Analysis through mathematical models of the dynamics of the adrenal cortical response to ACTH in the rat

The distribution and metabolism of ACTH and the dynamics of the adrenal cortical response to this tropic hormone were characterized in the rat, through mathematical models involving data derived from experiments, where plasma corticosterone concentrations were measured following both single injections and infusions of ACTH. The models, which incorporate a previously established model of the dynamics of plasma corticosterone, were statistically validated. The simulated dynamics of the different processes linking ACTH secretion by the adenohypophysis to corticosterone secretion by the adrenal cortex include: (1) a variable MCR for plasma ACTH, modeled as the sum of a constant and a saturable degradation process; (2) the ability of the adrenal gland to secrete at a maximal rate aven after the plasma ACTH concentration has become negligible, modeled as the accumulation of an intermediary productZ directly controlled by the plasma ACTH concentration; (3) a saturable secretion with a small time constant and which, for single injections, always starts in the same fashion, modeled as a “synthesis process” whose input is a saturable function ofZ; (4) an immediate fall of the plasma corticosterone concentration at the end of the ACTH infusions, modeled as a “release process” also controlled byZ. Supported by grants from the Medical Research Council of Canada (MT-1205, MT-1555, and MA-4970), and from INSERM, France (CRL-76-5-020-4).     

PK/PD modeling of aminoglycoside nephrotoxicity

Aminoglycosides are bactericidial antibiotics with a serum concentration-dependent activity. They are mainly eliminated by the kidneys and the main difficulty arising in clinical use is their uptake by the renal cortex which leads to nephrotoxicity. An ototoxicity is also reported. We propose a PK/PD modelling of aminoglycoside nephrotoxicity which unifies more fourty years of physiological knowledge. This deterministic model successively describes the pharmacokinetics of aminoglycosides, their storage into renal cortex, their effect on renal cells, their consequences on the renal function through tubuloglomerular feedback and the changes in the serum concentrations of creatinine that is considered as a toxicity marker. The simulation of the model displays the leading effect of the shape and daily-time of administration schedule on the search for minimizing toxicity.     

CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation

CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10. We found that CARMA1 was constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocated into lipid rafts upon TCR engagement. A CARMA1 mutant, defective for Bcl10 binding, had a dominant-negative (DN) effect on TCR-induced NF-kappa B activation and IL-2 production and on the c-Jun NH(2)-terminal kinase (Jnk) pathway when the TCR was coengaged with CD28. Together, our data show that CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation and CD28 costimulation-dependent Jnk activation.     

Synthèse de polystyrènes chlorométhylés renfermant des radicaux tétrathiafulvalénylphénoxyméthyles

In order to study the influence of the nature of the moiety bearing a tetrathiafulvalenyl group in the polymers upon the microlithographic properties of resists, poly(p-chloromethylstyrene)s and poly(styrene-co-p-chloromethylstyrene)s containing the 4-tetrathiafulvalenylphenoxymethyl group with a variety of controlled molecular weights and molecular weight distributions were studied. The copolymers were all prepared by reaction of poly(4-vinylbenzyl chloride) with potassium 4-tetrathiafulvalenylphenolate ( 3 ). Without exception, the resulting poly[p-chloromethylstyrene-co-p-(tetrathiafulvalenylphenoxymethyl)styrene]s are highly insoluble. However, by reaction of potassium 4-tetrathiafulvalenylphenolate with poly(styrene-co-p-chloromethylstyrene) soluble copolymers could be prepared.     

Chemical change and energy output during muscular contraction

1. The production of heat and (internal) work and the changes in the amount of phosphocreatine (PCr), ATP, inorganic phosphate (Pi) and sometimes lactate have been measured from moment to moment during and after tetanic isometric contractions of isolated frog muscles at 0° C.

2. Heat production was measured by thermopiles and a novel apparatus was employed for freezing the muscles rapidly at a chosen instant so as to halt the chemical processes before analysis.

3. Using unpoisoned muscles in oxygen, it was shown that neither oxidative recovery processes nor glycolytic ones led to appreciable restitution of PCr or ATP during 15 sec of contraction. However, clear signs of recovery processes could be seen within a minute. In our preparations artificial `ageing' by storage at low temperature did not interfere with the capacity for glycolysis.

4. Our clearest result was that the break-down of PCr was not nearly large enough to account for the rapid heat production during the first few sec of contraction. By the end of a 15 sec tetanus as much as 10 mcal/g remained unaccounted for.

5. The source of this heat is not clear. At no time is there any sign of net break-down of ATP; indeed there appears to be a slight increase of ATP in the stimulated muscle.

6. Break-down of PCr continues both during relaxation and during the minute following, while the muscle is at rest. Thus during contraction there is heat production without PCr break-down, while subsequently there is PCr break-down without heat production.

     

Polymethacrylic acid derivatives, 2. Spectroscopic study of the compact conformation to coil transition

The compact → coil conformational transition of hydrophilic-hydrophobic copolymers derived from poly(methacrylic acid) was studied by UV Spectroscopy. Two copolymers were used in this study: a Poly(N-methacryloylalanine-co-N-phenylmethacrylamide) (P50) and a poly(methacrylic acid-co-benzyl methacrylate) (S25). Both samples exhibit hypochromism in the absorption band of the aromatic chromophore when they are under the compact conformation: 7% and 30% hypochromism for P50 and S25, respectively. This difference is explained by differences in the hydrophobic side chain-side chain interactions between the aromatic residues. Increasing the temperature was found to increase strongly the hypochromism of S25 and to have little effect on P50.     

Tumor antigens and antigen-presenting capacity in breast cancer.

AIMS: Cancer cells frequently express antigens capable of being recognized by the host immune system; however, any resultant immune response is often ineffective. This may be related in part to tumor-induced defects in antigen presentation. We screened for dendritic cell infiltration, tumor MHC II expression and associated lymphocytic reaction in the context of three established breast tumor antigens. METHODS: Forty primary breast tumors were evaluated by immunohistochemical techniques for expression of her2/neu, p53, and MUC1 and MHC class II molecules. Twenty-five samples were further analyzed for p53 mutations by PCR-SSCP analysis and DNA sequencing. The phenotype of tumor-infiltrating inflammatory cells was evaluated using the following markers: CD1a, MHC Class II, CD3, CD45, and CD45RO. RESULTS: Tumors with p53 mutations and overexpression, but not her2/neu or MUC1 overexpressing tumors, more frequently harbored marked CD1a+ dendritic cell infiltrates. An overall correlation between CD1a+ cell infiltrates and HLA class II expression on tumor cells (p = 0.0008) was also observed and these tumors had greater CD45RO+ lymphocytic infiltrates. CONCLUSIONS: In breast cancer, p53 mutations may present a more visible signal to the immune system and hence provide a better target for immunotherapy. Infiltrating CD1a positive cells are associated with a more dense tumor lymphocytic infiltrate and tumor cell expression of MHC II molecules.     

Recombination pattern of the TCR γ locus in human peripheral T-cell lymphomas

The recombination events of the γ and β T-cell receptor (TCR) loci were analysed in a series of 39 peripheral T-cell lymphomas (PTCLs) in association with the expression of TCR chains. In TCR αβ PTCLs, 22/23 cases showed a γ-gene rearrangement while only 18/23 showed a concomitant β-gene rearrangement. The germline configuration of the β locus was found in angioimmunoblastic lymphadenopathy and lymphoepithelioid lymphomas. Three γδ PTCLs rearranged both γ and β genes. TCR silent PTCLs showed three different patterns of γ- and β-gene rearrangements. Three cases were in germline configuration for both loci; five cases had a rearranged γ and a germline β locus; and five cases had the two loci rearranged. Regarding the variable genes in the γ-rearranged alleles, members of the VγI subgroup were the most frequently presented (39/50), followed by VγII, VγIII, and VγIV (9/50, 1/50, and 1/50, respectively). Joining segment usage was as follows: J1 or J2 (32/50), JP1 or JP2 (17/50), and JP (1/50). Taken together, these data demonstrate that the γ locus is more frequently rearranged whatever the TCR expression. The γ-locus analysis provides a better diagnostic yield than the β locus in the study of PTCL clonality.     

Novel TAP1 polymorphisms in indigenous Zimbabweans: their potential implications on TAP function and in human diseases

Because of the essential role of transporter associated with antigen processing (TAP1 or TAP2) molecule in antigen processing, the implication of its polymorphism as a factor involved in human diseases and the possible genetic variation at this locus among ethnically diverse populations, we underwent a study to analyze the full extent of TAP1 polymorphism in an indigenous Zimbabwean population (Shona ethnic group). Using single-stranded conformation polymorphism and DNA direct sequencing procedures, we detected the presence of 11 nucleotide sequence variations in the entire coding region of TAP1. Of these variants, eight are nonconservative substitutions with respect to amino acid composition and are located in a critical part of the protein that could modulate its function. Five new polymorphic sites were identified in exon 1 (codons 7 Pro --> Ser, 17 Gly --> Arg, 141 Val --> Val), exon 6 (codon 419 Gly --> Cys), and exon 7 (codon 487 Arg --> Arg). Significant differences were seen in the distribution of TAP1*0201 and TAP1*0401 alleles, and codon 333 (Ile --> Val) polymorphism among African and non-African populations. Thus, TAP1 polymorphism has evolved differently among populations presumably because of the evolutionary pressures generated by prevalent pathogens in these geographically distinct regions.     

Physical activity improves gaze and posture control in the elderly

Ageing is associated with a decrease in the quality of balance regulation, in particular through dysfunctions of gaze control and postural stabilization, which results in an increased risk of falling. Conversely, the practice of physical and sporting activities has been shown to improve every level of postural regulation. This study is to assess the effects of the practice of physical activities on vestibulospinal reflex and ocular movements of visual and vestibular origins in elderly people. Gaze control and posture stabilization were evaluated in 13 healthy aged women who regularly practised physical activities and in 13 healthy aged sedentary women of a similar age, by dynamic posturographic test with electromyography, as well as electronystagmography with caloric and rotational vestibular tests, ocular saccades, smooth pursuit and optokinetic tests. The gaze and posture control performance of the active group was better; the proprioceptive and vestibular sensitivities were higher, visual detection quality was good, and reaction time was low. Regular physical activity develops or maintains the efficiency of the reflexes involved in postural control, especially through adequate neurosensorial information, which allows the central integrative structures to generate a more appropriate motor response.