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Biomedical subjects

L Turner

Publications and source records attributed to L Turner.

At least 55 records · Page 3Linked to original sources
PubMed1999

Hypoxia inhibits macrophage migration.

The chemokine monocyte chemoattractant protein (MCP)-1 plays a role in regulating the lymphocyte and macrophage infiltrate in ovarian cancer, but macrophages also accumulate in necrotic areas of the tumors where there is little MCP-1 expression (Negus, R. P. M. et al., Am. J. Pathol. 1997. 150: 1723-1734). Necrotic regions are likely to be hypoxic. In this study we show that hypoxia inhibits MCP-1-induced migration of THP-1 monocytic cells and human macrophages. In contrast, lymphocytes from peripheral blood migrate normally to an MCP-1 gradient in hypoxic conditions. The inhibition of monocyte migration by hypoxia is rapid and reversible. At the exposure times studied (30-90 min) hypoxia does not affect expression of the MCP-1 receptor CCR2B and cells exposed to hypoxia still respond to MCP-1 with an elevation of intracellular calcium. Although hypoxia is known to modulate gene expression, the inhibition of migration reported here was not due to the production of soluble factors, and mRNA expression of macrophage migration inhibitory factor was unchanged. Hypoxia-induced inhibition of chemotaxis was not limited to MCP-1. Hypoxia also inhibited the chemotactic response to macrophage inflammatory protein-1alpha, RANTES and the chemoattractant N-formyl-met-leu-phe, but hypoxic cells were still able to phagocytose opsonized red blood cells. We suggest that inhibition of migration by hypoxia is not due to gene regulation but is a reflection of metabolic changes in the cell. Transient hypoxia may regulate the distribution of macrophages in tumors and other inflammatory conditions.

Cell Hypoxia↗
PubMed1999

Temperature dependence of switching of the bacterial flagellar motor by the protein CheY(13DK106YW).

The behavior of the bacterium Escherichia coli is controlled by switching of the flagellar rotary motor between the two rotational states, clockwise (CW) and counterclockwise (CCW). The molecular mechanism for switching remains unknown, but binding of the response regulator CheY-P to the motor component FliM enhances CW rotation. This effect is mimicked by the unphosphorylated double mutant CheY13DK106YW (CheY**). To learn more about switching, we measured the fraction of time that a motor spends in the CW state (the CW bias) at different concentrations of CheY** and at different temperatures. From the CW bias, we computed the standard free energy change of switching. In the absence of CheY, this free energy change is a linear function of temperature (. Biophys. J. 71:2227-2233). In the presence of CheY**, it is nonlinear. However, the data can be fit by models in which binding of each molecule of CheY** shifts the difference in free energy between CW and CCW states by a fixed amount. The shift increases linearly from approximately 0.3kT per molecule at 5 degrees C to approximately 0.9kT at 25 degrees C, where k is Boltzmann's constant and T is 289 Kelvin (= 16 degrees C). The entropy and enthalpy contributions to this shift are about -0. 031kT/ degrees C and 0.10kT, respectively.

Allosteric Regulation↗
PubMed1999

Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis.

Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-alpha production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Building a better biotech company.

Invitrogen is a good case study for how to become successful in the rapidly changing field of biotechnology by observing basic business principles. It also shows that even the most successful companies make mistakes. The exciting opportunities that present themselves to high-technology companies in fast-growth fields can divert attention away from the most basic business tenets of quality, profitability, and market responsiveness. CEOs in the biotechnology sector would be well served to review their Business 101 lessons.

Biotechnology↗
PubMed1999

Extrusion of testosterone pellets: a randomized controlled clinical study.

BACKGROUND: It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side-effect. The present study aimed to reduce the extrusion rate. OBJECTIVE: To determine whether the washing of testosterone pellets to remove potentially surface-adherent particles decreased the rate of extrusion of pellet implants. DESIGN: Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group. PATIENTS: The study included 251 testosterone implantation procedures in men with known androgen deficiency. MEASUREMENTS: The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end-points included peri-procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow-up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors. RESULTS: In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI 0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77). CONCLUSIONS: The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow-up or a secular trend.

Drug Implants↗
PubMed1999

George Rupert Palmer--DRG carrier and champion.

Prompted by the retirement of the distinguished health economist, researcher and academic, Professor George Rupert Palmer, the purpose of this paper is to reflect upon and acknowledge one of his many contributions to health services research and development. By employing a conceptual framework devised by Kimberly and de Pouvourville (1993) for analysis of the diffusion of innovations, this paper argues that Palmer played a crucial role in the diffusion into and within Australia of a particular casemix method, diagnosis related groups (DRGs). Textual and interview evidence presented in the paper supports the identification of George Rupert Palmer as the principal carrier of DRGs into Australia, and as one of its key champions within Australia.

Australia↗
PubMed1999

Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men.

In order to evaluate the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH) in combination with urinary human chorionic gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin-deficient men, we conducted a prospective, open, non-comparative multicentre study in two Australian academic medical centres. Ten men with gonadotrophin deficiency requiring induction of spermatogenesis and fertility were treated with HCG for 3-6 months followed by the s.c. self-administration of injections of r-hFSH in combination with HCG for 18 months. Among the eight men who commenced r-hFSH treatment, seven demonstrated sperm output at a median of 6 months and five achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment. Three men produced pregnancies in their partners, two of which resulted in the birth of healthy babies and a third patient's partner had a miscarriage. We conclude that r-hFSH is well tolerated and effective in inducing testis growth, spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r-hFSH seems comparable with urinary FSH at restoring normal fertility in gonadotrophin-deficient men.

Adolescent↗
PubMed1999

Testing a random phase approximation for bounded turbulent flow.

Tractable implementation of a spectral closure requires that the modal representation of the energy satisfy a restricted random phase approximation (RRPA). This condition is exactly satisfied when the statistical system is homogeneous and the basis functions are Fourier modes. In this case, the ensemble average of the spectral covariance diagonalizes, i.e., =delta(k(1)+k(2)) , where c(k,t) is a Fourier coefficient in a Galerkin representation of the velocity field. However, for inhomogeneous statistical systems in which the Fourier system is inappropriate, the RRPA requires validation. We use direct numerical simulations (DNSs) of the Navier-Stokes and truncated Euler equations to test the degree to which the RRPA is satisfied when applied to a recent representation due to Turner (LANL Unclassified Report No. LA-UR-96-3257) of a bounded turbulent rectangular channel flow with free slip, stress free walls. It is shown that a complete test of the RRPA for a fully inhomogeneous DNS with N3 grid points actually requires N3+1 members in the ensemble. The "randomness" of the phase can be characterized by a probability density function (PDF) of the modulus of the normalized spectral covariance. Results reveal that for both the Navier-Stokes and Euler systems the PDF does not change in time as the turbulence decays, and that the PDF for the Euler system is virtually identical to the one produced from an ensemble of random fields. This result is consistent with the equipartition of energy for the Euler system, in which the RRPA becomes an exact result rather than an approximation as the number of realizations approaches N3+1. The slight differences observed between the PDF produced from the random fields and the one from the Navier-Stokes system are thus shown to be entirely a result of the presence of a finite viscosity. It is also shown that there is great variation between statistics computed over the ensemble and those for a single realization.

Journal Article↗
PubMed1999

Ethnicity and migration as determinants of human prostate size.

The roles of ethnicity and migration in determining the size of human prostate zones during midlife were explored. Prostate size was measured by planimetric ultrasound in 163 men residing in Sydney who were either Australian non-Chinese (AR; n = 116) or Chinese migrants (ACM; n = 47) and had lived in Australia for a median of 7.3 yr (range, 0.2-25 yr). These were compared with Chinese men residing in China (CR; n = 210). Central and total prostate volumes were estimated by a single observer using the same equipment at both sites. After adjustment for age, central and total prostate volumes were significantly smaller, and plasma prostate-specific antigen and 5alpha-dihydrotestosterone (DHT) concentrations and International Prostate Syndrome Scores were significantly lower, in CR compared with either ACM or AR, whereas the scores of the latter two groups were similar. Almost all of the population difference in total prostate volumes could be accounted for by differences in central prostate volumes. The strongest correlates of age-adjusted prostate volume were prostate-specific antigen and DHT, the latter presumably reflecting the quantitative importance of prostatic stromal type II 5alpha-reductase activity to circulating DHT concentrations. Sex hormone-binding globulin concentrations were significantly higher in CR and significantly lower in ACM compared with those in AR, but the significance of these observations is unclear. These findings highlight the importance of the central zone of the prostate as well as provide evidence for an environmental factor influencing prostate growth. This factor operates over a relatively short time period compared with the evolution of prostate disease. Hence, this study provides evidence that ethnicity and geographical factors, such as migration, can influence the growth of the normal human prostate during midlife and may facilitate future studies of the origins and pathogenesis of human prostate disease.

Adult↗
PubMed1998

Control of direction of flagellar rotation in bacterial chemotaxis.

The motile behavior of the bacterium Escherichia coli depends on the direction of rotation of its flagellar motors. Binding of the phosphorylated signaling molecule CheY to a motor component FliM is known to enhance clockwise rotation. It is difficult to study this interaction in vivo, because the dynamics of phosphorylation of CheY by its kinase CheA and the hydrolysis of CheY (accelerated by CheZ) are not under direct experimental control. Here, we examine instead the interaction with the flagellar motor of a double mutant CheY13DK106YW that is active without phosphorylation. The behavioral assays were carried out on tethered cells lacking CheA and CheZ. The effects of variation in intracellular concentration of the mutant protein were highly nonlinear. However, they can be explained by a thermal isomerization model in which the free energies of clockwise and counterclockwise states depend linearly on the amount of CheY bound.

Bacterial Proteins↗
PubMed1998

Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors.

Monocyte chemoattractant protein 1 (MCP-1) is likely to contribute to the macrophage infiltrate in human ovarian carcinomas. Although MCP-1 is predominantly expressed by the tumor parenchyma, macrophages accumulate at highest density in necrotic regions, which are associated with low oxygen tensions. Tumor necrosis factor alpha (TNF-alpha) can stimulate MCP-1 production and is also present within ovarian carcinomas. We have investigated the effect of hypoxia both on MCP-1 expression in ovarian cancer cell lines and monocyte migration. Hypoxia down-regulated TNF-alpha-induced MCP-1 mRNA and protein production by ovarian cancer cells. The effect was mimicked by cobalt chloride and desferrioxamine, consistent with a specific oxygen-sensing mechanism. Unlike antioxidants, hypoxia did not inhibit nuclear factor KB mobilization. Monocyte migration in response to MCP-1 was also diminished under hypoxic conditions. Down-regulation of MCP-1 expression and the inhibition of monocyte migration are independent effects of hypoxia that may contribute to the distribution of macrophages within ovarian tumors.

Antigens, CD↗
PubMed1998

Vascular reactivity is impaired in genetic females taking high-dose androgens.

OBJECTIVE: To assess the vascular effects of high-dose androgen treatment in genetic females. BACKGROUND: Male gender is an independent risk factor for coronary artery disease, suggesting either a protective effect of estrogens and/or a deleterious effect of androgens. We have recently demonstrated that androgen deprivation is associated with enhanced vascular reactivity in adult men, however, the effects of androgen excess on vascular function in humans has not been reported previously. METHODS: We studied vascular reactivity in two groups of genetic females: 12 female-to-male transsexuals receiving long-term high-dose androgens, and 12 healthy female control subjects, matched for age and smoking history. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (leading to flow-mediated dilatation [FMD], which depends on normal endothelial function) and after sublingual nitroglycerin (NTG), an endothelium-independent dilator. RESULTS: Testosterone levels were higher (15.2+/-8.7 vs. 1.9+/-1.3 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels were lower (1.2+/-0.2 vs. 1.6+/-0.4 mmol/L, p=0.02) in the transsexuals compared with the control subjects. In each group, nine of 12 subjects were current or ex-smokers, leading to impaired FMD in both groups (5.1+/-3.7% in the transsexuals vs. 6.9+/-4.1% in controls, p=0.28). The NTG response was significantly decreased in the transsexuals (15.9+/-4.9% vs. 22+/-5.8% in controls, p=0.01), independent of the effects of age, cholesterol or vessel size. CONCLUSIONS: Long-term treatment with high-dose androgens is associated with impaired vascular reactivity in genetic females, consistent with a deleterious effect of androgen excess on arterial physiology.

Adult↗
PubMed1998

An anthropological exploration of contemporary bioethics: the varieties of common sense.

Patients and physicians can inhabit distinctive social worlds where they are guided by diverse understandings of moral practice. Despite the contemporary presence of multiple moral traditions, religious communities and ethnic backgrounds, two of the major methodological approaches in bioethics, casuistry and principlism, rely upon the notion of a common morality. However, the heterogeneity of ethnic, moral, and religious traditions raises questions concerning the singularity of common sense. Indeed, it might be more appropriate to consider plural traditions of moral reasoning. This poses a considerable challenge for bioethicists because the existence of plural moral traditions can lead to difficulties regarding "closure" in moral reasoning. The topics of truth-telling, informed consent, euthanasia, and brain death and organ transplantation reveal the presence of different understandings of common sense. With regard to these subjects, plural accounts of "common sense" moral reasoning exist.

Bioethical Issues↗
PubMed1997

UNIFOLIATA regulates leaf and flower morphogenesis in pea.

BACKGROUND: The vegetative phenotype of the pea mutant unifoliata (uni) is a simplification of the wild-type compound leaf to a single leaflet. Mutant uni plants are also self-sterile and the flowers resemble known floral meristem and organ identity mutants. In Antirrhinum and Arabidopsis, mutations in the floral meristem identity gene FLORICAULA/LEAFY (FLO/LFY) affect flower development alone, whereas the tobacco FLO/LFY homologue, NFL, is expressed in vegetative tissues, suggesting that NFL specifies determinacy in the progenitor cells for both flowers and leaves. In this paper, we characterised the pea homologue of FLO/LFY. RESULTS: The pea cDNA homologue of FLO/LFY, PEAFLO, mapped to the uni locus in recombinant-inbred mapping populations and markers based on PEAFLO cosegregated with uni in segregating sibling populations. The characterisation of two spontaneous uni mutant alleles, one containing a deletion and the other a point mutation in the PEAFLO coding sequences, predicted that PEAFLO corresponds to UNI and that the mutant vegetative phenotype was conferred by the defective PEAFLO gene. CONCLUSIONS: The uni mutant demonstrates that there are shared regulatory processes in the morphogenesis of leaves and flowers and that floral meristem identity genes have an extended role in plant development. Pleiotropic regulatory genes such as UNI support the hypothesis that leaves and flowers derive from a common ancestral sporophyll-like structure. The regulation of indeterminancy during leaf and flower morphogenesis by UNI may reflect a primitive function for the gene in the pre-angiosperm era.

Alleles↗