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Biomedical subjects

M Warner

Publications and source records attributed to M Warner.

At least 19 recordsLinked to original sources
PubMed2001

Morphological abnormalities in the brains of estrogen receptor beta knockout mice.

Estrogen receptor beta (ERbeta) is expressed at high levels in both neurons and glial cells of the central nervous system. The development of ERbeta knockout (BERKO) mice has provided a model to study the function of this nuclear receptor in the brain. We have found that the brains of BERKO mice show several morphological abnormalities. There is a regional neuronal hypocellularity in the brain, with a severe neuronal deficit in the somatosensory cortex, especially layers II, III, IV, and V, and a remarkable proliferation of astroglial cells in the limbic system but not in the cortex. These abnormalities are evident as early as 2 mo of age in BERKO mice. As BERKO mice age, the neuronal deficit becomes more pronounced, and, by 2 yr of age, there is degeneration of neuronal cell bodies throughout the brain. This is particularly evident in the substantia nigra. We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain.

Animals↗
PubMed2001

In vitro activity of ketolides HMR 3004 and HMR 3647 and seven other antimicrobial agents against Corynebacterium diphtheriae.

The in vitro activities of two ketolides, HMR 3004 and HMR 3647 (telithromycin), and the comparator agents erythromycin A, azithromycin, clarithromycin, roxithromycin, levofloxacin, ofloxacin and penicillin G were determined by an agar dilution method against 410 isolates of Corynebacterium diphtheriae. Test isolates originated from diverse geographical locations, including the former USSR, where epidemic diphtheria has re-emerged during the 1990s. All isolates tested were susceptible to penicillin G, ofloxacin and levofloxacin. The two ketolides and four macrolides were highly active against 405 of the 410 isolates. HMR 3004 was the most active of the drugs, followed by HMR 3647, clarithromycin, erythromycin A, roxithromycin and azithromycin. Five isolates showed reduced susceptibility to all macrolides and ketolides tested; three were non-toxigenic isolates from Australia and the remaining two were from cases of diphtheria in Vietnam. Inducible (MLS(B)) resistance was detected in the isolates from Vietnam, but not in the isolates originating from Australia. Significant antimicrobial resistance remains rare amongst C. diphtheriae; nevertheless, new ketolide antimicrobials may have a role to play in the treatment and control of this re-emergent pathogen.

Anti-Bacterial Agents↗
PubMed2000

Signalling pathways regulating the dephosphorylation of Ser729 in the hydrophobic domain of protein kinase Cepsilon upon cell passage.

We have recently demonstrated that in quiescent fibroblasts protein kinase C (PKC) epsilon(95) is phosphorylated at Ser(729), Ser(703), and Thr(566) and that upon passage of quiescent cells phosphorylation at Ser(729) is lost, giving rise to PKCepsilon(87). Ser(729) may be rephosphorylated later, suggesting cycling between PKCepsilon(87) and PKCepsilon(95). Here we show that the dephosphorylation at Ser(729) is insensitive to okadaic acid, calyculin, ascomycin C, and cyclosporin A, suggesting that dephosphorylation at this site is not mediated through protein phosphatases 1, 2A or 2B. We demonstrate that this dephosphorylation at Ser(729) requires serum and cell readhesion and is sensitive to rapamycin, PD98059, chelerythrine, and Ro-31-8220. These results suggest that the phosphorylation status of Ser(729) in the hydrophobic domain at Ser(729) is regulated independently of the phosphorylation status of other sites in PKCepsilon, by a mTOR-sensitive phosphatase. The mitogen-activated protein kinase pathway and PKC are also implicated in regulating the dephosphorylation at Ser(729).

3T3 Cells↗
PubMed2000

Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice.

Clinical case reports have documented disturbances of carbohydrate and lipid metabolism in aromatase deficient and estrogen resistant males. The aim of the present study was to explore the metabolic functions of estrogens in male mice and to dissect the estrogen receptor (ER) specificity of such effects. Total body fat content and serum levels of leptin were followed in ERalpha knockout (ERKO), ERbeta knockout (BERKO), and ERalpha/beta double knockout (DERKO) mice. Neither the total body fat nor serum leptin levels were altered in any group before or during sexual maturation. However, after sexual maturation ERKO and DERKO, but not BERKO, demonstrated a clear increase in total body fat and enhanced serum leptin levels. Serum cholesterol was increased and a qualitative change in the lipoprotein profile, including smaller LDL particles, was observed in ERKO and DERKO mice. In conclusion, ERalpha but not ERbeta-inactivated male mice develop obesity after sexual maturation.

Adipose Tissue↗
PubMed2000

Estrogen receptor beta in the breast: role in estrogen responsiveness and development of breast cancer.

Breast cancer is one of the most common forms of cancer observed in women. Endogenous estrogen is thought to play a major role in its development and estrogen receptor blockers are the most important drugs in its treatment. It has long been thought that any conditions or exposures, which enhance estrogenic responses, would result in an increased risk for breast cancer. The discovery of the second estrogen receptor, ERbeta, which can have effects opposite to those of the well-known 'original' estrogen receptor (now called ERalpha) challenges this simplistic view. In order to understand breast cancer one must first understand how the normal breast is maintained. The functions of ERbeta in the breast remain to be defined but from what we have learnt about its activities in in vitro systems, this estrogen receptor may have a protective role in the breast. Studies in human and rodent breasts as well as in human breast cancer biopsies reveal that ERbeta is by far the more abundant of the two ERs. Despite the role of estrogen in proliferation of the breast, neither of the two ERs appears to located in epithelial cells which divide in response to estrogen. In order to define the functions of ERbeta in the normal and malignant breast, we have created mice in which the ERbeta gene has been inactivated. Studies of the breasts of ERbeta knock out mice (BERKO) revealed abnormal epithelial growth, overexpression of Ki67 and severe cystic breast disease as mice age.

Animals↗
PubMed2000

Untwisting of a cholesteric elastomer by a mechanical field

A mechanical strain field applied to a monodomain cholesteric elastomer will unwind the helical director distribution. There are similarities with the classical problem of an electric field applied to a cholesteric liquid crystal but also differences. Frank elasticity is of minor importance unless the gel is very weak. The interplay is between the director being helically anchored to the rubber elastic matrix and the external mechanical field. Stretching perpendicular to the helix axis induces the uniform unwound state via the elimination of sharp, pinned twist walls above a critical strain. Unwinding through conical director states occurs when the elastomer is stretched along the helical axis.

Journal Article↗
PubMed2000

Theory of chiral imprinting

We present a continuum model for a nematic elastomer network formed in a chiral environment, for instance, in the presence of a chiral solvent. When this environment is removed, the network can retain some memory of its chiral genesis. We predict the residual chiral order for a number of possible scenarios, and examine the robustness (stability) of the imprinted chirality. We show that a twist-untwist transition can take place, which determines whether the imprinting has been successful. A transition is via a coarsening of the helical director pattern and a lengthening of its pitch. Finally, the effect due to a subsequent swelling by an achiral solvent, or by a solvent of differing chirality, is considered.

Journal Article↗
PubMed2000

Estrogen receptor (ER) beta, a modulator of ERalpha in the uterus.

Many of the effects of estrogens on the uterus are mediated by ERalpha, the predominant ER in the mature organ. Because of the poor reproductive capacity of ERbeta knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ERbeta was explored. In the immature uterus, ERalpha and ERbeta are expressed at comparable levels in the epithelium and stroma, and 17beta-estradiol (E(2)) treatment decreases ERbeta in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E(2), as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1beta, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E(2) increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E(2) induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response to E(2) in BERKO suggest that ERbeta plays a role in modulation of the effects of ERalpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.

Animals↗
PubMed2000

The elasticity and failure of fluid-filled cellular solids: theory and experiment.

We extend and apply theories of filled foam elasticity and failure to recently available data on foods. The predictions of elastic modulus and failure mode dependence on internal pressure and on wall integrity are borne out by photographic evidence of distortion and failure under compressive loading and under the localized stress applied by a knife blade, and by mechanical data on vegetables differing only in their turgor pressure. We calculate the dry modulus of plate-like cellular solids and the cross over between dry-like and fully fluid-filled elastic response. The bulk elastic properties of limp and aging cellular solids are calculated for model systems and compared with our mechanical data, which also show two regimes of response. The mechanics of an aged, limp beam is calculated, thus offering a practical procedure for comparing experiment and theory. This investigation also thereby offers explanations of the connection between turgor pressure and crispness and limpness of cellular materials.

Biomechanical Phenomena↗
PubMed2000

Estrogen receptors alpha and beta in the rodent mammary gland.

An obligatory role for estrogen in growth, development, and functions of the mammary gland is well established, but the roles of the two estrogen receptors remain unclear. With the use of specific antibodies, it was found that both estrogen receptors, ERalpha and ERbeta, are expressed in the rat mammary gland but the presence and cellular distribution of the two receptors are distinct. In prepubertal rats, ERalpha was detected in 40% of the epithelial cell nuclei. This decreased to 30% at puberty and continued to decrease throughout pregnancy to a low of 5% at day 14. During lactation there was a large induction of ERalpha with up to 70% of the nuclei positive at day 21. Approximately 60-70% of epithelial cells expressed ERbeta at all stages of breast development. Cells coexpressing ERalpha and ERbeta were rare during pregnancy, a proliferative phase, but they represented up to 60% of the epithelial cells during lactation, a postproliferative phase. Western blot analysis and sucrose gradient centrifugation confirmed this pattern of expression. During pregnancy, the proliferating cell nuclear antigen was not expressed in ERalpha-positive cells but was observed in 3-7% of ERbeta-containing cells. Because more than 90% of ERbeta-bearing cells do not proliferate, and 55-70% of the dividing cells have neither ERalpha nor ERbeta, it is clear that the presence of these receptors in epithelial cells is not a prerequisite for estrogen-mediated proliferation.

Animals↗
PubMed2000

Mechanism of oestrogen signalling with particular reference to the role of ER beta in the central nervous system.

The discovery of a second oestrogen receptor (ER), ER beta, has drastically changed our view of oestrogen action. Since the two ERs, ER alpha and ER beta, have somewhat different tissue and cellular distribution as well as ligand binding specificity the possibility exists that they have different biological roles. Indeed, several observations seem to indicate that they may even have opposite effects so that ER beta diminishes the activity of ER alpha. The CNS contains both ER alpha and ER beta and it is conceivable that they may have specific and individual roles in oestrogen signalling in the brain.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Activity of linezolid against multi-resistant gram-positive bacteria from diverse hospitals in the United Kingdom.

The in vitro activity of linezolid, an oxazolidinone, was assessed against 374 gram-positive cocci, with an emphasis on testing multi-resistant, epidemiologically unrelated isolates. MICs of linezolid for staphylococci, pneumococci and streptococci had a narrow range, from 0.5 to 2 mg/L, whereas MICs for enterococci were uniformly 4 mg/L. For all the species tested, the MICs of linezolid were unrelated to those of other antimicrobials. Linezolid appears to be a potentially useful drug for infections caused by gram-positive cocci.

Acetamides↗
PubMed2000

Susceptibility to quinupristin/dalfopristin and other antibiotics of vancomycin-resistant enterococci from the UK, 1997 to mid-1999.

Susceptibility to quinupristin/dalfopristin and other antibiotics was studied for clinical isolates of vancomycin-resistant enterococci (VRE) referred by UK hospitals between January 1997 and June 1999. Single isolates of VRE from 858 patients in 136 hospitals were received, of which 76% were Enterococcus faecium and 21% were Enterococcus faecalis, the remainder comprising minor species. Most isolates were multi-resistant. After allowing for the effect of blood, which raised the MICs of quinupristin/dalfopristin four-fold, 98.3% of E. faecalis isolates and all the Enterococcus avium, Enterococcus casseliflavus and Enterococcus gallinarum appeared resistant to quinupristin/dalfopristin, whereas 98.8% of the E. faecium isolates and the single Enterococcus raffinosus isolate were susceptible.

Drug Therapy, Combination↗
PubMed2000

Susceptibility of gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid. The Linezolid Study Group.

The prevalence of antibiotic resistance amongst Gram-positive cocci from 25 UK hospitals was studied over an 8 month period in 1999. A total of 3770 isolates were tested by the sentinel laboratories using the Etest; these bacteria comprised 1000 pneumococci, 1005 Staphylococcus aureus, 769 coagulase-negative staphylococci (CNS) and 996 enterococci. To ensure quality, 10% of the isolates were retested centrally, as were any found to express unusual resistance patterns. The prevalence of penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci and methicillin-resistant S. aureus (MRSA) varied widely amongst the sentinel laboratories. The resistance rates to methicillin among S. aureus and CNS were 19.2 and 38.9%, respectively, with MRSA rates in individual sentinel sites ranging from 0 to 43%. No glycopeptide resistance was seen in S. aureus, but 6.5% of CNS isolates were teicoplanin resistant and 0.5% were vancomycin resistant. Vancomycin resistance was much more frequent among Enterococcus faecium (24.1%) than E. faecalis (0.5%) (P<0.05), with most resistant isolates carrying vanA. The rate of penicillin resistance in pneumococci was 8.9%, and this resistance was predominantly intermediate (7.9%), with only six hospitals reporting isolates with high level resistance. The prevalence of erythromycin resistance among pneumococci was 12.3%, with the majority of resistant isolates having the macrolide efflux mechanism mediated by mefE. All the organisms tested were susceptible to linezolid with MICs in the range 0.12-4 mg/L. The modal MICs of linezolid were 1 mg/L for CNS and pneumococci, and 2 mg/L for S. aureus and enterococci. Linezolid was the most potent agent tested against Gram-positive cocci, including multiresistant strains, and as such may prove a valuable therapeutic option for the management of Gram-positive infections in hospitals.

Acetamides↗
PubMed2000

Director rotation via photoinduced differential depletion in nematic dyes

We revisit the problem of director realignment induced by photoisomerization of rodlike dye molecules. We find a geometrical basis for the rotational rate, arising by the differential depletion of rods from the nematic distribution. A simple expression, valid for arbitrarily strong, Maier-Saupe-like nematic order, is given for this rate. Contact is made with the weak order scaling limit given in the literature.

Journal Article↗