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Biomedical subjects

J D Murray

Publications and source records attributed to J D Murray.

At least 19 recordsLinked to original sources
PubMed2006

Production and processing of milk from transgenic goats expressing human lysozyme in the mammary gland.

The potential for applying biotechnology to benefit animal agriculture and food production has long been speculated. The addition of human milk components with intrinsic antimicrobial activity and positive charge to livestock milk by genetic engineering has the potential to benefit animal health, as well as food safety and production. We generated one line of transgenic goats as a model for the dairy cow designed to express human lysozyme in the mammary gland. Here we report the characterization of the milk from 5 transgenic females of this line expressing human lysozyme in their milk at 270 microg/mL or 68% of the level found in human milk. Milk from transgenic animals had a lower somatic cell count, but the overall component composition of the milk and milk production were not different from controls. Milk from transgenic animals had a shorter rennet clotting time and increased curd strength. Milk of such nature may be of benefit to the producer by influencing udder health and milk processing.

Animals↗
PubMed2005

Transgene transmission to progeny by oMt1a-oGH transgenic mice.

Most studies utilizing transgenic technology focus on the impact to traits of interest, rather than propagation of the transgene to offspring. In animals containing growth hormone constructs, transgene transmission to progeny follows a Mendelian pattern of inheritance in the first few generations following generation of a founder animal, but decreases in subsequent generations. In the present study, the ovine metallothionein 1a-ovine growth hormone (oMt1a-oGH) transgenic mouse was used to determine whether transgene transmission rate to progeny was affected by overexpression of ovine growth hormone in the transgenic parent. The oMt1a-oGH mouse is a useful model for assessing transgene transmission, as the construct is easily regulatable and transgene inactivation results in a return of plasma GH to basal levels. Male and female hemizygous oMt1a-oGH mice were assigned to 1 of 3 treatment groups: (1) mice never actively expressing the transgene, (2) mice actively expressing the transgene from 3 weeks of age, and (3) mice actively expressing the transgene from 3 to 11 (males) or 3 to 8 (females) weeks of age. Transgenic mice were mated to wild type animals and the resulting progeny were genotyped. Males never actively expressing the transgene passed on the transgene to progeny in a Mendelian fashion, while males actively expressing the transgene transmitted the transgene to a smaller than expected number of progeny. However, following inactivation of the oMt1a-oGH construct in transgenic males, subsequent offspring demonstrated Mendelian inheritance of the transgene. In contrast, females expressing the transgene from 3 to 8 weeks of age were able to pass on the oMt1a-oGH construct in a Mendelian fashion, but females from other treatment groups were not. In oMt1a-oGH males, reduced transgene transmission appears to be due to selection against transgenic gametes. In females, however, selection against the transgenic genotype likely occurs at the embryonic level.

Animals↗
PubMed2004

Leptin modulates fertility under the influence of elevated growth hormone as modeled in oMt1a-oGH transgenic mice.

Elevated growth hormone (GH) concentrations suppress reproductive function in a variety of species, although it is unclear whether GH directly suppresses reproductive performance, or whether GH activates other pathways to achieve these effects. The ovine metallothionein 1a-ovine GH (oMt1a-oGH) transgenic mouse has been used to model the effects of GH on both body composition and reproductive function. A recent report has documented increased leptin levels in obese oMt1a-oGH mice. Given the importance of leptin in modulation of the reproductive endocrine axis, as well as the reports documenting reduced leptin signal transduction in animals with elevated leptin levels, we hypothesized that high leptin concentrations in response to elevated GH would reduce fertility. To determine the effects of high circulating leptin levels on the reproductive endocrine axis, we assessed hypothalamic neuropeptide Y (NPY) and GnRH expression. At weaning, oMt1a-oGH transgenic (TG) and wild-type (WT) female mice were allocated to one of four treatment groups: oMt1a-oGH females chronically expressing the transgene (TG ON); oMt1a-oGH females expressing the transgene from 3 to 8 weeks of age (TG ON/OFF); WT females receiving the transgene stimulus from 3 to 8 weeks of age (WT ON/OFF); and WT females never receiving the transgene stimulus (WT OFF). Eight-week-old females were housed with males for a 2-week period, after which females were isolated from males and allowed to carry pregnancies to term. Body and gonadal fat pad (GFP) weights, along with plasma leptin concentrations, estrous cyclicity, pregnancy rate and litter characteristics, were recorded for each female. Chronic expression of the oMt1a-oGH transgene resulted in larger leaner mice, and inactivation of the transgene produced obese females. Pregnancy rate was reduced in TG ON females when compared with all other groups, and infertility was associated with elevated leptin levels. In addition, high leptin levels were associated with increased NPY expression, suggesting reduced leptin-signaling capacity, which may contribute to suppression of the reproductive axis in oGH animals.

Animals↗
PubMed2004

Hot topic: using a stearoyl-CoA desaturase transgene to alter milk fatty acid composition.

Stearoyl-CoA desaturase enzyme converts specific medium- and long-chain saturated fatty acids to their monounsaturated form. Transgenic goats expressing a bovine beta-lactoglobulin promoter-rat stearoyl-CoA desaturase cDNA construct in mammary gland epithelial cells were produced by pronuclear microinjection. The fatty acid composition of milk from 4 female transgenic founders was analyzed on d 7, 14, and 30 of their first lactation. In 2 animals, the expression of the transgene changed the overall fatty acid composition of the resulting milk fat to a less saturated and more monounsaturated fatty acid profile at d 7 of lactation; however, this effect diminished by d 30. In addition, one animal had an increased proportion of the rumen-derived monounsaturated fatty acid C18:1 trans11 converted by stearoyl-CoA desaturase to the conjugated linoleic acid isomer C18:2 cis9 trans11. Milk that has higher proportions of monounsaturated fatty acids and conjugated linoleic acid may have benefits for human cardiovascular health.

Animals↗
PubMed2004

Dissociation of body growth and adipose deposition effects of growth hormone in oMt1a-oGH transgenic mice.

Chronic highly elevated expression of a growth hormone (GH) transgene enhances overall body growth with minimal adipose accretion, while moderate levels of circulating GH fail to enhance body growth yet promote adipose deposition. These findings suggest that the growth response to GH can be dissociated from adipose effects. This hypothesis was tested in the oMtla-oGH transgenic mouse model by titrating circulating GH levels through variable induction of transgene expression. Circulating GH levels in female transgenics were approximately 49, 132, and 750 ng/ml in response to the transgene stimulus at 0, 15, and 25 mM zinc sulfate, respectively. The highest level of circulating GH generated the largest body weight with the smallest fat accrual while the intermediate GH level generated a body weight equivalent to that for the highest GH but the heaviest gonadal fat pads. The lowest GH levels did not increase body size but did enlarge fat depots. Animals exposed to the highest level of GH had an extended growth phase relative to lower GH levels and the nontransgenic controls. In contrast, the duration of the growth phase for the 0 and 15 mM zinc stimulated transgenics was abbreviated relative to the growth phase of the control animals. The two highest levels of circulating GH increased all forms of the GH receptor, IGF-I, and hepatic lipoprotein lipase mRNA. The growth differential observed for the 0 vs. the 15 mM zinc stimulated transgenics may reflect the preferential increase in the full length GH receptor mRNA and the induction of the smaller IGF-I transcripts with the higher circulating GH while the lipid accrual paralleled the disproportionate induction of the truncated GH receptor mRNA form. Liver and bone content of zinc, manganese, copper, and iron primarily reflected dietary zinc supplementation and did not appear to play a role in the differential growth response. The dissociation of GH effects on growth and adipogenesis as a function of circulating GH levels suggests that the level of GHR and IGF-I expression acts through a threshold mechanism and low expression results in adipogenesis while high expression generates body growth.

Adipose Tissue↗
PubMed2003

Virtual and real brain tumors: using mathematical modeling to quantify glioma growth and invasion.

Over the last 10 years increasingly complex mathematical models of cancerous growths have been developed, especially on solid tumors, in which growth primarily comes from cellular proliferation. The invasiveness of gliomas, however, requires a change in the concept to include cellular motility in addition to proliferative growth. In this article we review some of the recent developments in mathematical modeling of gliomas. We begin with a model of untreated gliomas and continue with models of polyclonal gliomas following chemotherapy or surgical resection. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have recently been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter on a geometrically complex brain domain, including sulcal boundaries, with a resolution of 1 mm(3) voxels. We conclude that the velocity of expansion is linear with time and varies about 10-fold, from about 4 mm/year for low-grade gliomas to about 3 mm/month for high-grade ones.

Brain Neoplasms↗
PubMed2003

Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice.

Obesity plays a central role in the development of insulin resistance and type 2 diabetes. We therefore examined the effects of a modified form of ciliary neurotrophic factor [Axokine, which is hereafter referred to as ciliary neurotrophic factor (CNTF)Ax15], which uses a leptin-like mechanism to reduce body weight, in the db/db murine model of type 2 diabetes. In previous studies, weight loss produced by CNTF treatment could largely be attributed to its effects on food intake. In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone. These beneficial effects, above and beyond those seen in animals controlled for either food restriction or body weight, correlated with the ability of CNTFAx15 to increase metabolic rate and energy expenditure and reduce hepatic steatosis while enhancing hepatic responsiveness to insulin. The hepatic effects were linked to rapid alterations in hepatic gene expression, most notably reduced expression of stearoyl-CoA desaturase 1, a rate-limiting enzyme in the synthesis of complex lipids that is also markedly suppressed by leptin in ob/ob mice. These observations further link the mechanisms of CNTF and leptin action, and they suggest important, beneficial effects for CNTF in diabetes that may be distinct from its ability to decrease food intake; instead, these effects may be more related to its influence on energy expenditure and hepatic gene expression.

Animals↗
PubMed2003

Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice.

Similar to leptin, ciliary neurotrophic factor (CNTF) suppresses appetite and selectively reduces body fat in leptin-deficient ob/ob mice. To assess the relative importance of specific regions of the hypothalamus in mediating these effects, we administered a CNTF analogue (CNTFAx15) or leptin to mice made obese by administration of gold thioglucose (GTG), which destroys a well-defined portion of the medial basal hypothalamus. CNTFAx15 treatment reduced appetite and body weight in obese GTG-lesioned C57BL/6 mice, whereas leptin failed to effect similar changes regardless of whether treatment was initiated before or after the lesioned mice had become obese. Because leptin does not reduce food intake or body weight in most forms of obesity (a condition termed 'leptin resistance'), we also investigated the actions of leptin in GTG-lesioned leptin-deficient (ob/ob) mice. By contrast to C57BL/6 mice, leptin treatment reduced food intake and body weight in GTG-lesioned ob/ob mice, although the effect was attenuated. To further compare the neural substrates mediating the anorectic actions of leptin and CNTF, we determined the patterns of neurone activation induced by these proteins in the hypothalamus of intact and GTG-lesioned mice by staining for phosphorylated signal transducer and activator of transcription 3 (pSTAT3). CNTFAx15 stimulated robust pSTAT3 signalling in neurones of the medial arcuate nucleus in both intact and lesioned C57BL/6 and ob/ob mice. Leptin administration stimulated pSTAT3 signalling in only a few neurones of the medial arcuate nucleus in intact or lesioned C57BL/6 mice, but elicited a robust response in intact or lesioned ob/ob mice. By contrast to CNTFAx15, leptin treatment also resulted in prominent activation of STAT3 in several areas of the hypothalamus outside the medial arcuate nucleus. This leptin-induced pSTAT3 signal was at least as prominent in intact and GTG-lesioned C57BL/6 mice as it was in ob/ob mice, and thus was not correlated with appetite suppression or weight loss. These results indicate that the medial arcuate nucleus is a key mediator of appetite suppression and weight loss produced by CNTF and leptin, whereas GTG-vulnerable regions play a role only in leptin-induced weight loss. Other regions of hypothalamus in which pSTAT3 signal is induced by leptin may regulate energy metabolism through mechanisms other than appetite reduction.

Animals↗
PubMed2002

Virtual brain tumours (gliomas) enhance the reality of medical imaging and highlight inadequacies of current therapy.

Gliomas are brain tumours that differ from most other cancers by their diffuse invasion of the surrounding normal tissue and their notorious recurrence following all forms of therapy. We have developed a mathematical model to quantify the spatio-temporal growth and invasion of gliomas in three dimensions throughout a virtual human brain. The model quantifies the extent of tumorous invasion of individual gliomas in three-dimensions to a degree beyond the limits of present medical imaging, including even microscopy, and makes clear why current therapies based on existing imaging techniques are inadequate and cannot be otherwise without other methods for detecting tumour cells in the brain. The model's estimate of the extent of tumourous invasion beyond that defined by standard medical imaging can be useful in more accurately planning therapy regimes as well as predicting sites of potential recurrence without waiting for reemergence on follow-up imaging.

Brain↗
PubMed2002

Transient dynamics and pattern formation: reactivity is necessary for Turing instabilities.

The theory of spatial pattern formation via Turing bifurcations - wherein an equilibrium of a nonlinear system is asymptotically stable in the absence of dispersal but unstable in the presence of dispersal - plays an important role in biology, chemistry and physics. It is an asymptotic theory, concerned with the long-term behavior of perturbations. In contrast, the concept of reactivity describes the short-term transient behavior of perturbations to an asymptotically stable equilibrium. In this article we show that there is a connection between these two seemingly disparate concepts. In particular, we show that reactivity is necessary for Turing instability in multispecies systems of reaction-diffusion equations, integrodifference equations, coupled map lattices, and systems of ordinary differential equations.

Animals↗
PubMed2002

Quantifying efficacy of chemotherapy of brain tumors with homogeneous and heterogeneous drug delivery.

Gliomas are diffuse and invasive brain tumors with the nefarious ability to evade even seemingly draconian treatment measures. Here we introduce a simple mathematical model for drug delivery of chemotherapeutic agents to treat such a tumor. The model predicts that heterogeneity in drug delivery related to variability in vascular density throughout the brain results in an apparent tumor reduction based on imaging studies despite continual spread beyond the resolution of the imaging modality. We discuss a clinical example for which the model-predicted scenario is relevant. The analysis and results suggest an explanation for the clinical problem of the long-standing confounding observation of shrinkage of the lesion in certain areas of the brain with continued growth in other areas.

Antineoplastic Agents↗
PubMed2002

Linkage of the grey coat colour locus to microsatellites on horse chromosome 25.

The progressive loss of colour in the hair of grey horses is controlled by a dominantly inherited allele at the Grey locus (GG). In this study, two paternal Quarter Horse (QH) families segregating for the GG allele were genotyped with a set of 101 microsatellite markers spanning the 31 autosomes and the X chromosome. This genome scan demonstrated linkage of Grey to COR018 (RF=0.02, LOD=12.04) on horse chromosome 25 (ECA25). Further chromosome-specific analysis of seven total QH families confirmed the linkage of Grey to a group of ECA25 markers and the map order of NVHEQ43-(0.24)-UCDEQ405-(0.09)-COR080-(0.05)-GREY-(0.14)-UCDEQ464 was produced. Although G was found to be linked to TXN and COR018 in the chromosome-specific analysis, the data were not sufficiently informative to place either marker on our ECA25 map with significant LODs. Our results excluded the equine tyrosinase related protein 1 (TYRP1) and melanocyte protein 17 (Pmel17) genes as possible candidates for the grey phenotype in horses.

Alleles↗
PubMed2001

Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity.

Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.

Adipose Tissue↗
PubMed2001

Calciphylaxis, a poorly understood clinical syndrome: three case reports and a review of the literature.

Systemic calcification syndromes are a recognized complication occurring in some patients with end-stage renal disease (ESRD) and secondary hyperparathyroidism. These patients develop severe livedo reticularis and subcutaneous tissue lesions progressing to frank necrosis and ultimately large areas of eschar. Clinically this syndrome is known as calciphylaxis; these lesions are usually resistant to aggressive debridement, systemic antibiotics, and revascularization procedures. We report three patients with somewhat different clinical presentations but all sharing a common link of exquisitely painful leg ulcers initially being treated as ischemic lesions or venous stasis-type ulcerations. These three patients were diagnosed with calciphylaxis on the basis of clinical, biochemical, and histopathological criteria. Two patients underwent parathyroidectomy late in the progression of their disease, with some resolution of their ulcerative lesions.

Aged↗
PubMed2001

A quantitative model for the dynamics of serum prostate-specific antigen as a marker for cancerous growth: an explanation for a medical anomaly.

Prostate-specific antigen (PSA) is an enzyme produced by both normal and cancerous prostate epithelial cells. Although PSA is the most widely used serum marker to detect and follow patients with prostatic adenocarcinoma, there are certain anomalies in the values of serum levels of PSA that are not understood. We developed a mathematical model for the dynamics of serum levels of PSA as a function of the tumor volume. Our model results show good agreement with experimental observations and provide an explanation for the existence of significant prostatic tumor mass despite a low-serum PSA. This result can be very useful in enhancing the use of serum PSA levels as a marker for cancer growth.

Adenocarcinoma↗
PubMed2001

Vascular thoracic outlet syndrome: successful outcomes with multimodal therapy.

PURPOSE: Vascular thoracic outlet syndrome (TOS) can present with signs of arterial impingement or, more commonly, as venous obstruction. In an effort to decrease morbidity associated with vascular thoracic outlet syndrome, we have used an aggressive multimodal treatment approach. METHODS: Since November 1992, we have evaluated 29 patients with vascular thoracic outlet syndrome. Nine of ten patients with arterial thoracic outlet syndrome had first rib resections. Eighteen of 19 patients with venous occlusion underwent anticoagulation, thrombolysis, and first rib resection. Eight patients required additional endovascular therapy for persistent stenoses, either venous angioplasty alone (2) or angioplasty plus stent placement (6). RESULTS: Follow up extends to 75months with a mean of 24months. Patients with stents have been followed for a mean of 38months. Twenty-five of 28 patients managed with multimodal therapy were essentially asymptomatic at last follow up. CONCLUSION: Thrombolysis, anticoagulation, surgical decompression, and endovascular procedures act synergistically to improve results of therapy in patients with vascular thoracic outlet syndrome.

Adult↗