Biomedical subjects
Publications and source records attributed to M H Klein.
An atypical case of nonossifying fibroma involving the femoral neck of a 7-year-old white male is presented. The radiographic characteristics of the lesion were consistent with this diagnosis, although the location is rare. The differential diagnosis included fibrous dysplasia, unicameral bone cyst, chondroblastoma, and eosinophilic granuloma. A final diagnosis was obtained through tissue biopsy and histopathologic review.
Triggering of the T-cell receptor (TcR)alpha beta/CD3 receptor complex with anti-allotypic antibodies or concanavalin A (Con A) induced a rapid release of intracellular calcium in a murine T-cell hybridoma model system. Internal calcium release preceded the influx of extracellular calcium, as judged by comparative analysis of time-dependent changes in Quin 2 fluorescence following T-cell activation in the presence and absence of extracellular calcium. The magnitude of intracellular calcium release and extracellular calcium influx depended on the degree of receptor-occupancy and cross-linking. Correlations between the concentration of stimulating ligand, cytosolic calcium increase and IL-2 synthesis indicated a positive but non-linear relationship. Our data suggest that TcR cross-linking may provide a third T-cell activation signal which, in conjunction with protein kinase C activation and cytosolic calcium elevation, together form a signal triad responsible for interleukin-2 (IL-2) synthesis.
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Anemia is a well-defined complication of aluminum overload in chronic dialysis patients which may be present before other manifestations of aluminum toxicity are obvious. Causes of anemia in chronic renal failure are multiple, and at the present time there is no marker for aluminum-induced anemia. Deferoxamine (DFO) treatment can correct aluminum-related anemia and microcytosis, but may be associated with side effects. Because of the possible role of aluminum in red blood cells in causing the anemia associated with aluminum overload, we attempted to test red blood cell (RBC) aluminum as a marker for aluminum-associated anemia and to assess the prevalence of aluminum-associated anemia in an outpatient dialysis population. Both random plasma aluminum and RBC aluminum correlated well with the increase in plasma aluminum seen following DFO challenge. However, RBC aluminum was affected less by changes in oral aluminum intake than plasma aluminum. There were strong correlations of RBC and plasma aluminum to corpuscular volume (MCV) in our patients. Moreover, patients within the highest quartile of RBC aluminum had a lower mean MCV (82.1 +/- 1.7 vs 89.6 +/- 1.7, p less than .01) and hematocrit (HCT) (24.3 +/- 4 vs 28.2 +/- 1.5, p less than .05) than those within the lowest quartile. These data suggest that aluminum toxicity is an important cause of microcytic anemia in outpatient hemodialysis patients. Prospective long-term studies are needed to further define the usefulness of RBC aluminum in diagnosing and following hemodialysis patients with aluminum-induced anemia.
Previous in vitro and animal studies have suggested that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has important immunoregulatory properties. In this study, immune parameters were monitored in 16 patients the day before and 14 days after starting therapy with this hormone. Despite the absence of changes in the total white cell count, lymphocyte count and T lymphocyte count, CD4/CD8 ('helper/suppressor') ratio of T lymphocytes increased by 57% from the normal into the elevated range. Furthermore, a downward trend was seen in the percentage of stimulated lymphocytes expressing the interleukin-2 receptor. We conclude that in vivo administration of 1,25(OH)2D3 may have immunoregulatory effects in man. Whether these changes are the result of changes in intracellular or extracellular calcium concentration, parathyroid hormone concentration, or the concentration of 1,25(OH)2D3 itself remains to be answered.
This study examined a model specifying the causal links between the physical, functional, and subjective components of physical health status and life satisfaction among older women, and assessed the effects of three coping responses (direct-action, positive-cognitive, and passive-cognitive coping) at each point in the process. Based on interview data with 281 older women, a series of regression analyses indicated that, before the inclusion of the coping variables, physical conditions directly contributed to functional impairment, and both indirectly lowered life satisfaction through their direct negative effects on subjective health assessments. Further analyses indicated that positive-cognitive coping buffered the effects of physical conditions at each point in the model, that passive-cognitive coping generally had deleterious effects on health status, although it prevented negative health assessments from lowering life satisfaction, and that direct-action coping had little effect. These findings emphasize the importance of a multidimensional conceptualization of physical health status in understanding its relationship with life satisfaction as well as the specific functions of coping at different points in the process for older women.
As part of a prospective study in Toronto, Canada of male sexual contacts of men with either acquired immunodeficiency syndrome (AIDS) or an AIDS-related condition (primary cases), separate interviews were conducted in 1984-1985 with primary cases and their corresponding sexual contacts. Seventy-five primary cases and their corresponding sexual contacts were asked details concerning the sexual activities involved in their sexual encounters. Spearman correlation coefficients were calculated for the responses regarding frequency of various sexual activities between the primary case and his corresponding contact. Comparison of responses revealed good to excellent correlations for the majority of the sexual activities. Regression analysis of responses (dependent variable = contact's response; independent variable = primary's response) revealed the tendency for primary cases to report greater numbers of various activities than sexual contacts, as illustrated by regression coefficients that were consistently less than unity. Agreement between primary responses and sexual contact responses appeared to be affected by the time lapsed from the last sexual encounter with the contact and the date of the primary case's interview. No effect on agreement was observed when primary case diagnosis and the total number of other sexual partners of primary cases were considered. The authors conclude that such data can be captured with sufficient reliability and validity for use in epidemiologic investigations to assess the risk of acquisition of human immunodeficiency virus for the more common forms of sexual activity. However, some caution may be necessary in interpreting the results for some activities (anal digit insertion, anilingus) since agreement is less satisfactory for these activities.
A total of 246 healthy male sexual contacts of men with either acquired immunodeficiency syndrome (AIDS) or an AIDS-related condition were recruited into a prospective study in Toronto, Canada between July 1984 and July 1985. At induction, data were collected on the sexual relationship between the contact and his primary case, sexual activities with other men, history of sexually transmitted diseases and other diseases, and use of recreational drugs. At recruitment, 144 sexual contacts had antibodies to human immunodeficiency virus (HIV); 102 of the contacts were seronegative at induction and at three months following recruitment. No association between HIV seropositivity and total number of sexual partners could be demonstrated. In univariate and multivariate analyses, receptive and insertive anal intercourse with the primary cases, and activities which either indicated or potentially caused anorectal mucosal injury (rectal douching, perianal bleeding, receipt of objects in ano, and receptive fisting) were strongly associated with HIV seropositivity. In the final multiple logistic regression model, two significant interaction effects were observed: the interaction between receptive anal intercourse and insertive anal intercourse and that between receptive anal intercourse and the anorectal mucosal injury index. These two interaction terms had negative regression coefficients which suggested that change in one sexual activity would not decrementally reduce risk of HIV infection without a comparable modification in the other activity. No association could be demonstrated between oral-genital and oral-anal sexual contact and odds ratios for these sexual activities declined to levels below 1.0 when adjusted for frequency of receptive anal intercourse.
With H and L chains derived from the murine hybridoma and myeloma proteins NQ5-89.4, 93G7, AIDA10/3, AIDA10/16, HyHEL-10, HyHEL-9, HyHEL-8, HyHEL-5, XRPC25, J539, UPC10, 6684, and C101, the relationship between the relative affinity between H-L pairs, their antigen-binding characteristics, and the primary structure of their VH and VL domains was assessed. Using competitive chain reassociation assays in which two different L chains were allowed to compete for a limiting amount of an H chain, it was observed that different pairs of L chains tended to compete to the same degree regardless of which H chain was used as the limiting reagent and regardless of whether they were the autologous or heterologous L chain. In agreement with our previous results, it was also observed that when there was limited diversity between the Vk segments of the competing L chains, the relative competitive ability of an L chain was dictated by the nature of the first residue of the Jk segment, residue 96. However, when a high degree of diversity existed between the Vk segments of the competing L chains, the relative affinity was dictated by the V segment. It was further demonstrated that junctional diversity in the L chain may not necessarily be essential for antibody activity, determined using autologous and heterologous, noncovalently reassociated immunoglobulin molecules in antigen-binding assays. Combined with the results of the competitive reassociation assays, it was evident that no correlation between the competitive ability of these L chains existed or, by inference, the relative mutual affinity between different H-L pairs and their ability to form an antigen-binding site. These results were in agreement with the random rearrangement of VH and VL domain gene segments and argue against any restrictions in the expression of the full repertoire of immunoglobulin molecules due to combinatorial (H-L pairing) mechanisms.
The presumed antecedent infection which precedes Reiter's syndrome and reactive arthritis is frequently across a mucosal surface, and IgA immune responses may play a role in this process. Twelve of 29 patients with these conditions demonstrated elevation in serum IgA levels, and serum IgA levels in the postdysentery group (mean 3.21 g/liter +/- 1.27) were higher (P less than 0.01) than those in the posturethritis group (mean 2.40 g/liter +/- 0.80). In 10 of the 12 patients, IgA was the only immunoglobulin increased. There was no evidence of activation of complement in serum or synovial fluid. Using a complement-dependent assay, we were unable to demonstrate circulating IgA immune complexes. Sucrose density gradient ultracentrifugation analysis was used to assess IgA immune complexes in a non-complement-dependent manner. IgA of 11s was in fact demonstrated by this technique but appeared to be polymeric IgA on the basis of specific binding of secretory component and resistance to acid dissociation. IgA rheumatoid factor was not present. Synovial fluid revealed levels of polymeric IgA higher (mean 56.7% +/- 12.9) than did serum (23.7% +/- 13.9, P less than 0.001) despite higher levels of total IgA in serum than in synovial fluid (synovial fluid:serum ratio of IgA, mean 0.53 +/- 0.11). Although elevation in serum IgA in postdysenteric arthropathies suggests mucosal acquisition of antigen, the study does not implicate IgA circulating immune complexes in the pathogenesis of these diseases.
The nucleotide sequences of 27 T-cell receptor alpha-chain variable region (V alpha)-containing cDNA clones isolated from a cDNA library derived from human peripheral blood lymphocytes were determined. Eighteen different V alpha and 26 different joining (J alpha) gene segments are utilized in these clones. The V alpha gene segments belong to 12 different subfamilies, each containing from one to seven members. Comparisons with the 16 different V alpha and 21 different J alpha sequences previously reported suggest that the germ-line repertoires for these gene segments are greater than previously estimated. Flexibility in the sites of gene segment joining and possibly N-region diversification also contribute to human alpha-chain diversity. Comparisons of human V alpha regions indicate a high degree of variability spread uniformly across the entire V alpha region without obvious hypervariable regions. However, amino acids important for the maintenance of V gene structure are conserved.
The factors responsible for B cell regulation in stable renal transplant patients are unknown. To examine these control mechanisms, the B cell responses to 4 mitogens (pokeweed, wheat germ agglutinin, lipopolysaccharide, and SAC-1), which are known to stimulate B cells by different mechanisms, were measured in two groups of stable long-term (greater than 1 year post-transplant) renal transplant recipients. The first group were patients who had been transplanted under conditions of a negative crossmatch on all available pretransplant sera (negative crossmatch group) and the second group were patients who might have a unique regulation of B cell function in that they had been successfully transplanted under the conditions of a negative crossmatch using sera at the time of transplant but with pretransplant sera that gave a positive donor-specific T cell crossmatch (positive crossmatch group). Stable transplant patients were found to have significantly impaired responses to all four mitogens tested. Furthermore there were no differences in the responses of the negative crossmatch patients as compared with the positive crossmatch patients. The lack of response to mitogens was not due to a lack of proliferation of cells or to a loss of viability in culture. The number of cells in culture was the same in negative crossmatch patients and controls but was significantly less than controls in positive crossmatch patients (P less than 0.001). These findings suggest an intrinsic B cell defect in all stable transplant patients, and that the degree of the impaired B cell responses is the same in positive and negative crossmatch patients. In addition in positive crossmatch patients, there is a decrease in the percentage B cells that resulted after separation on a Ficoll-Paque gradient.
The Diagnostic Interview Schedule (DIS) was administered to 220 psychiatric patients by lay interviewers. Kappas for agreement between DIS and chart diagnoses ranged from .39 to -.03 and averaged .14 for 13 diagnostic categories. Agreement was best for affective, obsessive-compulsive, and schizophrenic disorders and was poorest for phobias where patients overemphasized fears. The authors suggest that clinician evaluation of information collected by the DIS is important, especially in diagnosing individual cases.
A group of 150 psychiatric patients were administered the Diagnostic Interview Schedule (DIS) on two occasions, once by a trained layperson and once using a computerized interview format in which the patient interacted directly with the computer. Agreement between the two methods on 15 diagnoses was relatively modest, as indicated by a mean kappa score of .51, but was similar to agreement rates reported in other studies of the DIS. The discrepancies may have been due to the high number of acutely ill inpatients studied, patients' reporting more symptoms in one of the interviews, and difficulty translating some of the DIS questions to the computer. Patients had positive feelings about both methods, but a significant majority liked the computer interview better and found it less embarrassing. The authors conclude that computerized administration of the DIS is as reliable as other methods but that exclusive reliance on the DIS for clinical diagnosis is inappropriate.
A computer interview program that uses a subjective Bayesian probability model to assess suicide risk was evaluated. Predictions made by clinicians for 52 patients were compared with predictions made by the computer for the same patients. The computer was significantly (p = .001) better at predicting attempters, and clinicians were significantly (p = .01) better at predicting nonattempters. An analysis of receiver operating characteristic curves showed that the computer had better overall discrimination, but the difference was nonsignificant.
Competitive reassociation experiments, in which equimolar amounts of two different L-chains were allowed to compete for a limiting amount of H-chain, were performed to assess the role of the V kappa- and J kappa-segments on the ability of an L-chain to compete. Using H- and L-chains from the murine anti-phosphorylcholine (PC) myelomas, TEPC15, MOPC167 and MCPC603, and a series of V kappa 21 L-chains, it was found that the V kappa 21 L-chains competed uniformly better than the anti-PC L-chains, when the anti-PC H-chains were used, despite any differences in the J-segments of the competing L-chains. In addition, when the anti-PC L-chains, which all employ identical J kappa-segments but very diverse V kappa-segments, were in competition against each other, a hierarchy of competitive ability existed which was independent of whether the chains were autologous or heterologous and independent of antigen binding activity. Competitive reassociation experiments between the V kappa 21 and anti-PC L-chains were also performed using the heterologous anti-lysozyme monoclonal HyHEL-10 H-chain or the anti-galactan J539 H-chain, and it was found that the relative competitive ability of the V kappa 21 L-chains with respect to the anti-PC L-chains was dependent on which H-chain was employed. The results suggested that the main factor favouring preferential reassociation by any particular L-chain was the V kappa-segment and that the effects of the J kappa-segment could not be observed where a high degree of diversity in the V-segments existed. Furthermore, while the results implied that specific pairs of VH- and VL-domains had a higher affinity for each other, this was not a necessary criterion in the formation of autologous pairs of H- and L-chains as demonstrated by the preferential heterologous reassociation of the V kappa 21 L-chains over the autologous anti-PC L-chains. These results were consistent with the independent, random rearrangement of immunoglobulin H- and L-chain V-domain gene segments and predict that the hypothetical repertoire of antibodies is not limited by the selection of specific pairs of high-affinity VH-VL domains.
The VL amino acid sequence of an anti-lysozyme hybridoma protein, HyHEL-5, was determined. HyHEL-5 expresses a V region of the VK4 family and JK1. The VK4 family also includes light chains from galactan binding antibodies, although sequence comparisons suggest that a different member of this family is used to encode HyHEL-5. The HyHEL-5 light chain has a deletion of residue 96, such that L3 is one residue shorter than the majority of murine L3. Chain recombination experiments, employing H and L chains from different anti-galactan and anti-lysozyme binding antibodies, were performed to examine the contribution of the H and L chain in dictating specificity for either galactan or the lysozyme epitope recognized by HyHEL-5. The results indicate that, although the ability to bind galactan vs lysozyme is absolutely heavy-chain dependent, having the appropriate heavy chain is not sufficient for specific high affinity binding. Both the L chains from HyHEL-5 and J539 (a galactan-binding myeloma protein) were capable of supporting binding to galactan in combination with the J539 H chain, but affinity for galactan is less with the HyHEL-5 L chain. Only VK4 L chains supported binding of the HyHEL-5 heavy chain to the HyHEL-5 epitope, although binding with the J539 L chain was low affinity and relatively nonspecific.
We evaluated 257 patients with rheumatoid arthritis (RA) to determine the frequency of circulating immune complexes (CIC) in the serum, relationships between the presence of CIC, clinical indices of disease activity and other laboratory features, and relationships between changes in CIC levels and changes in disease activity. CIC were detected by fluid phase Clq binding activity, conglutinin binding activity, anti-C3 assay, staphylococci protein A binding assay and the precipitation of cryoglobulins. CIC in the serum were found to correlate with indices of disease activity, extraarticular features and the presence of rheumatoid factor. A change in Clq binding activity correlated with a parallel change in the joint count.