Waste disposal. Where there's muck.
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Cost Savings↗
Biomedical subjects
A Moore
Publications and source records attributed to A Moore.
Numbers needed to treat derived from meta analysis. NNT is a tool, to be used appropriately.
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Clinical Trials as Topic↗
Primary care. Cheque it out.
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Attitude of Health Personnel↗
The adjuvant combination monophosphoryl lipid A and QS21 switches T cell responses induced with a soluble recombinant HIV protein from Th2 to Th1.
The induction of protective immunity with recombinant vaccines is dependent on the identification of adjuvant or delivery systems that can augment immune responses, especially cellular immune responses, to soluble protein antigen. In this study we demonstrate that an adjuvant formulation comprising QS21, a purified form of saponin and 3D-monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS), enhances cellular and humoral immune responses to a recombinant HIV protein. Analysis of cytokine secretion by antigen-specific T-cells from the spleen demonstrated that QS21 augmented Th1 and Th2 responses, whereas addition of 3D-MPL resulted in preferential induction of type 1 T-cells. Furthermore, analysis of the subclass of the IgG antibody in the serum in mice immunized with gp120 with the combined adjuvant formulation confirmed the selective activation of Th1 cells in vivo. 3D-MPL was found to enhance B7-1 expression and IL-12 production by macrophages, which are known to be involved in the LPS-induced enhancement of Th1 responses. Thus 3D-MPL appears to act as an adjuvant, without the toxicity associated with LPS, by controlled and selective potentiating effects on antigen presentation and T-cell activation.
AIDS Vaccines↗
Multiple roles for the Wilms' tumor suppressor, WT1.
Wilms' tumor is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry. A proportion of these tumors develop as a result of the loss of function mutations in the Wilms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lead to childhood kidney cancer, severe gonadal dysplasia, and life-threatening hypertension. Knockouts show that the gene is essential for the early stages of kidney and gonad formation. These tissues are completely absent in null mice. The WT1 gene encodes numerous protein isoforms, all of which share four zinc fingers. There is a large body of evidence supporting the notion that WT1 is a transcription factor, particularly a transcriptional repressor. Recently, however, we obtained evidence that WT1 colocalizes and is physically associated with splice factors. What is more, one alternative splice isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and 4) is preferentially associated with splice factors, whereas the other alternative splice version, lacking these three amino acids, preferentially associates with the transcriptional apparatus. Both genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evidence to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing. To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast artificial chromosomes directly into mice. These studies have allowed us to dissect the function of WT1 at late as well as at early stages in organogenesis and to identify new sites and surprising new potential functions for the gene.
Alternative Splicing↗
Biodegradation of polysiloxanes in lymph nodes of rats measured with 29Si NMR.
Linear and cyclic polysiloxanes and extracts (free polymer) from a silicone gel-filled implant are used to investigate the reactivity of silicones in vivo. Aqueous emulsions of polysiloxanes and controls (without polysiloxanes) are injected once (day 0, approximately 10% w/v) or six times (starting at day 0, every 14 days, approximately 3% w/v) in the right thigh of rats and the popliteal and lumbar lymph nodes are harvested (3 rats per time point and compound investigated) at 2, 16, 30, 44, 58 and 72 days after the injection. 29Si NMR spectroscopy is used to detect and evaluate the presence of polysiloxanes and their metabolites in the lymph nodes. In addition to the resonance associated with the polysiloxane injected (approximately -20 ppm), the NMR spectra of lymph nodes show new resonances that are attributed to partially hydrolyzed polysiloxanes (-5 to -15 ppm) and silica (-90 to - 120 ppm). These resonances are not present in polysiloxanes emulsions before injection or in the lymph nodes of controls. Our results demonstrate that all polysiloxanes and extracts from silicone gel-filled implants are biotransformed in the lymph nodes, but high molecular weight polymer degrades at a slower rate than oligomers.
Animals↗
Multi-channel cochlear implantation in patients with a post-traumatic sensorineural hearing loss.
There are few accounts of cochlear implantation in adults with post-traumatic sensorineural hearing loss. We report our experience with multichannel implantation in three such patients. Two patients experienced no cognitive or communication deficits as a result of their head injury. At nine months post-implant, compared with our experience of non-head-injured implantees, these patients achieved average or above average scores on audiological performance tests. The third patient presented with cognitive, behavioural and communicative deficits. The level of improvement achieved by this patient, when lip-reading was supplemented with electrical stimulation, in both BKB sentence and connected discourse tracking (CDT) tests was comparable with that of the non-head-injured group. However, his absolute performance at nine months post-implant was well below average. Performance at 18 months on BKB sentences and environmental sound recognition showed little change, and was again well below average, however his score on CDT with lip-reading and electrical stimulation improved considerably and was similar to the average achieved by the non-head-injured group. The major difficulties experienced with this patient were increasing depression and low implant use. Considerably more time was spent in the assessment and rehabilitation of this patient and involved liaison with a number of other agencies. When considering such patients for cochlear implantation it is strongly recommended that these additional requirements are taken into account.
Adult↗
Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG.
Intensity-series rod and cone ERGs were recorded in 19 patients with XLRS and 26 control eyes. All patients were examined by one ophthalmologist and diagnosed on the basis of fundus appearance and evidence of the disease in other males in the same family. Mutations in the XLRS1 gene have been identified in 15 of the patients. Dark-adapted ERGs were significantly different from controls for all test conditions and for both a-wave and b-wave responses. Abnormalities were detectable in all patients but there was considerable variation in the severity of abnormality. One third of the patients had the dark-adapted 'negative-wave' response typically associated with inner retinal disorder, but about one third showed only mild depression of the b-wave while the remainder had abnormally low a-waves in addition to depressed b-waves. Light-adapted responses were also affected and both a-wave and b-wave responses differed significantly from controls, but the 'negative-wave' response was not seen in any patient. The severity of the ERG abnormality did not correlate with the classification of fundus appearance or patient age suggesting that retinal function is relatively stable throughout life. The severity of ERG abnormalities did not correlate with the type of mutation and responses could differ between affected males within the same family. These results indicate considerable heterogeneity of ERG response without clinical, age or genetic correlate. The abnormal a-wave responses indicate that photoreceptor as well as inner retinal layer function may be affected in XLRS, at least in some patients.
Adult↗
Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia.
We report a patient with Philadelphia (Ph)-positive, BCR-ABL rearrangement positive, chronic myeloid leukemia (CML) with a prolonged chronic phase of 24 years who was first prescribed alpha-2 interferon 22 years after initial diagnosis. This therapy was tolerated poorly on account of thrombocytopenia, but an eventual major cytogenetic response was followed soon afterwards by transformation to terminal acute myeloid leukemia (AML). Cytogenetic studies indicated that the transformed myeloblasts were karyotypically normal and Ph negative. Although polymerase chain reaction (PCR) analysis of total leukemic mRNA remained BCR-ABL positive, other molecular studies, including Southern blotting and fluorescent in situ hybridization (FISH) analyses, showed that myeloblasts were BCR-ABL rearrangement negative. PCR-based clonality studies using an X-chromosome-linked restriction fragment polymorphism within the phosphoglycerate kinase gene (PGK1) further showed that the Ph-negative blast cells had a different clonal origin from the Ph-positive clone of chronic phase. We suggest that cases of underlying Ph-negative leukemic transformation in Ph-positive CML warrant further study and should be considered for trial of intensive remission induction therapy as appropriate for acute leukemia.
Acute Disease↗
Microinvasive carcinoma of the breast: can it be diagnosed reliably and is it clinically significant?
Deciding whether in-situ breast carcinoma is associated with microinvasion is a common problem. Histological features resembling invasion can be simulated by in-situ carcinoma distorted by inflammatory and reparative changes. Having expended the effort to diagnose genuine microinvasion, just how useful is this diagnosis in planning further treatment and follow-up? In the following articles, Hoda et al. comment on the utility of immunohistochemistry in resolving uncertainty about the presence of microinvasion, and Ellis et al. critically appraise the definition of microinvasion and its clinical significance.
Biomarkers, Tumor↗
Connexin46 mutations in autosomal dominant congenital cataract.
Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.
Amino Acid Sequence↗
A comparison of Tactaid II+ and Tactaid 7 use by adults with a profound hearing impairment.
OBJECTIVE: To evaluate and compare use of the Tactaid II+ and the Tactaid 7, in terms of speech perception, by adults with a hearing impairment. DESIGN: Eight adults used one device daily for approximately 10 wk and attended seven training sessions. Performance was measured with tests of phonetic contrast perception, closed-set vowel and consonant identification, word and phoneme recognition in monosyllabic word lists, word recognition in sentences and speechtracking rate. A questionnaire was also administered. The protocol was repeated with the alternative device. RESULTS: With each device, the group discriminated most phonetic contrasts at better-than-chance levels and demonstrated somewhat enhanced visual or auditory-visual perception when measured in terms of vowel identification, monosyllabic word recognition and speechtracking rate. An increase in speechtracking rate was also demonstrated for some individuals. Subjects generally reported little subjective improvement in speech perception and production, but were satisfied with the physical attributes of each device. Five of six subjects preferred the Tactaid 7. CONCLUSIONS: The Tactaid II+ and the Tactaid 7 provided suprasegmental and segmental information, enabling the group to discriminate phonetic contrasts and improve their perception of some speech materials. No consistent advantage was found for either device, thought most subjects preferred the Tactaid 7. Alternatives likely to provide a greater benefit to communication should be considered before a Tactaid fitting.
Acoustic Stimulation↗
Hilus cell tumour of the ovary in a virilized, premenopausal woman. Case report and review of hyperandrogenism of ovarian origin.
A 35 year-old woman presented with virilization and was found to have elevated serum testosterone levels. Investigation revealed an 11 mm hilus cell tumour in the left ovary. After unilateral oophorectomy, serum testosterone levels rapidly returned to normal levels. The various ovarian tumours and conditions causing virilization are described and a clinical approach to the investigation of virilization is outlined.
Adult↗
Clinical and genetic heterogeneity in autosomal dominant cataract.
AIMS: To determine the different morphologies of autosomal dominant cataract (ADC), assess the intra- and interfamilial variation in cataract morphology, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation. METHODS: Patients were recruited from the ocular genetic database at Moorfields Eye Hospital. All individuals underwent an eye examination with particular attention to the lens including anterior segment photography where possible. Blood samples were taken for DNA extraction and genetic linkage analysis was carried out using polymorphic microsatellite markers. RESULTS: 292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be affected. The cataract phenotypes could all be described as one of the eight following morphologies-anterior polar, posterior polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent. The phenotypes varied in severity but the morphology was consistent within each pedigree, except in those affected by the pulverulent cataract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously described loci. In one of the families the underlying mutation was isolated. Exclusion data were obtained on five families. CONCLUSIONS: Although there is considerable clinical heterogeneity in ADC, the phenotype is usually consistent within families. There is extensive genetic heterogeneity and specific cataract phenotypes appear to be associated with mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated.
Adolescent↗
Randomised comparison of electrode positions for cardioversion of atrial fibrillation.
OBJECTIVE: To compare the relative efficacy of anteroanterior v anteroposterior electrode pad positions for external cardioversion of atrial fibrillation. DESIGN: Prospective randomised trial. SETTING: Tertiary referral cardiology centre in the United Kingdom. PATIENTS: 90 patients undergoing elective cardioversion for atrial fibrillation. INTERVENTIONS: Cardioversion was attempted with self adhesive electrode pads with an area of 106 cm2 placed either in the anteroanterior (AA) or anteroposterior (AP) positions. Initial shock was 100 J which, if unsuccessful, was followed by 200 J, 300 J, and 360 J if required. Peak current and transthoracic impedance were measured. MAIN OUTCOME MEASURES: Cardioversion success rate and energy requirements. RESULTS: Cardioversion was successful in 81% of the patients (73/90). There was no statistically significant difference in the cardioversion success rate (AA 84%, 38/45 patients; AP 78%, 35/45 patients; p = 0.42) or mean (SD) energy requirement for all patients (AA 223 (96.1) J; AP 232 (110) J) or for patients who were successfully cardioverted (AA 197.9 (82.4) J; AP 195.4 (97.2) J; p = 0.9) between the two pad positions. The mean transthoracic impedance (TTI) for the first shock (AA 77.5 (18.4) ohms; AP 73.7 (18.7) ohms; p = 0.34) was not significantly different between the two groups. TTI correlated significantly with body mass index, percentage body fat, and chest AP diameter. There was a progressive decrease in TTI with serial shocks. While aetiology and TTI were the two independent significant predictive factors for energy requirement, duration of atrial fibrillation was the only independent predictor of cardioversion success in a multivariate analysis. CONCLUSIONS: Electrode pad position is not a determinant of cardioversion success rate or energy requirement.
Aged↗
Radiotherapy in the treatment of benign meningioma of the skull base.
OBJECT: This study was undertaken to assess the long-term efficacy and toxicity of conventional fractionated external-beam radiation in the treatment of benign skull base meningioma. METHODS: This is a retrospective study of 82 patients with histologically verified benign skull base meningioma treated by surgery followed by fractionated external-beam radiation at the Royal Marsden Hospital between 1962 and 1992. The 5- and 10-year progression-free survival (PFS) rates were 92% and 83%, respectively, with the site of disease being the only independent prognostic factor for tumor control according to multivariate analysis. The 10-year PFS rate for patients with sphenoid ridge meningiomas was 69% compared with 90% for those with tumors in the parasellar region. The overall 10-year survival rate was 71%, with performance status and patient age found to be significant independent prognostic factors. Six patients had worsening vision, which was due to cataract in five cases and retinopathy in one. There were no recorded cases of cranial nerve neuropathy. CONCLUSIONS: The excellent long-term tumor control and length of survival with minimal toxicity associated with conventional external-beam radiation should serve as a baseline for evaluation of new treatment strategies such as radiosurgery and skull base surgery.
Adolescent↗
Resurgence of sleeping sickness in Tambura County, Sudan.
Endemic foci of human African trypanosomiasis are present in southern Sudan. In 1996 and 1997, trypanosomiasis increased sharply in Tambura County. To define the magnitude and geographic distribution of the outbreak, we conducted a prevalence survey using population-based cluster sampling in 16 villages: 1,358 participants answered questions about routine activities and tsetse fly contact and received serologic testing. Seroprevalence in the surveyed area was 19.4% (95% confidence interval = 16.9%, 21.8%). We confirmed infection in 66% of seropositive persons who received one parasitologic examination and in 95% of those who had serial examinations of lymph node fluid and blood. Activities related to the civil war, such as temporary migration, were not associated with seropositive status. Since the previous population screening in 1988, the trypanosomiasis prevalence increased two orders of magnitude, and the proportion of villages affected increased from 54% to 100%. Our results suggest that there may be 5,000 cases in Tambura County. The absence of trypanosomiasis control for nearly a decade is a factor in the resurgence of the disease.
Adolescent↗
Implanon. A review of clinical studies.
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Acne Vulgaris↗