"Evidence-based" or "logic-based" medicine?

Low trauma fractures are the cardinal manifestation of osteoporosis. Their occurrence supersedes bone mineral density in deciding whether specific therapy is warranted. We therefore disagree with the notion that a densitometric threshold for treatment should be applied to patients over age 50 who suffer low trauma distal radius fracture.

Enhanced prediction of fracture risk combining vertebral fracture status and BMD.

UNLABELLED: Prevalent vertebral fractures are associated with increased fracture risk, but the magnitude of this effect across a range of BMD T-scores has not been quantified. In this analysis, for any given BMD T-score, incident fracture risk varied up to twelve fold when information regarding prevalent radiographic vertebral fracture status was considered. BACKGROUND: Clinical fracture risk evaluation of older women usually includes assessment of bone mineral density (BMD) but often not vertebral fracture status. In this analysis, we quantified the impact of vertebral fracture burden on two year fracture risk across a range of BMD T-scores. METHODS: Data were from 2,651 postmenopausal women who were assigned to the placebo groups of the Fracture Prevention Trial (median observation 21 months) and the Multiple Outcomes of Raloxifene Evaluation Trial (MORE; observation 2 years). Using the Genant visual semiquantitative criteria, we defined prevalent vertebral fracture status as: a) presence or absence of fracture; b) fracture number; c) maximum semi-quantitative (SQ) score (normal=0, mild fracture=1, moderate fracture=2, severe fracture=3); and d) spinal deformity index (SDI) score (sum of SQ scores of T4 to L4 vertebrae). Incident fractures over two years were identified via lateral spine radiographs and outside the spine by questioning of patients and review of radiographs or radiographic reports. RESULTS: Femoral neck BMD T-score provided significant information regarding fracture risk. Across the range of T-scores, vertebral fracture status provided additional prognostic information. The risk increased with increasing number and severity of prevalent vertebral fractures and SDI, a summary measure of spine fracture burden. Across a range of BMD values, prevalent spine fracture burden as assessed by SDI increased the risk of incident vertebral fractures by up to 12-fold, nonvertebral fractures by about twofold, and any fractures by up to sevenfold. CONCLUSIONS: These findings indicate that at any given BMD T-score, the risk of incident vertebral, non-vertebral, and any fracture depended heavily on prevalent radiographic vertebral fracture status. Assessment of vertebral fracture status, in addition to BMD, provides practical and relevant clinical information to aid in predicting fracture risk in postmenopausal women.

Polyspecific reactivity of a murine monoclonal antibody that binds to nuclear matrix-associated, chromatin-bound autoantigens.

To investigate polyspecific autoantibody interactions, we have characterized the binding of a cloned murine monoclonal IgM antibody termed (RTE-23) of strain BALB/c origin. By indirect immunofluorescence this antibody displayed a nuclear speckled and peripheral pattern in interphase cells from human and rodent cell lines. In contrast, in mitotic cells, antibody RTE-23 bound to the periphery of individual chromosomes. Immunoblot analysis of soluble and insoluble nuclear proteins from purified rat fibroblast nuclei showed that antibody RTE-23 bound to molecules of 28, 29, and 33 kDa. Furthermore, antibody RTE-23 demonstrated marked polyspecificity and reacted with cytoskeletal proteins (vimentin, keratin, actin), single-stranded DNA, specific synthetic polynucleotides, and cardiolipin. Antibody RTE-23 also showed a lupus anticoagulant-like activity. Screening of sera of autoimmune disease patients with antinuclear antibodies revealed two patients, both with SLE, whose sera blocked antibody RTE-23 binding to nuclei and recognized nuclear proteins identical to those recognized by antibody RTE-23. These results suggested that antibody RTE-23 displays a pattern of self-antigen binding that is represented as well in SLE patient sera.

Characterization of a monoclonal antibody, RTE-21, that binds to keratohyalin granule-associated proteins in epithelial cells of human skin and thymus.

The role of skin and thymic epithelium in the promotion of T-cell activation and maturation is currently an area of great interest. In thymus, epithelium is located in the cortex, medulla, and in medullary epithelial swirls called Hassall's bodies. During studies of antigens shared by skin and thymic epithelial cells, we produced a murine monoclonal antibody (RTE-21) raised against the rat thymic epithelial cell line, IT26R21, that identified an antigen present in terminally differentiated epithelium of normal human skin and thymus. In indirect immunofluorescence studies, antibody RTE-21 identified cytoplasmic granules located in the stratum granulosum of normal human skin, Hassall's bodies of human thymus, and in a subset of cells of the IT26R21 rat thymic epithelial cell line. Moreover, the granular reactivity pattern of antibody RTE-21 in the stratum granulosum could be extracted by 1 M potassium phosphate (1 M KPO4). A 1 M KPO4 extract of epidermis containing keratohyalin granule proteins was dialyzed against distilled water, solubilized in reduced sample buffer and subjected to polyacrylamide gel electrophoresis and Western immunoblot analysis. In this assay, antibody RTE-21 recognized proteins of 70, 36, 34, and 30 kDa. Using antibody RTE-21 and indirect immunofluorescence, we demonstrated that keratohyalin granules in human thymus were localized exclusively to Hassall's bodies. These data support the notion that human thymic Hassall's bodies result from terminal differentiation of medullary thymic epithelium. Thus, antibody RTE-21 should be an important probe for the study of skin and thymic epithelial cell maturation in vitro and in vivo.

The human thymic microenvironment: thymic epithelium contains specific keratins associated with early and late stages of epidermal keratinocyte maturation.

Normal T-cell development is dependent on interactions with the thymic microenvironment; thymic epithelial cells are thought to play a key role in the induction of thymocyte maturation, both through direct contact and, indirectly, via thymic hormone secretion. It has been postulated that thymic epithelial cells progress through an antigenically defined pathway of differentiation similar to that of epidermal keratinocytes. As keratins vary according to epithelial cell type and the stage of epithelial cell maturation, we used a panel of monoclonal antibodies against keratins to study specific types of keratin intermediate filaments within human thymic epithelium. The demonstration in human thymus of keratins previously shown to be associated with distinct stages of epidermal keratinocytic maturation would support the hypothesis that thymic epithelial cells undergo sequential stages of differentiation. Two-dimensional immunoblot analysis of cytoskeletal extracts from human thymus revealed that thymic epithelium contains the following keratins: 1-2, 5, 6, 7, 8, 10, 13, 14, 15, 16, and 17 (molecular masses, 65-67, 58, 56, 54, 52, 56.5, 51, 50, 50', 48, and 46 kilodaltons, respectively). Thus, in thymic epithelium, we found keratins previously observed in epidermal basal cells (5, 14, 15), as well as keratins specific for terminally differentiated keratinocytes in supra-basal epidermis (1-2, 10). Indirect immunofluorescence (IF) performed on fetal and postnatal human thymus demonstrated that keratin epitopes recognized by antibodies AE-3, 35 beta H11, and RTE-23 are present on epithelial cells of the subcapsular cortex, the cortex, the medulla, and Hassall's bodies. In contrast, antibodies AE-1 and RTE-22 reacted primarily with neuroendocrine thymic epithelium (subcapsular cortex, medulla, Hassall's bodies). The epithelial reactivity of antibody AE-2 was limited to epithelial cells in Hassall's bodies and did not appear until 16 weeks of fetal gestation i.e., when Hassall's bodies first formed. Two-dimensional gel analysis of thymic keratins demonstrated that antibody AE-2 identified only the keratins with molecular masses of 56.6 and 65-67 kilodaltons (10 and 1-2 respectively) in thymus. These data, together with the selective reactivity of AE-2 with Hassall's bodies in fluorescence assays, demonstrate the localization in Hassall's bodies of the high-molecular-weight keratins associated with the late stages of epidermal cell maturation. In summary, we demonstrated that human thymic epithelium contains specific keratins found in multiple epithelial types as well as keratins associated with both early and late stages of epidermal cell differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibody against T lymphoblastic leukemia-associated antigen (3-40) identifies vimentin and keratin intermediate filaments in normal cells.

Antibody 3-40 defines a 35- to 40-kd surface antigen present on T lymphoblastic leukemia (T-ALL) cells that is absent on normal hematopoietic cells (Naito et al, Blood 62:852, 1983). Using immunoblot analysis of cytoskeletal proteins and indirect immunofluorescence of cell lines treated with various cytoskeletal inhibitors, in this report we have demonstrated that antibody 3-40 also identifies vimentin intermediate filaments (IMF) within the HSB-2 (T-ALL) cell line as well as in normal thymocytes, peripheral blood mononuclear cells, and human and rodent fibroblast cell lines. Cross-reactivity with several keratin subclasses was demonstrated in both human and rodent epithelial cell lines, human thymus, and skin. In addition, we have shown that antibody 3-40 defined a 39-kd intracellular IMF-associated protein in HSB-2 cells, epithelial and fibroblast cell lines. This IMF-associated protein may be selectively expressed on the surface of human T cells during malignant transformation.

Group B streptococcal arthritis in adults.

Group B beta-hemolytic streptococci (Streptococcus agalactiae) have been a rare cause of septic arthritis in adults. Only 18 cases have been cited in the literature, eight of which were described since 1976. Two additional cases occurring in the last year are described herein. Like other infections caused by group B streptococci, the incidence of septic arthritis due to these organisms appears to be increasing. A review of these 20 cases revealed a history of prior arthritis or trauma to the involved joints in 30 percent, and an additional 30 percent occurred in potentially immunocompromised hosts. Four of the patients had probable oligoarticular group B streptococcal arthritis. Although most deaths occurred in the pre-penicillin era, early recognition and treatment are essential to prevent joint destruction.

Genetic factors predisposing to chronic lymphocytic leukemia and to autoimmune disease.

Among 320 relatives of 28 patients with chronic lymphocytic leukemia (CLL), 4 had CLL, 1 had lymphosarcoma, and 2 other adults had leukemia of unknown type. Autoimmune disease including hyperthyroidism, pernicious anemia, rheumatoid arthritis and systemic lupus erythematosus affected 18 relatives. HLA typing of members of two families demonstrated that within each family the patient with CLL shared a common haplotype with relatives with autoimmune disease, but the haplotype was different in the two kindreds. In contrast, CLL was encountered in only 1 and autoimmune disease in 4 of 396 relatives of a group of 28 control patients. These data together with information from earlier reports support the hypothesis that genetic factors distrubing the regulation of the immune system may predispose both to lymphoid neoplasms and to autoimmune disease. The concept is supported by an array of experimental studies in animals.