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Biomedical subjects

M Steel

Publications and source records attributed to M Steel.

At least 37 records · Page 2Linked to original sources
PubMed1995

A novel cytochrome P450 expressed primarily in brain.

hct-1 (hippocampal transcript) was detected in a differential screen of a rat hippocampal cDNA library. Expression of hct-1 was enriched in the formation but was also detected in rat liver and kidney, though at much lower levels; expression was barely detectable in testis, ovary, and adrenal. In liver, unlike brain, expression was sexually dimorphic; hepatic expression was greatly reduced in female rats. In mouse, brain expression was widespread, with the highest levels being detected in corpus callosum; only low levels were detected in liver. Sequence analysis of rat and mouse hct-1 cDNAs revealed extensive homologies with cytochrome P450s (CYPs), a diverse family of heme-binding monooxygenases that metabolize a range of substrates including steroids, fatty acids, and xenobiotics. Among the CYPs, hct-1 is most similar (39% at the amino acid sequence) to cholesterol 7 alpha-hydroxylase (CYP7) and contains a postulated steroidogenic domain present in other steroid-metabolizing CYPs but clearly represents a type of CYP not previously reported. Genomic Southern analysis suggests that a single gene corresponding to hct-1 is present in mouse, rat, and human. hct-1 is unusual in that, unlike all other CYPs described, the primary site of expression is in the brain. Similarity to CYP7 and other steroid-metabolizing CYPs may argue that hct-1 (CYP7B) plays a role in steroid metabolism in brain, notable because of the documented ability of brain-derived steroids (neurosteroids) to modulate cognitive function in vivo.

Amino Acid Sequence↗
PubMed1995

T helper 2 cells are subject to high dose oral tolerance and are not essential for its induction.

Oral administration of aqueous protein Ag results in profound immunologic tolerance, and it has been suggested previously that this reflects selective activation of Th subsets. Here we show that the induction of oral tolerance by feeding a single high dose of OVA to mice significantly reduces the production of both Th1- and Th2-dependent cytokines and is accompanied by a marked reduction of specific Abs of both the IgG2a and IgG1 isotypes in vivo. Oral tolerance was also induced normally in IL-4-deficient mice. These results indicate that both subsets of the Th cell are equally susceptible to the induction of tolerance with a single high dose of Ag delivered via the oral route and that this phenomenon does not require Th2 cells.

Administration, Oral↗
PubMed1995

A frequency-dependent significance test for parsimony.

We describe techniques for assessing evolutionary trees constructed by the parsimony criteria, when sequences exhibit irregular base compositions. In particular, we extend a recently described frequency-dependent significance test to handle any number of taxa and describe a modification of the Kishino-Hasegawa sites test. These modifications are useful for detecting historical signals beyond those patterns which arise purely from irregular base compositions between the compared sequences. We apply the test to extend our earlier studies on chloroplast origins using 16S rDNA sequences, where a failure to compensate for irregular base compositions between the compared sequences provides statistically significant support for unjustified phylogenetic inferences. We also describe how the techniques can be modified to determine how "tree-like" data are, given independent variation in the base frequencies.

Models, Statistical↗
PubMed1995

CD4+ but not CD8+ T cells are required for the induction of oral tolerance.

It has been suggested that oral tolerance is mediated by CD8+ T lymphocytes, but the functional properties of these cells are unclear. Here we show that the induction of tolerance by feeding mice ovalbumin (OVA) does not prime antigen-specific class I MHC-restricted cytotoxic T cells in vivo. Indeed, such responses are markedly suppressed in mice fed OVA, and the induction of oral tolerance is abolished by depletion in vivo of CD4+ but not CD8+ T cells. These results indicate that CD8+ lymphocytes are unlikely to play a major role in the induction of oral tolerance and are the first demonstration that specific cytotoxic responses to an exogenous antigen can be suppressed by feeding antigen.

Administration, Oral↗
PubMed1995

Improved analyses of human mtDNA sequences support a recent African origin for Homo sapiens.

New quantitative methods are applied to the 135 human mitochondrial sequences from the Vigilant et al. data set. General problems in analyzing large numbers of short sequences are discussed, and an improved strategy is suggested. A key feature is to focus not on individual trees but on the general "landscape" of trees. Over 1,000 searches were made from random starting trees with only one tree (a local optimum) being retained each time, thereby ensuring optima were found independently. A new tree comparison metric was developed that is unaffected by rearrangements of trees around many very short internal edges. Use of this metric showed that downweighting hypervariable sites revealed more evolutionary structure than studies that weighted all sites equally. Our results are consistent with convergence toward a global optimum. Crucial features are that the best optima show very strong regional differentiation, a common group of 49 African sequences is found in all the best optima, and the best optima contain the 16 !Kung sequences in a separate group of San people. The other 86 sequences form a heterogeneous mixture of Africans, Europeans, Australopapuans, and Asians. Thus all major human lineages occur in Africa, but only a subset occurs in the rest of the world. The existence of these African-only groups strongly contradicts multiregional theories for the origin of Homo sapiens that require widespread migration and interbreeding over the entire range of H. erectus. Only when the multiregional model is rejected is it appropriate to consider the root, based on a single locus, to be the center of origin of a population (otherwise different loci could give alternative geographic positions for the root). For this data, several methods locate the root within the group of 49 African sequences and are thus consistent with the recent African origin of H. sapiens. We demonstrate that the time of the last common ancestor cannot be the time of major expansion in human numbers, and our results are thus also consistent with recent models that differentiate between the last common ancestor, expansion out of Africa, and the major expansion in human populations. Such a two-phase model is consistent with a wide range of molecular and archeological evidence.

Africa↗
PubMed1994

Differential cytokine production associated with distinct phases of murine graft-versus-host reaction.

Previous studies which demonstrated that cytokines such as interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) are essential for the development of graft-versus-host reaction (GvHR) did not establish whether the individual cytokines were responsible for distinct features of the disease. In this report, we show that IFN-gamma production is associated with the early proliferative phase of the disease, whereas the late, destructive phase correlates with production of TNF-alpha. These studies may assist in the development of specific immunotherapies aimed at individual aspects of immunologically mediated disease.

Animals↗
PubMed1993

A role for interleukin-1 alpha in immunologically mediated intestinal pathology.

Interleukin-1 (IL-1) is an important mediator of inflammation and has been implicated in several forms of immunopathology. Here we have investigated whether IL-1 plays a role in the enteropathy which occurs during a graft-versus-host reaction (GVHR) in mice. Non-irradiated (CBA x BALB/c) F1 mice with GVHR had increased production of IL-1 and treatment with rabbit anti-IL-1 alpha antibodies abolished the crypt hyperplasia and significantly reduced the parallel increase in crypt length which occurs in the jejunum. Antibody treatment had no effect on the accompanying increase in intraepithelial lymphocyte (IEL) counts or on the splenomegaly. Recombinant IL-1 itself produced villus atrophy, crypt hyperplasia and increased IEL counts in normal mice and stimulated the proliferation of an intestinal epithelial cell line in vitro. We propose that IL-1 plays an effector role in immunologically mediated enteropathy, either via direct effects on epithelial cells or secondary to an action on other, stromal cells in the mucosa.

Animals↗
PubMed1992

Endocrine parameters associated with disruption of parturition after bilateral pelvic neurectomy.

Bilateral lesions of the pelvic nerve (BLPN) result in dystocia, but the processes which control this effect are not fully understood. Plasma progesterone, relaxin, and luteinizing hormone (LH) concentrations were measured in blood samples taken in the morning (AM) and evening (PM) of Days 20-23 of gestation from rats with BLPN or sham neurectomy. Ten of 11 sham-operated control animals delivered their entire litters by Day 23 of gestation, but animals with BLPN did not complete parturition by Day 23 when they were sacrificed. Progesterone concentrations were greater in rats with BLPN than in sham-operated rats on Day 20 PM and Day 21 AM, but hormone concentrations declined to minimal values by Day 22 in both groups. Relaxin concentrations were greater in rats with BLPN than in sham-operated rats on Day 21 PM. Thereafter, relaxin concentrations decreased to reach minimum values on Day 23 in both groups. LH concentrations were low throughout the period of study in rats with BLPN; however, a postpartum LH surge was detected in all sham-operated animals. Data from this study indicate that the pelvic nerve does not control parturition by modulating serum relaxin and progesterone concentrations; however, these data suggest that impulses carried by the pelvic nerve influence ovarian secretion of these hormones. In addition, these data indicate that the pelvic nerve transmits stimuli from the cervix to the hypothalamus to facilitate the postpartum LH surge.

Animals↗
PubMed1991

Genetic aspects of breast cancer.

Of all the factors contributing to breast cancer risk, a strong family history of the disease is the most powerful. Familial clustering is said to have been noted by the Ancient Romans but formal documentation began in the mid-nineteenth century (reviewed in Ref. 1). The French physician Paul Broca noted that in one family (probably his wife's) over four generations 10 out of 24 women had died from breast cancer while several more individuals, of both sexes, had suffered other malignancies. He concluded that this very large excess of cancers could not reasonably be attributed to chance. At the same time he recognized that occasional familial clusters of relatively common conditions would be expected even in the absence of any genetic predisposition and discounted several published reports of 'hereditary cancers', including some of the families collected by his English contemporary Sir James Paget.

Breast Neoplasms↗
PubMed1990

Failure of ADCC to predict HIV-associated disease progression or outcome in a haemophiliac cohort.

Antibody-dependent cell-mediated cytotoxicity (ADCC) has been described in a number of virus infections and occurs in HIV infection. In spite of numerous studies on the ability of HIV-positive sera to mediate ADCC, it remains unclear whether ADCC has any functional significance. Here we examine serial serum samples from a cohort of haemophilia patients who became infected from a common source in 1984, and show that there is no significant difference in ADCC values between those who remained asymptomatic and those who progressed to disease. This study does not compare effector cell function and clinical status and does not exclude activity against different target cell lineages in vivo.

Antibody-Dependent Cell Cytotoxicity↗