Biomedical subjects
Publications and source records attributed to P Lang.
Cell-mediated immunity in lethally irradiated graft-versus-host mice can be restored after repopulation with syngeneic bone marrow cells and thymus grafting. The thymus is not only required for the maturation of T lymphocytes, but also for the inhibition of a radioresistant mechanism resulting in lymphoid cell rejection.
In an open-labeled randomized study, prophylactic treatment with ganciclovir (day 15 to day 29) was administered to 23 cytomegalovirus seronegative patients who received a kidney from a cytomegalovirus seropositive donor. Both groups (control = 11, ganciclovir = 12) were similar in age, immunosuppressive treatments, acute rejection episodes and number of steroid pulses. A seroconversion occurred in 10 control patients (91 percent) and in 10 patients of the ganciclovir group (84 percent). A cytomegalovirus disease was observed in 10 control patients (91 percent) and in 8 patients of the ganciclovir group (66 percent). The delay between grafting and cytomegalovirus disease was significantly longer in the ganciclovir than in the control group (78.5 +/- 7.7 vs 46.5 +/- 5.5 days, P < 0.05). In conclusion, in renal transplant recipients who are at high risk of cytomegalovirus disease, prophylactic treatment with ganciclovir delays the onset of the disease and seems to decrease slightly its frequency.
Rac1 and Rac2 gene products are small GTP-binding proteins showing 92% homology to each other. According to recent studies performed in cell-free systems, Rac1 and Rac2 proteins may be involved in the activation of NADPH-oxidase, the superoxide-generating enzymatic complex active in phagocytes. Epstein-Barr virus (EBV) transformed B lymphocytes, which express rac1 and rac2 genes, also efficiently release superoxide anions when triggered by various cell surface stimuli. To investigate the regulatory role of Rac proteins in living cells, we analyzed superoxide production in response to cross-linking of surface immunoglobulins or phorbol ester treatment in human EBV-transformed B lymphocytes pretreated with Rac sense and antisense oligonucleotides. We report here that (i) the rac protein content estimated by immunoblotting can be decreased by 60% in Rac antisense pretreated cells and (ii) a strong (50-60%), dose-dependent inhibition of superoxide production is observed in antisense pretreated cells whereas cells pretreated with sense oligonucleotide are unaffected. The data presented show, for the first time in whole cells, that superoxide production is modulated by the Rac protein content, thus demonstrating the physiological role of Rac proteins in the regulation of NADPH-oxidase.
Nitric oxide (NO) has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at FiO2 0.9 for up to 30 minutes by 6 infants with persistent pulmonary hypertension of the newborn (PPHN). In all infants this treatment rapidly and significantly increased preductal oxygen saturation (SpO2); in 5 infants postductal SpO2 and oxygen tensions also increased. Inhalation of NO did not cause systemic hypotension or raise methaemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxaemia due to PPHN.
The Rho proteins are identified as a subgroup of the Ras superfamily of low molecular weight GTP-binding proteins. We have studied the expression of these proteins in human cytotoxic natural killer cells and found that RhoA is the most abundantly expressed member of the Rho family. The Rho proteins are specific substrates for ADP-ribosylation catalyzed by the C3 exoenzyme from Clostridium botulinum. We report here that introduction of recombinant C3 in electropermeabilized natural killer cells or in cytotoxic T lymphocytes resulted in a dose-dependent inhibition of their cytolytic function. Furthermore, a single substrate is efficiently ADP-ribosylated by C3 in extracts from cytotoxic cells. Biochemical analyses indicate that this substrate is RhoA, and subcellular fractionation experiments demonstrate that it is essentially present in the cytosol of the cells. Western blot analysis, however, revealed that a small proportion of the Rho protein can be found associated with the cell membrane as well as with the cytotoxic granules. These results indicate that the low molecular weight GTP-binding protein RhoA is present in cytotoxic lymphocytes and plays a critical role in cell-mediated cytotoxicity.
The distal femur contains usually only fatty marrow in the adult. We investigated the incidence of areas of residual and reconverted hematopoietic marrow in the distal femur in a series of 50 adult patients using conventional spin-echo and opposed-phase gradient-echo MR images. Zones with intermediate to low signal intensity in both sequences representing hematopoietic marrow within high signal intensity fatty marrow were observed in 17 of the 50 patients. Opposed-phase gradient-echo sequences demonstrated significantly greater red-yellow marrow contrast than conventional spin-echo sequences. Residual red marrow may represent a biologic variation of the normal adult pattern of red-yellow marrow distribution in women of menstruating age. Reconverted red marrow appears to be related to increased erythrocyte demand. It should not be mistaken for bone marrow malignancy. Absence of epiphyseal involvement, cortical destruction and soft-tissue mass in residual and reconverted hematopoietic marrow are helpful differential criteria.
In previous studies it was demonstrated that antibodies in sera from patients with primary biliary cirrhosis (PBC) and their relatives can recognize two different antigen systems in the ATPase fraction prepared from beef heart mitochondria, namely the PBC-related M2- and the naturally occurring mitochondrial antigen (NOMAg)-related epitopes. Since separation of these two antigen systems could not be achieved using mammalian mitochondria, mitochondria from a wide spectrum of plants were analysed with respect to the presence of mitochondrial antigens. Mitochondria from 29 species of plants were prepared and tested by ELISA and Western blot using marker sera from patients with PBC reacting in the Western blot with M2a,b,c,d (alpha-ketoacid-dehydrogenase complex) and NOMAg-specific sera recognizing the three major epitopes epsilon, zeta, and eta at 65, 61 and 58 kD. Naturally occurring mitochondrial antibody (NOMA)-positive marker sera reacted in the ELISA with mitochondria from all plants, and the zeta/eta positive sera gave also a positive reaction at 61/58 kD in the Western blot while the epsilon epitope could not be visualized by this method. In contrast, the M2 antigen was detected preferentially in lower plants such as algae, fungi, and ferns. Analysing these data with respect to the evolution of proteins one would have to assume that the M2 antigen was lost in most higher plants or underwent some structural alterations. Furthermore, considering the fact that the M2- and the NOMAg-related epitopes could be only partially separated, i.e. there were no plant mitochondria showing only M2 but no NOMAg, one could speculate that anti-M2 antibodies are derived from the pool of naturally occurring antibodies.
Secretory immunoglobulin A (IgA) was determined by means of an enzyme-linked immunosorbent assay (using as capture antibody an MoAb specific for secretory component) in saliva and serum from 46 patients with IgA mesangial nephritis (IgAGN), 36 with an idiopathic nephrotic syndrome (INS), 30 with an idiopathic membranous nephropathy (MGN) and 40 healthy controls. Secretory IgA levels were elevated in both saliva and serum of patients with primary glomerulonephritis (P < 0.05; Mann-Whitney test) regardless of the histological type of the primary glomerulonephritis. Salivary IgA1 and IgA2 levels were increased in the saliva of patients with IgAGN, INS and MGN (P < 0.05; Mann-Whitney test). The monomeric/total IgA ratio, and interferon-gamma and soluble IL-2 receptor levels, in saliva did not differ between the patients and controls (P > 0.05; Mann-Whitney test). We conclude that the mucosal immune system is activated in forms of glomerulonephritis other than IgAGN.
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We report here the case of a 55-year-old patient with chronic granular lymphocyte disorder associated with moderate neutropenia. The majority of peripheral blood lymphocytes displayed a CD3-, CD8-, CD16+, CD56(NKH1)- phenotype. The patient's cells showed high spontaneous cytotoxic activity against K562 targets and developed the ability to kill the natural killer (NK)-resistant target Daudi following activation with interleukin 2 (IL-2). Simultaneously, IL-2 induced proliferation of these cells, albeit to a low level. The effects of IL-2 are likely to be mediated through the IL-2R beta chain (p70) which is expressed on these cells in the absence of the IL-2R alpha chain (p55, Tac). IL-4 was demonstrated to be inhibitory of both the cytotoxic and proliferative effects of IL-2. Thus, despite an unusual CD56- phenotype, the expanded lymphocyte population in this patient display functional and phenotypic properties of normal, non-activated NK cells. These cells probably represent the counterpart of a minor NK cell subpopulation, present in normal individuals at a low frequency, and which has never been fully characterized functionally. In addition, we show that the cytolytic activity of this NK cell population can be blocked in vitro in the presence of a cAMP analog or of theophylline, possibly providing new means of investigating the role of NK cell cytotoxicity on the pathogenesis of associated symptoms in such patients.
The authors reviewed the applications and limitations of computed tomography (CT) and magnetic resonance (MR) imaging in the assessment of the most common hip disorders. Magnetic resonance imaging is the most sensitive technique in detecting osteonecrosis of the femoral head. Magnetic resonance reflects the histologic changes associated with osteonecrosis very well, which may ultimately help to improve staging. Computed tomography can more accurately identify subchondral fractures than MR imaging and thus remains important for staging. In congenital dysplasia of the hip, the position of the nonossified femoral head in children less than six months of age can only be inferred by indirect signs on CT. Magnetic resonance imaging demonstrates the cartilaginous femoral head directly without ionizing radiation. Computed tomography remains the imaging modality of choice for evaluating fractures of the hip joint. In some patients, MR imaging demonstrates the fracture even when it is not apparent on radiography. In neoplasm, CT provides better assessment of calcification, ossification, and periosteal reaction than MR imaging. Magnetic resonance imaging, however, represents the most accurate imaging modality for evaluating intramedullary and soft-tissue extent of the tumor and identifying involvement of neurovascular bundles. Magnetic resonance imaging can also be used to monitor response to chemotherapy. In osteoarthrosis and rheumatoid arthritis of the hip, both CT and MR provide more detailed assessment of the severity of disease than conventional radiography because of their tomographic nature. Magnetic resonance imaging is unique in evaluating cartilage degeneration and loss, and in demonstrating soft-tissue alterations such as inflammatory synovial proliferation.
Graft-versus-host reactions (GvHR) are initiated by T lymphocytes. In mice, the T cell subset involved depends on the incompatibility for minor or major histocompatibility antigens between donor and host. However, the correlation between phenotype and function is not absolute, and anti-host cytotoxic T cells can be detected in recipients without GvHR. We have presently investigated in a P----F1 model differing at the MHC, whether GvH associated immunosuppression was correlated with donor cytotoxic T cell activity. The immunodeficiency was tested by the ability of the F1 mice to generate a cytotoxic T cell response against TNP self or an alloantigen. F1 specific parental cytotoxic T cells generated in vitro induced less immunosuppression than naive parental spleen cells. Specific in vivo priming increased the cytotoxicity of parental spleen cells, but decreased their capacity to induce GvH associated immunosuppression. In contrast, non specific priming resulted the usual immunodeficiency. Spleens of the F1 mice injected with specific cytotoxic T cells were very enlarged, suggesting that these cells remained capable of inducing a GvHR without generating immunosuppression.
Sera from 192 consecutive HIV negative renal transplant patients with more than 6 months follow-up were investigated for monoclonal or oligoclonal immunoglobulins (mIg) by immunoelectrophoresis or immunofixation. Gammapathy was present in 25 patients (13 percent). Eleven patients had only one monoclonal band, whereas 14 had two or more bands. Sixty percent were IgG K, 29 percent IgG lambda and 11 percent IgM lambda or K. Ninety percent of these mIg did not exceed 2 g/l; mIg appeared within 2-27 months following the transplantation (mean time-lag 8 +/- 6.4 months). The mIg were often transient: 20 disappeared within 1-33 months, most of them (14) being absent after 1 year of follow-up. Some risk factors for mIg could be identified: the patient's age (a risk factor only in women); the duration of dialysis; the occurrence of prior CMV infection; treatment with cyclosporine. The persistence of mIg was characterised by one or more of the followings: high titer of mIg, EBV infection or reactivation, inability to switch from IgM to IgG CMV antibodies. No significant association was found with the hepatitis B surface antigenemia, previous infection with hepatitis C or the number of rejection episodes. In 6 patients, the clinical course was characterised by severe infection or tumours. Although long-term follow ups are not yet available, patients in whom one or more mIg have been demonstrated should be carefully followed.
The major polysaccharide in tamarind seed is a galactoxyloglucan for which the ratios galactose:xylose:glucose are 1:2:25:2.8. A minor polysaccharide (2-3%) contains branched (1----5)-alpha-L-arabinofuranan and unbranched (1----4)-beta-D-galactopyranan features. Small-angle X-ray scattering experiments gave values for the cross-sectional radius of the polymer in aqueous solution that were typical of single-stranded molecules. Marked stiffness of the chain (C infinity 110) was deduced from static light-scattering studies and is ascribed partially to the restriction of the motion of the (1----4)-beta-D-glucan backbone by its extensive (approximately 80%) glycosylation. The rigidity of the polymer caused significant draining effects which heavily influenced the hydrodynamic behaviour. The dependence of "zero-shear" viscosity on concentration was used to characterise "dilute" and "semi-dilute" concentration regimes. The marked dependence on concentration in the "semi-dilute" region was similar to that for other stiff neutral polysaccharide systems, ascribed to "hyper-entanglements", and it is suggested that these may have arisen through a tenuous alignment of stiffened chains.
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We have cloned by the polymerase chain reaction a 2.1-kb fragment carrying heavy-chain joining (JH) gene segments and a part of the JH-C mu intron of the rat. Sequencing showed that the rat genome has four functional JH segments and that only a slight divergence has occurred after the separation of rat and mouse. A systematic sequence comparison between the two species and human revealed an additional JH pseudogene in rat and mouse 5' of JH1 which has not been described so far. The implications in evolutionary terms are discussed. In addition, we give an assessment of the misincorporation rate of the Taq polymerase.
We report a transient neonatal nephrotic syndrome in two infants born to a mother with idiopathic nephrotic syndromes (INS). The mother, born in Mali in 1966, had a normal first pregnancy, with a normal live child. Six months later a nephrotic syndrome appeared with normal renal function; renal biopsy disclosed slight lesions of focal and segmental glomerulosclerosis. Prednisone and ciclosporin were totally ineffective. In 1986 and 1988 two pregnancies occurred with normal gestation outcome; however, the two births were premature (35 weeks) with hypotrophic infantas (2.160 and 2.080 kg). In both cases urine analysis revealed neonatal heavy proteinuria, with low serum protein and hypoalbuminemia; proteinuria decreased and disappeared within 2 and 3 weeks respectively; simultaneously protidemia and albuminemia were normalized. Thus, a transitory nephrotic syndrome, resolving spontaneously, occurred in two successive offsprings of a patient with INS. These cases are in keeping with the hypothesis that heavy proteinuria in nephrotic syndrome might be linked to a circulating humoral factor and that INS is a disorder linked to T-lymphocyte function with enhanced production of a lymphokine acting on vascular permeability.