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Biomedical subjects

L Gibson

Publications and source records attributed to L Gibson.

At least 19 recordsLinked to original sources
PubMed2003

Aromatase inhibitors as adjuvant therapies in patients with breast cancer.

There is increasing evidence that endocrine therapy has an important role in patients with oestrogen receptor positive breast cancer. Several large meta-analyses have reinforced the value of both ovarian ablation and tamoxifen in improving survival. Over the past decade, aromatase inhibitors have become the treatment of choice for second-line therapy of metastatic breast cancer, and the third generation inhibitors have now an established reputation for good patient tolerability. Early studies indicated that aminoglutethimide/hydrocortisone could benefit postmenopausal patients with primary breast cancer, and in 2001, the ATAC study showed that the third generation aromatase inhibitor, anastrozole, seemed superior to tamoxifen in that anastrozole-treated patients had a longer disease-free survival. Other studies will report on the relative merits of the steroidal inhibitor exemestane as well as non-steroidal letrozole. The exact duration and sequencing of treatment, together with the long-term effects on bone are at present, unknown.

Aromatase Inhibitors↗
PubMed2001

Principles for pressure ulcer prevention in the community.

This article aims to examine the prevention of pressure ulcers in the community. Pressure ulcers continue to cause needless distress and anxiety for patients, carers and their families. Health professionals in the community often face extreme challenges when caring for patients who are at risk of developing pressure ulcers. This could be due to lack of appropriate assessment skills and having insufficient time to conduct an appropriate assessment. Having an understanding and awareness of the function of the skin and the aetiology of pressure ulcer development can assist the health professional in attempting to take a proactive approach to prevent pressure ulcer formation in the community setting.

Community Health Nursing↗
PubMed1999

Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment.

To develop a method for targeting expression of genes to the full hematopoietic system, we have used transgenic mice to explore the transcriptional regulation of the vav gene, which is expressed throughout this compartment but rarely outside it. Previously, we showed that a cluster of elements surrounding its promoter could drive hematopoietic-specific expression of a bacterial lacZ reporter gene, but the expression was confined to lymphocytes and was sporadically silenced. Those limitations are ascribed here to the prokaryotic reporter gene. With a human CD4 (hCD4) cell surface reporter, the vav promoter elements drove expression efficiently and stably in virtually all nucleated cells of adult hematopoietic tissues but not notably in nonhematopoietic cell types. In multiple lines, hCD4 appeared on most, if not all, B and T lymphocytes, granulocytes, monocytes, megakaryocytes, eosinophils, and nucleated erythroid cells. Moreover, high levels appeared on both lineage-committed progenitors and the more primitive preprogenitors. In the fetus, expression was evident in erythroid cells of the definitive but not the primitive type. These results indicate that a prokaryotic sequence can inactivate a transcription unit and that the vav promoter region constitutes a potent transgenic vector for the entire definitive hematopoietic compartment.

Animals↗
PubMed1999

Role of ERAB/L-3-hydroxyacyl-coenzyme A dehydrogenase type II activity in Abeta-induced cytotoxicity.

Endoplasmic reticulum-associated amyloid beta-peptide (Abeta)-binding protein (ERAB)/L-3-hydroxyacyl-CoA dehydrogenase type II (HADH II) is expressed at high levels in Alzheimer's disease (AD)-affected brain, binds Abeta, and contributes to Abeta-induced cytotoxicity. Purified recombinant ERAB/HADH II catalyzed the NADH-dependent reduction of S-acetoacetyl-CoA with a Km of approximately 68 microM and a Vmax of approximately 430 micromol/min/mg. The contribution of ERAB/HADH II enzymatic activity to Abeta-mediated cellular dysfunction was studied by site-directed mutagenesis in the catalytic domain (Y168G/K172G). Although COS cells cotransfected to overexpress wild-type ERAB/HADH II and variant beta-amyloid precursor protein (betaAPP(V717G)) showed DNA fragmentation, cotransfection with Y168G/K172G-altered ERAB and betaAPP(V717G) was without effect. We thus asked whether the enzyme might recognize alcohol substrates of which the aldehyde products could be cytotoxic; ERAB/HADH II catalyzed oxidation of a variety of simple alcohols (C2-C10) to their respective aldehydes in the presence of NAD+ and NAD-dependent oxidation of 17beta-estradiol. Addition of micromolar levels of synthetic Abeta(1-40) to purified ERAB/HADH II inhibited, in parallel, reduction of S-acetoacetyl-CoA (Ki approximately 1.6 microM), as well as oxidation of 17beta-estradiol (Ki approximately 3.2 microM) and (-)-2-octanol (Ki approximately 2.6 microM). Because micromolar levels of Abeta were required to inhibit ERAB/HADH II activity, whereas Abeta binding to ERAB/HADH II occurred at much lower concentrations (Km approximately 40-70 nM), the latter more closely simulating Abeta levels within cells, Abeta perturbation of ERAB/HADH II was likely to result from mechanisms other than the direct modulation of enzymatic activity. Cells cotransfected to overexpress ERAB/HADH II and betaAPP(V717G) generated malondialdehyde-protein and 4-hydroxynonenal-protein epitopes, which were detectable only at the lowest levels in cells overexpressing either ERAB/HADH II or betaAPP(V717G) alone. Generation of such toxic aldehydes was not observed in cells contransfected to overexpress Y168G/K172G-altered ERAB and betaAPP(V717G). We conclude that the generalized alcohol dehydrogenase activity of ERAB/HADH II is central to the cytotoxicity observed in an Abeta-rich environment.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Retroviral transduction of enriched hematopoietic stem cells allows lifelong Bcl-2 expression in multiple lineages but does not perturb hematopoiesis.

Transduction of hematopoietic stem cells with a novel retrovirus has allowed long-term expression of human Bcl-2 in multiple hematopoietic lineages. Thy-1.2lo Sca-1+ H-2Khi stem cells enriched from the bone marrow of 5-fluorouracil-treated (Ly5-2) mice were infected with the bcl-2 retrovirus and injected into (Ly5-1) irradiated recipients. Analysis at 5 months indicated that reconstitution of hematopoiesis occurred predominantly from donor-derived (Ly5-2+) stem cells and that, in half the mice (18 of 35), most blood cells derived from virally transduced stem cells. The level of Bcl-2 expression achieved with the retroviral vector approached that of a well-characterized transgenic vector and could be sustained for life in several blood cell lineages. In the 25 mice assessed at 10 months, human Bcl-2 was readily detectable in 62+/-22% of Ly5-2+ peripheral blood leukocytes. More detailed analysis of a cohort killed between 14 and 20 months established that human Bcl-2 protein could be detected in B and T lymphocytes, granulocytes, macrophages, and some immature erythroid cells. Furthermore, hematopoietic stem cells from the bone marrow of these mice maintained Bcl-2 expression in hematopoietic tissues of secondary recipients for at least another 19 months. These data provide clear evidence for efficient infection of primitive hematopoietic stem cells and for maintenance of proviral expression for over 2.5 years, the lifespan of mice. The level of exogenous Bcl-2 was sufficient to enhance survival of B and T lymphoid cells, granulocytes, and myeloid colony-forming cells cultured under suboptimal conditions, but hematopoiesis in the mice was not notably perturbed.

Animals↗
PubMed1999

Eccentric exercise markedly increases c-Jun NH(2)-terminal kinase activity in human skeletal muscle.

Eccentric contractions require the lengthening of skeletal muscle during force production and result in acute and prolonged muscle injury. Because a variety of stressors, including physical exercise and injury, can result in the activation of the c-Jun NH(2)-terminal kinase (JNK) intracellular signaling cascade in skeletal muscle, we investigated the effects of eccentric exercise on the activation of this stress-activated protein kinase in human skeletal muscle. Twelve healthy subjects (7 men, 5 women) completed maximal concentric or eccentric knee extensions on a KinCom isokinetic dynamometer (10 sets, 10 repetitions). Percutaneous needle biopsies were obtained from the vastus lateralis muscle 24 h before exercise (basal), immediately postexercise, and 6 h postexercise. Whereas both forms of exercise increased JNK activity immediately postexercise, eccentric contractions resulted in a much higher activation (15.4 +/- 4.5 vs. 3.5 +/- 1.4-fold increase above basal, eccentric vs. concentric). By 6 h after exercise, JNK activity decreased back to baseline values. In contrast to the greater activation of JNK with eccentric exercise, the mitogen-activated protein kinase kinase 4, the immediate upstream regulator of JNK, was similarly activated by concentric and eccentric exercise. Because the activation of JNK promotes the phosphorylation of a variety of transcription factors, including c-Jun, the results from this study suggest that JNK may be involved in the molecular and cellular adaptations that occur in response to injury-producing exercise in human skeletal muscle.

Adult↗
PubMed1998

Apoptosis regulator bcl-w is essential for spermatogenesis but appears otherwise redundant.

Proteins of the Bcl-2 family are important regulators of apoptosis in many tissues of the embryo and adult. The recently isolated bcl-w gene encodes a pro-survival member of the Bcl-2 family, which is widely expressed. To explore its physiological role, we have inactivated the bcl-w gene in the mouse by homologous recombination. Mice that lack Bcl-w were viable, healthy, and normal in appearance. Most tissues exhibited typical histology, and hematopoiesis was unaffected, presumably due to redundant function with other pro-survival family members. Although female reproductive function was normal, the males were infertile. The testes developed normally, and the initial, prepubertal wave of spermatogenesis was largely unaffected. The seminiferous tubules of adult males, however, were disorganized, contained numerous apoptotic cells, and produced no mature sperm. Both Sertoli cells and germ cells of all types were reduced in number, the most mature germ cells being the most severely depleted. The bcl-w-/- mouse provides a unique model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility.

Animals↗
PubMed1998

CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo.

CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection of the human thymus. In contrast, infection with R5 strains of HIV-1 can result in a two-phase process in vivo, involving apparently nonpathogenic replication in medullary stromal cells followed by cytopathic replication in thymocytes.

Animals↗
PubMed1998

Epinephrine and insulin stimulate different mitogen-activated protein kinase signaling pathways in rat skeletal muscle.

Little is known about the regulation of the mitogen-activated protein (MAP) kinase signaling cascades by hormonal stimulation in vivo. The extracellular signal-regulated kinase (ERK) and the c-jun kinase (JNK) are two MAP kinase signaling pathways that could play a role in the cellular response to hormones such as insulin and epinephrine. We studied the effects of insulin (20 U/rat) and epinephrine (25 microg/100 g body wt) injected in vivo on ERK and JNK signaling in skeletal muscle from Sprague-Dawley rats. Insulin significantly increased ERK phosphorylation and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2), by 1.4-fold, but it had no effect on JNK activity. In contrast, epinephrine had no effect on ERK phosphorylation or RSK2 activity, but it increased JNK activity by twofold, an effect that was inhibited by the presence of combined alpha and beta blockade. Furthermore, the phosphorylation of both p46 and p55 isoforms of JNK, measured by phosphospecific antibody, was increased severalfold. The activity and phosphorylation of MAP kinase kinase (MKK)-4, an upstream regulator of JNK, was unchanged by epinephrine. Incubation of isolated soleus muscles in vitro with epinephrine (10(-5) mol/l) also increased JNK activity by twofold. These data are the first to demonstrate that epinephrine can increase JNK activity. Insulin and epinephrine have different effects on MAP kinase signaling pathways in skeletal muscle, which may be one of the underlying molecular mechanisms through which these hormones regulate opposing metabolic functions.

Animals↗
PubMed1997

Trends in invasive cervical cancer incidence in East Anglia from 1971 to 1993.

OBJECTIVE: To study the trends in the incidence of invasive cervical cancer in East Anglia. DESIGN: Statistical analysis of age specific incidence rate for the period 1971-93 using East Anglian Cancer Registry data. SUBJECTS: All cases of invasive cervical cancer registered with the East Anglian Cancer registry, diagnosed in the period 1971-93. MAIN OUTCOME MEASURES: Changing incidence of cervical cancer. RESULTS: For the 20 years 1971-90, trends varied widely by district and by age group, with little discernible overall effect of the increasing screening activity. Since 1990, rates have fallen sharply in the age groups targeted for screening, with a reduction of 34% (95% confidence interval 26% to 42%) from that expected based on 1971-90 trends. This fall was preceded by a rapid rise in the national uptake of screening. A shift to more favourable stage at diagnosis has also occurred. CONCLUSION: Changes in the organisation and management of the national screening programme introduced in 1988 and 1989 seem to have led to substantial improvements in effectiveness.

Adult↗
PubMed1996

bcl-w, a novel member of the bcl-2 family, promotes cell survival.

The prototypic mammalian regulator of cell death is bcl-2, the oncogene implicated in the development of human follicular lymphoma. Several homologues of bcl-2 are now known. Using a PCR-based strategy we cloned a novel member of this gene family, denoted bcl-w. The gene, which is highly conserved between mouse and human, resides near the T-cell antigen receptor alpha gene within the central portion of mouse chromosome 14 and on human chromosome 14 at band q11. Enforced expression of bcl-w rendered lymphoid and myeloid cells refractory to several (but not all) cytotoxic conditions. Thus, like Bcl-2 and Bcl-x, the Bcl-w protein promotes cell survival, in contrast to other close homologues, Bax and Bak, which facilitate cell death. Comparison of the expected amino acid sequence of Bcl-w with that of these relatives helps to delineate residues likely to convey survival or anti-survival function. While expression of bcl-w was uncommon in B or T lymphoid cell lines, the mRNA was observed in almost all murine myeloid cell lines analysed and in a wide range of tissues. These findings suggest that bcl-w participates in the control of apoptosis in multiple cell types. Its functional similarity to bcl-2 also makes it an attractive candidate proto-oncogene.

Amino Acid Sequence↗
PubMed1996

Body fat distribution in South Asian women and children.

OBJECTIVE: To compare levels of abdominal fatness in South Asian and European mothers and children. SUBJECTS: 49 mothers and children from South Asian backgrounds and 63 mothers and children from European backgrounds who took part in a study on family health behaviours. MEASUREMENTS: Anthropometric measures and abdominal fatness indices, including WHR and conicity. RESULTS: Asian mothers were shorter, and lighter than European mothers, but had a higher WHR and a higher conicity. Among children, boys had a higher WHR and conicity than girls but there were no ethnic differences in fat distribution. CONCLUSION: Different patterns of fat distribution were observed in South Asian and European women, with South Asian women having a relatively large waist circumference, relative either to hip circumference (WHR) or to overall size (conicity). Sex differences in fat distribution, but not ethnic differences, were observed in the children. This suggests that the adult patterns of fat distribution may not be established at this stage.

Abdomen↗
PubMed1995

Isolation, characterization, and chromosomal localization of mouse and human COUP-TF I and II genes.

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in many species, from Drosophila to human. The protein sequences of COUP-TFs are highly homologous across species, suggesting functional conservation. Two COUP-TF genes have been cloned from human, and their genomic organizations have been characterized. To determine whether the genomic organization is conserved between human and mouse, we isolated two mouse COUP-TF genes (I and II) and characterized their genomic structures. Both genes have relatively simple structures that are similar to those of their human counterparts. In addition, we mapped mouse COUP-TF I to the distal region of chromosome 13 and COUP-TF II to the central region of chromosome 7. Furthermore, we mapped human COUP-TF I to 5q14 of chromosome 5 and COUP-TF II to 15q26 of chromosome 15. The results demonstrate that COUP-TF genes are located in chromosomal regions that are syntenic between mouse and human.

Animals↗
PubMed1995

A de novo satellited short arm of the Y chromosome possibly resulting from an unstable translocation.

A satellited long arm of the Y chromosome (Yqs) is considered a normal variation, whereas the presence of a satellite on the short arm of the Y (Yps) has never been described in the literature. A Yps chromosome could be clinically significant if the translocation resulting in Yps has relocated the testis-determining gene, SRY, to another chromosome. A carrier of such a translocation would therefore be at increased risk for having XX male and XY female offspring. Here we describe the first reported case of de novo Yps present in a phenotypically normal male. This Yps chromosome was positive for C-banding and nucleolus organizer region (NOR) staining and showed a hybridization signal for the beta-satellite sequence. Fluorescence in situ hybridization (FISH) analysis indicated that SRY was retained on the Yps and the translocation breakpoint on Yps was distal to the pseudoautosomal region. At prenatal diagnosis, a normal appearing Y chromosome was found in his son, and thus the satellite on Yps was lost during meiotic Xp-Yp pairing. This Yps chromosome was likely the product of an "unstable" translocation.

Adult↗
PubMed1995

An assessment of partial rescreening as an internal quality control method for cervical smears.

Partial screening was performed on 10,800 cervical smears, comprising 8640 filed negative and unsatisfactory smears and 2160 newly received smears prior to conventional screening. Each slide was screened for 30 s and those considered abnormal were reviewed by standard screening. Partial screening led to the detection of 27 additional infections and 44 additional cytological abnormalities. These detection rates are better than those obtained with the traditional method of rescreening only a proportion of smears. Amongst the smears partially screened before conventional screening, partial screening detected 37-66% of infections and 22-71% of cytological abnormalities. We recommend the use of partial rescreening of all negatively reported smears as a method of internal quality control in cervical cytology laboratories.

Evaluation Studies as Topic↗