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Biomedical subjects

A Holmes

Publications and source records attributed to A Holmes.

At least 37 records · Page 2Linked to original sources
PubMed2002

Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts.

OBJECTIVE: As an initial approach to understanding the basis of the systemic sclerosis (SSc; scleroderma) phenotype, we sought to identify genes in the transforming growth factor beta (TGF beta) signaling pathway that are up-regulated in lesional SSc fibroblasts relative to their normal counterparts. METHODS: We used gene chip, differential display, fluorescence-activated cell sorter, and overexpression analyses to assess the potential role of TGF beta signaling components in fibrosis. Fibroblasts were obtained by punch biopsy from patients with diffuse cutaneous SSc of 2-14 months' duration (mean 8 months) and from age- and sex-matched healthy control subjects. RESULTS: Unexpectedly, we found that fibroblasts from SSc patients showed elevated expression of the endothelial cell-enriched TGF beta receptor endoglin. Endoglin is a member of the nonsignaling high-affinity TGF beta receptor type III family. The expression of endoglin increased with progression of disease. Transfection of endoglin in fibroblasts suppressed the TGF beta-mediated induction of connective tissue growth factor promoter activity. CONCLUSION: SSc is characterized by overproduction of matrix; that is, genes that are targets of TGF beta signaling in normal fibroblasts. Our findings suggest that lesional SSc fibroblasts may overexpress endoglin as a negative feedback mechanism in an attempt to block further induction of profibrotic genes by TGF beta.

Antigens, CD↗
PubMed2002

Galanin peptide levels in hippocampus and cortex of galanin-overexpressing transgenic mice evaluated for cognitive performance.

Galanin-overexpressing transgenic mice (GAL-tg) generated on a dopamine beta-hydroxylase promoter were previously shown to express high levels of galanin mRNA in the locus coeruleus, and to perform poorly on challenging cognitive tasks. The present study employed radioimmunoassay to quantitate the level of galanin peptide overexpression in two brain regions relevant to learning and memory, the hippocampus and cerebral cortex. Approximately 4-fold higher levels of galanin were detected in the hippocampus of GAL-tg as compared to WT. Approximately 10-fold higher levels of galanin were detected in the frontal cortex of GAL-tg as compared to WT. A second cohort of GAL-tg and WT again showed high levels of galanin overexpression in GAL-tg as compared to WT in both brain regions. Correlation analyses were conducted between galanin peptide concentrations and behavioral scores on four learning and memory tasks: the Morris water maze, social transmission of food preference, standard delay fear conditioning, and trace fear conditioning. While some significant correlations were detected, neither hippocampal nor cortical galanin levels in the two cohorts of GAL-tg consistently correlated with performance across these diverse cognitive tasks. Several interpretations of these findings are discussed, including the possibility that a threshold level of galanin overexpression is sufficient to impair performance on learning and memory tasks in mice.

Animals↗
PubMed2002

Assessment of health-related quality-of-life in males with Anderson Fabry Disease before therapeutic intervention.

Anderson Fabry Disease (AFD) is an extremely painful and debilitating multi-system X-linked disorder due to alpha-galactosidase enzyme deficiency. To date, no baseline data on health-related quality-of-life (HR-QoL) have been reported in males affected with this condition. In this study, 38 males with AFD completed Medical Outcomes Study Short Form, EuroQoL questionnaires and an AFD-specific questionnaire prior to the start of a trial involving replacement therapy with alpha-galactosidase. Results from these questionnaires were compared to the results from a similar HR-QoL study in males with severe haemophilia (factor VIII/IX deficiency) that used the same questionnaires and to the results of two large normative studies. The results on both questionnaires showed that in most instances males with AFD recorded significantly lower HR-QoL compared with males in the general population and individuals with severe haemophilia after adjusting for differences in age. These findings suggest therefore, that the scope for improvement in HR-QoL as a result of treatment with an appropriate agent is extremely large.

Adult↗
PubMed2002

Behavioral profiles of inbred strains on novel olfactory, spatial and emotional tests for reference memory in mice.

Studying the behavior of genetic background strains provides important information for the design and interpretation of cognitive phenotypes in mutant mice. Our experiments examined the performance of three commonly used strains (C57BL/6J, 129S6, DBA/2J) on three behavioral tests for learning and memory that measure very different forms of memory, and for which there is a lack of data on strain differences. In the social transmission of food preference test (STFP) all three strains demonstrated intact memory for an odor-cued food that had been sampled on the breath of a cagemate 24 hours previously. While C57BL/6J and 129S6 mice showed good trace fear conditioning, DBA/2J mice showed a profound deficit on trace fear conditioning. In the Barnes maze test for spatial memory, the 129S6 strain showed poor probe trial performance, relative to C57BL/6J mice. Comparison of strains for open field exploratory activity and anxiety-like behavior suggests that poor Barnes maze performance reflects low exploratory behavior, rather than a true spatial memory deficit, in 129S6 mice. This interpretation is supported by good Morris water maze performance in 129S6 mice. These data support the use of a C57BL/6J background for studying memory deficits in mutant mice using any of these tasks, and the use of a 129S6 background in all but the Barnes maze. A DBA/2J background may be particularly useful for investigating the genetic basis of emotional memory using fear conditioning.

Animals↗
PubMed2001

Complete genome sequence of Salmonella enterica serovar Typhimurium LT2.

Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets.

Animals↗
PubMed2001

Prior test experience compromises the anxiolytic efficacy of chlordiazepoxide in the mouse light/dark exploration test.

It is now well established that prior test experience can alter behavioural baselines and attenuate/abolish the anxiolytic efficacy of benzodiazepines in the elevated plus-maze paradigm. In view of evidence that different models of anxiety measure qualitatively distinct forms of anxiety-like behaviour, it is important to establish whether the effects of prior experience extend to other widely-used tests. The present study assessed the behavioural and pharmacological sequelae of a single undrugged prior exposure to the light/dark exploration (L/D) test in mice, using ethological scoring methods. One group of adult male Swiss-Webster mice was given a single undrugged exposure to the L/D test 24 h prior to drug testing, while another group was completely naïve to the apparatus. On test day, half the animals in each experiential condition were treated with saline and half with an anxiolytic dose (10 mg/kg) of chlordiazepoxide (CDP). When administered to test-naïve animals, CDP induced a clear reduction in anxiety-like behaviour as evidenced by significant increases in exploration of the light compartment (line crossings, % line crossings, and % time) as well as reductions in stretched attend postures (SAPs) and the proportion of SAPs displayed toward the light compartment. The behavioural specificity of these effects was confirmed by the absence of a drug effect on line crossings in the dark compartment, total rearing and grooming. In complete contrast, with the sole exception of a decrease in total SAPs, CDP was without significant behavioural effect in test-experienced mice. As prior test experience did not significantly alter behavioural baselines in the L/D test, a second experiment was designed to investigate the possibility that handling/intraperitoneal injection may have precluded detection of experientially-induced changes in baseline behaviour. Results showed that handling/injection had no effect upon L/D behavioural profiles in either test-naïve or test-experienced subjects, and confirmed that prior experience itself did not modify the primary indices of anxiety in this test. Present data indicate that prior test experience seriously compromises the anxiolytic efficacy of CDP (10 mg/kg) in the mouse L/D test and, together with recent findings in the four-plate test, appear to confirm that an experientially-induced reduction in sensitivity to the anxiolytic effects of benzodiazepines is by no means unique to the elevated plus-maze.

Animals↗
PubMed2001

Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.

Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.

Alzheimer Disease↗
PubMed2001

CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling.

In normal adult fibroblasts, transforming growth factor-beta (TGFbeta) induces the expression of connective tissue growth factor (CTGF). CTGF independently promotes fibroblast proliferation and matrix deposition, and in acute models of fibrosis promotes cell proliferation and collagen deposition acting synergistically with TGFbeta. In contrast to normal fibroblasts, fibroblasts cultured from fibrotic tissues express high basal levels of CTGF, even in the absence of added TGFbeta. Induction of transcription by TGFbeta requires the action of SMAD proteins. In this report we have investigated the role of SMADs in the TGFbeta-induction of CTGF in normal fibroblasts and in the elevated levels of CTGF expression found in dermal fibroblasts cultured from lesional areas of patients with scleroderma, a progressive fibrotic disorder that can affect all organs of the body. We have identified a functional SMAD binding site in the CTGF promoter. TGFbeta-induction of CTGF is dependent on SMAD3 and SMAD4 but not SMAD2 and is p300-independent. However, mutation of the SMAD binding site does not reduce the high level of CTGF promoter activity observed in dermal fibroblasts cultured from lesional areas of scleroderma patients. Conversely, the previously termed TGFbetaRE in the CTGF promoter is required for basal CTGF promoter activity in normal fibroblasts and for the elevated level of CTGF promoter activity in scleroderma fibroblasts. Thus, the maintenance of the fibrotic phenotype in scleroderma fibroblasts, as visualized by excess CTGF expression, appears to be independent of SMAD-dependent TGFbeta signaling. Furthermore, given CTGF's activities, the high level of CTGF expression observed in scleroderma lesions may contribute to the excessive scarring observed in this disorder.

3T3 Cells↗
PubMed2001

Rapid and radical amniodrainage in the treatment of severe twin-twin transfusion syndrome.

We have evaluated the role of a rapid and radical method of amniodrainage in the treatment of severe twin-twin transfusion. The outcome of 15 patients with severe twin-twin transfusion for which a amniodrainage was performed by means of a vacuum bottle system was compared with the outcome of 15 patients with a similar condition, matched for gestational age at the time of the initial procedure and drained using a standard procedure. In the study group the amniodrainage ended when no amniotic fluid could be aspirated, whereas the women in the standard group were drained with a syringe system and the fluid was removed until the deepest amniotic fluid pool was <8 cm. At the initial procedure, the mean volume of amniotic fluid drained was significantly (p<0.05) higher (3252 vs 2153 ml) and the length of the procedure significantly (p<0.001) shorter (21 vs 41 min) in the study group than in the standard group. The mean post-procedure amniotic fluid index was significantly (p<0.001) smaller (2.9 vs 7.7 cm) after radical amniodrainage than after the standard amniodrainage. The mean number of procedures was significantly (p<0.001) lower (1.5 vs 5.6) in the study group compared to the standard group. In the study group the mean placental thickness increased significantly (p<0.001) from 9 mm before the procedure to 49 mm after, and the overall perinatal survival rate was 80% and the proportion of pregnancies with at least one survivor was 93%. The present data indicate that early, rapid and radical amniodrainage is an effective and low-cost therapy for severe twin-twin transfusion syndrome. Compared to the standard amniodrainage technique it also appears to reduce the need for multiple procedures.

Amnion↗
PubMed2001

Comparison of time-frequency distribution techniques for analysis of spinal somatosensory evoked potential.

Spinal somatosensory evoked potential (SSEP) has been employed to monitor the integrity of the spinal cord during surgery. To detect both temporal and spectral changes in SSEP waveforms, an investigation of the application of time-frequency analysis (TFA) techniques was conducted. SSEP signals from 30 scoliosis patients were analysed using different techniques; short time Fourier transform (STFT), Wigner-Ville distribution (WVD), Choi-Williams distribution (CWD), cone-shaped distribution (CSD) and adaptive spectrogram (ADS). The time-frequency distributions (TFD) computed using these methods were assessed and compared with each other. WVD, ADS, CSD and CWD showed better resolution than STFT. Comparing normalised peak widths, CSD showed the sharpest peak width (0.13+/-0.1) in the frequency dimension, and a mean peak width of 0.70+/-0.12 in the time dimension. Both WVD and CWD produced cross-term interference, distorting the TFA distribution, but this was not seen with CSD and ADS. CSD appeared to give a lower mean peak power bias (10.3%+/-6.2%) than ADS (41.8%+/-19.6%). Application of the CSD algorithm showed both good resolution and accurate spectrograms, and is therefore recommended as the most appropriate TFA technique for the analysis of SSEP signals.

Evoked Potentials, Somatosensory↗
PubMed2001

Antenatal waist circumference and hypertension risk.

OBJECTIVE: To assess whether waist circumference at the first antenatal visit predicts risk of developing hypertension later in pregnancy. METHODS: Pregnant women with singleton pregnancies (n = 1142, median age 29 years, interquartile range 25-32 years, 387 primigravidas) were recruited at their first antenatal visits. Using standardized methods, midwives determined the weights, heights (for calculation of body mass index [BMI]), and waist circumferences of all women. Eighty-two women developed pregnancy-induced hypertension, and 21 developed preeclampsia (hypertension with proteinuria). RESULTS: The median waist circumference between 6 and 16 weeks' gestation was 79 cm (interquartile range 72-84 cm), and there was no significant relationship between waist circumference and gestational age. Greater waist circumference was noted in subjects who subsequently developed pregnancy-induced hypertension (median 81 versus 77 cm, Mann-Whitney U test, P =.002) or preeclampsia (median 80 versus 77 cm, P =.02). The conventional, nonpregnant waist circumference action level of 80 cm gave a Mantel-Haenszel odds ratio (OR) for pregnancy-induced hypertension of 1.8 (95% confidence interval [CI] 1.1, 2.9) and for preeclampsia of 2.7 (95% CI 1.1, 6.8), compared with waists of less than 80 cm. Body mass index values were higher in women who developed pregnancy-induced hypertension (median 26 versus 24, P =.001) or preeclampsia (median 26 versus 24, P =.02). The conventional action limit for a BMI of 25 had an OR for pregnancy-induced hypertension of 2.0 (95% CI 1.2, 3.4) and for preeclampsia of 1.9 (95% CI 0.7, 4.8). Results were similar when the analysis was restricted to data from primigravidas. CONCLUSION: We conclude that waist circumference up to 16 weeks' gestation can predict pregnancy-induced hypertension and preeclampsia. Therefore, waist circumference could form the basis for health promotion involving raising awareness of the importance of or urging weight reduction for women planning pregnancies.

Adult↗
PubMed2001

Targeted gene mutation approaches to the study of anxiety-like behavior in mice.

Studying the behavioral phenotypes of transgenic and gene knockout mice is a powerful means to better understand the pathophysiology of neuropsychiatric disorders and ultimately improve their treatment. This paper provides an overview of the methods and findings of studies that have tested for anxiety-related behavioral phenotypes in gene mutant mice. In the context of improving the side effect burden of benzodiazepines, gene targeting has been valuable for dissociating the functional roles (i.e., anxiolytic, sedative, amnestic) of individual GABA(A) receptor subunits. Supporting the link between abnormalities in CRH function and anxiety, CRH overexpressing transgenic mice and CRH-R2 receptor knockout mutants have displayed significantly increased anxiety-like behavior, while CRH-R1 receptor knockout mice have shown an anxiolytic-like phenotype. Consistent with an important role for the serotonergic system in anxiety, 5-HT1(A) receptor deficient mice have consistently exhibited heightened anxiety-like behavior, while the evidence from 5-HT1(B) and 5-HT2(C) deficient mice remains somewhat equivocal. Mutant mice lacking either of the monoamine degrading enzymes, MAOA or COMT, have shown a number of behavioral and neurological effects, including alterations in anxiety-like behavior. With enhanced spatial and temporal control over gene mutations, in combination with an improved battery of behavioral tests, gene mutant mice will provide an increasingly valuable tool for understanding the neural substrates of anxiety.

Animals↗
PubMed2001

Can attention select only a fixed number of objects at a time?

Several previous studies have suggested that we may attend only a fixed number of 'objects' at a time. However, whereas findings from two-target experiments suggest that we can attend only one object at a time, other results from object-tracking and enumeration paradigms point instead to a four-object limit. Here, we note that in these previous studies the number of objects covaried with the overall size and complexity of the stimulus, such that apparent one-object or four-object limits in those tasks may reflect changes in the complexity of attended stimuli, rather than the number of objects per se. Accordingly, in the current experiments we employ stimuli in which the number of objects varies, while overall size and complexity are held constant. Using these refined measures of object-based effects, we find no evidence for a one-object or four-object limit on attention. Indeed, we conclude that the number of attended objects does not affect how efficiently we can attend a given stimulus. We propose and test an alternative approach to object-based attention limitations based on within-object and between-object feature-binding mechanisms in human vision.

Adult↗
PubMed2001

Nuchal translucency measurement and pregnancy outcome after assisted conception versus spontaneously conceived twins.

BACKGROUND: Nuchal translucency (NT) measurement for Down's syndrome screening or detecting various fetal anomalies is a reliable sonographic marker. This study evaluates the contribution of NT screening in spontaneously conceived and assisted conception twin pregnancies. METHODS AND RESULTS: Maternal age at measurement, chorionicity, ultrasound features, karyotype results and pregnancy outcome were recorded prospectively and compared in 83 assisted reproduction treatment and 91 spontaneously conceived twins. Pregnancy outcome was evaluated according to maternal age, method of conception, NT data and chorionicity. NT measurements (> or =95 centiles of the normal range) were considered screen-positive and mid-pregnancy fetal karyotyping was advised. Complicated pregnancy outcome, which could be signalled by increased NT, was defined as either chromosomal abnormalities, severe structural defects or fetal demise. Based on NT measurements, 16 fetuses (4.6%) were found to be screen-positive. Five of them had chromosomal aneuploidy and selective termination was performed. The parents also opted for this procedure in another five fetuses because of major structural abnormality diagnosed during NT assessment. No other chromosomal or major fetal abnormality were found post-natally. Although no difference was found in NT, crown-rump length and maternal age between spontaneous and assisted reproduction technology twin pregnancies, the former group had a significantly higher rate of screen-positive results (7 versus 2%, P = 0.047), amniocentesis uptake (33 versus 22%, P = 0.014), monochorionic twining (32 versus 4%, P = 0.001) and complicated pregnancy outcome (11 versus 5%, P = 0.02). CONCLUSION: The present study confirms that first trimester target scanning can improve outcome by early detection and management of cases with an anomalous co-twin. It also identifies some differences between spontaneously and artificially conceived twin pregnancies in relation to this area of testing.

Abortion, Induced↗