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Biomedical subjects

A R Williams

Publications and source records attributed to A R Williams.

At least 19 recordsLinked to original sources
PubMed2006

Seminal plasma and prostaglandin E2 up-regulate fibroblast growth factor 2 expression in endometrial adenocarcinoma cells via E-series prostanoid-2 receptor-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase pathway.

BACKGROUND: Prostaglandin E(2) (PGE(2)) has been shown to modulate angiogenesis and tumour progression via the E-series prostanoid-2 (EP2) receptor. Endometrial adenocarcinomas may be exposed to endogenous PGE(2) and exogenous PGE(2), present at high concentration in seminal plasma. METHODS: This study investigated fibroblast growth factor 2 (FGF2) mRNA expression and cell signalling in response to seminal plasma or PGE(2), using an endometrial adenocarcinoma (Ishikawa) cell line stably expressing the EP2 receptor (EP2 sense cells) and endometrial adenocarcinoma explants. RESULTS: Seminal plasma and PGE(2) induced a significant up-regulation of FGF2 expression in EP2 sense but not parental untransfected Ishikawa (wild-type) cells (P < 0.05). These effects were inhibited by co-treatment with EP2 receptor antagonist or inhibitors of protein kinase A, c-Src, epidermal growth factor receptor (EGFR) kinase or extracellular signal-regulated kinase (ERK) signalling. The treatment of EP2 sense cells with seminal plasma induced cAMP accumulation and phosphorylation of c-Src, EGFR kinase and ERK via the EP2 receptor. Finally, seminal plasma and PGE(2) significantly increased FGF2 mRNA expression in endometrial adenocarcinoma tissue explants via the EP2 receptor (P < 0.05). CONCLUSIONS: Seminal plasma and PGE(2) can similarly activate FGF2 expression and EP2 receptor signalling in endometrial adenocarcinoma cells. These data highlight the potential for seminal plasma exposure to facilitate tumorigenesis-angiogenesis in endometrial adenocarcinomas in vivo.

Adenocarcinoma↗
PubMed2003

Effect of long-term treatment with low-dose mifepristone on the endometrium.

BACKGROUND: Mifepristone in low daily doses has contraceptive potential by inhibiting ovulation and menstruation. Because follicular development is maintained, the endometrium is exposed to estrogen for prolonged periods unopposed by progesterone. METHODS: Endometrial biopsies were collected from 90 women in Edinburgh and Shanghai before (late proliferative) and 60 and 120 days after taking 2 or 5 mg mifepristone per day for 120 days. RESULTS: Ovulation and menstruation were inhibited in >90% of cycles and estrogen production was similar to that observed during the follicular phase of the control cycle. By 120 days, endometrial thickness increased significantly in women in Edinburgh but decreased in Shanghai. Endometrial histology showed inactive proliferative or cystic changes with dense stroma. There was a significant decrease in markers of proliferation, i.e. mitotic index and Ki67 staining. There were no pregnancies in a total of 200 women-months in 50 sexually active women who used no other method of contraception. CONCLUSIONS: We confirm that ovulation and menstruation were suppressed in the majority of cycles and there was asynchrony between ovarian activity and endometrial histology, which showed no signs of hyperplasia or atypia. These preliminary data suggest that daily low-dose mifepristone is potentially a safe estrogen-free contraceptive pill which has the added health benefit of amenorrhoea.

Adult↗
PubMed2002

Transforming growth factor-beta3 (Tgf-beta3) down-regulates Tgf-beta3 receptor type I (Tbetar-I) during rescue of cranial sutures from osseous obliteration.

Appropriate biochemical regulation of intramembranous bone growth from sutures is necessary to achieve correct craniofacial morphology. Failure to form sutures (agenesis) or to maintain sutures in their unossified state (craniosynostosis) can result in severe facial dysmorphology. Several factors such as Twist, Msx2, fibroblast growth factors (Fgfs), bone morphogenetic proteins (Bmps) and transforming growth factors-beta (Tgf-betas) regulate suture patency, likely by interacting with one another. Tgf-beta2 and Tgf-beta3 use the same cell surface receptors, yet have opposite effects on suture patency, cellular proliferation and apoptosis within the suture. One possible mechanism by which Tgf-beta3 rescues sutures from obliteration is by regulating the ability of suture cells to respond to Tgf-beta2. As Tgf-beta3 does not regulate protein levels of Tgf-beta2 in sutures, Tgf-beta3 could regulate tissue responsiveness to Tgf-beta2 by regulating Tgf-beta2 access to receptors. Tgf-beta3 is a more potent competitor than Tgf-beta2 for cell surface receptors, so it is proposed that Tgf-beta3 binds to and down-regulates Tgf-beta receptor type I (Tbetar-I) expression by suture cells. This down-regulation would limit the ability of cells to respond to all Tgf-betas, including Tgf-beta2. To test this hypothesis, an in vitro culture model was used in which fetal rat sutures either remain patent or are induced to fuse when cultured in the presence or absence of dura mater, respectively. Tgf-beta3 was added to cultured calvaria and changes in the number of receptor positive cells within the suture were established. Data were compared with that seen in control sutures and in normal sutures in vivo. It was found that the numbers of cells expressing Tbetar-I within the suture matrix increased over time in sutures remaining patent. Osteoblastic cells lining the bone fronts on either side of sutures were Tbetar-I positive during early morphogenesis, but these numbers declined as sutures fused, both in vivo and in vitro. Addition of Tgf-beta3 to calvaria in culture decreased the number of Tbetar-I expressing cells in both fusing and non-fusing sutures, with dramatic decreases in the numbers of osteoblasts expressing Tbetar-I.

Activin Receptors, Type I↗
PubMed2001

2-Aryl indole NK(1) antagonists: optimisation of the amide substituent.

The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.

Administration, Oral↗
PubMed2001

Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils.

The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Expression of COX-2 and PGE synthase and synthesis of PGE(2)in endometrial adenocarcinoma: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors.

This study was designed to investigate the possible role of cyclo-oxygenase-2 (COX-2) and prostaglandin E(2)(PGE(2)) in endometrial adenocarcinoma. COX-2 RNA expression was confirmed in various grades of adenocarcinoma by ribonuclease protection assay. COX-2 and microsomal glutathione-dependent prostaglandin E synthase (mPGES) expression and PGE(2)synthesis were localised to the neoplastic epithelial cells and endothelial cells. In order to establish whether PGE(2)has an autocrine/paracrine effect in adenocarcinomas, we investigated the expression of 2 subtypes of PGE(2)receptors, namely EP2 and EP4, by real time quantitative PCR. Expression of EP2 and EP4 receptors was detected in adenocarcinomas from all grades of differentiation and was significantly higher than that detected in normal secretory phase endometrium (P< 0.01). The fold induction of expression in adenocarcinoma compared with normal secretory phase endometrium was 28.0 +/- 7.4 and 52.5 +/- 10.1 for EP2 and EP4 receptors respectively. Immunohistochemistry localised the site of expression of EP4 receptor in neoplastic epithelial cells and in the endothelium of carcinomas of all grades of differentiation. Finally, the functionality of the EP2/EP4 receptors was assessed by investigating cAMP generation following in vitro culture of adenocarcinoma tissue in the presence or absence of 300 nM PGE(2). cAMP production in response to PGE(2)was significantly higher in carcinoma tissue than that detected in normal secretory phase endometrium (3.42 +/- 0.46 vs 1.15 +/- 0.05 respectively; P< 0.001). In conclusion, these data suggest that PGE(2)may regulate neoplastic cell function in an autocrine/paracrine manner via the EP2/EP4 receptors.

Adenocarcinoma↗
PubMed2001

Treatment type and symptom severity among oncology patients by self-report.

Oncology patients receiving chemotherapy (n=109) and radiation therapy RT (n=161) reported symptom concerns and severity on the 25-item therapy-related symptom checklist (TRSC). Secondary analysis of the self-reports of the two treatment groups was done using the Mann-Whitney U Test. Thirteen symptoms differed significantly between the two groups. RT patients reported significantly greater severity of five symptoms (p<0.05) during therapy. Chemotherapy patients reported significantly greater severity of eight different symptoms. The other 14 items showed a heterogeneous pattern of self-reported patient symptom concerns. The TRSC appears to be a clinically useful self-report checklist that captures the more important symptom concerns of both RT and chemotherapy patients. Earlier efforts to develop this checklist are reviewed briefly.

Antineoplastic Agents↗
PubMed2001

Photodisruptive laser nucleation of ultrasonic cavitation for biomedical applications.

Pulses of high intensity laser light, when focused into transparent materials, may produce localized electron-ion plasmas through optical breakdown. By simultaneously incorporating the resulting volume of vaporized material within the focal volume of a high intensity ultrasound source, the photodisruption (1.05 microm wavelength) void served as a nucleation site for ultrasonic cavitation. Dilute suspensions of canine erythrocytes in phosphate buffered saline were exposed in a flow-through exposure chamber and the percentage of lysed cells was used as a measure of the biologically effective cavitation activity produced in the chamber. Brief (about 30 micros) acoustic emissions were detected from the photodisruption alone (indicating laser nucleation of bubbles), but the cell lysis produced was undetectable against the background. However, combined exposure greatly increased both the duration of the acoustic emissions (up to 1.5 ms) and the amount of cell lysis above an ultrasonic pressure amplitude threshold of about 4.3 MPa at 2.5 MHz. The amount of cell lysis (sometimes approaching 100%) increased with increasing ultrasonic intensity, laser pulse energy and laser PRF. Addition of 5% serum albumin enhanced the effect, apparently by stabilizing bubbles and nuclei. Photodisruptive laser nucleation of ultrasonic cavitation can provide controlled and synergistic enhancement of bioeffects.

Animals↗
PubMed2001

Direct and maternal genetic effects on birth and weaning traits in multibreed cattle data and predicted performance of breed crosses.

Direct and maternal additive effects and heterosis were estimated using data from straightbred Angus, Brahman, Charolais, Hereford, and four generations of rotational crosses among these breeds. Traits of interest were birth weight, Julian day of birth, average daily gain from birth to weaning, 205-d weight, and weaning weight per cow exposed. Complete data were available on 3,445 calves produced from 4,733 matings. Discrete generations of 4-yr duration were produced from 1970 through 1988. Brahman was included in each rotational crossbreeding system. Genetic effects were estimated by regression. Direct and maternal additive effects of Brahman, Charolais, and Hereford were estimated as deviations from Angus. Direct and maternal heterosis effects were assumed proportional to expected heterozygosity. The Brahman direct additive effect resulted in later-born calves (P < 0.01). Brahman, Charolais, and Hereford direct additive effects increased birth weight, and the Brahman maternal additive effect decreased birth weight compared with Angus (P < 0.05). Charolais direct and maternal additive effects were greater than Angus for average daily gain and 205-d weight (P < 0.01). The Hereford maternal additive effects on average daily gain and 205-d weight were less than those of the other breeds (P < 0.01). Breed combinations including Brahman had greater direct heterosis for birth weight, average daily gain, and 205-d weight than other combinations (P < 0.01). Angus, Charolais, and Hereford direct additive effects on weaning weight per cow exposed were greater than Brahman (P < 0.05). Predicted average daily gain, 205-d weight, and weaning weight per cow exposed were, on average, greater in four-breed rotation systems than in three- and two-breed systems. Among two-breed rotation systems, predicted average daily gain and 205-d weaning weight were greatest for Charolais-Brahman and least for Angus-Hereford. Calves from the Angus-Charolais-Hereford system weighed less at weaning than any other three-breed combination. However, weaning weight per cow exposed from the Angus-Charolais-Hereford system was greatest among three-breed systems. Within three- and four-breed rotation systems, ranges in predicted birth and weaning weights among generations varied by up to 10.0 and 25.2 kg, respectively. The choice of breeds affects performance, and the sequence of their use may affect intergenerational variation in performance.

Animals↗
PubMed2001

Memory for humorous cartoons.

Incidental memory for three types of cartoons was compared: original cartoons, literal translations of the originals, and weird cartoons created by inserting incongruous material into the literal translations. In Experiment 1, the three types of cartoons were mixed together in lists. In Experiment 2, each list contained only two cartoon types. In both experiments, original cartoons were remembered better than the literal and the weird cartoons, whereas the literal and the weird cartoons were equally well remembered. The detection of incongruities, or attempts to resolve those incongruities, cannot adequately explain the observed humor effects. The results were also inconsistent with both rehearsal and distinctiveness interpretations. Rather, humor per se appears to support good memory performance. Perhaps participants elaborated or gave sustained attention to humorous material at the expense of less humorous material.

Cartoons as Topic↗
PubMed2000

Synthesis and structures of polymeric Mn, Co, Cu, and Zn complexes of 3-diphenylamino-4-hydroxycyclobut-3-ene-1,2-dione (diphenylaminosquarate) and of the salt [Ni(H2O)6][(C6H5)2NC4O3]2.2H2O.

Reaction of M(NO3)2.xH2O (M = Mn, Co, Ni, Cu, Zn) with 3-diphenylamino-4-hydroxycyclobut-3-ene-1,2-dione (diphenylaminosquarate) produces the neutral polymeric species (M[mu-(C6H5)2NC4O3]2[H2O]2)n [M = Mn (1), Cu (2)]; (M[mu-(C6H5)2NC4O3][(C6H5)2NC4O3][H2O]3)n [M = Co (3), Zn (4)]; and in the case of Ni, the salt [Ni(H2O)6][(C6H5)2NC4O3]2.2H2O (5). Complexes 1 and 2 are isomorphous and crystallize in the monoclinic space group P2(1)/c with, for 1, a = 13.138(1) A, b = 10.900(2) A, c = 9.269(2) A, beta = 96.07(1) degrees, and Z = 2. Complexes 3 and 4 are also isomorphous and crystallize in the space group P2(1)/c with, for 3, a = 13.211(1) A, b = 11.038(1) A, c = 18.748(1) A, beta = 97.75(1) degrees, and Z = 4. The nickel salt, 5, crystallizes in the triclinic space group P1 with a = 6.181(1) A, b = 9.417(1) A, c = 15.486(1) A, alpha = 101.37(1) degrees, beta = 95.51(1) degrees, gamma = 107.57(1) degrees, and Z = 1. In 1 and 2, the metal coordination is octahedral, comprising four mu-1,3-bridging diphenylaminosquarate ligands and two trans aqua ligands. In 3 and 4, the metal coordination is again octahedral, comprising two mu-1,3-bridging and one pendant diphenylaminosquarate ligands, the octahedron being completed by three aqua ligands in a meridional configuration. In 5, the hexaaquanickel(II) ion is linked by O-H...O hydrogen bonds to a pair of diphenylaminosquarate anions. These anion-cation units are linked via included water molecules to form hydrogen-bonded chains. The diphenylaminosquarate ligands in the polymeric complexes 1-4 display multiple-bond localization, a feature which is absent in 5. Complex 1 exhibits weak antiferromagnetic coupling, whereas 2 shows no significant magnetic interactions.

Journal Article↗
PubMed2000

Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

Acetals↗
PubMed2000

Mothers' developmental expectations for young children in the Philippines.

The purpose of the study was to investigate the developmental timetables of rural and urban mothers in the Central Visayas, Philippines. Examined were mothers' expectations for children's development (physical/perceptual-motor, cognitive, and psychosocial) and mothers' child rearing practices, as influenced by four selected variables (child's gender and ordinal position, mother's education, and rural or urban residence). The total sample size was 303 mothers [153 of rural residence and 150 urban] in two provinces. Mothers responded to a structured questionnaire which was read to them aloud by trained interviewers who then recorded the responses. All the mothers had children between 4-6 years old; equal numbers of male and female children were included, and the entire economic and educational ranges were represented. MANOVA results showed significant main effects of all four variables on maternal expectations of child development and on maternal child rearing practices. Also, significant interaction effects of residential location and maternal education on mothers' expectations of children's physical/perceptual motor development were found (F[2, 256]=3.05, P=0.05). Significant interaction effects also were found of maternal education and the child's ordinal position (F[4,256]=2. 95, P=0.02) on maternal expectations of children's psychosocial development.

Adult↗
PubMed2000

Therapy use and discharge outcomes for elderly nursing home residents.

This study examines therapy use and discharge outcomes (community discharge, mortality, or remaining in the facility) over a 90-day period for 1,419 elderly, post-acute care nursing home admissions in South Dakota. Subjects met criteria as rehabilitation candidates (i.e., absence of serious behavioral or medical conditions that would limit rehabilitation potential). Receipt of therapies was related significantly to age (younger), Medicare coverage, hip fracture or stroke diagnosis, absence of cancer diagnosis, and resident or staff expectations for functional improvement. Therapy use was related positively to community discharge and negatively to mortality when controlling for covariates such as age, marital status, payment source, functional status, cognitive status, and major diagnoses. Also, community discharge was related positively to the facility's volume of therapy provision and percentage of Medicare-covered stays.

Aged↗