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Biomedical subjects

M Williams

Publications and source records attributed to M Williams.

At least 37 records · Page 2Linked to original sources
PubMed2001

Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor..

Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC(50) = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC(50) = 1.7 nM) non-nucleoside AK inhibitor with oral activity in animal models of pain and inflammation.

Adenosine Kinase↗
PubMed2001

Three loci modify growth of a transgene-induced mammary tumor: suppression of proliferation associated with decreased microvessel density.

In earlier studies it was observed that the genetic background significantly affected the phenotype of a transgene-induced mammary tumor. Tumors arising in an (I/LnJ x PyMT) F1 hybrid background appeared earlier than in the FVB/N-TgN(MMTV-PyVT)(634Mul) parent, but accumulated less tumor mass, indicating a net decrease in tumor growth. Quantitative genetic mapping in a backcross identified three loci that were associated with the decreased proliferative capacity of the I/LnJ F1 tumors. Molecular analysis of the tumors suggests that these loci may act by restricting the tumor's ability to recruit microvessels. The three loci, designated Mmtg1-3, are unlinked to the angiogenic genes Fgf2, Flt1, Flk4, Flk1, Vegf, and Vegfc, as well as the precursors of the endogenous antiangiogenic molecules angiostatin and endostatin. The Mmtg loci may therefore provide novel targets for antiangiogenic therapeutic strategies.

Animals↗
PubMed2001

Contribution of soft tissue deformation below the sacrum to the measurement of total height loss in sitting.

This study investigated the contribution of soft tissue deformation below the sacrum (S) and vertical spinal creep to total height loss (THL) measured in sitting. Eight asymptomatic subjects (four males, four females) aged between 21 and 51 years were measured. Simultaneous measurement of THL and S were commenced after the subjects had been sitting for 5 min. THL was recorded while subjects were positioned in a seated stadiometer, which controlled their spinal posture. S was measured by placing an ultrasound transducer at the level of the top of the subject's sacrum. Over 25 min of sitting with loaded and unloaded interventions applied to their spine, different response characteristics between S and THL were noted. This study demonstrated that soft tissues below the sacrum could contribute up to 30% on average of total height loss. This suggests that researchers should take into account the soft tissue deformation outside the spine when studying vertical creep in sitting.

Adult↗
PubMed2001

HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.

HIV causes a chronic infection by evading immune eradication. A key element of HIV immune escape is the HIV-1 Nef protein. Nef causes a reduction in the level of cell surface major histocompatibility complex class I (MHC-I) protein expression, thus protecting HIV-infected cells from anti-HIV cytotoxic T lymphocyte (CTL) recognition and killing. Nef also reduces cell surface levels of the HIV receptor, CD4, by accelerating endocytosis. We show here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules. The main effect of Nef is to block transport of MHC-I molecules to the cell surface, leading to accumulation in intracellular organelles. Furthermore, the effect of Nef on MHC-I molecules (but not on CD4) requires phosphoinositide 3-kinase (PI 3-kinase) activity. We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.

Blotting, Western↗
PubMed2001

Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery study [PACS(2)].

Atrial fibrillation (AF) after cardiac surgery is thought to increase length of stay (LOS). A clinical pathway focused on the management of postoperative AF, including prophylaxis with beta blockers, was implemented to assess the effect of AF on LOS after cardiac surgery. Data were obtained on consecutive cardiac surgery patients in preoperative normal sinus rhythm, no prior history of AF, and no chronic antiarrhythmic therapy from January to May 1995 (control) and November 1996 to June 1997 (pathway). Statistical analysis was performed to assess the effect of postoperative AF on the LOS, clinical outcomes, and cost after cardiac surgery. Despite the clinical pathway, the LOS (7 days for both periods; p = 0.12) and incidence of AF (28.9% vs 28.4%; p = 0.92) remained unchanged. Unadjusted direct costs were 15% higher in the pathway period (p <0.001). Increased rates of beta-blocker therapy had a marginal effect on the incidence of postoperative AF, except in the group who only underwent primary coronary artery bypass graft surgery (31.2% vs 25.3%; p = 0.31). Multivariate analysis revealed that AF contributed only 1 to 1.5 days to the LOS. Thus, this investigation represents the most recent analysis of the effects of postoperative AF on LOS, clinical outcomes, and cost after cardiac surgery. Unlike prior studies, the impact of postoperative AF is less prominent in the current era of cardiac surgical care regardless of the presence of a clinical pathway addressing AF.

Adrenergic beta-Antagonists↗
PubMed2001

Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2.

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha(1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha(1A-2) subunit, together with human beta(4) and alpha(2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.

Amino Acid Sequence↗
PubMed2001

Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production.

Curcumin, the yellow pigment in turmeric, has been shown to prevent malignancies in a variety of tissues in rodents, especially in the intestinal tract. Pharmacological activities of curcumin in cells in situ germane to chemoprevention, such as inhibition of expression of cyclooxygenase-2 (COX-2), require drug concentrations in the 10(-5) - 10(-4) M range. The systemic bioavailability of curcumin is low, so that its pharmacological activity may be mediated, in part, by curcumin metabolites. To investigate this possibility, we compared curcumin metabolism in human and rat hepatocytes in suspension with that in rats in vivo. Analysis by high-performance liquid chromatography with detection at 420 and 280 nm permitted characterization of metabolites with both intact diferoylmethane structure and increased saturation of the heptatrienone chain. Chromatographic inferences were corroborated by mass spectrometry. The major metabolites in suspensions of human or rat hepatocytes were identified as hexahydrocurcumin and hexahydrocurcuminol. In rats, in vivo, curcumin administered i.v. (40 mg/kg) disappeared from the plasma within 1 h of dosing. After p.o. administration (500 mg/kg), parent drug was present in plasma at levels near the detection limit. The major products of curcumin biotransformation identified in rat plasma were curcumin glucuronide and curcumin sulfate whereas hexahydrocurcumin, hexahydrocurcuminol, and hexahydrocurcumin glucuronide were present in small amounts. To test the hypothesis that curcumin metabolites resemble their progenitor in that they can inhibit COX-2 expression, curcumin and four of its metabolites at a concentration of 20 microM were compared in terms of their ability to inhibit phorbol ester-induced prostaglandin E2 (PGE2) production in human colonic epithelial cells. Curcumin reduced PGE2 levels to preinduction levels, whereas tetrahydrocurcumin, previously shown to be a murine metabolite of curcumin, hexahydrocurcumin, and curcumin sulfate, had only weak PGE2 inhibitory activity, and hexahydrocurcuminol was inactive. The results suggest that (a) the major products of curcumin biotransformation by hepatocytes occur only at low abundance in rat plasma after curcumin administration; and (b) metabolism of curcumin by reduction or conjugation generates species with reduced ability to inhibit COX-2 expression. Because the gastrointestinal tract seems to be exposed more prominently to unmetabolized curcumin than any other tissue, the results support the clinical evaluation of curcumin as a colorectal cancer chemopreventive agent.

Adult↗
PubMed2001

In vivo studies of Gd-DTPA-monoclonal antibody and gd-porphyrins: potential magnetic resonance imaging contrast agents for melanoma.

New tumor-specific contrast agents for clinical imaging and therapy for cancer are required. To this end Gd-H (Gd-hematoporphyrin), Gd-TCP (Gd-tetra-carboranylmethoxyphenyl-porphyrin), Gd-DTPA-WM53, and Gd-DTPA-9.2.27 were synthesized and administered by systemic injection to nude mice with human melanoma (MM-138) xenografts. The biodistribution T1 relaxation times and magnetic resonance (MR) image signal enhancement of the contrast agents are presented for the first time and compared for each group of five mice. A change (20%) in T1 relaxation times of water in human melanoma tumor xenografts was revealed 24 hours after injection of the labeled immunoconjugate Gd-DTPA-9.2.27. The percent of injected antibody or gadolinium that localized to the tumor was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) to be approximately 35%. A higher concentration of gadolinium was achieved compared with nonspecific compounds, indicating selective delivery of Gd-DTPA-9.2.27 to the melanoma xenografts. Porphyrin-based contrast agents (Gd-H and Gd-TCP) also showed significant uptake in melanomas. The uptake of Gd-TCP by the tumor was sufficient to deliver boron atoms into the tumor, making possible dual use for both MR imaging (MRI) and boron neutron capture therapy (BNCT). The linear relationship found between the paramagnetic contribution to the relaxation rates and contrast agent concentration allows quantitative studies of paramagnetic contrast agent uptake.

Animals↗
PubMed2001

USPIO-enhanced dynamic MRI: evaluation of normal and transplanted rat kidneys.

To evaluate first-pass renal perfusion with ultrasmall superparamagnetic iron oxide (USPIO) particles by MRI, 40 normal rats (20 Dark Agouti (DA) rats and 20 Brown Norway (BN) rats) and 16 transplanted rats (12 allografts and four isografts) were studied on day 4 post-transplantation with different USPIO doses (3.0-18.1 mg Fe/kg/body weight). All animals underwent 128 consecutive snapshot fast low-angle shot (FLASH) coronal dynamic studies in 43 s. In the normal rats, a larger maximum signal decrease (MSD) in the cortex and the outer medulla is observed with an increasing dose of USPIO particles (P < 0.01). No significant differences were observed between the right and left kidneys at all doses studied. Higher MSD, time of occurrence of MSD (tMSD), and wash-in slope appear with higher doses of USPIO particles. The dynamic curves for DA rats show similar shapes when compared to those for BN rats. In the transplanted rats, allograft kidneys show lower MSD, longer tMSD, and lower wash-in slope compared to those in the normal kidneys. Isograft kidneys show perfusion patterns similar to those of normal kidneys in the cortex and the outer medulla. Histopathology indicates acute vascular rejection in all allografts and normal kidney architecture in all isografts. The results clearly show good agreement between the renal graft perfusion measurements and histopathological changes associated with rejection. This work also introduces a new signal analysis methodology for the automatic detection of transplanted organ rejection. This method compares the dynamics of the intrarenal signal intensities for native and transplanted kidneys. A quantitative measurement to detect significant differences between these signals was developed, and showed that this technique exhibits good performance in identifying renal rejection.

Animals↗
PubMed2001

Vertical anthropometric measures and low back pain in adolescents.

BACKGROUND AND PURPOSE: The present paper explores aspects of a large dataset of adolescent potentiates of low back pain. Standing, trunk and shoulder height, subischial height, weight and mean leg length are examined in relation to reports of low back pain in the last two weeks, in strata of age and gender. METHOD: The present study examined 1254 adolescents, aged 11-18 years, drawn from 12 Adelaide public high schools during 1998. RESULTS: At each year of age, girls reported significantly more low back pain than boys. Girls and boys at each year of age provided different relationships between low back pain and anthropometric features, highlighting the unique nature of adolescent growth. The most consistent findings were anthropometric differences between 16-year-old boys, and 13- and 15-year-old girls, with and without low back pain, who may be at critical stages of the peak growth curve. CONCLUSION: We suggest a high prevalence of low back pain in adolescents, and that young sufferers with low back pain may be reflecting attributes of their stage of anthropometric growth.

Adolescent↗
PubMed2001

Assessment of tolerant sunfish populations (Lepomis sp.) inhabiting selenium-laden coal ash effluents. 2. Tissue biochemistry evaluation.

Sunfish were collected from a fly ash pond-receiving stream and an Ohio River reference site to assess biochemical responses to coal ash effluent exposure. Selenium levels in sunfish from the receiving stream were higher than toxic thresholds associated with adverse population effects and reproductive impairment. Tissue biochemistry was found to be indicative of metal exposure and effect, but varied widely. Liver glycogen was positively correlated with increased liver metal levels, indicating no adverse effect upon stored carbohydrate levels. Lipid levels decreased with increasing metals, indicating possible nutritional stress. Protein levels increased with increasing metal levels, possibly due to the synthesis of proteins to sequester the metals. ATPase, dUTPase, and alkaline phosphatase activity generally decreased with exposure to ash pond metals, but remained within normal physiological ranges. Fish condition factors and liver somatic indices were correlated with liver lipid levels, dUTPase activity, and gill ATPase and alkaline phosphatase activity. Exposure to coal ash effluents produced biochemical markers of exposure that were associated with fish condition indicators; however, the indices themselves were not significantly affected by effluent exposure.

Adaptation, Physiological↗
PubMed2001

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.

Adult↗
PubMed2001

Prospective analysis of endoscopic vein harvesting.

BACKGROUND: Utilization of bridging vein harvesting (BVH) of saphenous vein grafts (SVG) for coronary artery bypass grafting (CABG) results in large wounds with great potential for pain and infection. Endoscopic vein harvesting (EVH) may significantly reduce the morbidity associated with SVG harvesting. METHODS: A prospective database of 200 matched patients receiving EVH and BVH was compared. The patients all underwent CABG done over a period of 4 months (April to August 2000). Patients were excluded if they had prior vein harvesting. RESULTS: The EVH and BVH group included 100 patients each with similar demographics. The patients in the EVH group had significantly fewer wound complications, mean days to ambulation, and total length of stay (P <0.05). There was no difference in harvest time or vein injuries. CONCLUSION: Endoscopic vein harvesting results in significantly fewer wound complications, decrease in days to ambulation, and the total length of stay. EVH is superior to BVH in patients undergoing CABG.

Coronary Artery Bypass↗
PubMed2001

Algal growth control by a barley straw extract.

In recent years, there has been an apparent increase in the occurrence of harmful algal blooms occurring in potable waters. The potential of a simple barley straw extract to inhibit algal growth was assessed. Algal growth in lakewater was inhibited by the addition of barley straw (1% w/v), with the chlorophyll a concentration remaining below the original level (40 micrograms l-1) throughout the experiment. In contrast, in the presence of wheat straw, algal biomass increased, reaching a final chlorophyll a concentration of 1160 micrograms l-1 after 28 days. Analysis of the remaining particulate straw at the end of the experiment showed that the lignin content of barley straw had increased significantly from 10-33% (w/w). Further, a preparation of a simple aqueous extract from the decomposed-barley straw was found to inhibit the cyanobacteria Microcystis sp. and the algal species Scenedesmus, with chlorophyll a levels some 10-fold lower than in untreated flasks. This study shows that a decomposed-barley extract, even in a very dilute concentration (0.005%) was capable of inhibiting the growth of Microcystis sp., a commonly occurring cyanobacterium which produces the toxin microcystin and has been responsible for some of the most serious pernicious algal blooms in the UK.

Chlorophyll↗
PubMed2001

The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury.

1. Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. 2. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. 4. Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine-mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.

Adenosine Kinase↗