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Biomedical subjects

M Kaufman

Publications and source records attributed to M Kaufman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Counseling sexually active teenagers treated with potential human teratogens.

Adolescents with hemoglobinopathies need daily chelation therapy with drugs which are known or suspected to be teratogenic. The prevention of fetal exposure to such drugs is therefore a major task for health professionals caring for these patients. We describe a pilot program aiming to prevent pregnancy among sexually active adolescents treated with iron chelators in Toronto. Most of them had normal response to GnRH, suggesting endocrinologic fertility, and unlike the literature concerning their healthy peers, all sexually active patients in this study reported use of at least one form of contraception.

Adolescent↗
PubMed1997

Cell activation influences cell staining kinetics.

Stimulation of cells has so far been observed, among other methods, by the decrease of the intracellular fluorescein fluorescence polarization (IFFP). It is shown that the rate constant of leakage of the fluorescent marker out of the cells increases with stimulation much more significantly than the polarization decreases; thus it might provide a more sensitive method to observe cells stimulation. It is also shown that due to negligible leakage of the marker out of the cells shortly after initiation of the staining of the cell suspension, the fluorescein fluorescence polarization (FFP) of the cell suspension, is very close to IFFP.

Fluoresceins↗
PubMed1996

Toxicity and neuroendocrine regulation of the immune response: a model analysis.

Various models have been proposed for the regulation of the primary immune response. Most of the models focus on the ability of the immune system to control a multiplying pathogen, and take into account the cross-regulations between different immune components. In the present study, we integrate the immune system in the general physiology of the host and consider the interaction between the immune and neuroendocrine systems. In addition to pathogen growth and toxicity, our four-variable model takes into account the toxic consequences for the organism of the immune response itself, as well as a neuro-hormonal retro-control of this immune response. Formally, the dynamics of the model is first explored on the basis of a discrete caricature, with special emphasis on the role of the constitutive feedback loops for determining the essential dynamical behavior of the system. This logical analysis is then completed by a classical continuous approach using differential equations. From a biological point of view, our model accounts for four stable regimes which can be described as "pathogen elimination/organism healthy", "pathogen elimination/ organism death", "pathogen growth/organism death" and "chronic infection". The size of the basins of attraction of these different regimes varies as a function of some crucial parameters. Our model allows moreover to interpret the interplay between pathogen immunogenicity and neuro-hormonal feedback, the effects of stress on immunity and the toxic shock syndrome, in terms of transitions among the steady states.

Animals↗
PubMed1996

Translocation of annexin I to plasma membranes and phagosomes in human neutrophils upon stimulation with opsonized zymosan: possible role in phagosome function.

Annexin I in the cytosol of resting neutrophils was translocated to the plasma membranes upon addition of opsonized zymosan (OZ). Maximum translocation could be detected 1 min after stimulation with OZ, and decreased thereafter. Subcellular fractionation studies demonstrated that annexin I could not be detected in the granule fractions in either resting or activated cells, but was found in association with the phagosome fraction. The marked translocation of annexin I was unique to OZ, since formyl-Met-Leu-Phe induced only slight translocation of annexin I to the plasma membranes, and phorbol 12-myristate 13-acetate had no effect at all. The mechanism regulating the translocation of annexin I is not clear. Annexin I is not phosphorylated in resting or stimulated cells. The correlation between the elevation in the intracellular calcium ion concentration ([Ca2+]i) and the degree of translocation of annexin I to the plasma membranes induced by the different stimuli, together with the inhibition of these processes by the addition of EGTA, indicate that the translocation of annexin I can probably be attributed to the rise in [Ca2+]i. However, this cannot be the sole mechanism since ionomycin, which caused an increase in [CA2+]i similar to that induced by OZ, was less efficient than OZ in inducing translocation of annexin I. The induction of annexin I translocation to the plasma membrane by OZ, which was the only agent that induced phagosome formation, and the detection of annexin I in the phagosome fraction, suggest that annexin I participates in phagosome function.

Annexin A1↗
PubMed1996

Endocrine and paracrine hormones in the promotion, progression and recurrence of breast cancer.

Both normal and neoplastic breast tissues are stimulated by endocrine and paracrine hormones. Epidemiological studies have demonstrated the significant role that hormones, growth factors and cytokines have in the promotion, progression and recurrence of breast cancer. Significant variations in the hormonal environment occur based on age, the cyclical changes occurring during the menstrual cycle and (mammographically determined) variations in breast composition. These variations have a significant influence on rates of local recurrence of breast cancer and survival. This review analyses data relevant to these issues and suggests means by which operative results may be improved.

Adult↗
PubMed1996

A model for antigen-induced T cell unresponsiveness based on autophosphorylative protein tyrosine kinase activity.

Helper T cell signaling is initiated by the aggregation of TCR with the induction of tyrosine kinase activity as one of the earliest consequences. Here, a theoretical model for antigen-induced unresponsiveness is presented that relies on a cascade of tyrosine phosphorylation-dephosphorylation cycles. A mechanism is described for both desensitization in the presence of antigen and persistent lowering of cell responsiveness after stimulus removal. An important component of the model, leading to bistability, is the presence of autophosphorylating protein tyrosine kinases in the early steps of TCR signaling. One of its predictions is that, following stimulation, the net phosphorylative activity of these receptor-associated tyrosine kinases will remain above background level after removal of the antigen. It is proposed that this residual tyrosine kinase activity is linked to a deficient signal transduction capacity of the TCR system that leads to a state of prolonged unresponsiveness. In addition, the present analysis defines the notion of a signaling threshold for hyporesponsiveness induction, associated with a durable switch and amplification of the net tyrosine kinase activity. This approach emphasizes the role of tyrosine kinases in the down-regulation of cellular competence.

Antigen Presentation↗
PubMed1996

A modified occlusal registration and implant transfer technique.

The technique for the transfer of implant and abutment position to a working cast has been hindered by multiple transfers and record reproductions. These serve only to delay completion of the patient's prosthetic requirements. A transfer technique that uses custom impression trays fabricated from surgical templates allows for a single-visit transfer of centric occlusion, vertical dimension, tooth position, and implant or abutment location in one procedure. This streamlines treatment and allows for quicker delivery of final prostheses.

Dental Abutments↗
PubMed1995

Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state.

In the field of biological regulation, models dictated by experimental work are usually complex networks comprising intertwined feedback loops. In this paper the biological roles of individual positive loops (multistationarity, differentiation) and negative loops (homeostasis, with or without oscillations, buffering of gene dosage effect) are discussed. The relationship between feedback loops and steady states is then clarified, and the problem: "How can one conveniently disentangle complex networks?" is then considered. Initiated long ago, logical descriptions have been generalized from various viewpoints; these developments are briefly discussed. The recent concept of the loop-characteristic state, defined as the logical state located at the level of the thresholds involved in the loop, together with its application, are then presented. Biological applications are also discussed.

Arginine↗
PubMed1995

Characterization of alternative amino acid substitutions at arginine 830 of the androgen receptor that cause complete androgen insensitivity in three families.

We have studied two different missense mutations at arginine-830 in exon 7 of the human androgen receptor (hAR) gene that cause complete androgen insensitivity (CAIS) in three families. These substitutions result from point mutations at nucleotide 2489: a G-->T transversion causes Arg830Leu and a G-->A transition causes Arg830Gln. Genital skin fibroblasts of the patients have negligible androgen-binding capacity. The mutations were recreated in an hAR cDNA expression vector that was transiently transfected into COS-1 cells. Both mutant androgen receptors have increased dissociation rate constants and apparent equilibrium rate constants when measured with 5 alpha-dihydrotestosterone or the synthetic, nonmetabolizable androgens, mibolerone or methyltrienolone. The mutant androgen-binding activities share a distinctive thermal misbehavior. At 37 degrees C R830Q and R830L are about 40% and 10% of normal, respectively. At 22 degrees C both mutants gain androgen binding while the normal decreases by 20%; for R830Q the augmented value approaches 60% of the normal. During prolonged 18 h incubation at 37 degrees C, androgen binding of the normal AR is stable while that of both mutants decreases by at least 85%. Both mutants have a very reduced ability to transactivate a cotransfected androgen-responsive reporter gene, but R830Q is better than R830L. We conclude that arginine-830 is important for A-R complex stability, and that its replacement by glutamine or leucine yields distinctive functional aberrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

T cell long-term hyporesponsiveness follows antigen receptor engagement and results from defective signal transduction.

T cell receptor (TCR)-mediated stimulation of T hybridomas leads to cell activation and lymphokine production that is followed by a long-term hyporesponsiveness. To investigate the biochemical events involved in the induction and maintenance of this antigen receptor hyporesponsiveness or anergy, we have expressed a G protein/PLC beta 1-coupled muscarinic subtype 1 acetylcholine receptor in a murine T cell hybrid. Transfected cells were capable of responding to both muscarinic agonists and TCR ligands by inducing interleukin-2 secretion that was sensitive to cyclosporin A and dexamethasone. Both receptors induced tyrosine kinase (TK) activity, but muscarinic stimulation did not affect tyrosine phosphorylation of PLC gamma 1, nor did the TK inhibitor, herbimycin, block muscarinic receptor-mediated calcium mobilization. These data indicate that in T cells, the muscarinic receptor mediates T cell effector functions by regulating a TK-independent proximal pathway which later converges with the TCR pathway. Using these cells, we have explored the long-term consequences of T cell stimulation via antigen or muscarinic receptors. Our results show that hyporesponsiveness specifically follows TCR engagement and appears to result from a defect in the early signal transduction initiated by TCR cross-linking. A study of TCR-mediated signaling supports this model by showing that tyrosine phosphorylation and calcium mobilization are deficient in hyporesponsive T cells.

Animals↗
PubMed1994

Complete androgen insensitivity due to mutations in the probable alpha-helical segments of the DNA-binding domain in the human androgen receptor.

We describe different single-amino acid aberrations in the DNA-binding domain (DBD) of the human androgen receptor (hAR) in three families with complete androgen insensitivity. No additional alteration was found in the translated portion of each mutant gene. In one family, an in-frame 3 nt deletion removes codon 581-(or 582) and, thereby, one of two phenylalanines that invariably occupy adjacent positions in the N-terminal alpha-helical region of the DBD in the steroid/thyroid/vitamin D receptor superfamily. In the second, an in-frame 3 nt loss deletes Arg614, an invariant residue in the C-terminal alpha-helix of the DBD. In the third, a G-->A transition causes Arg614His. Following transient transfection of COS cells with each mutant AR plasmid, there is a normal concentration of specific androgen-binding activity that has a reduced ability to bind two types of androgen response element (ARE), and to transregulate an androgen-responsive human growth hormone reporter gene. In genital skin fibroblasts with delta Phe581 or Arg614His, androgen-binding, AR protein and AR mRNA are markedly reduced; in gonadal fibroblasts with delta Arg614, AR mRNA may be reduced. Our data substantiate the primary contributions of Phe581 and Arg614 to normal hAR-ARE binding, and expose important secondary effects of the mutations affecting each residue.

Amino Acid Sequence↗
PubMed1994

Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.

We aim to correlate point mutations in the androgen receptor gene with receptor phenotypes and with clinical phenotypes of androgen resistance. In two families, the external genitalia were predominantly female at birth, and sex-of-rearing has been female. Their androgen receptor mutation changed arginine-839 to histidine. In a third family, the external genitalia were predominantly male at birth, and sex-of-rearing has been male: their codon 839 has mutated to cysteine. In genital skin fibroblasts, both mutant receptors have a normal androgen-binding capacity, but they differ in selected indices of decreased affinity for 5 alpha-dihydrotestosterone or two synthetic androgens. In transiently cotransfected androgen-treated COS-1 cells, both mutant receptors transactivate a reporter gene subnormally. The His-839 mutant is less active than its partner, primarily because its androgen-binding activity is more unstable during prolonged exposure to androgen. Adoption of a nonbinding state explains a part of this instability. In four other steroid receptors, another dibasic amino acid, lysine, occupies the position of arginine-839 in the androgen receptor. Androgen receptors with histidine or cysteine at position 839 are distinctively dysfunctional and appear to cause different clinical degrees of androgen resistance.

Adult↗