SAGE. The serial analysis of gene expression.
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Animals↗
Biomedical subjects
J Powell
Publications and source records attributed to J Powell.
A novel chromosomal rearrangement associated with therapy-related acute leukemia.
We describe a 7-year-old girl with therapy-related acute myeloid leukemia (AML) associated with a single and novel karyotypic abnormality. The patient had been treated with alkylating agents and etoposide for hypothalamic pilocytic astrocytoma at age 17 months, and developed mixed lineage AML. Cytogenetic analysis of the leukemic blasts showed 46,XX,der(7)t(7;11)(q22;q14) in all cells examined. Southern blot analysis revealed three copies of an unrearranged MLL gene on chromosome 11q. This is the first report of a triplicated, unrearranged MLL gene in association with a deletion of 7q anomaly and an unbalanced translocation in therapy-related leukemia.
Acute Disease↗
Targeted correction of an episomal gene in mammalian cells by a short DNA fragment tethered to a triplex-forming oligonucleotide.
Triplex-forming oligonucleotides (TFOs) can bind to polypurine/polypyrimidine regions in DNA in a sequence-specific manner and provoke DNA repair. We have coupled a TFO to a short donor fragment of DNA that shares homology to a selected gene as a strategy to mediate gene targeting and correction. In this bifunctional oligonucleotide, the TFO domain is designed to bind the target gene and stimulate repair and recombination, with the donor domain positioned for recombination and information transfer. A series of these tethered donor-TFO (TD-TFO) molecules with donor domains of 40-44 nucleotides and TFO domains in both the purine and pyrimidine triplex motifs were tested for their ability to mediate either gene correction or mutation of a supF reporter gene contained in a SV40 shuttle vector in mammalian cells. In vitro binding assays revealed that the attachment of the donor domain via a flexible linker did not significantly alter the binding affinity of the TFO domain for the polypurine site in the supF target DNA, with equilibrium dissociation constants in the 10(-8) M range. Experiments in which the target vector and the linked TD-TFOs were pre-incubated in vitro and co-transfected into cells led to conversion frequencies approaching 1%, 4-fold greater than with the two domains unlinked. When cells that had been previously transfected with the SV40 vector were electroporated with the TD-TFOs, frequencies of base pair-specific gene correction were seen in the range of 0.04%, up to 50-fold over background and at least 3-fold over either domain alone or in unlinked combinations. Sequence conversion by the TD-TFOs was achieved using either single- or double-stranded donor domains and either triplex motif. Substitution of either domain in the TD-TFO with control sequences yielded reagents with diminished activity, as did mixtures of unlinked TFO and donor DNA segments. The boost in activity provided by the attached TFO domain was reduced in cells deficient in the nucleotide excision repair factor XPA but was restored in a subclone of these cells expressing XPA cDNA, suggesting a role for nucleotide excision repair in the pathway of triple helix-stimulated gene conversion. The ability to correct or mutate a specific target site in mammalian cells using the TD-TFO strategy may provide a useful tool for research and possibly for therapeutic applications.
Animals↗
CYP2D6 polymorphisms in Alzheimer's disease, with and without extrapyramidal signs, showing no apolipoprotein E epsilon 4 effect modification.
BACKGROUND: Allelic variation at the CYP2D6 gene has been reported to be associated with Parkinsons' disease (PD) and Lewy body dementia (LBD), but not with Alzheimer's disease (AD). AD has been associated with apolipoprotein E (apoE) epsilon 4 allele loading. METHODS: We examined CYP2D6 and apoE polimorphisms in a sample of 259 patients with dementia, 210 of whom had a diagnosis of AD, and 107 healthy controls. RESULTS: We found that the allelic frequency in our AD sample did not vary from that in the controls. The debrisoquine hydroxylase poor metabolize phenotype was not more prevalent among AD cases than among controls in contrast to that reported for PD and LBD. We also found that CYP2D6 status does not modify the risk effect for AD conferred by apoE epsilon 4 alleles. CONCLUSIONS: These findings provide some support to the notion that, at a genetic level, at least at this locus, AD could be distinct from PD and LBD.
Age of Onset↗
In-hospital versus out-of-hospital presentation of life-threatening ventricular arrhythmias predicts survival: results from the AVID Registry. Antiarrhythmics Versus Implantable Defibrillators.
OBJECTIVES: This study describes the outcomes of patients from the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study Registry to determine how the location of ventricular arrhythmia presentation influences survival. BACKGROUND: Most studies of cardiac arrest report outcome following out-of-hospital resuscitation. In contrast, there are minimal data on long-term outcome following in-hospital cardiac arrest. METHODS: The AVID Study was a multicenter, randomized comparison of drug and defibrillator strategies to treat life-threatening ventricular arrhythmias. A Registry was maintained of all patients with sustained ventricular arrhythmias at each study site. The present study includes patients who had AVID-eligible arrhythmias, both randomized and not randomized. Patients with in-hospital and out-of-hospital presentations are compared. Data on long-term mortality were obtained through the National Death Index. RESULTS: The unadjusted mortality rates at one- and two-year follow-ups were 23% and 31.1% for patients with in-hospital presentations, and 10.5% and 16.8% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted mortality rates at one- and two-year follow-ups were 14.8% and 20.9% for patients with in-hospital presentations, and 8.4% and 14.1% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted long-term relative risk for in-hospital versus out-of-hospital presentation was 1.6 (95% confidence interval [CI] 1.3-1.9). CONCLUSIONS: Compared with patients with out-of-hospital presentations of life-threatening ventricular arrhythmias not due to a reversible cause, patients with in-hospital presentations have a worse long-term prognosis. Because location of ventricular arrhythmia presentation is an independent predictor of long-term outcome, it should be considered as an element of risk stratification and when planning clinical trials.
Aged↗
Identification of changes in gene expression associated with minimal residual disease.
Minimal residual disease (MRD), the tumour burden which remains after a course of treatment that has resulted in clinical remission [1], appears to differ in certain characteristics from the primary tumour population. Certainly the cells which comprise MRD have had to escape from the constraints of the primary tumour mass, invade normal tissue and penetrate small vessels in order to enter the circulation in which they then have had to survive. Such activities are the consequence of the expression of specific proteins and these may well be a reflection of alterations in DNA or RNA levels. Identifying the changes in RNA expression levels between related cell groups exhibiting different phenotypes recently has become a great deal easier as a consequence of developments in analytical procedures such as Differential Display (DD) and Serial Analysis of Gene Expression (SAGE). Application of these procedures to MRD cells recovered from blood, bone marrow or lymph node, should identify novel sequences associated with tumour progression and the development of disseminated disease.
Animals↗
Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease.
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Alleles↗
Benign familial Degos disease worsening during immunosuppression.
We describe a 61-year-old woman with skin lesions consistent with those found in Degos disease, both in clinical and in histological appearance. She had had several of these lesions for many years, as had her mother, sister and niece. In 1991, she underwent cadaveric renal transplantation and was treated with immunosuppression: prednisolone, azathioprine and cyclosporin. At that time, she developed many more characteristic skin lesions, and these were slightly larger and more noticeable than those she had had previously. She and the other affected family members appear to fit into the more benign subgroup of Degos disease, and it seems that her immunosuppression aggravated her cutaneous disease.
Female↗
Netherton's syndrome: increased likelihood of diagnosis by examining eyebrow hairs.
Netherton's syndrome is a rare autosomal recessive condition with variable expression. It comprises an ichthyosiform dermatitis and erythroderma of variable intensity and manifestations, associated with hair abnormalities. The pathognomonic finding (required for diagnosis) is that of trichorrhexis invaginata identified by light and scanning electron microscopic examination of hair shafts. This may be difficult to establish because the hair is sparse and not all hairs exhibit abnormalities. In one patient, cutaneous and hair problems had existed since infancy, and despite repeated examination of scalp hairs, the definitive diagnosis was made only by examining eyebrow hairs at the age of 30 years. We subsequently compared the number of diagnostic lesions found on scalp and eyebrow hairs from two other patients with previously diagnosed Netherton's syndrome. The density of lesions was greater in eyebrow than scalp hair, and furthermore, all eyebrow hairs had at least one lesion. It is proposed that microscopic examination, if possible, of both scalp and eyebrow hair from patients in whom Netherton's syndrome is suspected would increase the chance of a positive diagnosis.
Adult↗
Obstetric outcomes in an aboriginal community: a comparison with the surrounding rural area.
Antenatal, intranatal and postnatal features of all Aboriginal women who lived at Cherbourg Aboriginal Community and delivered during 1990, 1991 and 1992 were compared with all non-Aboriginal women in the same rural area who delivered at Kingaroy Base Hospital during 1991. Almost all the Aboriginal women also delivered at Kingaroy. The data for 146 Aboriginal and 139 non-Aboriginal women were taken from the hospital records. The Aboriginal women were generally younger at delivery (Aboriginal 35% younger than 20 years vs non-Aboriginal 12%), made their first antenatal visit later (Aboriginal 49% after 20 weeks vs non-Aboriginal 10%) and made fewer antenatal visits (Aboriginal 43% < 4 visits vs non-Aboriginal 2% < 4 visits). They were more likely to be anaemic (Aboriginal 65% < 110 g/L vs non-Aboriginal 13% < 110 g/L), have a sexually transmitted disease (STD; Aboriginal 13% vs non-Aboriginal 2%) and drink alcohol (Aboriginal 54% vs non-Aboriginal 32%). After making an allowance for repeat Caesarean sections, there was no significant difference in the proportion of abnormal deliveries, but birthweights of Aboriginal infants were lower. Postnatally, the only significant difference between the two groups was a lower incidence of jaundice in Aboriginal infants. Multifactorial analysis showed that birthweights were significantly decreased by primagravidy, alcohol intake and STD. It is likely that the effects of STD and alcohol on birthweight were due to associated lifestyle factors. When these factors were allowed for, ethnic background had no significant effect on birthweight.
Adolescent↗
Update on hemangiomas and vascular malformations.
Hemangiomas and vascular malformations are frequently encountered in pediatric practice, especially hemangiomas and port-wine stains. These lesions may cause physical and psychological complications and it is important to recognize which lesions need to be treated and how. Great progress has been made in the classification of vascular anomalies. Angiogenesis and molecular genetics are areas of active research; recent findings relating to hemangiomas and vascular malformations are presented. New clinical features of hemangiomas are described, such as association of extensive facial hemangiomas with various malformations and the occurrence of Kasabach-Merritt phenomenon, not with common hemangiomas, but with other vascular tumors (Kaposiform hemangioendothelioma and tufted angioma). Interferon alfa is effective for treatment of complicated hemangiomas but may cause serious neurological side effects. It is to be hoped that early diagnosis of Sturge-Weber syndrome will soon be possible with new, noninvasive, functional imaging techniques. New issues surrounding pulsed dye laser therapy for port-wine stains are also discussed in this article.
Child↗
Electrical stimulation of wrist extensors in poststroke hemiplegia.
BACKGROUND AND PURPOSE: It has been suggested that cyclic neuromuscular electrical stimulation (ES) may enhance motor recovery after stroke. We have investigated the effects of ES of the wrist extensors on impairment of wrist function and on upper-limb disability in patients being rehabilitated after acute stroke. METHODS: We recruited 60 hemiparetic patients (mean age, 68 years) 2 to 4 weeks after stroke into a randomized, controlled, parallel-group study comparing standard rehabilitation treatment with standard treatment plus ES of wrist extensors (3 times 30 minutes daily for 8 weeks). Isometric strength of wrist extensors was measured using a device built for that purpose. Upper-limb disability was assessed with use of the Action Research Arm Test (ARAT). Observations were continued for 32 weeks (24 weeks after the finish of ES or the control intervention phase). RESULTS: The change in isometric strength of wrist extensors (at an angle of 0 degrees extension) was significantly greater in the ES group than the control group at both 8 and 32 weeks (P=0.004, P=0.014 by Mann Whitney U test). At week 8 the grasp and grip subscores of the ARAT increased significantly in the ES group compared with that in the control group (P=0.013 and P=0.02, respectively); a similar trend was seen for the total ARAT score (P=0.11). In the subgroup of 33 patients with some residual wrist extensor strength at study entry (moment at 0 degrees extension >0), the ARAT total score had increased at week 8 by a mean of 21.1 (SD, 12.7) in the ES group compared with 10.3 (SD, 9.0) in the control group (P=0.024, Mann Whitney U test); however, at 32 weeks the differences between these 2 subgroups were no longer statistically significant. CONCLUSIONS: ES of the wrist extensors enhances the recovery of isometric wrist extensor strength in hemiparetic stroke patients. Upper-limb disability was reduced after 8 weeks of ES therapy, with benefits most apparent in those with some residual motor function at the wrist. However, it is not clear how long the improvements in upper-limb disability are maintained after ES is discontinued.
Aged↗
Immunolocalization and expression of the steroidogenic acute regulatory protein during the transitional stages of rat follicular differentiation.
This study was designed to determine the pattern of expression and cellular distribution of the steroidogenic acute regulatory protein (StAR) during the transitional stages of follicular differentiation in rat ovary. Using specific antisera against the StAR, immunohistochemistry, Western blotting, and immunoprecipitation analyses provide evidence confirming the localization and expression of StAR in granulosa cells (GCs) of juvenile rat ovaries before and after PMSG treatment. The results also show that StAR expression occurs in theca intersitial cells surrounding preantral, antral, and larger antral follicles in adult diestrous ovaries. Furthermore, we have demonstrated heterogenous StAR immunoreactivity in the granulosa cell layers and cells of the corpora lutea. A novel finding presented here is that, during ongoing growth and differentiation of the follicle, the immunoreactivity of StAR tends to shift from the GC of early antral follicles to the theca cell layers in the adult. The spatiotemporal changes or shifts in StAR expression and cellular localization also coincide with the appearance of more acidic isoforms of the 30-kD protein, as determined by two-dimensional gel electrophoresis. Although the functional implications of these observations remain unclear, the acute temporal changes in StAR expression and localization may not only reflect the dynamic steroidogenic capacity of follicular cells but may also support a possible role for FSH in the induction of follicular maturation.
Animals↗
Acupuncture for vulvodynia.
Vulvodynia is the sensation of burning and/or pain of the vulva in the absence of abnormal clinical findings. We offered acupuncture to twelve patients with this syndrome. All had experienced severe distress and impairment of sexual function and usual treatments had failed. The patients attended weekly for acupuncture and progress was monitored at each visit by enquiry, a questionnaire and a visual analogue scale for pain. Half had treatment for the first five weeks only, the other half for the second five weeks only. Side-effects were negligible. Two patients felt so much improved that they declared themselves 'cured'; three believed their symptoms had improved and wished to continue acupuncture; four felt slightly better and judged acupuncture more effective than any other treatment; and three noted no effect at all. Acupuncture is time-consuming and a large part of its beneficial effect in this study may have come from the regular specialist contact. However, in view of the patients' lack of response to other measures their satisfaction with the acupuncture was surprisingly high.
Acupuncture Therapy↗
Gambling and risk-taking behavior among university students.
The present study examines the relationships between risk taking, sensation seeking, and level of gambling involvement. The intent of this research was to investigate whether risk taking and/or sensation seeking are determinants in distinguishing pathological gamblers from problem gamblers and whether risk taking and gambling behavior for a university population are positively correlated for both males and females. Results indicated that the Risk-Taking Questionnaire (RTQ), the Arnett Inventory of Sensation Seeking (AISS), and the Sensation Seeking Scale (SSS) distinguished between probable/pathological gamblers and nonproblem gamblers with probable/pathological gamblers scoring the highest on each measure. However, the RTQ was the only measure able to distinguish probable/pathological gamblers from gamblers experiencing some problems relating to their gambling behavior. Females encountering some problems resulting from their gambling behavior consistently reported higher risk-taking and sensation seeking scores than males with no gambling problems. Results indicate that excessive gamblers are significantly greater risk takers than social gamblers, a finding which could prove useful in advising treatment regimens.
Adolescent↗
Theoretical analysis of "Switching" in a localized model for mountain pine beetle mass attack
The dynamic interaction between mountain pine beetles (MPB) and hosts (generally lodgepole pine) is reviewed briefly. In particular, successful "switching" from initial foci of attack to nearby hosts which may be higher-quality resources is a potentially critical element initiating the transition from endemic to epidemic population levels. A coupled partial differential equation model for MPB dispersal and host response is reviewed. The equations are decoupled making an adiabatic assumption for MPB chemotaxis, and a "local" projection is made using the leading eigenfunction for the MPB density equation. This projection yields a system of ordinary differential equations for the spatio-temporal responses at individual trees. These equations are analysed to determine what factors control successful "switching" in a two-tree model. The results suggest that stand thinning ameliorates outbreaks mainly through interference with the chemical ecology via a change in micro-climate rather than by altering host vigor.Copyright 1998 Academic Press Limited
Journal Article↗
Enhanced concatemer cloning-a modification to the SAGE (Serial Analysis of Gene Expression) technique.
The Serial Analysis of Gene Expression (SAGE) method, described in 1995 by Velculescu et al ., represents a powerful means to compare gene expression between two mRNA populations. An improvement to SAGE that removes contaminating linker molecules, which compromise the efficiency of the method, has been developed. This modification utilises biotinylated PCR primers, which generate biotinylated linkers at an early stage in the SAGE protocol, thus allowing removal of the unwanted linkers by binding to streptavidin-coated magnetic beads at a later stage. The application of this modification resulted in the rapid generation of high ditag yields and clones with large average insert sizes.
Base Sequence↗