Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children

We have prospectively studied the occurrence of monoclonal serum immunoglobulins in 38 recipients of BMT. Patients were young children with primary immunodeficiencies (n = 31), other inherited diseases (n = 4), leukemia (n = 2), or aplastic anemia (n = 1). Twenty-nine received an HLA-nonidentical marrow and nine an HLA-identical marrow. Serum monoclonal immunoglobulins were detected by the immunofixation method. Monoclonal immunoglobulins were found in 26 patients. Monoclonal components were more frequently detected in patients with primary severe T cell deficiencies (21/25) rather than in the other patients (6/13). In 7 of 29 recipients of HLA-nonidentical transplants, versus 0 out of 9 recipients of HLA-identical transplants, serum monoclonal immunoglobulins were found associated with a B lymphocyte proliferation syndrome due to an Epstein-Barr virus infection. In this group, monoclonal immunoglobulins were detected early, prior to the onset of the clinical syndrome. The simultaneous occurrence of several monoclonal immunoglobulins was more frequent in these patients, while monoclonal immunoglobulin concentrations increased faster, especially those of IgM isotype. These characteristics may allow in patients at risk (recipients with primary T cell immunodeficiencies and receiving HLA-nonidentical transplantation) an earlier diagnosis of B lymphocyte proliferative syndrome that may eventually lead to early and more efficient therapy.     

Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development.

Hodgkin disease (HD) is characterized by a small number of putative malignant cells [Hodgkin and Reed-Sternberg (HRS) cells] among a background of lymphocytes and histiocytes. The lineage of HRS cells is still elusive and a clonal origin of these rare cells has not formally been demonstrated. We isolated HRS cells by micromanipulation from histological sections of three cases of Hodgkin lymphoma (each representing a distinct subtype of the disease) and analyzed individual cells for immunoglobulin variable (V) gene rearrangements by PCR. In each of the three cases a single heavy-chain V (VH) (and in one case, in addition, a kappa light-chain) gene rearrangement was amplified from the HRS cells, identifying these cells as members of a single clone. A potentially functional VH rearrangement was obtained from a case of nodular sclerosis HD. Somatic mutations and intraclonal diversity in the VH genes indicate a germinal center B-cell origin of the HRS cells in a case of lymphocyte-predominant HD, whereas in a case of mixed-cellularity HD the sequence analysis revealed only nonfunctional V gene rearrangements, suggesting a pre-B-cell origin. This indicates that HRS cells can originate from B-lineage cells at various stages of development.     

Investigations of the acute toxic, cytogenetic, and embryotoxic activity of buminafos.

The organophosphorus herbicide buminafos (O,O-dibutyl-(1-butylaminocyclohexyl)-phosphonate) was tested for its acute toxic, cytogenetic, and embryotoxic activity on different strains of mice. The oral LD50 value for male NMRI mice was determined to be 3500 mg/kg. Single oral doses of 175, 1000, and 2000 mg/kg did not cause any significant enhancement in the percentage of chromosome aberrations in bone marrow cells of male NMRI mice. After oral administration of 500 and 1000 mg/kg buminafos to pregnant Halle:DBA and Halle:AB mice at Days 6-15 of gestation no embryotoxic effects were observed. The cytogenetic inactivity of buminafos in the bone marrow chromosome assay corresponds to negative findings in other mutagenicity tests.     

Conservatively Treated Breast Cancer: Outcome by Histologic Subtype

Abstract: Between 1970 and 1990, 1,008 patients with early-stage breast cancer were treated by conservative surgery without axillary dissection followed by radiation therapy to the intact breast in the Department of Therapeutic Radiology at Yale-New Haven Hospital. The patient population, broken down by histologic subtype, was as follows: 761 patients presented with infiltrating ductal carcinoma, 70 patients with pure intraductal, 38 intraductal with focal invasion, 54 infiltrating lobular, 21 tubular, 17 medullary, 16 mucinous, and 29 with other various histologic subtypes. Patients were followed on a regular basis by the referring physicians and radiation oncologists. Diagnostic studies for distant metastases were performed as clinically indicated. Annual mammography was a routine component of the follow-up program. As of 3/96, with a median follow-up of 10.5 years, 83 patients developed an ipsilateral breast tumor recurrence, and 109 patients developed distant metastases resulting in an overall 10-year breast recurrence-free rate of 84%, and a 10-year distant metastasis-free rate of 78%. There were significant differences in clinical stage, pathological nodal involvement, and administration of systemic therapy between various histologic subtypes. As expected, those patients with histologies of low metastatic potential (such as intraductal, tubular, and mucinous) had significantly superior distant recurrence-free survival rates. With respect to breast relapse rates, there were no statistically significant differences in the 5- and 10-year breast recurrence-free rates between any of the histologic subtypes. Patients with intraductal carcinoma with or without focal invasion had similar breast relapse rates as those with other histologic subtypes. Patients with lobular carcinoma in situ as a histologic component also had a similar overall breast relapse-free recurrence rate. In conclusion, long-term follow-up of conservatively treated breast cancer patients demonstrates no significant differences in ipsilateral breast tumor recurrence rates between various histologic subtypes. There are no histologies which had a statistically significantly higher breast-relapse rate than infiltrating ductal carcinomas and therefore no primary histologic subtype represents a relative contraindication to breast conservation therapy.     

Expression of S14-mRNA and its translational product in differentiating 3T3-L1 cells

During adipogenic conversion of 3T3-L1 cells S14-mRNA increased from undetectable levels in preadipocytes to high levels in differentiated adipocytes (adipocyte-like cells). In vitro translation of hybrid-selected S14-mRNA revealed an identical protein in 3T3-L1 adipocytes and in rat liver with regard to migration properties in two-dimensional gel electrophoresis. No translation product was found in 3T3-L1 preadipocytes. In conclusion, protein-S14 is very similar or even identical in rat lipogenic tissues and in 3T3-L1 adipocytes. Therefore, this cell line can be employed to elucidate further physiological aspects of protein-S14.     

Geographic patterns of urban trauma according to mechanism and severity of injury

The purpose of this study was to investigate the distribution of various mechanisms of injury and the relative severity of such injury cases throughout the different geographic zones of a large urban area using a computerized emergency medical services (EMS) dispatch/patient record database. The study city (population, 2 million residents) was divided into 156 geographic grids (each 4.5 by 3 miles) and the incidence and relative severity of various injury mechanisms were determined for each zone. Results: In one year (1988), there were more than 115,000 separate EMS incidents involving more than 150,000 patients, 26,000 of whom were transported for injuries incurred in 10,064 motor vehicle accidents, 4,587 falls, 4,015 lacerations/stabwounds, 1,796 beatings, 1,270 gunshots, and 952 auto-pedestrian accidents. Analysis of the 156 zones showed a disproportionate number of EMS responses in the city center with two centralmost grids accounting for about 25% of all responses. Call volume then progressively diminished toward the periphery of the city. However, with some very minor exceptions, the relative incidence and severity of the various injury mechanisms remained proportionally uniform within each zone, regardless of geographic location. Therefore, contrary to popular notoriety, the incidence and associated severity of any given injury type generally was not necessarily predicted by any particular neighborhood predilection for it, but rather by the overall demand for EMS in that zone of the city.     

Differential apoptotic response of J774 macrophages to alumina and ultra-high-molecular-weight polyethylene particles.

We recently identified apoptosis in in vitro wear particle-stimulated macrophages. The recent explosion of interest in apoptosis lies in the fact that it is under positive and negative regulation through evolutionary conserved biochemical pathways. It may also be possible to modulate macrophage apoptosis in the treatment of periprosthetic osteolysis. The purpose of this study was to compare the macrophage response to identically sized particles of alumina ceramic (Al2O3) and ultra-high-molecular-weight polyethylene (UHMWPE) in terms of TNF-alpha release and induction of apoptosis. J774 mouse macrophages were incubated for 0-24 h in the presence of Al2O3 and UHMWPE particles. TNF-alpha release was measured by ELISA; Poly(ADP-ribose)polymerase (PARP) and caspase-3 expression was analyzed by Western blot; DNA fragmentation (DNA laddering) was visualized on agarose gel containing ethidium bromide. Al2O3 particles induced TNF-alpha release after 4 h incubation with concentrations reaching 483 and 800 pg/ml after 24 h with 125 and 250 particles/macrophage, respectively (control = 161 pg/ml) (P < 0.05 vs. control). The same concentrations of UHMWPE particles induced a much larger and significant TNF-alpha release after only 1 h incubation, increasing up to 6250 pg/ml after 24 h (P < 0.05 vs. control). Western blot analysis demonstrated that the active caspase-3 fragment (17 kDa) and the proteolytic PARP fragment (85 kDa) were expressed after 2 h incubation with 125 and 250 Al2O3 particles/macrophage. The active caspase-3 and the PARP fragment had lower expression and appeared after a longer incubation time (8 h) with 125 and 250 UHMWPE particles/macrophage. Finally, DNA fragmentation (DNA laddering) was observed after 16 h with 125 and 250 particles of Al2O3 per macrophage whereas no laddering was induced by UHMWPE particles even after 24 h incubation. This study shows that although both Al2O3 and UHMWPE particles induce TNF-alpha release, this stimulation was much greater (8-10 times higher) with UHMWPE than Al2O3 (P < 0.05 vs. control). As well, the induction of apoptosis, as measured by activation of caspase-3, PARP cleavage and DNA laddering, is different for these two particles, being faster and more important with Al2O3 than UHMWPE. We hypothesize that the ability of Al2O3 to induce macrophage apoptosis may explain the lower TNF-alpha release observed with these particles and explain the differences seen in osteolysis patterns of ceramic-ceramic (CC) vs. metal-polyethylene (Mpe) articulations. In conclusion, apoptosis may be a major internal mechanism to decrease macrophage activity and may be a desired therapeutic endpoint. The identification of an apoptosis-related pathway in the macrophage response to ceramic particles provides crucial data for a rational approach in the treatment and/or prevention of periprosthetic osteolysis.