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Biomedical subjects

S Mathias

Publications and source records attributed to S Mathias.

At least 37 records · Page 2Linked to original sources
PubMed1996

Anomalous inheritance of a paternally derived trophoblast antigen.

PROBLEM: Recurrent spontaneous abortion occurs in 1 in 500 random matings and usually results in abortion of all pregnancies. If absence of antibody to a paternally derived antigen caused abortion, the woman would be expected to make antibody to the other paternal antigen and abort only half her pregnancies. METHODS: Microvesicles were prepared from equine placentae. Acid-eluted IgG antibody was eluted from the polymorphic R80K antigen and used to type the residual R80K antigen on vesicles or on peripheral blood leucocytes. RESULTS: In several equine sibships all the half-sibs had the same paternal R80K alloantigen. In the extended horse family descended from the stallion Nearco, three allotypes were found. The allele present was usually the grandpaternal one, but exceptions are seen. Whichever allele is transmitted all the progeny have the same alloantigen (probability of this occurring by chance = 2(-45)). CONCLUSION: Because only one paternal allotype is present in all progeny, lack of antibody to the R80K antigen would result in loss of all pregnancies, not one half.

Alleles↗
PubMed1996

Effect of interleukin-1 beta on EEG power density during sleep depends on circadian phase.

The cytokine interleukin (IL)-1 is a key mediator of the somnogenic response to immune challenge. In this vehicle-controlled study we evaluated circadian interference with the sleep-promoting effects of IL-1 beta. In two randomized experiments, rats were injected intracerebroventricularly with 5 ng IL-1 beta either at the beginning of the rest phase or at the beginning of the activity phase. Recordings were made during the 24 h preceding the injections (baseline) and during the first 12 postinjection hours. To avoid masking effects of light, the rats were maintained under a skeleton photoperiod during recording. During both the rest and activity phase, IL-1 beta induced fever and initially promoted non-rapid eye movement sleep (REMS). The effect of IL-1 beta on the duration of non-REMS and electroencephalogram (EEG) power densities within non-REMS was related to circadian phase. During the rest phase, IL-1 beta resulted in a minor increase in non-REMS duration but a prominent enhancement in EEG activity in the delta (0.5-4 Hz) and most other frequency bands. During the activity phase, IL-1 beta evoked a larger increase in the duration of non-REMS but hardly affected EEG activity within this state. Thus the effects of IL-1 beta on non-REMS are strongly influenced by diurnal phase. The alterations in EEG power density are in contrast to those elicited by sleep deprivation, which are largely independent of time of day. It is concluded that IL-1 beta activates EEG regulatory mechanisms mediated by processes that depend on circadian phase.

Animals↗
PubMed1995

Phosphorylation of Raf by ceramide-activated protein kinase.

The sphingomyelin pathway, initiated by hydrolysis of sphingomyelin to ceramide and stimulation of a Ser/Thr ceramide-activated protein (CAP) kinase, mediates tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta action. CAP kinase is membrane-bound and proline-directed, recognizing the minimal substrate motif Thr-Leu-Pro. TNF may use the sphingomyelin pathway to signal Raf1 to activate the MAP kinase cascade. Evidence shows that cytoplasmic Raf1 binds to GTP-ras upon cellular stimulation, is recruited to the plasma membrane, and activated. How membrane-bound Raf1 is activated is uncertain, but regulation of its kinase activity may involve its phosphorylation. Specific Raf kinases, however, have not hitherto been identified. Here we report that CAP kinase phosphorylates Raf1 on Thr 269, increasing its activity towards MEK (MAP kinase or ERK kinase). Moreover, in intact HL-60 cells, CAP kinase complexes with Raf1 and, in response to TNF and ceramide analogues, phosphorylates and activates Raf1, implicating CAP kinase as a link between the TNF receptor and Raf1.

Amino Acid Sequence↗
PubMed1995

Cell-free reconstitution of Fas-, UV radiation- and ceramide-induced apoptosis.

Cell-free systems are valuable tools for the dissection of complex cellular processes. Here we show that cytoplasmic extracts from cells exposed to anti-Fas antibody or UV radiation contain an activity capable of reproducing morphological changes typical of apoptosis in nuclei added to these extracts, as well as internucleosomal cleavage of DNA and proteolysis of a protein known to be cleaved during the apoptosis of intact cells. Extracts from control cell populations were inactive in this respect. These effects were partly blocked by the addition of purified Bcl-2 protein or a competitive inhibitor peptide of interleukin-1 beta-converting enzyme to the extracts. Furthermore, apoptotic activity was induced in cytoplasmic extracts from untreated cells by the addition of ceramide, a lipid second messenger implicated recently in apoptosis signaling. These extracts should prove highly useful in the dissection of molecular events that occur during apoptosis.

Animals↗
PubMed1995

Serial measurement of peripheral oestrogen and progesterone concentrations in oestrous mares to determine optimum mating time and diagnose ovulation.

Rapid enzyme-based immunoassays were used to measure concentrations of oestradiol-17 beta and progesterone in daily blood samples recovered throughout oestrus and for a few days after ovulation from 34 Thoroughbred and 8 pony-type maiden, barren and foaling mares. The first detectable fall in oestradiol-17 beta levels occurred in 88% of the mares within the interval -72 to 0 h with respect to ovulation and in 65% of mares within the interval of -48 to 0 h. The results indicated that serial daily hormone assays of this type could, in a high proportion of animals, predict a correct time for a single mating and diagnose the occurrence of ovulation in Thoroughbred mares at stud in the absence of the present management system which includes repeated veterinary examinations of the ovaries. However, the absolute need for serial daily sampling from all mares to produce interpretable hormone profiles, and the cost of this sampling and the hormone assays, make the method impractical at the present time.

Animals↗
PubMed1994

Renaturation and tumor necrosis factor-alpha stimulation of a 97-kDa ceramide-activated protein kinase.

Recent investigations identified a new signal transduction pathway, termed the sphingomyelin pathway, which may mediate the action of tumor necrosis factor (TNF) alpha and interleukin-1 beta (Mathias, S., Younes, A., Kan, C., Orlow, I., Joseph, C., and Kolesnick, R. N. (1993) Science 259, 519-522). This pathway is initiated by hydrolysis of sphingomyelin to ceramide by a neutral sphingomyelinase and stimulation of a ceramide-activated Ser/Thr protein kinase. Recent investigations demonstrated that kinase activity is proline-directed, recognizing substrates in which the phosphoacceptor site is followed by a proline residue. Until now, the kinase has been defined only as a membrane-bound activity capable of phosphorylating a peptide derived from the sequence surrounding Thr669 of the epidermal growth factor receptor. In the present studies, the kinase was quantitatively extracted from membrane with detergent and separated from protein kinase C by anion-exchange chromatography and isoelectric focusing. Ceramide-activated protein kinase was resolved as an exclusively membrane-bound, 97-kDa protein with a pI of 7.05. Kinase activity toward the epidermal growth factor receptor peptide co-purified with activity toward a generic proline-directed substrate, myelin basic protein. Kinase activity was reconstituted by a denaturation-renaturation procedure and demonstrated activity toward self (autophosphorylation) and exogenous substrate (myelin basic protein). Autophosphorylation occurred exclusively on serine residues. These activities were enhanced to 7-fold of control by ceramide and TNF alpha. These investigations provide additional evidence for a role for ceramide-activated protein kinase in signal transduction for TNF alpha.

Cell Line↗
PubMed1993

Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta.

The mechanism of interleukin-1 (IL-1) signaling is unknown. Tumor necrosis factor-alpha uses a signal transduction pathway that involves sphingomyelin hydrolysis to ceramide and stimulation of a ceramide-activated protein kinase. In intact EL4 thymoma cells, IL-1 beta similarly stimulated a rapid decrease of sphingomyelin and an elevation of ceramide, and enhanced ceramide-activated protein kinase activity. This cascade was also activated by IL-1 beta in a cell-free system, demonstrating tight coupling to the receptor. Exogenous sphingomyelinase, but not phospholipases A2, C, or D, in combination with phorbol ester replaced IL-1 beta to stimulate IL-2 secretion. Thus, IL-1 beta signals through the sphingomyelin pathway.

Amino Acid Sequence↗
PubMed1993

Ceramide: a novel second messenger.

The data discussed in the preceding sections suggest that information may be transmitted both through synthesis and through degradation of sphingomyelin. Although the sphingomyelin pathway holds promise as a new signaling system coupling TNF receptor activation to cellular stimulation (Fig. 5), the work is still at a preliminary stage. A physical association of receptors with neutral sphingomyelinase has yet to be established and the ceramide-activated protein kinase has yet to be isolated. Endogenous substrates for the kinase have also to be identified. Furthermore, the exact role of this pathway has not been defined. It is unclear whether this pathway is specific to monocyte differentiation or cytokine action. It also seems unlikely that a single signal transduction mechanism can account for all the diverse effects of TNF-alpha in different systems (Vilcek and Lee, 1991). Interactions with other signaling systems are sure to complicate elucidation of the exact role(s) of this pathway. Nevertheless, availability of cell-permeable analogs of ceramide, localization of many components of the system at the cell surface, and recent development of anti-TNF receptor antibodies to receptor isotypes may allow for greater definition of the sphingomyelin pathway in the near future.

Ceramides↗
PubMed1992

Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system.

The mechanism of tumor necrosis factor (TNF)-alpha signaling is unknown. TNF-alpha signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase. In a cell-free system, TNF-alpha induced a rapid reduction in membrane sphingomyelin content and a quantitative elevation in ceramide concentrations. Ceramide-activated protein kinase activity also increased. Kinase activation was mimicked by addition of sphingomyelinase but not by phospholipases A2, C, or D. Reconstitution of this cascade in a cell-free system demonstrates tight coupling to the receptor, suggesting this is a signal transduction pathway for TNF-alpha.

Cell-Free System↗
PubMed1992

Videoendoscopic evaluation of the mare's uterus: II. Findings in subfertile mares.

Videoendoscopy of the reproductive tract was performed in 87 Thoroughbred mares with histories of reduced fertility. During hysteroscopy samples for cytological, microbiological and histological examinations were obtained under visual control. Common findings in these broodmares included: (a) endometrial degeneration, as assessed by an uneven distribution or atrophy of endometrial folds and/or a scarred appearance of the endometrium (49 mares, 56%); (b) endometrial cysts of various sizes and locations within the uterus with the most common location being at the base of the uterine horns (48 mares, 55%); (c) fluid accumulation in the uterine lumen (28 mares, 32%). A few mares had transluminal adhesions (7 mares, 8%) and in 2 mares the adhesions appeared to obstruct one uterine horn completely. A solitary discrete lump was detected in the wall of the uterine body in one mare and the suspicion of it being a leiomyoma was confirmed histologically with the aid of a visually directed biopsy sample. Free intraluminal structures were present in the uterine lumen in 3 mares, including one inspissated blood clot and two suspected remnants of resorbing pregnancies. Flexible biopsy forceps and scissors passed through the working channel of the endoscope were used to sever small thin adhesions, but this method proved inadequate for multiple adhesions or cysts. Solitary endometrial cysts were removed by means of conventional rigid biopsy forceps passed alongside the endoscope, although bleeding from the operation site usually limited this type of intervention.

Anestrus↗
PubMed1991

Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha.

Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.

Amino Acid Sequence↗
PubMed1990

The kinetics of gene expression and maturation of IL-1 alpha after induction with the surface coat of Trypanosoma brucei rhodesiense or lipopolysaccharide.

The purpose of this study was threefold: to determine if the variant surface coat glycoprotein (VSG) of Trypanosoma brucei rhodesiense induces IL-1 alpha; to study the kinetics of IL-1 alpha transcription, maturation and secretion; and to compare VSG to LPS in its ability to induce IL-1 alpha. VSG was added to cultures of the P388D1 murine macrophage cell line. RNA was dotted onto nitrocellulose and hybridized with a murine IL-1 alpha cDNA probe. Maximal production of IL-1 alpha mRNA occurred in a dose- and time-dependent manner, peaking at 25 micrograms/ml VSG, within 2 h. Induction of IL-1 alpha was not due to contaminants because 1) absorption of VSG with a mAb abrogated IL-1 alpha mRNA synthesis, 2) the addition of polymyxin B did not affect mRNA levels, and 3) cellular IL-1 alpha was detectable in VSG-treated splenocytes from endotoxin nonresponder C3H/HeJ mice. Murine splenic macrophages also had enhanced levels of IL-1 alpha mRNA after administration of VSG in vivo or during an acute infection. Antiserum generated against the synthetic peptide SGDDSKYPV (amino acids 177-185 from the murine IL-1 alpha sequence) was used to measure the levels of the 33-, 22-, and 14-kDa proteins in cell lysates and medium of VSG-stimulated P388D1 cells. The 22-kDa protein was the predominant cellular form until secretion started. Secretion of the 14-kDa form began abruptly 6 to 8 h after the addition of VSG. By 12 h, the 33-kDa precursor was the major cytoplasmic form. In comparative analyses, LPS-stimulated P388D1 cells produced more transcript, generated peak levels of 22-kDa protein 3 h earlier, and began to secrete the 14-kDa molecule 5 h earlier. The rate of IL-1 alpha accumulation in the medium was linear between 6 and 24 h after LPS treatment, but began to drop by 8 h in VSG-treated cells. Functional (comitogenic) IL-1 activity was also detected in media from VSG-treated splenic macrophages and P388D1 cells. Activity peaked at 50 micrograms/ml and was lost if 0.2% IL-1 antisera were added to the cultures.

Animals↗
PubMed1986

Balance in elderly patients: the "get-up and go" test.

The "get-up and go test" requires patients to stand up from a chair, walk a short distance, turn around, return, and sit down again. This test was conducted in 40 elderly patients with a range of balance function. Tests were recorded on video tapes, which were viewed by groups of observers from different medical backgrounds. Balance function was scored on a five-point scale. The same patients underwent laboratory tests of gait and balance. There was agreement among observers on the subjective scoring of the clinical test, and good correlation with laboratory tests. The get-up and go test proved to be a satisfactory clinical measure of balance in elderly people.

Accident Prevention↗
PubMed1985

Coffee, plasma cholesterol, and lipoproteins. A population study in an adult community.

The associations between intake of coffee or decaffeinated coffee and plasma cholesterol and lipoprotein measurements were examined in a probability sample from a defined community of adults. The results were based on 24-hour dietary recall interviews and laboratory measurements carried out in 1972-1974 on 381 women and 320 men conducted as part of the La Jolla Lipid Research Clinic study. Intake of 8+ oz (230+ ml) of coffee per day was reported by 65% of women and 70% of men. Plasma cholesterol increased with increasing coffee drinking in women as follows: 0-7 oz (0-229 ml), 214 mg/dl; 8-32 oz (230-960 ml), 222 mg/dl; and 33+ oz (961+ ml), 234 mg/dl. This trend was significant at p less than 0.01. Almost all of the difference could be accounted for by an increase in low density lipoprotein cholesterol. Plasma cholesterol was not affected by coffee intake in men or by decaffeinated coffee intake in either sex. The results were unaffected by adjustment for age, obesity index, number of cigarettes smoked per day, ml of alcohol consumed per day, oral contraceptive use, regular exercise, daily intake of saturated, monounsaturated, and polyunsaturated fat, polyunsaturated/saturated fat ratio, use of cream in coffee, and use of sugar in coffee. This study confirms the previously reported significant increase in plasma cholesterol and low density lipoprotein levels with increasing coffee intake in women, and demonstrates that the increase is due largely to elevation of low density lipoprotein cholesterol. The reasons for a differential response to coffee in women and men, reported previously and in this study, deserve further investigation.

Adult↗
PubMedDate not supplied

Placental localization of relaxin in the pregnant mare.

In situ hybridization employing a cRNA probe derived from a 428-bp fragment of equine relaxin was used to localize relaxin mRNA, and immunocytochemistry was used to localize relaxin itself, in tissues of the placenta-endometrium interface recovered between 33 and 153 days of gestation from mares carrying intraspecific horse, interspecific mule and extraspecific donkey conceptuses. Immunocytochemical staining was also used to localize trophoblast-specific and class I major histocompatibility complex (MHC) antigens on some specimens. Relaxin mRNA and relaxin were both present in the single-cell non-invasive trophoblast layer of the allantochorion between 45 and 153 days of gestation in all three types of equine pregnancy examined. Both, however, were absent from the invasive trophoblast cells of the progenitor chorionic girdle and the differentiated trophoblast cells of the endometrial cups throughout the latters' 60-80-day period of development and regression. Discrete and irregularly spaced clusters of elongated pseudostratified trophoblast cells on the allantochorion remained negative for relaxin mRNA and ligand, but stained strongly for equine trophoblast-specific antigens. These areolae-like structures of the mature horse placenta overlie the mouths of endometrial glands between adjacent microcotyledons and they are clearly involved with the uptake of uterine milk for fetal sustenance. It is speculated that their loose attachment to the endometrium and weak expression of class 1 MHC antigens may serve to tolerize the mother to the paternally-inherited histocompatibility antigens of the fetus.

Animals↗
PubMedDate not supplied

The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects.

Aging is associated with a dramatic decrease in slow wave sleep (SWS) and sleep consolidation. Previous studies revealed that various GABA(A) agonists and the GABA uptake inhibitor tiagabine augment slow frequency components in the EEG within non-REM sleep, and thus promote deep sleep in young individuals and/or rats. In the present double-blind, placebo-controlled study, we assessed the effect of a single oral dose of 5 mg tiagabine on nocturnal sleep in ten healthy elderly volunteers (6 females). During the placebo night the subjects displayed a low sleep efficiency, due to high amounts of intermittent wakefulness, and little SWS. Tiagabine significantly increased sleep efficiency, tendentially decreased wakefulness and prominently increased both SWS and low-frequency activity in the EEG within non-REM sleep. The present findings demonstrate that tiagabine increases sleep quality in aged subjects. Moreover, the effects of tiagabine closely match those evoked by the GABA(A) agonist gaboxadol in young subjects and indicate that such compounds may have prospects in the treatment of sleep disturbances, particularly of those commonly occurring in the elderly.

Administration, Oral↗