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Search Results: 1 - 10 of 166428 matches for " Richard B Anderson "
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Genetic interactions and modifier genes in Hirschsprung's disease
Adam S Wallace,Richard B Anderson
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i45.4937
Abstract: Hirschsprung’s disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung’s disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung’s disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung’s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung’s disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.
A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause
Thomas W. Kelsey, Phoebe Wright, Scott M. Nelson, Richard A. Anderson, W. Hamish B Wallace
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022024
Abstract: Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.
Effects of NGF, NT-3 and GDNF family members on neurite outgrowth and migration from pelvic ganglia from embryonic and newborn mice
Ashley L Stewart, Richard B Anderson, Kazuto Kobayashi, Heather M Young
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-73
Abstract: Cell migration assays showed that GDNF strongly stimulated migration of tyrosine hydroxylase (TH) cells of pelvic ganglia from E11.5, E14.5 and P0 mice. Other factors also promoted TH cell migration, although to a lesser extent and only at discrete developmental stages. The cells and neurites of the pelvic ganglia were responsive to each of the GDNF family ligands – GDNF, neurturin and artemin – from E11.5 onwards. In contrast, NGF and NT-3 did not elicit a significant neurite outgrowth effect until E14.5 onwards. Artemin and NGF promoted significant outgrowth of sympathetic (TH+) neurites only, whereas neurturin affected primarily parasympathetic (TH-negative) neurite outgrowth, and GDNF and NT-3 enhanced both sympathetic and parasympathetic neurite outgrowth. In comparison, collagen gel assays using gut explants from E11.5 and E14.5 mice showed neurite outgrowth only in response to GDNF at E11.5 and to neurturin only in E14.5 mice.Our data show that there are both age-dependent and neuron type-dependent differences in the responsiveness of embryonic and neo-natal pelvic ganglion neurons to growth factors.The pelvic ganglia provide the majority of autonomic innervation to the urogenital organs and part of the extrinsic innervation of the lower bowel [1-3]. In humans, the plexus is extensive and is frequently injured during pelvic surgical procedures [4-7]. The development of regenerative therapies may be facilitated by improved knowledge of the processes that occur during the normal development of the pelvic neuronal circuits. In mice and rats, the structure of the pelvic ganglia is simpler than in humans, and consists of paired, morphologically discrete, major pelvic ganglia [8]. Hence, developing rodent pelvic ganglia are an accessible system in which to study developmental processes involved in formation of pelvic autonomic circuits [9].Unlike other autonomic ganglia, the pelvic ganglia are comprised of a mixture of sympathetic and parasympathetic post-ganglioni
Diethylstilboestrol Exposure Does Not Reduce Testosterone Production in Human Fetal Testis Xenografts
Rod T. Mitchell, Richard M. Sharpe, Richard A. Anderson, Chris McKinnell, Sheila Macpherson, Lee B. Smith, W. Hamish B. Wallace, Christopher J. H. Kelnar, Sander van den Driesche
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061726
Abstract: In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production. We show, using a xenograft approach, that testosterone production is not reduced in human fetal testis following DES exposure. Human fetal testes (15–19 weeks’ gestation, n = 6) were xenografted into castrate male nude mice which were then treated for 35 days with vehicle or 100 μg/kg DES three times a week. For comparison, similar treatment was applied to pregnant rats from e13.5–e20.5 and effects on fetal testes evaluated at e21.5. Xenograft testosterone production was assessed by measuring host seminal vesicle (SV) weights as an indirect measure over the entire grafting period, and single measurement of serum testosterone at termination. Human fetal testis xenografts showed similar survival in DES and vehicle-exposed hosts. SV weight (44.3 v 26.6 mg, p = 0.01) was significantly increased in DES compared to vehicle-exposed hosts, respectively, indicating an overall increase in xenograft testosterone production over the grafting period, whilst serum testosterone at termination was unchanged. In contrast intra-testicular testosterone levels were reduced by 89%, in fetal rats exposed to DES. In rats, DES effects are mediated via Estrogen Receptor α (ESR1). We determined ESR1 protein and mRNA expression in human and rat fetal testis. ESR1 was expressed in rat, but not in human, fetal Leydig cells. We conclude that human fetal testis exposure to DES does not impair testosterone production as it does in rats, probably because ESR1 is not expressed in human fetal Leydig cells. This indicates that DES exposure is likely to pose minimal risk to masculinization of the human fetus.
Fetal Cyclophosphamide Exposure Induces Testicular Cancer and Reduced Spermatogenesis and Ovarian Follicle Numbers in Mice
Paul B. Comish, Ana Luiza Drumond, Hazel L. Kinnell, Richard A. Anderson, Angabin Matin, Marvin L. Meistrich, Gunapala Shetty
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093311
Abstract: Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ~70% of control and induced atrophic seminiferous tubules in ~30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.
Tuning in on Cepheids: Radial velocity amplitude modulations. A source of systematic uncertainty for Baade-Wesselink distances
Richard I. Anderson
Physics , 2014, DOI: 10.1051/0004-6361/201423850
Abstract: [Abridged] I report the discovery of modulations in radial velocity (RV) curves of four Galactic classical Cepheids and investigate their impact as a systematic uncertainty for Baade-Wesselink distances. Highly precise Doppler measurements were obtained using the Coralie high-resolution spectrograph since 2011. Particular care was taken to sample all phase points in order to very accurately trace the RV curve during multiple epochs and to search for differences in linear radius variations derived from observations obtained at different epochs. Different timescales are sampled, ranging from cycle-to-cycle to months and years. The unprecedented combination of excellent phase coverage obtained during multiple epochs and high precision enabled the discovery of significant modulation in the RV curves of the short-period s-Cepheids QZ Normae and V335 Puppis, as well as the long-period fundamental mode Cepheids l Carinae and RS Puppis. The modulations manifest as shape and amplitude variations that vary smoothly on timescales of years for short-period Cepheids and from one pulsation cycle to the next in the long-period Cepheids. The order of magnitude of the effect ranges from several hundred m/s to a few km/s. The resulting difference among linear radius variations derived using data from different epochs can lead to systematic errors of up to 15% for Baade-Wesselink-type distances, if the employed angular and linear radius variations are not determined contemporaneously. The different natures of the Cepheids exhibiting modulation in their RV curves suggests that this phenomenon is common. The observational baseline is not yet sufficient to conclude whether these modulations are periodic. To ensure the accuracy of Baade-Wesselink distances, angular and linear radius variations should always be determined contemporaneously.
Amplitude Modulation of Cepheid Radial Velocity Curves as a Systematic Source of Uncertainty for Baade-Wesselink Distances
Richard I. Anderson
Physics , 2014, DOI: 10.1017/S1743921314006942
Abstract: I report on the recent discovery of modulation in the radial velocity curves in four classical Cepheids. This discovery may enable significant improvements in the accuracy of Baade-Wesselink distances by revealing a not previously considered systematic source of uncertainty.
Could Sequential Residual Centering Resolve Low Sensitivity in Moderated Regression? Simulations and Cancer Symptom Clusters  [PDF]
Richard B. Francoeur
Open Journal of Statistics (OJS) , 2013, DOI: 10.4236/ojs.2013.36A004

Multicollinearity constitutes shared variation among predictors that inflates standard errors of regression coefficients. Several years ago, it was proven that the common practice of mean centering in moderated regression cannot alleviate multicollinearity among variables comprising an interaction, but merely masks it. Residual centering (orthogonalizing) is unacceptable because it biases parameters for predictors from which the interaction derives, thus precluding interpretation of moderator effects. I propose and validate residual centering in sequential re-estimations of a moderated regression—sequential residual centering (SRC)—by revealing unbiased multicollinearity conditioning across the interaction and its related terms. Across simulations, SRC reduces variance inflation factors (VIF) regardless of distribution shape or pattern of regression coefficients across predictors. For any predictor, the reduced VIF is used to derive a lower standard error of its regression coefficient. A cancer sample illustrates SRC, which allows unbiased interpretations of symptom clusters. SRC can be applied efficiently to alleviate multicollinearity after data collection and shows promise for advancing synergistic frontiers of research.

Determinants of Inapparent and Symptomatic Dengue Infection in a Prospective Study of Primary School Children in Kamphaeng Phet, Thailand
Timothy P. Endy ,Kathryn B. Anderson,Ananda Nisalak,In-Kyu Yoon,Sharone Green,Alan L. Rothman,Stephen J. Thomas,Richard G. Jarman,Daniel H. Libraty,Robert V. Gibbons
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0000975
Abstract: Background Dengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Inapparent dengue is an important component of the overall burden of dengue infection. It provides a source of infection for mosquito transmission during the course of an epidemic, yet by definition is undetected by health care providers. Previous studies of inapparent or subclinical infection have reported varying ratios of symptomatic to inapparent dengue infection. Methodology/Principal Findings In a prospective study of school children in Northern Thailand, we describe the spatial and temporal variation of the symptomatic to inapparent (S:I) dengue illness ratio. Our findings indicate that there is a wide fluctuation in this ratio between and among schools in a given year and within schools over several dengue seasons. The most important determinants of this S:I ratio for a given school were the incidence of dengue infection in a given year and the incidence of infection in the preceding year. We found no association between the S:I ratio and age in our population. Conclusions/Significance Our findings point to an important aspect of virus-host interactions at either a population or individual level possibly due to an effect of heterotypic cross-reactive immunity to reduce dengue disease severity. These findings have important implications for future dengue vaccines.
Inverse association between gastroesophageal reflux and blood pressure: Results of a large community based study
Liam J Murray, Peter McCarron, Roger B McCorry, Lesley A Anderson, Athene J Lane, Brian T Johnston, George Smith, Richard F Harvey
BMC Gastroenterology , 2008, DOI: 10.1186/1471-230x-8-10
Abstract: Linear regression was used to examine the association between systolic and diastolic blood pressure and the frequency of heartburn and acid regurgitation in 4,902 of 10,537 participants aged 20–59 years.In multivariable analyses, adjusted mean systolic blood pressure was 4.2 (95% confidence interval 1.5 to 7.0) mm Hg lower in participants with daily acid regurgitation compared to those with less frequent symptoms. Similarly, for diastolic blood pressure, a reduction of 2.1 (0.0 to 4.3) mm Hg wasobserved.People who experience daily symptoms of gastro-oesophageal reflux have lower blood pressure than people with less frequent or no symptoms. It is possible that factors influencing nitric oxide concentrations both at the lower oesophageal sphincter and within the vasculature may be involved. This hypothesis requires confirmation.ISRCTN44816925In 2003 we reported reduced stroke mortality among patients with oesophageal columnar epithelium (Barrett's oesophagus), with cerebrovascular deaths in patients with specialised intestinal metaplasia of the oesophagus being half that of the general population [1]. Subsequently, a postmarketing surveillance study of 18,000 patients on omeprazole in the United Kingdom has not shown any reduction in stroke mortality in these patients compared to the general population [2] but this drug is often prescribed for upper gastrointestinal conditions other than gastro-oesophageal reflux and Barrett's oesophagus. We hypothesised that the association we observed may be due to individuals with reduced lower oesophageal sphincter (LOS) pressure, (a risk factor for gastro-oesophageal reflux and Barrett's oesophagus) also having low vascular tone and blood pressure, resulting in reduced stroke risk. To investigate this, we examined whether blood pressure is associated with symptoms of gastro-oesophageal reflux.From 1996 to 1998, 10,537 individuals, aged 20–59 years, registered with seven general practices in Southwest England were enrolled in a co
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