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Biomedical subjects

J A McDonald

Publications and source records attributed to J A McDonald.

At least 19 recordsLinked to original sources
PubMed2005

Decontamination of uranium-contaminated steel surfaces by hydroxycarboxylic acid with uranium recovery.

We developed a simple, safe method to remove uranium from contaminated metallic surfaces so that the materials can be recycled or disposed of as low-level radioactive or nonradioactive waste. Surface analysis of rusted uranium-contaminated plain carbon-steel coupons by X-ray photoelectron spectroscopy and Rutherford backscattering spectroscopy showed that uranium was predominantly associated with ferrihydrite, lepidocrocite, and magnetite, or occluded in the matrix of the corrosion product as uranyl hydroxide and schoepite (UO3 x 2H2O). Citric acid formulations, consisting of oxalic acid-hydrogen peroxidecitric acid (OPC) or citric acid-hydrogen peroxidecitric acid (CPC), were used to remove uranium from the coupons. The efficiency of uranium removal varied from 68% to 94% depending on the extent of corrosion, the association of uranium with the iron oxide matrix, and the accessibility of the occluded contaminant. Decontaminated coupons clearly showed evidence of the extensive removal of rust and uranium. The waste solutions containing uranium and iron from decontamination by OPC and CPC were treated first by subjecting them to biodegradation followed by photodegradation. Biodegradation of a CPC solution by Pseudomonas fluorescens resulted in the degradation of the citric acid with concomitant precipitation of Fe (>96%), whereas U that remained in solution was recovered (>99%) by photodegradation as schoepite. In contrast, in an OPC solution citric acid was biodegraded but not oxalic acid, and both Fe and U remained in solution. Photodegradation of this OPC solution resulted in the precipitation of iron as ferrihydrite and uranium as uranyl hydroxide.

Biodegradation, Environmental↗
PubMed2001

Stem-loop SL4 of the HIV-1 psi RNA packaging signal exhibits weak affinity for the nucleocapsid protein. structural studies and implications for genome recognition.

Encapsidation of the genome of the human immunodeficiency virus type-1 (HIV-1) during retrovirus assembly is mediated by interactions between the nucleocapsid (NC) domains of assembling Gag polyproteins and a approximately 110 nucleotide segment of the genome known as the Psi-site. The HIV-1 Psi-site contains four stem-loops (SL1 through SL4), all of which are important for genome packaging. Recent isothermal titration calorimetry (ITC) studies have demonstrated that SL2 and SL3 are capable of binding NC with high affinity (K(d) approximately 140 nM), consistent with proposals for protein-interactive functions during packaging. To determine if SL4 may have a similar function, NC-interactive studies were conducted by NMR and gel-shift methods. In contrast to previous reports, we find that SL4 binds weakly to NC (K(d)=(+/-14 microM), suggesting an alternative function. NMR studies indicate that the GAGA tetraloop of SL4 adopts a classical GNRA-type fold (R=purine, N=G, C, A or U), a motif that stabilizes RNA tertiary structures in other systems. In combination with previously reported gel mobility studies of Psi-site deletion mutants, these findings suggest that SL4 functions in genome recognition not by binding to Gag, but by stabilizing the structure of the Psi-site. Differences in the affinities of NC for SL2, SL3 and SL4 stem-loops can now be rationalized in terms of the different structural properties of stem loops that contain GGNG (SL2 and SL3) and GNRA (SL4) sequences.

Amino Acid Sequence↗
PubMed2001

Codon optimization markedly improves doxycycline regulated gene expression in the mouse heart.

Tetracycline regulated gene expression in transgenic animals is potentially a very powerful technique (Furth et al., 1994; Gossen & Bujard 1992). We have utilized this system in an attempt to overcome the perinatal lethality resulting from constitutive transgenic expression in the heart (Valencik & McDonald, Am J Physiol Heart Circ Physiol 280: H361-H367). We found that compound hemizygous animals created by mating selected reverse tetracycline transactivator (rtTA) and transresponder (TR) lines display tightly regulated TR expression in the heart. However, we identified two fundamental problems. First, codon usage bias appeared to severely limit the expression of the rtTA driven by the cardiac alpha-myosin heavy chain promoter. Second, co-injection of rtTA and TR transgenes led to compound hemizygous animals that exhibited unregulated TR gene expression. Codon optimization of the rtTA construct leads to marked improvement (increasing the average induction from 20-fold to 832-fold) in cardiac myocyte expression. The resulting opt-rtTA lines can be bred to homozygosity, facilitating rapid screening of F0 TR animals for doxycycline regulated transgene expression.

Animals↗
PubMed2001

Cardiac expression of a gain-of-function alpha(5)-integrin results in perinatal lethality.

Communication between the extracellular matrix and the intracellular signal transduction and cytoskeletal system is mediated by integrin receptors. alpha(5)beta(1)-Integrin and its cognate ligand fibronectin are essential in development of mesodermal structures, myocyte differentiation, and normal cardiac development. To begin to explore the potential roles of alpha(5)beta(1)-integrin specifically in cardiomyocytes, we used a transgenic expression strategy. We overexpressed two forms of the human alpha(5)-integrin in cardiomyocytes: the full-length wild-type alpha(5)-integrin and a putative gain-of-function mutation created by truncating the cytoplasmic domain, designated alpha(5-1)-integrin. Overexpression of the wild-type alpha(5)-integrin has no detectable adverse effects in the mouse, whereas expression of alpha(5-1)-integrin caused electrocardiographic abnormalities, fibrotic changes in the ventricle, and perinatal lethality. Thus physiological regulation of integrin function appears essential for maintenance of normal cardiomyocyte structure and function. This strengthens the role of inside-out signaling in regulation of integrins in vivo and suggests that integrins and associated signaling molecules are important in cardiomyocyte function.

Animals↗
PubMed2001

A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects.

Normal cardiovascular development is exquisitely dependent on the correct dosage of the angiogenic growth factor and vascular morphogen vascular endothelial growth factor (VEGF). However, cardiac expression of VEGF is also robustly augmented during hypoxic insults, potentially mediating the well-established teratogenic effects of hypoxia on heart development. We report that during normal heart morphogenesis VEGF is specifically upregulated in the atrioventricular (AV) field of the heart tube soon after the onset of endocardial cushion formation (i.e. the endocardium-derived structures that build the heart septa and valves). To model hypoxia-dependent induction of VEGF in vivo, we conditionally induced VEGF expression in the myocardium using a tetracycline-regulated transgenic system. Premature induction of myocardial VEGF in E9.5 embryos to levels comparable with those induced by hypoxia prevented formation of endocardial cushions. When added to explanted embryonic AV tissue, VEGF fully inhibited endocardial-to-mesenchymal transformation. Transformation was also abrogated in AV explants subjected to experimental hypoxia but fully restored in the presence of an inhibitory soluble VEGF receptor 1 chimeric protein. Together, these results suggest a novel developmental role for VEGF as a negative regulator of endocardial-to-mesenchymal transformation that underlies the formation of endocardial cushions. Moreover, ischemia-induced VEGF may be the molecular link between hypoxia and congenital defects in heart septation.

Animals↗
PubMed2000

Prognostic factors in early-onset epithelial ovarian cancer: a population-based study.

OBJECTIVE: To investigate the clinical prognostic factors that influence ovarian cancer survival in women with early-onset epithelial ovarian cancer using population-based data. METHODS: Subjects in the current study were from a population-based series of 197 patients with invasive ovarian cancer and 60 patients with ovarian cancer of low malignant potential who were identified from the Cancer and Steroid Hormone study. All subjects were between 20 and 54 years of age at diagnosis for ovarian cancer. Epidemiologic data were obtained from each participant. Immunohistochemical staining was performed to assess p53 expression in paraffin-embedded ovarian cancers. Univariate and multivariate analyses for survival were conducted using the proportional hazards model to test the prognostic significance of several clinicopathologic factors among subjects. RESULTS: Among women with invasive tumors, the proportional hazards model revealed that advanced stage at diagnosis [hazard ratio = 4.1, 95% confidence interval (CI) = 2.5, 6.6], age at diagnosis 46-54 (hazard ratio = 2.0, 95% CI = 1.3, 3.0), and overexpression of p53 (hazard ratio = 1.5, 95% CI = 1.1, 2.3) were significantly associated with decreased survival. CONCLUSION: These results provide evidence that stage, age, and p53 overexpression are independent predictors of decreased survival in women with invasive ovarian cancer diagnosed younger than age 55. Further investigation of the effect of age at diagnosis on the relationship between p53 overexpression and ovarian cancer survival is warranted.

Adult↗
PubMed2000

Sensory neuropathy in the prodromal phase of hepatitis A and review of the literature.

We report an unrecognized clinical presentation of hepatitis A with unilateral peripheral acute sensory loss in the prodromal phase of the illness. Although rare, focal neurological signs are known to occur in hepatitis A before, during and after the icteric phase; a pure peripheral sensory neuropathy is distinctly uncommon. Possible lesions could include radiculopathy of the lower thoraco-lumbo-sacral dorsal nerve roots or a partial transverse myelitis of Brown-Séquad like distribution. The signs and symptoms lasted only a few days and the patient had an uneventful recovery.

Adult↗
PubMed2000

Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.

We identified hyaluronan synthase-2 (Has2) as a likely source of hyaluronan (HA) during embryonic development, and we used gene targeting to study its function in vivo. Has2(-/-) embryos lack HA, exhibit severe cardiac and vascular abnormalities, and die during midgestation (E9.5-10). Heart explants from Has2(-/-) embryos lack the characteristic transformation of cardiac endothelial cells into mesenchyme, an essential developmental event that depends on receptor-mediated intracellular signaling. This defect is reproduced by expression of a dominant-negative Ras in wild-type heart explants, and is reversed in Has2(-/-) explants by gene rescue, by administering exogenous HA, or by expressing activated Ras. Conversely, transformation in Has2(-/-) explants mediated by exogenous HA is inhibited by dominant-negative Ras. Collectively, our results demonstrate the importance of HA in mammalian embryogenesis and the pivotal role of Has2 during mammalian development. They also reveal a previously unrecognized pathway for cell migration and invasion that is HA-dependent and involves Ras activation.

Animals↗
PubMed2000

Applications of three dimensional echocardiography beyond the left ventricle: other chambers and structural detail.

The authors' system for quantitative three-dimensional echocardiography (3D echo) now enables analysis of all four heart chambers, valves and associated structures. After image acquisition using freehand scanning and a magnetic field tracking device, the borders of cardiac structures are manually traced. Chambers are reconstructed with a piecewise smooth subdivision surface. The mitral and tricuspid annuli are fitted using a 4 term Fourier series. Other valves and orifices are reconstructed as ellipses. Anatomic labeling enables identification of the chordae, coronary sinus, intervalvular fibrosa, septum, and right and left ventricular apex. The dimensions, shape, and function of cardiac components and the spatial relationships between them such as distance and angle can be determined. These methods provide capability and flexibility for clinical applications such as modeling heart motion, investigating the mechanism of functional mitral regurgitation, and tracking left ventricular remodeling.

Cardiomyopathies↗
PubMed1999

Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties.

Three mammalian hyaluronan synthase genes, HAS1, HAS2, and HAS3, have recently been cloned. In this study, we characterized and compared the enzymatic properties of these three HAS proteins. Expression of any of these genes in COS-1 cells or rat 3Y1 fibroblasts yielded de novo formation of a hyaluronan coat. The pericellular coats formed by HAS1 transfectants were significantly smaller than those formed by HAS2 or HAS3 transfectants. Kinetic studies of these enzymes in the membrane fractions isolated from HAS transfectants demonstrated that HAS proteins are distinct from each other in enzyme stability, elongation rate of HA, and apparent K(m) values for the two substrates UDP-GlcNAc and UDP-GlcUA. Analysis of the size distributions of hyaluronan generated in vitro by the recombinant proteins demonstrated that HAS3 synthesized hyaluronan with a molecular mass of 1 x 10(5) to 1 x 10(6) Da, shorter than those synthesized by HAS1 and HAS2 which have molecular masses of 2 x 10(5) to approximately 2 x 10(6) Da. Furthermore, comparisons of hyaluronan secreted into the culture media by stable HAS transfectants showed that HAS1 and HAS3 generated hyaluronan with broad size distributions (molecular masses of 2 x 10(5) to approximately 2 x 10(6) Da), whereas HAS2 generated hyaluronan with a broad but extremely large size (average molecular mass of >2 x 10(6) Da). The occurrence of three HAS isoforms with such distinct enzymatic characteristics may provide the cells with flexibility in the control of hyaluronan biosynthesis and functions.

Animals↗
PubMed1999

Evidence of continuing bone recovery at a mean of 7 years after liver transplantation.

Patients with end-stage liver disease have low bone-turnover osteoporosis, and there is often further bone loss of 20% to 30% after orthotopic liver transplantation (OLT). Bone recovery after OLT has been reported, but data are limited. We undertook studies to determine whether bone recovery continues in the long term. Twenty-eight adult patients alive at least 5 years after OLT were studied (14 men, 14 women). Bone mineral density (BMD), serum parathyroid hormone (PTH), osteocalcin, and vitamin D levels were measured pretransplantation, at 3 months, 12 months, a mean of 46 months, and a mean of 85 months (range, 63 to 117 months) after transplantation. When BMD is expressed as a z score, the results were as follows: x0.82 +/- 0.22 pre-OLT; -2.04 +/- 0.27 at 3 months; -1.68 +/- 0.24 at 12 months; -1.23 +/- 0.24 at a mean of 46 months; and -1.0 +/- 0.26 at a mean of 85 months after OLT. The results at 46 and 85 months were significantly greater than the measurement at 3 months after OLT (P <.05). Furthermore, mean BMD (expressed as a z score) returns to the pre-OLT level at a mean of 85 months. At final follow-up, 9 of 28 patients had elevated PTH levels, and 14 of 27 patients had elevated osteocalcin levels. Five patients had spontaneous fractures in the first 12 months after transplantation, and 5 more patients had fractures by final follow-up. Even at 7 years after OLT, there was a significant increase in BMD (expressed as a z score) compared with 3 months after transplantation. Elevation of serum PTH and osteocalcin levels in some patients suggests continuing bone remodeling.

Adult↗
PubMed1999

Performance of a Fourier-based program for three-dimensional reconstruction of the mitral annulus on application to sparse, noisy data.

OBJECTIVES: We investigated the accuracy of mitral annular reconstruction from noisy, sparse data typical of three-dimensional (3D) transthoracic echocardiograms. BACKGROUND: Our Fourier-based method for reconstructing the annulus from dense, accurate 3D transesophageal echo (TEE) data has been validated in vitro with four harmonics in the x, y, and z coordinates (4,4,4). METHODS: Thirteen mitral annuli were reconstructed from 'complete' 3D TEE data using four harmonics (4,4,4) and used to measure area, eccentricity. height, perimeter, and interpeak and intervalley distances; these were the 'true values'. To simulate transthoracic echo data, the TEE data sets were reduced evenly and unevenly (randomly). The complete and reduced data sets were used to reconstruct the annuli using three sets of fitting parameters: (4,4,4), (1,1,3), and (1,1,4). The resulting size and shape measurements were compared with true values. RESULTS: Regardless of the fitting parameters used, area, 2D perimeter, and 3D perimeter measurements were more accurate using reconstructions from evenly-reduced than randomly-reduced data sets (p < 0.006), and depended significantly on both data density (p < 0.015 for all) and data distribution (p < 0.02 for all). Perimeter, height, and eccentricity of the reconstructed annuli were more accurately measured using four harmonics (4,4,4). CONCLUSIONS: Mitral annuli can be reconstructed from sparse, noisy data using the (4,4,4) fit if at least 25 points are obtained from evenly distributed imaging planes. These results suggest that detailed analysis of mitral annular size and shape can be made accurately from 3D transthoracic echocardiograms.

Case-Control Studies↗
PubMed1999

Case report: a rare association of primary biliary cirrhosis and systemic lupus erythematosus and review of the literature.

We report a rare occurrence of systemic lupus erythematosus in a patient known to have had well-documented primary biliary cirrhosis for 10 years. The presentation was dramatic with pericardial tamponade, but responded well to high dose corticosteroid. There are only five such definite associations reported in the literature. In the present case, other possible causes were considered, such as drug-induced cholestasis, drug-induced lupus, autoimmune chronic active hepatitis and the overlap syndrome.

Biopsy↗
PubMed1999

Cholestasis of pregnancy.

Cholestasis of pregnancy is the commonest liver disease unique to pregnancy and is characterized by pruritus in the mother in late pregnancy, without any skin rashes. This is accompanied by an elevation of the serum bile acids. Liver function test abnormalities may occur. Abdominal pain is not a feature and liver failure does not occur. The diagnosis is made by a suggestive history and exclusion of other causes by the history, serology and an upper abdominal ultrasound. All symptoms and signs should disappear within 4 weeks post-partum; prolonged post-partum courses should prompt a search for other causes, such as primary biliary cirrhosis. The syndrome is associated with a five-fold increased incidence of stillbirth, intra-partum foetal distress and pre-term labour. The reason is not clear and not predictable. The accepted management is induction or delivery at 38 weeks, which has led to a reduction in poor foetal outcome. Preliminary studies using ursodeoxycholic acid show symptomatic and biochemical improvement in most women treated. There is also a suggestion of an improved foetal outcome and treatment should be considered in women who present with the condition earlier in pregnancy.

Antipruritics↗