were used to identify *2, *3, *4, *6, *7, *8, *9 and *41 in 2 sequencing reactions. Additional primers were designed for reverse sequencing in samples with 1 or 3 b.p. deletions. Previously published assays were used to detect *5, *10 and *16 alleles to complete genotype assignment. RESULTS: We reliably detected the nonfunctional alleles, *3, *4, *6, *7 and *8, which are associated with the poor metabolizer phenotype, and 2 important alleles associated with decreased enzyme activity, *9 and *41. Observed allele frequencies were comparable to those found previously in Caucasian populations. CONCLUSION: CYP2D6 genotype has been shown in previous clinical studies to be a good predictor of CYP2D6 phenotype and, therefore, related to therapeutic response and the risk of drug toxicity. This genotyping method is simple and reliable, and, therefore, can be routinely performed on an isolated patient sample, providing a relatively quick turnaround time needed for clinical practice. In addition, the simultaneous drawing of blood with the commencement of drug therapy will allow dosage adjustment on the basis of the CYP2D6 genotype to reduce the risk of adverse drug reactions.
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The successful completion of puberty is a pre-requisite for reproduction. Therefore, the gynecologist, who deals daily with reproductive issues, should have a basic knowledge of puberty and the pathology associated with it. The understanding of the basic biological processes involved in pubertal development has advanced considerably in recent years. Also, changes in the timing of normal puberty and modern treatment for pubertal disorders have altered the clinical approach to these problems. In this review we discuss some of the basic science and clinical advances in this field and present the state of the art approach as we see it today.
The Na+/H+ exchanger (NHE) becomes activated by hyperosmolar stress, thereby contributing to cell volume regulation. The signaling pathway(s) responsible for the shrinkage-induced activation of NHE, however, remain unknown. A family of mitogen-activated protein kinases (MAPK), encompassing p42/p44 Erk, p38 MAPK and SAPK, has been implicated in a variety of cellular responses to changes in osmolarity. We therefore investigated whether these kinases similarly signal the hyperosmotic activation of NHE. The time course and osmolyte concentration dependence of hypertonic activation of NHE and of the three sub-families of MAPK were compared in U937 cells. The temporal course and dependence on osmolarity of Erk and p38 MAPK activation were found to be similar to that of NHE stimulation. However, while pretreatment of U937 cells with the kinase inhibitors PD98059 and SB203580 abrogated the osmotic activation of Erk and p38 MAPK, respectively, it did not prevent the associated stimulation of NHE. Thus, Erk1/2 and/or p38 MAPK are unlikely to mediate the osmotic regulation of NHE. The kinetics of NHE activation by hyperosmolarity appeared to precede SAPK activation. In addition, hyperosmotic activation of NHE persisted in mouse embryonic fibroblasts lacking SEK1/MKK4, an upstream activator of SAPK. Moreover, shrinkage-induced activation of NHE still occurred in COS-7 cells that were transiently transfected with a dominant-negative form of SEK1/MKK4 (SEK1/MKK4-A/L) that is expected to inhibit other isoforms of SEK as well. Together, these results demonstrate that the stimulation of NHE and the activation of Erk, p38 MAPK and SAPK are parallel but independent events.
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PURPOSE: To evaluate effectively interventions to increase physical activity among older persons, reliable and valid measures of physical activity are required that can also detect the expected types of physical activity changes in this population. This paper describes a self-report physical activity questionnaire for older men and women, developed to evaluate the outcomes of the Community Healthy Activities Model Program for Seniors (CHAMPS), an intervention to increase physical activity. METHODS: The questionnaire assesses weekly frequency and duration of various physical activities typically undertaken by older adults. We estimated caloric expenditure/wk expended in physical activity and created a summary frequency/wk measure. We calculated measures of each of these for: 1) activities of at least moderate intensity (MET value >/= 3.0); and 2) all specified physical activities, including those of light intensity. Six-month stability was estimated on participants not likely to change (assessment-only control group, physically active cohort). Several tests of construct validity were conducted, and sensitivity to change was analyzed based on response to the CHAMPS intervention. RESULTS: The sample (N = 249) comprised underactive persons (N = 173 from the CHAMPS trial) and active persons (N = 76). The sample was aged 65-90 yr (mean = 74, SD = 6); 64% were women, and 9% were minorities. Six-month stability ranged from 0.58 to 0.67, using intraclass correlation coefficients. Nearly all construct validity hypotheses were confirmed, though correlations were modest. All measures were sensitive to change (P < or = 0.01), with small to moderate effect sizes (0.38-0.64). CONCLUSIONS: The CHAMPS measure may be useful for evaluating the effectiveness of programs aimed at increasing levels of physical activity in older adults.
Four children with familial short stature were diagnosed with celiac disease (CD) by positive serology for antigliadin and antiendomysial antibodies and characteristic intestinal biopsy findings. These patients complied well with their diet as evidenced by their parents' reports, increase in weight standard deviation scores in all but one child, and reversion to seronegativity for antigliadin and antiendomysial antibodies in all four. However, typical catch-up for linear growth did not occur. In our view, the poor response of linear growth is evidence that the original stunting was not due to CD. Since the advent of sensitive tests for antiendomysial antibodies, many asymptomatic children have been diagnosed as having CD. Some of these children are short and despite a history of familial short stature their growth stunting may be wrongly attributed to CD. This report highlights this new problem and emphasizes the need for caution when predicting growth response to a gluten-free diet.
It is often difficult to assess small bowel recovery in adults with coeliac disease on a gluten-free diet (GFD). This prospective study compares changes in intestinal permeability with changes in intestinal biopsy at various intervals after commencing a GFD. Intestinal permeability was measured by lactulose/rhamnose absorption from 1 week to 24 months after commencing a GFD. Intestinal morphometry was measured by villus area, crypt length and mitotic count per crypt at diagnosis and after commencing a GFD. Median intestinal permeability values decreased from 0.47 (n = 35) at diagnosis to 0.25 (n = 17) after 1 week and to 0.16 (n = 18) after 2 months of a GFD. Rhamnose absorption improved significantly at an early stage, from 6.6% (untreated) to 15.4% at 3 months of a GFD, whereas the decrease in lactulose permeation took longer: from 3.4% (untreated) to 0.8% after 12 months of a GFD. Mean villus area (n = 29) was reduced to 16% of control values at diagnosis, and improved to a maximum of 48% after 6 months on a GFD, but did not change thereafter. Mean crypt length and mitotic count per crypt were increased by 222% and 356% respectively at diagnosis, and these parameters remained elevated at 172% and 216% above control values after 6 months of a GFD. We conclude that intestinal permeability improves within 2 months after starting a GFD, but that measurable intestinal biopsy improvement requires ingestion of a GFD for at least 3-6 months, and even then remains incomplete.
We compared cost-benefit and cost-effectiveness analyses of hepatitis A prevention with immune serum globulin (ISG) vs inactivated hepatitis A vaccine (iHAV) in the Israel Defence Forces. Personnel were grouped according to conditions and duration of service and analyses were performed based on maximum and minimum hepatitis A projected incidences for each group. For standing army soldiers in field units, iHAV is economically superior compared with ISG. For the five other groups studied, the reverse is true. Expected increases in production costs of ISG and expected decreases in costs of iHAV are likely to make iHAV more economical in the future.
During the 50's and 60's there were large scale epidemics of hepatitis A every 3-4 years in the Israel Defense Forces. During these epidemics the annual incidence exceeded 10/1000 soldiers at risk. There has been a highly significant decrease in rates during the past 30 years. The average annual incidence of clinically identified viral hepatitis A decreased from an average of 6/1000 during the 60's to 2.5/1000 during the 70's. The decrease coincided with the introduction in the 1970's of wide-scale post-exposure prophylaxis with immune serum globulin (ISG). The incidence was further significantly reduced to 0.5-1.0/1000 with the introduction of pre-exposure prophylaxis with ISG, starting in 1978 (p < 0.001). Other factors probably played a role in accelerating the decline in morbidity, such as improvement in personal hygiene and sanitation facilities, and in waste disposal and other aspects of military environmental health. These improvements were probably more pronounced in the civilian sector, leading to decreased exposure of children to the virus and consequently a higher proportion of seronegatives at induction. Increase in the proportion of recruits without natural immunity to the virus poses greater risk, both in terms of personal morbidity as well as military operational ability. This risk, combined with problems of ISG use and availability, has propelled hepatitis A prevention policy towards the use of the new inactivated vaccines.
We describe an 8 year-old girl with established diabetes insipidus who developed cyclophosphamide-associated antidiuresis. The patient had received cyclophosphamide as part of a high-dose chemotherapy regimen for recurrent suprasellar dysgerminoma prior to autologous bone marrow transplantation. Urinary output decreased and specific gravity increased shortly after a 1 hour i.v. infusion of 50 mg/kg cyclophosphamide and the effect lasted some 5 hours. No other drug could be implicated. This response, occurring in a patient with no ability to secrete vasopressin, suggests a direct tubular effect of one or more cyclophosphamide metabolites. Administering i.v. cyclophosphamide requires careful monitoring of fluid balance in order to avoid water intoxication. Further research is warranted both into the mechanism of this effect and the metabolite responsible for it.
OBJECTIVE: We evaluated the clinical relevance and pathogenic significance of anti-salivary duct autoantibodies (ASDA) in Sjögren's syndrome (SS) and rheumatoid arthritis (RA) by examining (1) their frequency in healthy controls, patients with sicca symptoms, and patients with various autoimmune and infective disorders; (2) their localization by confocal microscopy; and (3) their tissue distribution and cross reactivity with blood group antigens. METHODS: Indirect immunofluorescence (IF) was performed on commercial cryostat sections of monkey parotid salivary gland. Sections were examined by fluorescence and confocal laser scanning microscopy. Sera giving positive staining on the ducts were tested by IF on a range of monkey tissues and salivary glands from several mammalian species. Blocking experiments were performed with human erythrocytes of different ABO blood groups and AB antigens. RESULTS: We identified 2 distinct ductal staining patterns. The first resembled ASDA described in earlier studies and showed patchy bright staining of the apical (luminal) surfaces of the ducts and staining of apical cytoplasmic vesicles. The other was only observed with anti-mitochondrial antibody positive sera and stained the mitochondrial-rich ductal epithelium in a distinctive punctate pattern. Antibodies staining the apical surface of ducts were detected rarely in patients with antiRo/La autoantibody-positive primary SS (1/76) and RA (1/36) and were found in only 1115 with RA and secondary SS. ASDA were detected in sera from 13/51 (25.5%) of patients referred to our clinic with limited sicca symptoms who were anti-Ro/La antibody-negative and had no typical clinical or laboratory features of classical primary SS. The apical ductal staining pattern was not observed with sera from 63 healthy controls without sicca symptoms or in patients with autoimmune and infective disorders. Twelve of the 13 patients whose sera gave ASDA-like staining were blood group O and one group A. Ductal staining was abolished in all sera after absorption with blood group AB erythrocytes or AB antigen. In 5 patients ductal staining was removed by absorption with B erythrocytes but not with A erythrocytes; in the remainder ductal reactivity was abolished by both A and B erythrocytes. CONCLUSION: ASDA seem to occur rarely in patients with primary SS and RA. However, isotype-switched IgG AB blood group antibodies cross react with primate salivary ducts and may produce false positive ASDA staining. Detection of ASDA may be of value in identifying a subset of patients who present with mild sicca symptoms without other autoimmune features.
Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.
BACKGROUND: Anticardiolipin antibodies (aCL) are associated with accelerated coronary atherosclerosis. Beta2-glycoprotein 1 is a cofactor necessary for the binding of aCL. AIM: The aim of this study was to determine whether antibodies to beta2-glycoprotein 1 (anti-beta2GP1) predispose to coronary artery disease (CAD), and whether the measurement of anti-beta2GP1 will be more useful than aCL alone in the evaluation of coronary risk. METHODS: Persons who had undergone coronary angiography were invited to participate, and risk factors for coronary atherosclerosis recorded. IgG aCL and anti-beta2GP1 were measured and fasting triglyceride (TG) and total cholesterol (TC) levels were determined. Angiographic score (AS) was defined as the number of diseased vessels (0, 1, 2, 3), (>50% stenosis). Ethics Committee approval was obtained. Statistical comparison used the Student's t test and Chi-squared test. RESULTS: Ninety-seven subjects (63 male) with age range 38-81 years (mean 66.0) participated. There were 31 subjects with AS=0, 27 with AS=1, 22 with AS=2, and 17 with AS=3. The three subjects with positive aCL all had CAD, as did three of the four subjects with positive anti-beta2GP1. Among patients with CAD, there was an equal incidence (4.5%, three/66) of aCL and anti-beta2GP1, and an incidence of either aCL or anti-beta2GP1 of 7.6% (five/66). Compared to the group with AS=0, those with AS=1, 2 or 3 comprised a higher mean age (p=0.001) however, there was no significant difference in the prevalence of other coronary risk factors between the two groups. There was no difference in the proportions of patients with either aCL or anti-beta2GP1 in the group with AS=1, 2, or 3, compared to the group with AS=0 (5/66 c.f. 1/31, chi2=0.146, p>0.5). CONCLUSIONS: Our study has not supported an association between anti-beta2GP1 and CAD. The measurement of anti-beta2GP1 (or aCL) in the investigation of premature CAD is not justified on the basis of our results.