Influence of pravastatin on lipoproteins, and on endothelial, platelet, and inflammatory markers in subjects with peripheral artery disease.
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Aged↗
Biomedical subjects
E Hughes
Publications and source records attributed to E Hughes.
Identification of novel functional regions important for the activity of HOXB7 in mammalian cells.
Members of the HOX family of homeobox transcription factors play a role in pattern formation in diverse developmental systems. The clearly documented role of HOX genes in the proliferation and differentiation of primary hematopoietic cells and cell lines provides a convenient system to pursue a biochemical analysis of HOX gene function in mammalian cells. To explore the role of HOXB7 in myeloid hematopoiesis, a number of mutations and deletions in the gene were constructed that targeted sequences with known functions or in regions that had not been examined previously. The wild-type and mutant B7 constructs were introduced into the murine myelomonocytic cell line, 32D, and assayed for their effects on G-CSF-induced myeloid differentiation. Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. A model proposing a role for these regions of HOXB7 is presented.
3T3 Cells↗
Hyperkalaemic cardiac arrest in a manifesting carrier of Duchenne muscular dystrophy following general anaesthesia.
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Anesthesia, General↗
Psychomotor EEG variant of Gibbs: an association with underlying structural pathology.
OBJECTIVE: To describe the association between a unilateral mid-temporal rhythmic theta discharge ("psychomotor variant of Gibbs") with neuroimaging-demonstrated underlying mass lesion. METHODS: Standard routine awake and scalp electroencephalography, continuous video-EEG monitoring and magnetic resonance brain imaging were employed in the diagnostic work-up of a 9-year-old boy with a severe behavioural disturbance and episodic outbursts of aggression. RESULTS: EEG showed a unilateral mid-temporal rhythmic discharge which was continuous in drowsiness and which remained confined to the right hemisphere. MRI showed a lesion in the temporal horn of the right lateral ventricle displacing superiorly the white matter stem of the right temporal lobe. CONCLUSION: A rhythmic mid-temporal theta discharge, commonly regarded as a benign EEG variant, may, in some patients, reflect underlying structural pathology. Neuroimaging should be considered particularly when this EEG pattern remains confined to one hemisphere.
Brain Diseases↗
Comparison of methods for assessment of minimal residual disease in childhood B-lineage acute lymphoblastic leukemia.
The level of minimal residual disease (MRD) early in treatment of acute lymphoblastic leukemia (ALL) strongly predicts the risk of marrow relapse. As a variety of methods of varying complexity have been separately used for detecting and quantifying MRD, we compared the prognostic utility of three methods measurement of blast percentage on day 14 of treatment, detection of monoclonality on day 14 or day 35, and measurement of MRD by PCR-based limiting dilution analysis on day 14 or day 35. The study group comprised 38 children aged 1-15 with Philadelphia-negative B-lineage ALL who were uniformly treated and followed until relapse or for a minimum of 5 years. We also studied some of the technical factors which influence the ability to detect MRD. Measurement of blast percentage on day 14 by an expert morphologist, detection of monoclonality on day 35, and PCR-based measurement of MRD levels on days 14 and 35 all showed significant ability to divide patients into prognostic groups. Measurement of blast percentage on day 14 by routine morphology or detection of monoclonality on day 14 were not useful. The quality of DNA samples varied greatly, as determined by amplifiability in the PCR. However, virtually all amplifiable leukemic targets in a sample were detectable which suggests that the level of detection achieved by limiting dilution analysis is essentially determined by the amount of DNA which it is practicable to study. We conclude that quantification of MRD at the end of induction provides the full range of prognostic information for marrow relapse but is complex; detection of monoclonality on day 35 is simple and has good positive predictive value; and quantification of MRD on day 14 merits further study. PCR-based methods for measurement of MRD levels should incorporate a correction for variation in DNA amplifiability.
Antineoplastic Combined Chemotherapy Protocols↗
Molecular relapse can be detected in blood in a sensitive and timely fashion in B-lineage acute lymphoblastic leukemia.
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Adolescent↗
Structure, stability and folding of the alpha-helix.
Pauling first described the alpha-helix nearly 50 years ago, yet new features of its structure continue to be discovered, using peptide model systems, site-directed mutagenesis, advances in theory, the expansion of the Protein Data Bank and new experimental techniques. Helical peptides in solution form a vast number of structures, including fully helical, fully coiled and partly helical. To interpret peptide results quantitatively it is essential to use a helix/coil model that includes the stabilities of all these conformations. Our models now include terms for helix interiors, capping, side-chain interactions, N-termini and 3(10)-helices. The first three amino acids in a helix (N1, N2 and N3) and the preceding N-cap are unique, as their amide NH groups do not participate in backbone hydrogen bonding. We surveyed their structures in proteins and measured their amino acid preferences. The results are predominantly rationalized by hydrogen bonding to the free NH groups. Stabilizing side-chain-side-chain energies, including hydrophobic interactions, hydrogen bonding and polar/non-polar interactions, were measured accurately in helical peptides. Helices in proteins show a preference for having approximately an integral number of turns so that their N- and C-caps lie on the same side. There are also strong periodic trends in the likelihood of terminating a helix with a Schellman or alpha L C-cap motif. The kinetics of alpha-helix folding have been studied with stopped-flow deep ultraviolet circular dichroism using synchrotron radiation as the light source; this gives a far superior signal-to-noise ratio than a conventional instrument. We find that poly(Glu), poly(Lys) and alanine-based peptides fold in milliseconds, with longer peptides showing a transient overshoot in helix content.
Amino Acid Sequence↗
What did we learn about the impact on students' clinical education?
Analysis of the impact of the Interdisciplinary Generalist Curriculum (IGC) Project would be incomplete without discussion of how it affected students' clinical education. This article explores the impact of the IGC Project on medical students' clinical education at the ten IGC schools. The schools typically lacked pre-IGC Project baseline data for comparison, although they all collected data on the impact of the new curriculum on the clinical education of students. Measures included some objective indicators and various subjective measures of the perceptions of the students, faculty, and community preceptors. The impact of curricular innovations at the IGC Project schools on students was immediate as they began to see patients early and continuously as part of their medical education. Students, faculty, and community preceptors who interacted with these students during their third year believed they were "different" because of their participation in the IGC. Not only did the IGC students approach patients with better integrated basic science knowledge, but also a different kind of student arrived at the third year, the traditional beginning of clinical experiences in medical education.
Curriculum↗
Is there a relation between docosahexaenoic acid concentration in mothers' milk and visual development in term infants?
BACKGROUND: Docosahexaenoic acid (DHA), present in high concentrations in the brain and retina, has a role in visual development. DHA is present in human milk, but not in most infant formulas. It is, however, under discussion whether DHA should be added to formulas intended for term infants. The concentration of DHA in human milk, which is influenced by maternal diet, varies considerably, but it is unknown whether this variation affects visual development in term infants. METHODS: The authors investigated 39 4-month-old fully breast-fed term infants in a cross-sectional study. Visual acuity was measured by swept visual evoked potentials, milk DHA was determined by gas chromatography, and maternal fish intake was assessed by a frequency questionnaire. RESULTS: Frequency of fish intake correlated positively to the DHA level in breast-milk (P = 0.001). Mothers who ate fish the day before sampling had a milk DHA level higher than expected from habitual fish intake (P = 0.002). If this was taken into account, 57% of the variation in milk DHA could be explained by fish intake. Multiple linear regression analysis revealed a significant association between visual acuity and milk DHA (P = 0.02, R2 = 0.09). CONCLUSION: This finding suggests a cause-and-effect relationship between infant milk DHA intake and visual acuity. If these data are confirmed, there is a need to consider the optimal intake of DHA for the lactating mother.
Animals↗
The expression of thyrotropin receptor in the brain.
The regulation of the thyroid gland by TSH is mediated by a heterotrimeric G protein-coupled receptor. Nonthyroid effects of TSH have been reported, and expression of its receptor has been described in adipocytes and lymphocytes. We have previously reported the existence of specific and saturable binding sites of TSH and specific TSH effects in primary cultured rat brain astroglial cells. We now report expression of the TSH receptor gene in these cells; the coding sequence of the corresponding complementary DNA is identical to that previously established in thyroid. Using specific antisense RNA probe, expression of this gene was detected in some isolated or clustered glial fibrillary acidic protein-positive primary cultured cells by in situ hybridization. With this technique, we further detected TSH receptor messenger RNA (mRNA) expression in rat brain cryoslices in both neuronal cells and astrocytes. Its presence predominated in neuron-rich areas (pyriform and postcingulate cortex, hippocampus, and hypothalamic nuclei) and was mostly colocalized with neuron-specific enolase. In astrocytes, this mRNA was detected in the ependymal cell layer and the subependymal zone, and several isolated cells were also found in the brain parenchyma. We also detected TSH receptor mRNA and protein in primary cultured human astrocytes. The protein was detected as well in both rat and human brain cryoslices. Together, these findings clearly demonstrate the expression of the TSH receptor gene in the brain in both neuronal cells and astrocytes.
Animals↗
E-health and online teaching: a successful synergy.
Knowledge of the successes and failures of a variety of e-health applications has contributed to the teaching process as well as the content of an online e-health course. Examining the synergy between e-health and online teaching as forms of technologically mediated communication is useful in developing knowledge about both. Two conclusions may be drawn. The first is that success rests on the ability to make sense of the information that is communicated. The second is that success depends on building social networks. We have developed an online course in e-health in which participants develop an understanding of the domain both through sharing their own experience of online delivery and through course content that illustrates the successes and failures of others.
Education, Distance↗
Transverse asymmetry AT' from the quasielastic 3He(e,e') process and the neutron magnetic form factor.
We have measured the transverse asymmetry A(T') in 3He(e,e(')) quasielastic scattering in Hall A at Jefferson Laboratory with high precision for Q2 values from 0.1 to 0.6 (GeV/c)(2). The neutron magnetic form factor G(n)(M) was extracted based on Faddeev calculations for Q2 = 0.1 and 0.2 (GeV/c)(2) with an experimental uncertainty of less than 2%.
Journal Article↗
Early resistance to therapy during induction in childhood acute lymphoblastic leukemia.
Many patients with acute lymphoblastic leukemia (ALL) are not cured by current therapy because of the development of drug resistance. It is not clear when resistance develops during the growth of the leukemic clone and whether resistant cells are already present at diagnosis or develop later during treatment. Twenty-two uniformly treated children with ALL were studied throughout induction treatment. The size of the leukemic clone in blood and marrow was estimated by limiting dilution PCR analysis, using the rearranged immunoglobulin heavy chain gene as a molecular marker. The decline in the number of leukemic cells was biphasic in virtually all patients. For both marrow and blood, the logarithmic mean of the number of leukemic cells fell by approximately four orders of magnitude during the first 2 weeks, one order of magnitude during the third week, and not at all during the last two weeks of induction treatment. For marrow, the median of the fraction of leukemic cells in each patient that survived per week of treatment was 0.008 for the first 2 weeks, 0.12 for the third week, and 1.4 for the last 2 weeks; for blood, the corresponding figures were 0.003, 0.14, and 0.69, respectively. In individual patients, the results for marrow and blood showed good correlation. The biphasic decline of leukemic cell number suggests that most leukemic cells were sensitive to treatment and were rapidly killed, leaving behind a minor but substantial population of drug-resistant cells. The most likely explanation for this phenomenon is that these resistant cells were already present at diagnosis, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemic clone.
Antineoplastic Combined Chemotherapy Protocols↗
Inhibition of toxicity in the beta-amyloid peptide fragment beta -(25-35) using N-methylated derivatives: a general strategy to prevent amyloid formation.
beta-(25-35) is a synthetic derivative of beta-amyloid, the peptide that is believed to cause Alzheimer's disease. As it is highly toxic and forms fibrillar aggregates typical of beta-amyloid, it is suitable as a model for testing inhibitors of aggregation and toxicity. We demonstrate that N-methylated derivatives of beta-(25-35), which in isolation are soluble and non-toxic, can prevent the aggregation and inhibit the resulting toxicity of the wild type peptide. N-Methylation can block hydrogen bonding on the outer edge of the assembling amyloid. The peptides are assayed by Congo red and thioflavin T binding, electron microscopy, and a 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) toxicity assay on PC12 cells. One peptide (Gly(25) N-methylated) has properties similar to the wild type, whereas five have varying effects on prefolded fibrils and fibril assembly. In particular, beta-(25-35) with Gly(33) N-methylated is able to completely prevent fibril assembly and to reduce the toxicity of prefolded amyloid. With Leu(34) N-methylated, the fibril morphology is altered and the toxicity reduced. We suggest that the use of N-methylated derivatives of amyloidogenic peptides and proteins could provide a general solution to the problem of amyloid deposition and toxicity.
Amyloid beta-Peptides↗
Bromocriptine for unexplained subfertility in women.
BACKGROUND: Bromocriptine improves hyperprolactinemic amenorrhea and so could also be helpful in the treatment of unexplained subfertility in women. OBJECTIVES: To assess the effects of bromocriptine in women with unexplained subfertility. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched. SELECTION CRITERIA: Randomised trials comparing bromocriptine with placebo or no treatment in women with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Two reviewers applied the eligibility criteria and assessed trial quality independently. MAIN RESULTS: Three trials involving of 127 women were included. All trials were double-blind comparisons with placebo, and one was of crossover design. Conception rates with bromocriptine treatment did not improve compared with placebo (odds ratio was 1.12, 95% confidence interval 0.48 to 2.57). REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate bromocriptine use in women with unexplained subfertility. However trials for women with unexplained subfertility who also have expressible galactorrhea may be worthwhile.
Bromocriptine↗
Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea.
BACKGROUND: The administration of clomiphene citrate is followed by an enhanced release of pituitary gonadotropins resulting in follicular recruitment. After the drug is stopped, there is continuing secretion of estradiol, selection of the dominant follicle and, in successful cases, ovulation. Clomiphene is indicated as the initial treatment in the majority of women with amenorrhoea and oligomennorhoea. In women with irregular ovulation it seems to re-establish typical frequency of ovulation. Its effectiveness in oligo-amenorrhoeic women was tested in a number of randomized controlled trials at that time. These trials form the basis for the following review. OBJECTIVES: Clomiphene citrate enhances the release of pituitary hormones, often resulting in ovulation. The objective of this review was to assess the effects of clomiphene citrate on ovulation and pregnancy in women with oligo-ovulatory subfertility. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched. SELECTION CRITERIA: Randomised trials of clomiphene compared with placebo or no treatment in women with oligo-ovulatory subfertility of at least 12 months duration. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Four studies were included. They were all of crossover design. Since it was not possible to separate data from the first and second phases of these trials, the effect of clomiphene may be overestimated. Compared with placebo, clomiphene citrate was associated with increased ovulation. The odds ratio for high doses (50-250 milligrams per day) was 6.82 (95% confidence interval 3.92 to 11.85). This dropped to a non-significant odds ratio of 1.29 (95% confidence interval 0.48 to 3.49) with low doses (10 milligrams per day). Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle (odds ratio 3.41, 95% confidence interval 4.23 to 9.48). REVIEWER'S CONCLUSIONS: Clomiphene citrate (at doses between 50 to 250 milligrams per day) appears to be an effective method of inducing ovulation and improving fertility in oligo-ovulatory women. However adverse effects include possible ovarian cancer risk and risk of multiple pregnancy.
Amenorrhea↗
Clomiphene citrate for unexplained subfertility in women.
OBJECTIVES: Clomiphene citrate appears to increase ovulation in women with oligo-ovulatory subfertility. It may also work in women with unexplained subfertility, perhaps by correcting an unidentifiable ovulatory dysfunction. The objective of this review was to assess the effects of clomiphene citrate in women with unexplained subfertility. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched". SELECTION CRITERIA: Randomised trials of clomiphene citrate (doses of 50 to 250 milligrams per day up to 10 days) compared to placebo or no treatment in women with unexplained subfertility. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Five studies were included. Four trials were of crossover design, and quality of the randomisation was variable. Compared to placebo, clomiphene citrate was associated with an increase in pregnancy rates. The odds ratio for pregnancy per patient was 2.38 (95% confidence interval 1.22 to 4.62). The odds ratio of pregnancy per cycle was 2.5 (95% confidence interval 1.35 to 4.62). REVIEWER'S CONCLUSIONS: Clomiphene citrate appears to modestly improve pregnancy rates in women with unexplained subfertility. However adverse effects include a possible ovarian cancer risk and risk of multiple pregnancy.
Clomiphene↗