Increased synthesis of extracellular spleen glycosaminoglycans in an experimental myeloproliferative syndrome.

The changes occurring in the hematopoietic extracellular matrix in an experimental myeloproliferative syndrome were explored by comparing the glycosaminoglycan (GAG) composition of normal mouse spleens and spleens infected with myeloproliferative sarcoma virus (MPSV). Large quantities of hyaluronate and of sulfated GAGs accumulated in the extracellular matrix of infected spleens, as shown by histoimmunoassay and alcian blue staining, respectively. The splenic GAGs were either labeled with 35S-sulfate injected in vivo or unlabeled. The spleens were fractionated to separate hematopoietic cells from the stromal component containing extracellular matrix material and fibroblasts, and the GAGs were extracted from each fraction. Specific degradative treatments and electrophoresis indicated that sulfated GAGs were mostly chondroitin sulfate and heparan sulfate. Three hours after in vivo injection of 35S-sulfate, the amount of 35S-GAGs was increased approximately fivefold per mg stromal proteins. The bulk of these 35S-GAGs (70%) was recovered in the stromal fraction. The higher amount of sulfated GAGs in leukemic spleen was due both to the presence of more producer cells (infected fibroblasts and hematopoietic cells) and to a stimulation of GAG synthesis per cell, as evidenced 35S-labeling in in vitro experiments. Chondroitin sulfate was the main sulfated GAG present in the culture medium of both hematopoietic and fibroblastic cells and in the pericellular material released by trypsin from fibroblastic cells. High amounts of chondroitin sulfate, which has a possible role in the detachment of hematopoietic cells from the stromal cells, may favour the release of hematopoietic cells from the spleen into the peripheral blood. Heparan sulfate was produced by fibroblastic cells and it was principally present in their pericellular material. Considering the capacity of heparan sulfate to retain cytokines, as demonstrated by others in vitro, large amounts of heparan sulfate may result in the retention of large amounts of the cytokines, which production is enhanced in the infected spleen. This phenomenon may contribute to promote the hematopoietic stem cell proliferation characteristic of the MPSV-induced myeloproliferative disease.     

Oro-facial diagnosis of battered children (Silverman syndrome). Management

In France, 6 children on 1,000 are abused or neglected. The orofacial lesions are most often evocatives, but the diagnosis is sometimes delicate. The laws and the deontologic code are not precise concerning the attitude of the dentist facing a Silverman syndrome. In U.S.A., 8% of all dentists responding saw suspected cases of child abuse. We have not such statistics in France. The structures of protection and taking in care seems to be unknown of our collegues.     

Cardiac membrane cholesterol in dystrophic and verapamil-treated hamsters

Cardiac muscle degeneration features prominently in the pathology of the dystrophic hamster. Since cholesterol is important in maintaining membrane integrity cholesterol and cholesterol ester levels were examined in cardiac subcelullar fractions of the UMX-7.1 strain of dystrophic hamster. In 50-day-old dystrophic animals cardiac microsomal fractions contained 135 ± 18 μg cholesterol per mg protein compared to control levels of 49 ± 8 μg/mg. The cholesterol content in the mitochondrial fraction was 65 ± 5 μg/mg and 17 ± 3 μg/mg respectively. In 180-day-old animals similar differences in cholesterol content were observed. Esterified cholesterol was elevated in the microsomal and mitochondrial fractions but only at 180 days. Pretreatment of dystrophic hamsters for 20 days with verapamil, a drug which has been shown to prevent cardiac necrosis in dystrophic hamsters did not alter the cholesterol content of the subellular fractions.     

Treatment of leukemias and lymphomas with interferons: I. Trial of myeloma therapy with human beta-interferon

Eighteen patients with malignant gammapathies (16 with myeloma and 2 with Waldenstr?m's disease) for a short time because in a phase II-I trial were treated with human (IF beta) given i. v. 6 X 10(6) units weekly (7 patients) or 3 X 10(6) units twice weekly (11 patients) during at least 3 months if tolerated. Treatment was discontinued because of side-effects in three patients. Reduction of the M component of at least 25% from the initial value was obtained in 3 patients. In one case, was also observed in disappearance of the urinary Bence-Jones protein, in 4 cases a significant reduction of bone marrow infiltration by plasma cells and, in 5 cases, major alleviation or disappearance of bone pain. Length of treatment seems an important factor for activity. Immune monitoring with currently available tests, mainly NK cell activity, yielded no correlation with therapeutic effect in these patients. This very preliminary study demonstrates the effect of fibroblastic interferon in myeloma, but further studies are mandatory to determine the population of patients likely to benefit from treatment, the best modalities, possible special indication, dose schedule and duration of treatment. Interferon, however, already appears in this population of patients as giving results similar to those of single agent chemotherapy. As it is not myelosuppressive, it could be indicated in that frequent situation of advanced myeloma with bone marrow failure contra-indicating combination chemotherapy.     

Media conditioned by human leukemic T-cells induce expression of IL2 receptors and proliferation of normal T lymphocytes

Peripheral blood T-colony-forming cells (T-CFC) from patients with T-cell acute lymphoblastic leukemias (T-ALL) and T-cell non-Hodgkin lymphomas (T-NHL) can generate colonies in methylcellulose in the absence of added growth factors and/or mitogenic stimulation. In the present study, we show that media conditioned (LCM) by unstimulated mononuclear cells (MNC) from these patients can induce proliferation (proliferating inducing activity; PIA) and promote colony growth (T-cell colony promoting activity; T-CPA) of normal T lymphocytes in the absence of any other mitogenic stimulation. Preincubation of normal E+ lymphocytes with some TCPA+, PIA(-)-LCM for 48 hr leads to IL2-induced cell proliferation in the absence of any other stimulation. Moreover, staining of the cells with anti-Tac monoclonal antibody (Mab) reveal 9%-26% Tac+ cells. Both PIA and IL2 receptor-inducing activities were abrogated by treatment of LCM with proteolytic enzymes or by heating at 47 degrees C for 30 min. Modulation of the T3 molecule by OKT3 MAb on normal E+ cells did not abrogate the capacity of LCM to induce expression of IL2-receptors, suggesting that this activity was not mediated by triggering the Ti-T3 molecular complex. These activities were detected in media conditioned by both unfractionated MNC and blast-enriched cell fractions, and their production required DNA and RNA synthesis by actively dividing cells. Taken together, these findings indicate that human leukemic T cells spontaneously release activities which can activate normal resting T lymphocytes.     

Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia

Summary Endocrine functions were examined in 21 patients with mitochondrial myopathies presenting with chronic progressive external ophthalmoplegia and other additional neurological and multisystemic symptoms. Ten patients had the features of the Kearns-Sayre syndrome. Deletions of the mitochondrial DNA were found in 4 out of 5 patients examined. Fourteen patients, including 3 with deletions of the mitochondrial DNA, had various and often multiple endocrine abnormalities: 6 patients were of short stature, 3 had irregular menstrual cycles, 3 had undersized testicles, 5 showed an insufficient rise of growth hormone following the administration of growth-hormone-releasing hormone, 4 showed an insufficient rise in FSH after administration of gonadotropin-releasing hormone, 5 had manifest diabetes mellitus, 3 showed an impaired glucose tolerance, and 2 patients had subnormal serum levels of parathormone in combination with hypocalcaemia. One patient additionally had Klinefelter's syndrome with a kariotype 47, XXY and increased levels of FSH and LH, subnormal levels of testosterone and subnormal testicular volume. The occurrence of endocrine defects correlated with the duration of disease. The data demonstrate that endocrine abnormalities are frequently associated with mitochondrial myopathy, indicating that this multisystemic disease also involves various endocrine tissues.Abbreviations ACTH adrenocorticotropic hormone - CoQ coenzyme Q₁₀ - CRH corticotropin-releasing hormone - FSH follicle-stimulating hormone - GH growth hormone - GHRH growth-hormone-releasing hormone - GnRH gonadotropin-releasing hormone - LH luteinizing hormone - mtDNA mitochondrial DNA - PTH parathormone - TRH thyrotropin-releasing hormone - TSH thyroid-stimulating hormone - T₃ triiodothyronine - T₄ thyroxine