Sleep disturbance and Huntingdon's disease.
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Humans↗
Biomedical subjects
N Taylor
Publications and source records attributed to N Taylor.
Reconstitution of T cell receptor signaling in ZAP-70-deficient cells by retroviral transduction of the ZAP-70 gene.
A variant of severe combined immunodeficiency syndrome (SCID) with a selective inability to produce CD8 single positive T cells and a signal transduction defect in peripheral CD4+ cells has recently been shown to be the result of mutations in the ZAP-70 gene. T cell receptor (TCR) signaling requires the association of the ZAP-70 protein tyrosine kinase with the TCR complex. Human T cell leukemia virus type I-transformed CD4+ T cell lines were established from ZAP-70-deficient patients and normal controls. ZAP-70 was expressed and appropriately phosphorylated in normal T cell lines after TCR engagement, but was not detected in T cell lines from ZAP-70-deficient patients. To determine whether signaling could be reconstituted, wild-type ZAP-70 was introduced into deficient cells with a ZAP-70 retroviral vector. High titer producer clones expressing ZAP-70 were generated in the Gibbon ape leukemia virus packaging line PG13. After transduction, ZAP-70 was detected at levels equivalent to those observed in normal cells, and was appropriately phosphorylated on tyrosine after receptor engagement. The kinase activity of ZAP-70 in the reconstituted cells was also appropriately upregulated by receptor aggregation. Moreover, normal and transduced cells, but not ZAP-70-deficient cells, were able to mobilize calcium after receptor ligation, indicating that proximal TCR signaling was reconstituted. These results indicate that this form of SCID may be corrected by gene therapy.
CD4-Positive T-Lymphocytes↗
Correction of interleukin-2 receptor function in X-SCID lymphoblastoid cells by retrovirally mediated transfer of the gamma-c gene.
X-SCID, the most common form of human SCID, is due to mutations in the common gamma chain gene (gamma-c) that encodes an essential component of the cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. Activation of the Janus family tyrosine kinases Jak1 and Jak3 is necessary for appropriate signalling through the IL-2 receptor (IL-2R). Neither Jak1 nor Jak3 was phosphorylated after IL-2 stimulation of an Epstein-Barr virus-transformed cell line (LCL) from an X-SCID patient with a gamma-c null mutation. However, we now show that appropriate IL-2R function can be restored in an X-SCID LCL by transduction of a wild-type gamma-c gene. A retroviral vector, G1gamma-cSvNa, was constructed and produced in the PG13 packaging line. Transduced X-SCID LCL expressed the G1gamma-cSvNa transcript. IL-2 stimulation of the transduced cell line resulted in appropriate tyrosine phosphorylation of both Jak1 and Jak3. Thus, retroviral-mediated transduction of normal gamma-c can reconstitute downstream signalling through the IL-2R in X-SCID cell lines, suggesting that gene therapy may be a treatment for this disease.
B-Lymphocytes↗
Omeprazole and visual disorders: seeing alternatives.
In the WHO data base, visual disorders reported spontaneously with omeprazole, ranitidine and cimetidine, are very rare in the context of the widespread use of these drugs. There is a maximum reporting rate of severe visual impairment possibly ascribed to i.v. omeprazole of 0.94 reports per million treatment days in one year and in one country, Germany. This gives the worst quantitative case scenario for omeprazole by a single route of administration, to be compared with the worldwide reporting rate of all severe visual disorders by all routes of administration--0.008 reports per million treatment days. Moreover, the reported visual abnormalities have a varied pathophysiological aetiology and their number increased in Germany after the first signal was raised in that country. Thus, apart from a direct causal relationship, solicited reporting artifact is one alternate plausible explanation for the apparent excess of cases of visual disturbance to omeprazole compared with cimetidine and ranitidine. That reporting rates of clinical events on newly marketed drugs are generally higher than with older drugs is a second factor for higher reporting rates with omeprazole. Vasculitis has been suggested as an aetiological factor, but the even lower reporting rate of this reaction makes this an unlikely hypothesis without any other supporting evidence. The authors are unaware of any drug that has caused a vasculities solely affecting the eye. Information on the prevalence of relevant visual disorders in the community would have been of considerable help in interpreting this signal, and a case control study of visual events in relationship to severe illness would be of public health interest, since no data seems to exist concerning this.
Journal Article↗
Is patient-controlled analgesia controlled by the patient?
Using patient-controlled analgesia (PCA) after surgery, a patient can obtain pain-relieving injections of morphine without the direct involvement of a nurse or doctor. The present study was a response to the conventional view that patients value PCA because of the control which it affords them over their own treatment. Twenty-six patients underwent semi-structured interviews postoperatively, shortly after discontinuation of PCA. Responses were examined qualitatively to identify recurring themes in patients' experience of PCA. Negative as well as positive evaluation was found. PCA was only rarely described as a way of gaining control over analgesia and, in general, this was not valued. Instead, PCA was valued as a way to avoid the difficulty of disclosing pain or securing pain relief within the usual nurse-patient relationship. In turn, PCA strained the nurse-patient relationship where it impeded either the patient's or the nurse's wish for the nurse to take responsibility for pain relief. The results showed that the professionally and theoretically constructed concept of PCA as a method of self-control over pain is inconsistent with patients' experience of it.
Adult↗
Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways.
Both IL-2 and IL-4 bind to receptors containing the common gamma chain and JAK3. Although JAK3 is required for proper lymphoid development, the precise roles of this kinase in IL-2 and IL-4 signaling in lymphocytes have not been defined. Here, we have studied IL-2 and IL-4 signaling in B cell lines lacking JAK3. Although IL-2-induced phosphorylation of IL-2R beta, JAK1, and STAT5 all required the presence of JAK3, IL-4-mediated phosphorylation of JAK1, STAT6, and insulin receptor substrates 1 and 2 did not. However, IL-4-induced effects were clearly improved following JAK3 expression. These data indicate that IL-4 signaling occurs in the absence of of JAK3, but is comparatively inefficient. These findings may help in understanding the pathogenesis of the immunodeficiency that occurs with mutations of JAK3 and may suggest a mechanism for the pleiotropic effects of IL-4.
B-Lymphocytes↗
Regeneration of transgenic cassava plants (Manihot esculenta Crantz) from microbombarded embryogenic suspension cultures.
A protocol was established for the introduction of DNA into embryogenic suspension-derived tissues of cassava via microparticle bombardment, for the selection of genetically transformed cells, and for the regeneration of fully transgenic plants from these cells. The plasmid DNA used for bombardment contained a gene encoding neomycin phosphotransferase (nptII) and a gene encoding beta-glucuronidase (uidA). Selection of bombarded tissue with paromomycin resulted in the establishment of putative transgenic embryogenic calli. In most of these calli, beta-glucuronidase was detected histochemically. Molecular analysis of paromomycin-resistant embryogenic calli and of plants regenerated from these calli, confirmed the stable integration of bombarded DNA into the cassava genome.
Biolistics↗
Urinary excretion of adrenocortical steroid metabolites by pre-term human infants: trends from birth until 3 months post term.
We report trends in urinary steroid excretion in serial 24 hour collections made using a novel method based on "Supersorb" type disposable nappies. Using capillary column gas chromatography, we quantified nine cortisol metabolites (FM) and 11 steroid sulphates (SM) in 6 infants born at 29-31 weeks gestation on 9 occasions until 24 weeks post delivery. In all infants, SM excretion increased progressively until 33-39 weeks (mean 36.8) post conception to maxima of (all values mg/24 h) 2.6-11.7 and then declined to 5-15% of peak values at the end of the study period in 4 infants born after a period of labour but to only 54 and 71% in 2 infants born without labour. FM levels showed a wide range which was not correlated with body weight, eg: on week 1, 0.06-0.20 and on week 24, 0.15-0.72. progression over this period was essentially linear. The ratio (mean (SD)) of 11-oxo/11-hydroxy metabolites decreased from 10.0 (8.2) to 2.3 (0.4) in the same period, p = < 0.10, while that of 20-oxo/20-hydroxy metabolites increased from 0.18 (0.07) to 1.08 (0.42), p = < 0.04. The ratio of metabolites with 5 oxygen functions relative to 6 increased from 0.38 (0.16) to 1.36 (0.43), p = < 0.04. Excretion of 5 alpha-tetrahydrocortisol began to rise at 44-47 wk post conception, but, unexpectedly, that of the 5 beta epimer began to rise sooner, at 39-41 wk, reaching a peak at 44-51 wk and then declining. The ratio of 5 beta/5 alpha epimers was 11.71 (11.1) at the peak and 1.14 (0.87) at 24 weeks, p = < 0.07. We conclude that, using a collection method which is reliable, non-stressful and repeatable at frequent intervals, new information on the evolution of steroid secretion and metabolism postpartum is emerging.
Adrenal Cortex Hormones↗
Postoperative symptoms following LLETZ or radical cervical diathermy with fulgaration: a randomized double-blinded prospective study.
Fifty-five patients were randomized in a double-blinded manner to large loop excision of the transformation zone (LLETZ) (29 patients) or radical cervical diathermy with fulgaration (RCDF) (26 patients) for treatment of cervical intraepithelial neoplasia (CIN). Patients completed a 2-month diary of symptoms and completed a 10-week postoperative questionnaire. White vaginal discharge lasted 7.3 (4.6) days (SD) for RCDF compared to 3.4 (1.6) days (SD) for LLETZ. There was no significant difference in any other symptoms on analysis This appears to be the first report clearly assessing the length and severity of postoperative symptoms following LLETZ or RCDF. There is no reason on length and severity of postoperative symptoms to choose 1 of these 2 treatment methods over the other.
Adult↗
Comparing transcriptional activation and autostimulation by ZEBRA and ZEBRA/c-Fos chimeras.
The lytic cycle of Epstein-Barr virus (EBV) can be activated by transfection of the gene for ZEBRA, a viral basic-zipper (bZip) transcriptional activator. ZEBRA and cellular AP-1 bZip activators, such as c-Fos, have homologous DNA-binding domains, and their DNA-binding specificities overlap. Moreover, EBV latency can also be disrupted by phorbol esters, which act, in part, through AP-1 activators. It is not known whether ZEBRA and AP-1 factors play equivalent roles in the initial stages of reactivation. Here the contribution of ZEBRA's basic DNA recognition domain to disruption of latency was analyzed by comparing ZEBRA with chimeric mutants in which the DNA recognition domain of ZEBRA was replaced with the analogous domain of c-Fos. Chimeric ZEBRA/c-Fos proteins overexpressed in Escherichia coli bound DNA with the specificity of c-Fos; they bound a heptamer AP-1 site and an octamer TPA response element (TRE). ZEBRA bound the AP-1 site and an array of ZEBRA response elements (ZREs). In assays with reporter genes, both ZEBRA and ZEBRA/c-Fos chimeric mutants activated transcription from Zp, a promoter of the ZEBRA gene (BZLF1) that contains the TRE and multiple ZREs. However, despite their capacity to activate reporters bearing Zp, neither ZEBRA nor the c-Fos chimeras activated transcription from Zp in the context of the intact latent viral genome. In contrast, ZEBRA but not ZEBRA/c-Fos chimeras activated Rp, a second viral promoter that controls ZEBRA expression. Hence, transcriptional autostimulation by transfected ZEBRA occurred preferentially at Rp. Both ZEBRA and the ZEBRA/c-Fos chimeras activated transcription from reporters with multimerized AP-1 sites. However, in the context of the virus, only ZEBRA activated the promoters of two early lytic cycle genes, BMRF1 and BMLF1, that contain an AP-1 site. Thus, overexpression of an activator that recognized AP-1 and TRE sites was not sufficient to activate EBV early lytic cycle genes.
B-Lymphocytes↗
Origins of the sex difference in human urinary free cortisol excretion.
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Female↗
Injuries resulting from bicycle collisions.
OBJECTIVE: To review all bicycle crash-related injuries reported to the Oregon Injury Registry for 1989 to compare patterns of injury and other features in adults vs children and adolescents. METHODS: A retrospective descriptive study was conducted using data from the Oregon Injury Registry. For 1989, this registry included all injury-related deaths and approximately 75% of hospital admissions of 24 hours or more for injury in the State of Oregon. Deaths, helmet use, neurologic injuries, and concurrent ethanol use were evaluated for all patients and for the two age groups. RESULTS: There were 311 bicycle-related injured patients in the registry for 1989; 122 (40%) were adults (age > or = 21 years) and 189 (60%) were children/adolescents (age < 21 years). Approximately 69% of both age groups were male. All of the 15 deaths involved male patients and most deaths [10/15 (67%)] involved injured adults. Bicycle vs motor vehicle collisions accounted for 14 (93%) deaths and 106 (34%) of all registry entries. While only 19 (15%) of the injured adults had elevated blood alcohol levels, half the adults who died had been intoxicated. Helmet use was rare with only 12 (4%) of all the injured riders known to have been helmeted; no rider who died was known to have been helmeted. Neurologic injuries were common. In children, 27 (14%) had sustained skull fractures, 36 (19%) intracranial injuries, and one (0.5%) a spinal injury. In adults, 13 (10%) had sustained skull fractures, 32 (26%) intracranial injuries, and three (2%) spinal injuries. CONCLUSIONS: Although children account for 60% of the serious bicycle injuries in Oregon, adults account for 67% of the deaths. Helmet use is rare, brain injuries are frequent, and alcohol use appears to be a contributing factor in cycling deaths among adults. Public education efforts should be directed to both adult and pediatric populations, emphasizing safe cycling practices and helmet use.
Accidents, Traffic↗
Cloning, expression, and characterization of the lon gene of Erwinia amylovora: evidence for a heat shock response.
The gene encoding the Lon protease of Erwinia amylovora has been cloned by complementation of an Escherichia coli lon mutant. Analysis of the determined nucleotide sequence of the lon gene revealed extensive homology to the nucleotide sequences of cloned lon genes from E. coli, Myxococcus xanthus, and Bacillus brevis. The predicted amino acid sequence of the E. amylovora Lon protease was 94, 59, and 54% identical to the predicted amino acid sequences of the Lon proteases of E. coli, M. xanthus, and B. brevis, respectively. The -10 and -35 promoter regions of the cloned lon gene had extensive homology to the respective consensus sequences of E. coli heat shock promoters. Promoter mapping of the lon gene located the start site 7 bases downstream of the -10 region. Cloning of the lon promoter upstream of a cat reporter gene demonstrated that expression of the E. amylovora lon gene was inducible by a heat shock. This is the first demonstration of a heat shock-regulated gene in E. amylovora. Site-directed mutagenesis of the -10 region of the lon promoter confirmed that the heat shock expression of the E. amylovora lon gene may be mediated by a sigma 32-like factor. Insertional inactivation of the E. amylovora chromosomal lon gene confirmed that the lon gene was not essential for either vegetative growth or infection of apple seedlings. E. amylovora lon mutants had increased sensitivity to UV irradiation and elevated levels of extracellular polysaccharide, suggesting comparable roles for the Lon proteases in both E. amylovora and E. coli.
ATP-Dependent Proteases↗
Partnering with disease state management vendors: is it risky business?
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Case Management↗
Dentistry in Norway.
Norway's health care system, which includes dentistry, is highly developed and well funded. In the light of the recently published Green paper, 'Improving NHS Dentistry' there are certain aspects of the delivery of both general dental care and orthodontic treatment in Norway which may be of interest to practitioners in the UK.
Cleft Lip↗
Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase.
BACKGROUND: Hyperandrogenemia is the hallmark of the polycystic ovary syndrome, yet the relative contributions of the adrenal cortex and ovary to the overproduction of androgen remain unclear. To identify possible causes of adrenocortical overactivity, we studied the metabolism of adrenal and ovarian steroid hormones in women with this disorder. METHODS: We measured 24-hour urinary excretion of steroid hormone metabolites by high-resolution capillary gas chromatography in 65 women with the polycystic ovary syndrome and 45 normal women matched for body-mass index. RESULTS: After adjustment for body-mass index, the urinary excretion of testosterone and androstenedione metabolites was 1.9 times higher in the women with the syndrome than in the normal women, and the excretion of dehydroepiandosterone metabolites (C19 steroid sulfates) and cortisol metabolites was 1.5 and 1.3 times higher, respectively (P < 0.01 for all comparisons). The affected women also had significantly higher ratios of 11-oxo (oxygenated) metabolites to 11-hydroxy metabolites of cortisol (1.4 times higher, P < 0.001) and of 11-oxo to 11-hydroxy metabolites of corticosterone (1.8 times higher, P < 0.001). In the group with the polycystic ovary syndrome, 55 percent of the nonobese women and 24 percent of the obese women had ratios above the upper limit of normal; the ratios in the obese women did not differ significantly from those in the nonobese women. CONCLUSIONS: Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.
11-beta-Hydroxysteroid Dehydrogenases↗