Biomedical subjects
Publications and source records attributed to M Samson.
A 35 year-old right-handed woman with a history of alcoholism presented signs of interhemispheric disconnection. CT of the brain revealed a low-density areas in the corpus callosum. Two months later, clinical examination was normal, but the CT showed cystic area in the genu and splenium. MRI was also consistent with a lesion of the corpus callosum. CT and MRI did not show lesions in the hemispheric white matter.
The domain structure of the insulin receptor was investigated in liver and brown adipose tissue of developing rabbits. The structure of the binding domain (alpha-subunit) was analysed after covalent labelling with a 125I photo-reactive insulin analogue. The structure of the tyrosine kinase domain (beta-subunit) and the transmission of the hormonal signal from the alpha-to the beta-subunit were analysed by stimulating with insulin the autophosphorylation of the beta-subunit. Finally, the immunoreactivity of the receptor in developing tissues was assessed with anti-receptor antibodies. The results show that a functional insulin receptor can be detected at the early stages of fetal development in both tissues and is conserved throughout ontogenesis to adulthood.
Molecular association between major histocompatibility complex (MHC) antigens and cellular proteins are thought to be involved in various immunological and nonimmunological functions of MHC antigens, including hormone signaling. The existence of physical interactions between insulin receptors and MHC class I antigens was investigated in liver plasma membranes from congenic H-2k mice. Insulin receptors were specifically labeled with a 125I-labeled photoreactive insulin analogue, and cellular proteins were solubilized and incubated with various monoclonal antibodies. Immunoprecipitates were analyzed by polyacrylamide gel electrophoresis followed by autoradiography. Antibodies reacting with distinct epitopes on H-2k class I antigens were all able to precipitate up to 25% of the labeled insulin receptors in H-2k mouse liver membranes, whereas no insulin receptors were precipitated in H-2b mouse liver membranes. Sequential immunoprecipitations showed that insulin receptors and H-2 antigens were coprecipitated and that no cross-reactivity occurred. The specificity of the interaction between insulin receptors and H-2 antigens was demonstrated after double labeling of membrane proteins by photoreactive insulin and lactoperoxidase-catalyzed iodination. These results thus show that, in mouse liver membranes, insulin receptors are physically associated to class I antigens of the MHC.
Explore the source record for details and available documents.
The heart is the source of about 50 p. 100 of cerebral emboli. In the absence of clinically obvious cardiac disease, the heart is nevertheless suspected to be the origin, especially in young patients without atherosclerosis. Cardiac catheterisation and angiography were performed systematically to detect minor predisposing cardiac abnormalities which did not appear on standard clinical examination, and which could increase the risk of recurrent embolism. 64 patients aged 21 to 69 years were studied prospectively a few weeks after a cerebral vascular accident attributed to embolism on the results of complementary neurological investigation, or, more rarely, after systemic embolism to one of the limb arteries. Clinical examination, chest X-ray and the electrocardiogram were normal in all cases. The investigation consisted in right and left cardiac catheterisation, global angiography after right atrial injection, selective left ventricular angiography and coronary angiography in all patients over 40 years of age. Unsuspected cardiac abnormalities were detected in 39 of the 64 patients (60 p. 100); the main abnormalities were mild or moderate mitral valve prolapse (30 p. 100 of cases) and slight decreases in left ventricular contractility possibly related to a minor form of cardiomyopathy (23 p. 100 of cases). Ambulatory 24 hour monitoring showed supraventricular arrhythmias in 30 p. 100 of cases. The results of echocardiography were disappointing in the diagnosis of these minor abnormalities. In conclusion, cardiac abnormalities were detected in the majority of cases of cerebral embolism by cardiac catheterisation. These results support the indications for long-term anticoagulant and/or anti-arrhythmic treatment in these patients.
Explore the source record for details and available documents.
The effects of natural aliphatic polyamines on basal and hormone-stimulated protein phosphorylations in hepatocytes were studied. Cells isolated from adult rats were incubated in suspension with [32P]orthophosphate, in the absence or presence of polyamines at varying concentrations and for different times; hepatocytes were then exposed to various hormones for 10 min. Phosphoproteins contained in total cell lysates were analyzed by one- and two-dimensional gel electrophoresis and autoradiography. Spermine, the most effective amine, decreased the basal level of phosphorylation of proteins with 46, 34 and 22 kDa, and increased that of a 18 kDa protein. These effects, maximal with an external concentration of 7.5-10 mM, were detectable after a lag period of about 10 min and reached a plateau after 45 min. Pretreatment of cells with the polyamine almost completely prevented stimulation of the phosphorylation of the 46 and 34 kDa proteins by insulin; in contrast, the effects of phenylephrine on the same proteins were only partly inhibited, whereas those of glucagon appeared largely unaffected. The major polyamine effect observed in intact cells (i.e., decreased phosphorylation) could be reproduced in a cell-free system where no kinase activity persisted. Indeed, spermine added directly to cell extracts strongly accelerated dephosphorylation of the 46 kDa protein and also of the 61 kDa protein identified as pyruvate kinase; furthermore, restoration of the activity of this enzyme occurred concomitantly with dephosphorylation of the 61 kDa protein in the presence of spermine.
Explore the source record for details and available documents.
Cis-diamminedichloroplatinum (DDP) was administered at 100 mg/m2 intravenously bolus with every 3-week schedule in patients with measurable and nonmeasurable incurable gastric cancer. Twenty patients were treated, 12 with measurable and 8 with nonmeasurable disease. Four of the 12 (33%) patients with measurable lesions had objective remissions. One remission was complete, lasting 60+ weeks. Patients with nonmeasurable disease were not eligible for response evaluation; they were followed for toxicity and survival. Hematologic, renal, and gastrointestinal toxicities were similar to those reported in other patient populations receiving DDP. Neurotoxicity proved to be dose limiting in two patients. The median survival was 38+ weeks for responders, 24 weeks for all patients, and 13 weeks for those 8 patients with nonmeasurable disease. DDP should be considered an active drug against gastric cancer. A better understanding of the dose response relationship for DDP in gastric cancer is necessary before the best dose and schedule can be chosen for DDP in combination with other active agents.
Fifteen patients with advanced hematopoietic and other malignancies were treated with recombinant DNA produced Alpha 2 Interferon (IFN) (Schering) by intravenous (IV) and intramuscular (IM) routes at weekly intervals in escalating doses from 1 X 10(6) IU to 100 X 10(6) IU in order to determine the tolerance and pharmacokinetics. The most common side effects included fever, chills, myalgia, and arthralgia. At doses of 60 X 10(6) or above, severe but reversible hypotension was observed in five patients receiving interferon by intravenous route. Patients receiving interferon by intramuscular route had fever, chills, and myalgias but did not develop hypotension at the same dosage. Two patients with non-Hodgkin lymphoma showed objective evidence of regression. Our data suggest a biphasic pattern of elimination with terminal half-life ranging from 1.9 to 2.9 hours and peak titer of 16,000 units and under for IV interferon, and terminal half-life of 6 hours with peak titers of 600 units for intramuscular interferon. However, interpatient variability precludes a definite conclusion. Although the areas under the serum concentration vs time curves were similar, the intravenous route provided higher but unsustained levels of interferon than the intramuscular route.
The Southwest Oncology Group entered 453 patients with extensive small cell carcinoma into a combined modality treatment program, involving a randomized comparison of three different chemotherapy regimens for remission induction, and of maintenance chemotherapy alone versus maintenance treatment with cycles of reinduction added at six and 12 months. In addition, there was systematic comparison of diagnosis by institutional pathologist versus review panel pathologist. No difference was observed among the three different induction arms with respect to the incidence of response to treatment (61%), complete response (16%), or survival duration (median, 31 weeks). Neither overall response rate nor survival are superior to previous results. However, patients who achieved a complete response demonstrated significant survival benefit if they were in the group who received reinduction chemotherapy, as opposed to maintenance alone. This observation may apply most importantly to patients with small cell lung cancer of limited extent, for whom complete response is achieved in a majority. Agreement of institutional and review panel pathologists on the diagnosis of small cell lung cancer was observed in 94% of reviewed cases. A final observation is that the omission of chest irradiation results in a dramatic increase in the incidence of initial relapse at the primary tumor site. This suggests that future studies will need to use better therapy for local control in responding patients.
We have analysed the effects of natural aliphatic polyamines on hormonal induction of tyrosine aminotransferase (TAT) in suspensions of hepatocytes isolated from adult fed rats. Glucagon or cyclic AMP derivatives (dibutyryl and 8-bromo) used alone caused a 4-5 fold increase in enzyme activity within 4h. This effect was independent of glucocorticoids, which also increased TAT activity (2.5-fold); when combined, the effects of the two inducers were additive. Spermine and putrescine totally inhibited the hormonally-mediated increase in enzyme activity when added at the onset of incubation with the inducers. Furthermore, polyamines could block the hormonal effect at any time during the course of TAT induction, with, however, a 30 min lag period, suggesting that they must enter the cells. Hepatocytes were indeed shown to take up spermine. At low external concentrations (less than 50 microM), an Na+-dependent, saturable and concentrative mechanism was predominant; at high concentrations (greater than 0.5 mM) transport occurred mainly through a non-saturable, Na+-independent mechanism, building up intracellular concentrations slightly lower than those in the medium. Dose-dependence analysis of the polyamine effect on enzyme induction indicated that half-maximal and maximal inhibition occurred with 0.75 mM- and 2.5 mM-spermine respectively, whereas 2.5mM- and 7.5 mM-putrescine were required respectively to obtain similar effects. Spermidine was much less effective and cadaverine had virtually no effect. None of the polyamines affected the rate of decay of TAT, nor did they directly or indirectly cause enzyme inactivation, indicating that a post-translational modification was unlikely to account for the polyamine effects. Similarly, these effects could not be ascribed to a non-specific inhibition of overall protein synthesis. We conclude that, in hepatocytes, polyamines (or their metabolites) directly interfere with one or several steps controlled by hormones in the synthesis of tyrosine aminotransferase.
In primary cultures of rat hepatocytes, epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and foetal-calf serum (FCS) prevented the stimulation of amino acid transport by glucagon (cyclic AMP-dependent) and by catecholamines (cyclic AMP-independent), but not by insulin. The insulin effect, as well as the effect of other hormones, were totally inhibited by thrombin through a mechanism independent of its proteolytic activity. The inhibitory effect of growth factors, not found in freshly isolated hepatocytes, was expressed very early in culture (4h). Induction of tyrosine aminotransferase by glucagon or dexamethasone, which, like stimulation of transport, represents a late hormonal effect, was not affected by EGF, PDGF or FCS, but was inhibited by thrombin. In contrast, none of the rapid changes in protein phosphorylation caused by hormones was altered by growth factors. Thus the inhibition by growth factors of hormonal stimulation of transport presumably involves late step(s) in the cascade of events implicated in this hormonal effect.
The effects of natural polyamines on cyclic AMP-mediated stimulation of amino acid transport in isolated rat hepatocytes were analyzed. Despite the fact that polyamines could directly compete with alpha-aminoisobutyric acid (AIB) for uptake, preincubation of hepatocytes with polyamines did not significantly alter basal AIB transport. The stimulatory effect of glucagon or cyclic AMP analogs was differently affected by polyamines, since it was reduced in the presence of spermine and, inversely, potentiated by spermidine, putrescine, and cadaverine. Dose-dependence analysis showed that half maximal and maximal effects occurred with 2-3 and 6-10 mM external concentrations, respectively. None of the polyamine effects could be ascribed to transstimulation or transinhibition of amino acid uptake. The inhibitory effect exerted by spermine correlated its capacity to inhibit [3H]-leucine incorporation into proteins partially. The potentiating effect of the other polyamines did not result from stabilization of newly synthesized carrier proteins. Instead, the increase in Vmax of the high affinity transport component suggested that more carriers became available, presumably because polyamines facilitated their synthesis by interacting directly with one or several steps controlled by cyclic AMP. Polyamines appear to represent a new class of factors capable of modulating the cyclic AMP-mediated stimulation of amino acid transport, in hepatocytes.
Congenital oculomotor apraxia is characterized by the inability of the young child to produce horizontal saccades when his head is fixed; two cases are reported. In a free condition this trouble is compensated by thrust head movements allowing the child to lead his gaze to the stimulus or to reach it by successive hypometric jerks released by movement. A blink usually precedes the eye movement probably allowing the child to escape from an excessive fixation. This apraxia is combined with a motor and psychological development delay. The evolution of all the troubles is usually good with minimal sequelaes (difficulty for reading). Without any anatomical argument, it may be assumed that a dysfunction of area 8 and of the fronto-mesencephalic pathway is responsible for this abnormality. The resemblance of this disturbance to an earlier phylogenic period of the oculomotor development (inferior mammalian) and its spontaneous good evolution evoke more a maturation delay of the supranuclear control system of saccades than a true disease.
Explore the source record for details and available documents.
From November 1976 to March 1979 the Southwest Oncology Group treated 298 patients with limited (disease confined to the chest and encompassed by one radiotherapy port) small-cell carcinoma of the lung with combination chemotherapy and radiotherapy with or without BCG immunotherapy. Two induction chemotherapy programs were utilized: (1) cyclophosphamide, vincristine, methotrexate, fluorouracil; or (2) cyclophosphamide, doxorubicin, and vincristine. Patients received 4500 rads of radiation therapy to the bulk primary tumor and 3000 rads to whole brain followed by maintenance chemotherapy. One-half of all the patients were randomized to receive one vial (5 x 10(8)) of high viability Pasteur BCG by scarification technique given on days 8 and 15 of each 21--28 day treatment cycle. Increased granulocytopenia accompanied the addition of BCG immunotherapy. Patients receiving BCG achieved a response rate of 49% vs. those patients not receiving BCG of 44% (P = 0.579). Median response duration was 40 weeks for the BCG arms and 38 weeks for the arms without BCG; survival was no different, 42 weeks for the BCG arms vs. 50 weeks for the arms without BCG. In patients who responded to therapy and survived longer than one year, those who continued to receive BCG therapy demonstrated a slight, yet significant, survival benefit over those patients not receiving BCG (93 weeks vs. 81 weeks, P = 0.03). It appears that BCG immunotherapy has no beneficial effect on response rate, duration of response, or survival in programs using chemotherapy and radiotherapy for control of limited small-cell carcinoma of the lung except in this small group of long-term survivors.
We have investigated the effect of cyclic AMP on hepatic amino acid transport by measuring the uptake of L-alanine in plasma membrane vesicles purified from hepatocytes incubated without or with dibutyryl cyclic AMP. The application of an Na+ gradient to vesicles from hepatocytes exposed to dibutyryl cyclic AMP, compared to control, resulted in a greater transient accumulation of L-alanine, whereas in the presence of a K+ gradient a similar slow equilibration of L-alanine was observed. Kinetic analysis of L-alanine influx revealed that the increased uptake resulted from an increased capacity (Vmax) with no change in the affinity (Km) of the carriers for L-alanine. These results strongly suggest that dibutyryl cyclic AMP induces stable changes at the membrane level probably by increasing the number of amino acid carrier molecules.