Low incidence of rejection after synchronous pancreas-kidney transplantation with Neoral.
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Administration, Oral↗
Biomedical subjects
E Wright
Publications and source records attributed to E Wright.
Stroke prevention trial in sickle cell anemia.
Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.
Adolescent↗
The significance of choroid plexus cysts in an unselected population: results of a multicenter study.
OBJECTIVES: Choroid plexus cysts are commonly found at the time of a routine second-trimester scan, but there is much debate as to their clinical significance. The aims of this study were to define the incidence of choroid plexus cysts in an unselected population and describe their association with aneuploidy. DESIGN: This was a prospective, observational multicenter study. SUBJECTS: Subjects were all fetuses found to have choroid plexus cysts with a maximum diameter of 3 mm or greater and who were between 14 and 24 weeks' gestation when scanned in the routine ultrasound department at any of the 13 participating hospitals. RESULTS: There were 658 fetuses with choroid plexus cysts in a total of 101,600 births. The overall incidence of aneuploidy was 2.1%, but in fetuses with isolated choroid plexus cysts the incidence of proven aneuploidy was 0.5% (95% confidence interval (CI), 0.1-1.4%). If age is taken into consideration, then the incidence of aneuploidy in fetuses with isolated choroid plexus cysts where the mother is under the age of 36 years was 0.36% (95% CI, 0.04-1.3%), and 2.4% (95% CI, 0.06-12.6%) in older women. CONCLUSIONS: We conclude that the presence of choroid plexus cysts increases the risk for aneuploidy, mainly trisomy 18. In the majority of cases, the final risk will remain small, but will increase as maternal age increases.
Aneuploidy↗
Genetic instability in radiation-induced leukaemias: mouse models.
PURPOSE: Genetic instability plays a major role in multi-stage carcinogenesis. Ionizing radiation induces delayed genetic instability which can be transmitted to the clonal offspring of the irradiated cell, so it is of considerable importance to determine whether radiation-induced genetic instability contributes to radiation-leukaemogenesis. RESULTS: The experimental data obtained using radiation-induced leukaemias in mouse models were reviewed, and an attempt was made to distinguish between the instability detectable in de novo cancers and that which is associated with ionising radiation. Genetic lesions identified in mouse leukaemias include non-clonal chromosomal aberrations, loss of heterozygosity, and minisatellite/microsatellite mutations. CONCLUSIONS: Studies of mouse radiation-induced leukaemias have detected evidence of genetic instability. However, with few exceptions, most of this instability was also observed during de novo multi-stage carcinogenesis. This raises the possibility that radiation induces ongoing genetic instability that is functionally indistinguishable to that implicated in de novo tumour progression.
Animals↗
Expression of IgE heavy chain transcripts in the sinus mucosa of atopic and nonatopic patients with chronic sinusitis.
We have recently shown the increased mRNA expression of interleukin (IL)-4 and IL-13 in sinus biopsies from allergic subjects with chronic sinusitis (ACS), whereas only IL-13 mRNA was elevated in biopsies obtained from nonallergic subjects with chronic sinusitis (NCS). In the lymph nodes and spleen, these cytokines may promote IgE production through transcriptional activation of the germline IgE heavy chain promoter, an event which precedes immunoglobulin isotype switching to IgE in B cells. We hypothesized that local expression of IL-4 and/or IL-13 might act by inducing germline IgE heavy chain transcript expression locally in the sinus mucosa of chronic sinusitis patients. Mucosal sinus biopsies were obtained from 13 patients with ACS, 12 subjects with NCS, and 11 normal control individuals. The numbers of B cells in the sinus mucosa were studied by immunocytochemistry with anti-CD20 monoclonal antibodies. In situ hybridization was performed using antisense radiolabeled riboprobes complementary to the IgE epsilon -heavy chain germline (Iepsilon) and heavy chain constant region (Cepsilon) gene transcripts. Riboprobes specific for the IgG gamma-heavy chain constant region (Cgamma) were used as an isotype control. Immunocytochemical analysis indicated augmented numbers of CD20-positive B cells in the biopsies obtained from ACS patients compared with NCS subjects (P < 0.05) and normal control subjects (P < 0.01). Statistically significant increases were observed in the numbers of cells expressing Iepsilon and Cepsilon transcripts in the sinus mucosa of ACS patients compared with those with NCS (P < 0. 001) and normal controls (P < 0.001), while Cgamma RNA expression did not differ significantly between the groups. In three randomly selected ACS biopsies, 92-100% of cells expressing Cepsilon transcripts and 100% of Iepsilon RNA-positive cells coexpressed CD20 immunoreactivity. Cells expressing Cepsilon transcripts were also significantly increased in NCS compared with normal controls (P < 0. 05). The results of this study suggest that local IgE class switching occurs in the pathogenesis of ACS and that ACS and NCS are both associated with increased expression of Cepsilon transcripts.
Adult↗
A controlled trial of an educational program to prevent low back injuries.
BACKGROUND: Low back injuries are common and costly, accounting for 15 to 25 percent of injuries covered by workers' compensation and 30 to 40 percent of the payments made under that program. The high costs of injury, the lack of effective treatment. and the evidence that there are behavioral risk factors have led to widespread use of employee education programs that teach safe lifting and handling. The effectiveness of those programs, however, has received little rigorous evaluation. METHODS: We evaluated an educational program designed to prevent low back injury in a randomized, controlled trial involving about 4000 postal workers. The program, similar to that in wide use in so-called back schools, was taught by experienced physical therapists. Work units of workers and supervisors were trained in a two-session back school (three hours of training), followed by three to four reinforcement sessions over the succeeding few years. Injured subjects (from both the intervention and the control groups) were randomized a second time to receive either training or no training after their return to work. RESULTS: Physical therapists trained 2534 postal workers and 134 supervisors. Over 5.5 years of follow-up, 360 workers reported low back injuries, for a rate of 21.2 injuries per 1000 worker-years of risk. The median time off from work per injury was 14 days (range, 0 to 1717); the median cost was $204 (range, zero to $190,380). After their return to work, 75 workers were injured again. Our comparison of the intervention and control groups found that the education program did not reduce the rate of low back injury, the median cost per injury, the time off from work per injury, the rate of related musculoskeletal injuries, or the rate of repeated injury after return to work; only the subjects' knowledge of safe behavior was increased by the training. CONCLUSIONS: A large-scale, randomized, controlled trial of an educational program to prevent work-associated low back injury found no long-term benefits associated with training.
Adolescent↗
SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse.
Two lines of evidence suggest that the Sry-related gene Sox9 is important for chondrogenesis in mammalian embryos. Sox9 mRNA is expressed in chondrogenic condensations in mice, and mutations in human SOX9 are known to cause skeletal dysplasia. We show here that mouse SOX9 protein is able to bind to a SOX/SRY consensus motif in DNA and contains a modular transcriptional activation domain, consistent with a role for SOX9 as a transcription factor acting on genes involved in cartilage development. One such gene is Col2a1, which encodes type II collagen, the major structural component of cartilage. We have compared, in detail, the expression of Sox9 and Col2a1 during mouse development. In chondrogenic tissues the expression profiles of the two genes were remarkably similar. Coexpression was detected in some nonchondrogenic tissues such as the notochord, otic vesicle, and neural tube, but others such as heart and lung differed in their expression of the two genes. Immunohistochemistry using an antibody specific for SOX9 revealed that expression of SOX9 protein mirrored the distribution of Sox9 mRNA. Our results suggest that SOX9 protein is involved in the regulation of Col2a1 during chondrogenesis, but that this regulation is likely to depend on additional cofactors.
Animals↗
[Vascular protection with estrogen. In-vitro and in-vivo effects--mechanisms and clinical implication].
Myocardial infarction is the major cause of death in the western world. Men are more prone to develop coronary artery disease than women of the same age, in whom coronary disease is rare before menopause. Epidemiological data have shown that estrogens are vasoprotective--especially in the coronary circulation--but the underlying mechanisms have been investigated more thoroughly only in recent years. Only up to half of the protective effect of estrogen replacement therapy an be attributed to its positive effects of the lipid profile. However, a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Actions of natural estrogens on human vascular cells and arteries will be discussed. Estrogens modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17-beta estradiol is a potent inhibitor of vascular smooth muscle cell proliferation and migration, which play a major role in atherosclerotic vascular disease and in the remodeling process. 17-beta estradiol also acutely affects vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies showed that 17-beta estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies showed positive effects of natural estrogens on vascular function which could explain in part their protective actions against coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after menopause appears to be a new approach to reduce cardiovascular mortality in women.
Adult↗
Expression of the Sox11 gene in mouse embryos suggests roles in neuronal maturation and epithelio-mesenchymal induction.
Sry, the mammalian Y-linked testis determining gene, is a member of a family of genes known as Sox genes, which encode transcription factors related by a DNA-binding motif termed the HMG box. Sox genes are known to have diverse roles in vertebrate differentiation and development. We report here the cloning and characterisation of one of these genes, Sox11, in mice. In addition to an N-terminal HMG box domain, the deduced SOX11 protein contains a number of highly conserved C-terminal motifs, which may function in transcriptional regulation. Expression of Sox11 in mouse embryos was prominent in the periventricular cells of the central nervous system, suggesting a role in neuronal maturation. Expression was also observed in a wide range of tissues involved in epithelial-mesenchymal interactions, suggesting an additional role in tissue modelling during development.
Amino Acid Sequence↗
Minimal access surgery of the frontonasal duct through a simultaneous transfrontal and intranasal approach.
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Aged↗
Nonlinear mixed effects modeling of single dose and multiple dose data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam.
PURPOSE: NONMEM was applied to single dose and multiple dose bioavailability data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam to acquire additional information from the data which are not easily obtainable by traditional means. METHODS: The objective function value (OBJ) and diagnostic plots were used as measures of goodness of fit of the model to the data. A change in the OBJ value of 7.9 was necessary to show statistical significance (p < 0.005) between two models when the two models differed by 1 parameter. RESULTS: A two-compartment linear model with first-order absorption and elimination best describes the data. Including a lag time, two different rates of absorption (KAIR and KACR), and bioavailability for the CR relative to the IR dosage form significantly improved the fit of the model to the data. Cigarette smoking was associated with a 100% increase in clearance of alprazolam as compared to non-smokers. The higher residual variability observed in this study, where interoccasion variability (IOV) was not initially modeled, could be explained to a large extent by the presence of significant interoccasion variability (IOV). CONCLUSIONS: Since alprazolam has been suggested to be mainly metabolized by the CYP3A4 isozyme in humans, it appears that tobacco could be an inducer of CYP3A4 and/or alprazolam may be metabolized by other isozyme(s) (specifically, CYP1A1/1A2) that are induced by cigarette smoke. The population pharmacokinetic model approach combined with exploratory graphical data analysis is capable of identifying important covariates from well-controlled "data rich" Phase I studies early in drug development.
Adult↗
Mini- and microsatellite mutations in radiation-induced acute myeloid leukaemia in the CBA/H mouse.
Radiation-induced acute myeloid leukaemia (AML) in the CBA/H mouse is a clonal disorder and therefore amenable to the analysis of genetic instability during radiation leukaemogenesis. The genotype of a single minisatellite and 20 microsatellite loci was compared in tail and leukaemic spleen DNA prepared from the same mouse. Somatic mutation at the Ms6-hm minisatellite locus was nearly seven times higher (27%, 4/15) than the spontaneous germline mutation rate (4%). Only 1/15 AMLs exhibited microsatellite mutations, but 5/20 loci were mutated in the same AML, indicating that it was deficient in mismatch repair. Thus, whereas somatic minisatellite mutations, which are associated with complex intra-allelic gene conversion events, occur at a very high rate in the radiation-induced AMLs, microsatellite instability, which has been associated with the acquisition of the replication error repair (RER+) phenotype, is infrequent but detectable.
Acute Disease↗
Ongoing Y-chromosome instability defines sub-clonal variants in radiation-induced leukaemias in the mouse.
Forty primary leukaemias that arose in vivo as a consequence of 3 Gy X-irradiation of inbred mouse strains were analysed for Y-chromosome aberrations by conventional cytogenetics and fluorescent in situ hybridization (FISH). Compared with control mice which were X-irradiated but which exhibited no overt signs of leukaemia, the loss and gain of Y-chromosomes in leukaemic spleen cells defined subclonal variants in the radiation-induced haemopoietic malignancies that arose in CBA/H, DBA/2 and (C57BL/6 x DBA/2)F1 mice. This Y-chromosome instability was significantly higher than that observed in spleen cells of age-matched (or older) irradiated control mice that had not developed overt leukaemia. The detection of Y-chromosome aberrations is considered in the context of the high numbers of potential gene regulatory sequences in the murine Y-chromosome and the potential for the insertional activation of cellular genes during multi-stage radiation leukaemogenesis.
Acute Disease↗
Paternal X-chromosome inactivation in human trophoblastic cells.
Dosage compensation for X-chromosome-linked genes between male and female mammals occurs by inactivation of one of the two X chromosomes in the female. In somatic cells, either the paternal or the maternal X chromosome is randomly inactivated in a given cell. In contrast, in the extra-embryonic tissues of mice, the paternally-derived X chromosome is preferentially inactivated. The evidence for paternal X-chromosome inactivation in humans is controversial and remains to be clarified. In this study, we have developed a sensitive polymerase chain reaction (PCR) technique to investigate the methylation pattern of the X-linked androgen receptor (AR) gene. The 5' CpG island of this gene is methylated on the inactive X chromosome and hypomethylated on the active X chromosome in somatic cells. The paternal and the maternal alleles of the AR gene may be distinguished by a polymorphism in the number of CAG triplet repeats within the CpG island. As a source of human extra-embryonic tissue, we used chorionic villus (CV) samples from female conceptuses of 10-12 weeks gestation. From a tiny branch of a CV sample, two distinct cell lineages, the trophoblastic and mesodermal lineages, were dissected apart by trypsin digestion and micromanipulation and DNA was extracted separately from these purified tissues. Digestion of the DNA with the methylation-sensitive restriction enzyme, Hpall, followed by PCR amplification revealed that the paternal allele is preferentially methylated in trophoblastic cells, but not in mesodermal cells. These results strongly suggest that the paternal X chromosome is preferentially inactivated in the human extra-embryonic tissues early in development.
Animals↗
Fertility and reproductive choice in women with HIV-1 infection.
OBJECTIVE: To measure fertility and birth rates and to describe the reproductive histories of women diagnosed with HIV-1 infection in Australia. METHODS: The medical records of 294 women with HIV-1 infection in four states of Australia were reviewed. Expected fertility and birth rates were calculated using national statistics. RESULTS: In the study population, 152 (52%) women had at least one pregnancy prior or subsequent to HIV-1 diagnosis. At maternal HIV-1 diagnosis, 71 (24%) women had a total of 106 children aged under 15 years. During the study period, 246 women were aged 15, 44 years and 58 (23%) of these became pregnant after HIV-1 diagnosis. Women whose exposure to HIV-1 was injecting drug use were twice as likely to become pregnant and more likely to have multiple pregnancies than women who did not report injecting drug use. The annual general fertility rate was 30 per 10,000 compared with 63 per 10,000 for the Australian female population aged 15-44 years, and the birth rate in women with HIV-1 infection was one-half that of the general female population. Of pregnancies confirmed after HIV-1 diagnosis, 47% were voluntarily terminated, a rate more than double that of the general population. All multiple terminations were among women whose exposure to HIV-1 was injecting drug use. CONCLUSIONS: Fertility and birth rates among women with HIV-1 infection are lower than the general population and the rate of termination higher. The results of this study provide a basis for the management of women with HIV-1 infection who are considering pregnancy.
Adolescent↗
In vivo analysis of DNA-protein interactions on the human erythropoietin enhancer.
The erythropoietin (EPO) gene is one of the best examples of a mammalian gene controlled by oxygen tension. The DNA elements responsible for hypoxia-induced transcription consist of a short region of the proximal promoter and a <50-bp 3' enhancer. The elements act cooperatively to increase the transcriptional initiation rate approximately 100-fold in response to low oxygen tension in Hep3B cells. Two distinct types of transactivating proteins have been demonstrated to bind the response elements in the human EPO enhancer in vitro: one shows hypoxia-inducible DNA binding activity, while the other activity binds DNA under normoxic and hypoxic conditions. We have investigated the DNA-protein interactions on the human EPO enhancer in living tissue culture cells that produce EPO in a regulated fashion (Hep3B) and in cells that do not express EPO under any conditions tested (HeLa). We have identified in vivo DNA-protein interactions on the control elements in the human EPO enhancer by ligation-mediated PCR technology. We show that the putative protein binding sites in the EPO enhancer are occupied in vivo under conditions of normoxia, hypoxia, and cobalt exposure in EPO-producing cells. These sites are not occupied in cells that do not produce EPO. We also provide evidence for a conformational change in the topography of the EPO enhancer in response to hypoxia and cobalt exposure.
Base Sequence↗
A randomised prospective comparison of operative peripheral iridectomy and Nd:YAG laser iridotomy treatment of acute angle closure glaucoma: 3 year visual acuity and intraocular pressure control outcome.
AIM: To compare visual acuity and intraocular pressure outcomes 3 years after treatment of acute angle closure glaucoma (AACG) by operative peripheral iridectomy (PI) or Nd:YAG laser iridotomy (YAG PI). METHODS: A prospective study of consecutive patients presenting to one ophthalmology department with uniocular AACG during a 2 year period. Following informed consent patients were randomised to bilateral PI or bilateral YAG PI. Three years after treatment the mean Snellen visual acuity converted to logMAR scores of the two groups was compared using the unpaired Student's t test. The number of patients with normal intraocular pressure with no further treatment in each group was compared using the chi 2 test with Yates's correction. RESULTS: 21 patients underwent bilateral PI and 27 bilateral YAG PI. Three years after treatment visual acuity was 0.30 (SD 0.28) log MAR units for PI eyes and 0.57 (0.67) logMAR units for YAG PI eyes (p = 0.08, NS). 15 (70.4%) PI eyes and 19 (71.8%) YAG PI eyes had an intraocular pressure less than 21 mm Hg with no further treatment (NS). CONCLUSIONS: There was no significant difference in visual acuity or intraocular pressure control 3 years after treatment of AACG with PI or YAG PI.
Aged↗
Protamine sulphate used in combination with thrombin to remove fibrinogen prior to electrophoresis of heparinised plasma.
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Blood Protein Electrophoresis↗