Biomedical subjects
Publications and source records attributed to D Schatz.
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The long asymptomatic period before the onset of chronic diseases offers good opportunities for disease prevention. Indeed, many chronic diseases may be preventable by avoiding those factors that trigger the disease process (primary prevention) or by use of therapy that modulates the disease process before the onset of clinical symptoms (secondary prevention). Accurate prediction is vital for disease prevention so that therapy can be given to those individuals who are most likely to develop the disease. The utility of predictive markers is dependent on three parameters, which must be carefully assessed: sensitivity, specificity and positive predictive value. Specificity is important if a biomarker is to be used to identify individuals either for counseling or for preventive therapy. However, a reciprocal relationship exists between sensitivity and specificity. Thus, successful biomarkers will be highly specific without sacrificing sensitivity. Unfortunately, biomarkers with ideal specificity and sensitivity are difficult to find for many diseases. One potential solution is to use the combinatorial power of a large number of biomarkers, each of which alone may not offer satisfactory specificity and sensitivity. Recent technological advances in genetics, genomics, proteomics, and bioinformatics offer a great opportunity for biomarker discovery. The newly identified biomarkers have the potential to bring increased accuracy in disease diagnosis and classification, as well as therapeutic monitoring. In this review, we will use type 1 diabetes (T1D) as an example, when appropriate, to discuss pertinent issues related to high throughput biomarker discovery.
The pathogenic mechanisms underlying Batten disease are unclear. Patients uniformly possess autoantibodies against glutamic acid decarboxylase (GAD) that are predominantly reactive with a region of GAD (amino acids 1 to 20) distinct from subjects with autoimmune type 1 diabetes or stiff-person syndrome. Batten patients did not possess autoantibodies against other type 1 diabetes-associated autoantigens and human leukocyte antigen genotypes revealed no specific associations with this disease.
Two toxic, microcystin-producing, Microcystis sp. strains KLL MG-K and KLL MB-K were isolated as single colonies on agar plates from Lake Kinneret, Israel. Two non-toxic subcultures, MG-J and MB-J spontaneously succeeded the toxic ones under laboratory conditions. Southern analyses showed that MG-J and MB-J are lacking at least 34 kb of the mcy region, encoding the microcystin synthetase. Analyses of the 16S rRNA genes, the intergenic spacer region between cpcB and cpcA and the patterns of the polymerase chain reaction products of randomly amplified polymorphic DNA and highly iterated palindrome, and presence of mobile DNA elements did not allow unequivocal distinction between toxic and non-toxic subcultures. Laboratory and field experiments indicated an advantage of the toxic strain over its non-toxic successor. When grown separated by a membrane, which allowed passage of the media but not the cells, MG-K severely inhibited the growth of MG-J. Furthermore, when MG strains were placed in dialysis bags in Lake Kinneret during the season in which Microcystis is often observed, cells of MG-J lysed, whereas MG-K survived. Mechanisms whereby the non-toxic subcultures emerged and prevailed over the corresponding toxic ones under laboratory conditions, as well as a possible role of microcystin under natural conditions, are discussed.
AIMS/HYPOTHESIS: Immunological and genetic markers can be used to assess risk of developing type 1 diabetes prior to the onset of clinical symptoms. Autoantibody-positive relatives of patients with type 1 diabetes are at increased risk for disease, while the presence of HLA DQA1*0102/DQB1*0602 is thought to confer protection. Using the unique population identified by the Diabetes Prevention Trial--Type Diabetes (DPT-1), our aim was to determine if these individuals were protected from type 1 diabetes. METHODS: We described metabolic and immunological characteristics of islet cell cytoplasmic autoantibodies-positive relatives with DQB1*0602 identified as part of DPT-1. RESULTS: We found that 32% of DQB1*0602-positive relatives identified through the DPT-1 had abnormalities of glucose tolerance despite the fact that only 19% had multiple type 1 diabetes-associated autoantibodies and only 13% had abnormal insulin secretion, markers typically associated with the disease. In addition, these markers were not associated with abnormal glucose tolerance. In contrast, the DQB1*0602-positive relatives had elevated fasting insulin (117+/-10 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (4.90+/-0.5) values, which are more commonly associated with type 2 diabetes. The later marker of insulin resistance was associated with glucose tolerance status. CONCLUSIONS/INTERPRETATION: Our data indicate that DQA1*0102/DQB1*0602 relatives identified through DPT-1 have a high frequency of abnormal glucose tolerance and a disease phenotype with characteristics of type 1 and type 2 diabetes. Thus, multiple pathways to abnormal glucose tolerance are present within families of these type 1 patients.
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METHODS: We examined monocyte prostaglandin synthase 2 (PGS2/COX2) expression in individuals at risk for or with type 1 diabetes including: (i) 58 established type 1 and 2 diabetic patients; (ii) 34 autoantibody positive (AA+) children and adults; (iii) 164 infants and young children with insulin-dependent diabetes mellitus (IDDM) susceptibility human leukocyte antigen (HLA) alleles; and (iv) 37 healthy control individuals, over a 5-yr period. RESULTS: Established type 1 diabetic patients (1 month to 30+ yr post-disease onset) had significantly higher PGS2 expression than healthy controls; by contrast, insulin-treated type 2 diabetic patients had significantly lower PGS2 expression than healthy controls. Longitudinal studies of AA+ subjects at risk for type 1 diabetes indicated that 73% (11/15) of individuals who developed this disease during the study period expressed high levels of PGS2 prior to or after onset. We also found high level PGS2 expression in genetically at-risk infants and young children that correlated with having a first-degree relative with type 1 diabetes, but not with age, gender, or HLA genotype. In this population, high level PGS2 expression coincided with or preceded autoantibody detection in 30% (3/10) of subjects. CONCLUSIONS: These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.
Type 1 (insulin-dependent) diabetes is one of the most costly chronic diseases of children and adolescents in North America and Europe. It occurs in genetically predisposed individuals when the immune system attacks and destroys specifically the insulin-producing beta cells of the pancreatic islets of Langerhans. Although routine insulin injections can provide diabetic patients their daily insulin requirements, non-compliance commonly results in blood glucose excursions that eventually lead to microvascular and macrovascular complications and early death. The only real 'cure' for type 1 diabetes is replacement of the beta-cell mass which, today, is either an ectopancreatic transplant or an islet of Langerhans implant. Two new developments may offer additional options: surrogate, non-endocrine cells genetically modified to secrete insulin in response to high blood glucose levels; and stem cells that possess the capacity to differentiate to endocrine pancreas. In this short review, we discuss the efforts currently being made to regulate pancreatic stem cell growth in order to produce large numbers of functional islets that can be used as implants. Hopefully, autologous stem cell-derived islet cell implants without lifelong immunosuppressive therapy may one day be realized.
305 extracted human front teeth and premolars were investigated for their dynamic resistance to fracture. Morphological factors, such as the anatomical class of tooth and root lengths, and patho-anatomical factors, such as infractions, occlusal and cervical abrasions, composite and amalgam restorations and damage resulting from previous traumatic impacts, were taken into consideration. A comparison of stability after a defined impact stress showed that maxillary canines and premolars had the highest resistance to fracture; this differs significantly from the resistance of maxillary and mandibular incisors. The root length correlates directly with fracture energy and therefore to stability. Composite restorations with an adhesive joint were found to increase the resistance of a tooth to fracture, but amalgam restorations had a weakening effect. Cervical wedge-shaped defects of the tooth cause considerable destabilization, but occlusal abrasion and infractions have only a moderate weakening influence. Previous traumatic stress reduces the resistance to fracture of a tooth by up to 85%. The fracture patterns generated were very similar to clinically observed tooth fractures, indicating the results to be clinically relevant.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by flare-ups, the cause of which is unknown. According to new stress concepts, two "integrative single-case studies" have been conducted in order to gather evidence about whether daily stressful incidents and associated emotions interfere with the dynamics of urine cortisol and urine neopterin in SLE. Patients under study collected their urine at home, for a period of at least 50 days, on a daily basis, divided into day and night urine. Additionally, patients filled out questionnaires twice a day to determine their emotional state, life style and disease activity. Each week, patients were examined clinically and interviewed to identify the past week's stressors using the Incidents and Hassles Inventory (IHI, Brown and Harris). Statistical analysis of the serial data was performed using time-series analysis according to Box and Jenkins. In both "integrative single-case studies" we were able to demonstrate that stressful incidents predicted an increase in urine neopterin 36 hours (Case 1) to 60 hours (Case 2) later (p < 0.05). Additionally, in Case 1 the neopterin levels were highly associated with stress resulting from the weekly examinations and interviews. Furthermore, in Case 2 it turned out that depending on their predictability stressful incidents were preceded by a decrease in urine cortisol 12 hours earlier or were followed by a decrease in urine cortisol 36 hours later. And finally, emotional irritation was highly correlated with the course of urine-neopterin. In Case 2 irritation led to an increase in urine neopterin 84 hours later. There were no clinical signs of SLE during both prospective studies. In conclusion, our results validate the idea of "integrative single-case studies" as a new "bio-psycho-social" approach in psychoneuroimmunology. Further studies with SLE patients as well as with healthy probands will be necessary in order to both strengthen and generalize these results.
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Large-scale programs designed to assess risk for type 1 diabetes through serologic assessment of autoantibodies to recombinant beta-cell autoantigens are hampered by several limitations, including the methods for sample collection and assay performance, as well as the volume required for autoantibody determinations. The present study was designed to develop a low sample-volume, primary screening method for autoantibody detection of high specificity and sensitivity, and to determine the feasibility of dried blood spots collected on filter paper in serving as vehicles for such determinations. Autoantibodies to glutamic acid decarboxylase (GAD) and ICA512bdc (IA-2), both individually and in combination, were determined in persons with type 1 diabetes, healthy controls, or individuals with other autoimmune disorders. Autoantibody results for serum, plasma, and dried blood spots were compared. GAD, IA-2, and combined GAD/IA-2 autoantibodies were concordant in their measurement from minimal volumes of serum, plasma, and whole blood extracted from dried filter paper. The autoantibody levels from the dried blood spots were, however, lower than corresponding serum samples, and, as currently designed, failed to detect low-titer autoantibodies. Despite this limitation, screening for diabetes risk can be performed using small volumes of whole blood, serum, or plasma collected onto filter paper. These methodological improvements should simplify matters, reduce costs, and increase the efficacy of screening programs for type 1 diabetes. Further development of better substrates/methods for blood-specimen collection seems necessary to exploit the full potential of this and other autoantibody measurement strategies for screening large populations.
BACKGROUND: Previous studies reported an association between maternal psychological factors and adverse pregnancy outcomes. The objective of this study was to evaluate the relationships between maternal personality characteristics, as determined by the Minnesota Multiphasic Personality Inventory (MMPI), and infant birth outcomes and development. METHOD: The inventory was administered during pregnancy to 638 pregnant women enrolled in a staff model health maintenance organization. MMPI validity as well as clinical and research scales were evaluated in relationship to infant birth outcomes (low birthweight, preterm birth) and 15-month-old infant development as assessed by the Bayley Scales of Infant Development. RESULTS: Mothers of low birthweight infants scored significantly lower on the hypochondriasis scale, a relationship which was no longer significant after controlling for ethnicity. No other relationships were observed between infant birth outcomes and maternal MMPI scale scores. A higher infant Mental Developmental Index (MDI) was related to higher maternal masculinity-femininity and ego-strength scale scores and lower lie and hypochondriasis scale scores. Only the relationship between infant MDI and maternal masculinity-femininity scale score remained significant after controlling for ethnicity and socioeconomic index (beta = 0.104, p = 0.036). CONCLUSIONS: Maternal personality characteristics, as determined by the MMPI, did not appear to be significantly related to the occurrence of preterm birth or low birthweight in this healthy, general population. Maternal personality characteristics reflected in the MMPI masculinity-femininity scale appeared to be related to infant mental development, above and beyond the effects of socioeconomic status and ethnicity.
We report here our prospective study of 15,224 non-diabetic, first-degree relatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined islet cell, insulin, GAD65, insulinoma-associated antigen-2 and 2beta autoantibodies (ICA, IAA, GAD65A, IA-2A and IA-2betaA), on the first available serum samples. The latter three autoantibodies were however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relatives who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of diabetes was however negligible when ICA was found in the absence of the others (5-year risk=5.3%), but increased dramatically whenever two or more autoantibodies were present (5-year risk=28.2% and 66.2%, respectively). The most predictive combination of markers was ICA plus IA-2A and/or IA-2beta A. Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant beta-cell damage is seen only when the underlying autoimmunity has spread to multiple antigenic islet cell determinants. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relatives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the prevention of type 1 diabetes could be designed based on testing for these autoantibodies alone, without the need for HLA typing and IVGTT testing.
Prostaglandins (PGs) are lipid molecules that profoundly affect cellular processes including inflammation and immune response. Pathways contributing to PG output are highly regulated in antigen-presenting cells such as macrophages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expression of the normally inducible cyclooxygenase PG synthase 2 (PGS(2)/ COX-2) in nonactivated monocytes of humans with insulin-dependent diabetes mellitus (IDDM) and those with islet autoantibodies at increased risk of developing this disease. Constitutive PGS(2) appears to characterize a high risk for diabetes as it correlates with and predicts a low first-phase insulin response in autoantibody-positive subjects. Abnormal PGS(2) expression in at-risk subjects affected immune response in vitro, as the presence of a specific PGS(2) inhibitor, NS398, significantly increased IL-2 receptor alpha-chain (CD25) expression on phytohemagglutinin-stimulated T cells. The effect of PGS(2) on CD25 expression was most profound in subjects expressing both DR04 and DQbeta0302 high-risk alleles, suggesting that this cyclooxygenase interacts with diabetes-associated MHC class II antigens to limit T-cell activation. These results indicate that constitutive PGS(2) expression in monocytes defines an antigen-presenting cell defect affecting immune response, and that this expression is a novel cell-associated risk marker for IDDM.
Investigations of humans and nonobese diabetic mice suggest that proinsulin and/or a fragment of the region spanning C-peptide and the B-chain of insulin (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we analyzed cellular immune reactivities against these molecules in people with or at varying risks for the disease to clarify their role in the pathogenesis of IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were determined in 60 individuals with newly diagnosed IDDM (< or = 1 day from diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody-negative first-degree relatives of the IDDM subjects, and in 28 autoantibody-negative control subjects. Unlike previous reports suggesting diabetes-associated elevations in cellular immunity to other beta-cell antigens (e.g., GAD, IA-2, etc.), we observed equivalent levels of phytohemaglutinin stimulation and cellular proliferation in all groups against these antigens (all P values were not significant). The mean stimulation index +/- SD and frequency of reactivity to proinsulin for healthy control subjects and IDDM patients, respectively, were as follows: 1 microg/ml (1.5 +/- 1.0, 1 out of 17 [6%]; 1.9 +/- 1.4, 4 out of 33 [12%]); 10 microg/ml (1.7 +/- 1.3, 1 out of 17 [6%]; 1.2 +/- 0.6, 0 out of 28 [0%]); and 50 microg/ml (1.2 +/- 0.6, 1 out of 16 [6%]; 1.1 +/- 0.6, 1 out of 27 [4%]). The response in healthy control subjects, autoantibody-negative relatives, and IDDM patients, respectively, against the proinsulin peptide fragment were as follows: 1 microg/ml (0.9 +/- 0.4, 1 out of 12 [8%]; 1.3 +/- 1.1, 4 out of 34 [11%]; 1.1 +/- 0.3, 2 out of 28 [7%]); 10 microg/ml (0.9 +/- 0.6, 1 out of 12 [8%]; 1.2 +/- 0.6, 3 out of 34 [9%] 1.4 +/- 1.7, 2 out of 28 [7%]); and 50 microg/ml (1.0 +/- 0.7, 1 out of 12 [8%]; 1.2 +/- 0.5, 2 out of 34 [6%]; 1.3 +/- 0.5, 2 out of 28 [7%]). Taken together with previous studies reporting relatively infrequent occurrences of autoantibodies to proinsulin, the role of immunity to this molecule in the pathogenesis of IDDM in humans remains unclear.
Cyanobacteria possess an inducible mechanism which enables them to concentrate inorganic carbon (Ci) within the cells. An inactivation library was used to raise the high-CO2-requiring mutant of Synechococcus PCC 7942, IL-2, impaired in HCO3- transport. Analysis of the relevant genomic DNA detected several modifications, probably due to the single crossover recombination, leading to inactivation of ORF467 (designated ictB) in IL-2. IctB contains 10 trans-membrane regions and is homologous to several transport-related proteins from various organisms. Kinetic analyses of HCO3- uptake in the wild type and IL-2 suggested the presence of two or three HCO3- carriers exhibiting different affinities to HCO3-.
The period of efficacious immune reactivity afforded by tetanus immunization and the need for continuing some forms of tetanus vaccination programs have been the subjects of recent debates. Our studies demonstrate that the level of antitetanus immunity based on immunological memory (i.e., cellular immune responsiveness) varies dramatically as a function of age, with older individuals constituting a population which is increasingly susceptible to tetanus infection.