Urinary incontinence in rabbits.
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Adrenergic alpha-Agonists↗
Biomedical subjects
L Scott
Publications and source records attributed to L Scott.
Using unaffected child trios to test for transmission distortion.
The transmission disequilibrium test (TDT), an alternative to case-control analysis that is not influenced by population stratification, focuses on affected child trios (ACTs) comprising affected cases and their parents. Unaffected child trios (UCTs) have also been proposed but mainly to rule out segregation distortion. To explore situations when UCTs are preferable to detect transmission distortion, we compared the number of UCTs and ACTs needed to achieve 80% power for a wide variety of scenarios. For a given genetic model, UCT sample size declined rapidly with increasing disease prevalence, whereas ACT sample size remained constant. Furthermore, at some prevalence value (40-60% depending on model parameters), detection of transmission distortion could be accomplished with fewer UCTs than ACTs. Such high prevalence may be found in special populations (diabetes among Pima Indians), secondary conditions (renal/retinal complications in diabetes), and pharmacogenetics (responders to treatment). Also, because exposure to an additional risk factor can increase the disease prevalence in an exposed sub-group, we explored how sample size requirements vary by exposure status. Whereas power differences between exposed and unexposed ACTs could be explained solely by genetic risk ratios, sub-group-specific disease prevalence also played an important role in UCTs. Finally, we considered the impact of including 5, 10, 20, or 30% misclassified ACTs in the UCT sample and found that a 24, 58, 180, or 550% larger sample would be required. In conclusion, UCTs can detect transmission distortion more effectively than ACTs when disease prevalence reaches 40-60%, although some efficiency may be lost owing to misclassification. Moreover, focusing on particular sub-groups defined by exposure status can potentially increase power, but such gains depend heavily on the nature of the gene-exposure interaction.
Child↗
Does left ventricular shape influence clinical outcome in heart failure?
BACKGROUND: Left ventricular (LV) shape tends to become spherical in patients with dilated cardiomyopathy of diverse etiology. Clinical and echocardiographic factors which affect the degree of LV spherical distortion and the impact of altered LV shape on prognosis have not been studied adequately. HYPOTHESIS: This study was undertaken to investigate the prognostic implications of altered LV shape on clinical outcome in dilated cardiomyopathy. METHODS: In 112 patients with depressed LV ejection fraction (19 +/- 9%) and symptomatic heart failure, and in 10 age- and gender-matched normal controls, we performed 2-dimensional echocardiography to assess LV shape using the eccentricity index. Eccentricity index was defined as the ratio of the LV long axis to the LV transverse diameter, measured at end systole and end diastole in the apical four-chamber view. We sought univariate and multivariate clinical and echocardiographic correlates of LV shape. Further, we sought correlations between eccentricity index and clinical outcomes (death and composite outcome of death or emergent heart transplant). RESULTS: Compared with controls, patients with cardiomyopathy had significantly lower systolic (2.04 vs. 1.56; p = 0.001) and diastolic (1.75 vs. 1.53; p = 0.003) eccentricity index, implying a more spherical LV shape. Of all clinical and echocardiographic variables tested, mitral regurgitation, right ventricular dysfunction, and increased LV mass were independently associated with spherical LV shape. At a follow-up period of 17 +/- 12 months, no correlation was found between eccentricity index and the occurrence of death or the combined endpoint of death or emergent heart transplant, in univariate or multivariate analysis. CONCLUSIONS: In patients with dilated cardiomyopathy, the degree of spherical distortion of the LV does not correlate with prognosis.
Age Factors↗
Pregnancy rates after embryo transfer depend on the provider at embryo transfer.
OBJECTIVE: To evaluate the effect of individual providers on pregnancy outcome after embryo transfer. DESIGN: Retrospective data analysis. SETTING: University-based tertiary-care assisted reproductive technology program with 10 physician-providers. PATIENT(S): Six hundred and seventeen women who underwent 854 fresh embryo transfers between January 1996 and January 1999. INTERVENTION(S): Pregnancies after embryo transfer were recorded for each provider. MAIN OUTCOME MEASURE(S): Establishment of a clinical pregnancy. RESULT(S): Three hundred ninety-three clinical pregnancies resulted from 854 embryo transfers, for an overall clinical pregnancy rate of 46.0% per embryo transfer. Three hundred forty-seven (40.6%) pregnancies were ongoing. The clinical pregnancy rate varied significantly between providers: for example, 17.0% (47 transfers) vs. 54.3% (57 transfers) (P<.05). Similarly, the ratio of high-grade embryos required to produce a gestational sac differed between providers. The number or quality of embryos transferred did not differ significantly. CONCLUSION(S): Significant differences were observed in pregnancy rates after embryo transfer done by different providers, suggesting that embryo transfer technique may influence pregnancy outcome in assisted reproductive technology.
Adult↗
Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in Type 1 diabetes mellitus.
AIMS: To investigate association and linkage between DNA sequence variants in the aldose reductase (AR) gene on chromosome 7q35 and diabetic nephropathy (DN) in Type 1 diabetes mellitus. METHODS: By sequencing the promoter region and 10 exons in eight DN cases and eight controls, a frequent bi-allelic polymorphism (C-106T) was discovered. This polymorphism and the known 5'ALR2 dinucleotide repeat polymorphism were genotyped in unrelated cases with advanced nephropathy (n = 221) and unrelated controls with normoalbuminuria (n = 193). For a family based study, 166 case-trios (case and both parents) and 83 control-trios (control and both parents) were also genotyped. RESULTS: In the case-control study, carriers of the Z-2 allele of the 5'ALR2 polymorphism had a significantly higher risk of DN than non-carriers (odds ratios: 1.6 for heterozygotes and 2.1 for homozygotes, P<0.05 for each). The same was true for carriers of the T allele of the C-106T polymorphism (odds ratios: 1.6 for heterozygotes and 1.9 for homozygotes, P<0.05 for each). Moreover, the haplotype carrying both risk alleles was in excess in DN cases. In the family study, transmission of risk alleles from heterozygous parents was consistent with the case-control study, excess transmission in case-trios and deficient in control-trios. CONCLUSIONS: Association between DN and two DNA sequence variants in the promoter region of the AR gene implicates the polyol pathway in the development of kidney complications in Type 1 diabetes mellitus. Further examination of the molecular mechanisms underlying these findings may provide insight into the pathogenesis of DN.
Adolescent↗
Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells.
The effects of arginine deprivation (-Arg) has been examined in 26 cell lines. Less than 10% of those with transformed or malignant phenotype survived for > 5 days, and many died more rapidly, notably leukaemic cells. Bivariate flow cytometry confirmed that vulnerable cell lines failed to move out of cell cycle into a quiescent state (G0), but reinitiated DNA synthesis. Many cells remained in S-phase, and/or had difficulty progressing through to G2 and M. Two tumour lines proved relatively 'resistant', A549 and MCF7. Although considerable cell loss occurred initially, both lines showed a 'cell cycle freeze', in which cells survived for > 10 days. These cells recovered their proliferative activity in +Arg medium, but behaved in the same manner to a second -Arg episode as they did to the first episode. In contrast, normal cells entered G0 and survived in -Arg medium for several weeks, with the majority of cells recovering with predictable kinetics in +Arg medium. In general, cells from a wide range of tumours and established lines die quickly in vitro following -Arg treatment, because of defective cell cycle checkpoint stringency, the efficacy of the treatment being most clearly demonstrated in co-cultures in which only the normal cells survived. The findings demonstrate a potentially simple, effective and non-genotoxic strategy for the treatment of a wide range of cancers.
Animals↗
Panniculectomy at the time of gynecologic surgery in morbidly obese patients.
OBJECTIVE: Our goal was to demonstrate that panniculectomy performed at the time of gynecologic surgery aids in reducing the operative time and exposure and does not increase the wound infection rate in morbidly obese patients. STUDY DESIGN: A retrospective survey was performed of massively obese patients who underwent panniculectomy at the time of gynecologic surgery at Northeastern Ohio Universities College of Medicine consortium hospitals from 1990-1999. Data collected during surgery included the patient's weight, operative opening and closing times, blood loss, and weight of the removed panniculus adiposus. Postoperative wound infection rates were monitored, and patients were followed up for 6 months. RESULTS: Seventy-eight patients underwent the following operations: radical hysterectomy (n = 19), extrafascial hysterectomy (n = 18), standard hysterectomy (n = 32), or other gynecologic surgery (n = 9). The average blood loss was 71 mL. Opening and closing times were 27 and 33 minutes, respectively, adding a minimal amount of operative time to the required gynecologic surgery. The average removed panniculus adiposus weighed 4745 g. Efficiency in obtaining exposure to the operative site was noted. A total of 2 wound infections were recorded in the postoperative period. In 1 case debridement was required, and in the other healing occurred by secondary intention. Minimal separation occurred in 4 other cases and required no intervention. CONCLUSION: Massively obese patients can safely undergo panniculectomy simultaneously with a gynecologic procedure. The difficulty with operative exposure is reduced, and these patients are better served intraoperatively. Postoperatively, the wound infection rates quoted for this population were markedly improved from prior studies and involved a larger group of patients.
Adult↗
The end of the LINE?: lack of recent L1 activity in a group of South American rodents.
L1s (LINE-1: Long Interspersed Nuclear Element 1) are present in all mammals examined to date. They occur in both placental mammals and marsupials and thus are thought to have been present in the genome prior to the mammalian radiation. This unusual conservation of a transposable element family for over 100 million years has led to speculation that these elements provide an advantage to the genomes they inhabit. We have recently identified a group of South American rodents, including rice rats (Oryzomys), in which L1s appear to be quiescent or extinct. Several observations support this conclusion. First, genomic Southern blot analysis fails to reveal genus-specific bands in Oryzomys. Second, we were unable to find recently inserted elements. Procedures to enrich for young elements did not yield any with an intact open reading frame for reverse transcriptase; all elements isolated had numerous insertions, deletions, and stop codons. Phylogenetic analysis failed to yield species-specific clusters among the L1 elements isolated, and all Oryzomys sequences had numerous private mutations. Finally, in situ hybridization of L1 to Oryzomys chromosomes failed to reveal the characteristic L1 distribution in Oryzomys with either a homologous or heterologous probe. Thus, Oryzomys is a viable candidate for L1 extinction from a mammalian host.
Animals↗
The morphology of human pronuclear embryos is positively related to blastocyst development and implantation.
Human embryos are selected for transfer using morphology at the cleaving and blastocyst stages. Zygote morphology has been related to implantation and pregnancy. The aim of this study was to relate pronuclear morphology to blastocyst development. Zygotes were scored according to distribution and size of nucleoli within each nucleus. Zygotes displaying equality between the nuclei had 49.5% blastocyst formation and those with unequal sizes, numbers or distribution of nucleoli had 28% blastocyst formation. Cleaving embryos that were selected initially by zygote morphology and secondarily by morphology on day 3 had increased implantation (IR) and pregnancy rates (PR; 31 and 57%), compared with those selected by morphology alone (19 and 33% respectively; P: < 0.01). There was a significant difference between zygote-scored and non-scored cycles on day 3 (PR: 57 versus 33%; IR: 31 versus 19%) and on day 5 (PR: 73 versus 58%; IR; 52 versus 39%). Zygote scoring can maintain pregnancy rates for both day 3 and day 5 transfers, increase implantation rates and reduce the numbers of embryos required to achieve a pregnancy.
Adult↗
Close genetic similarity between two sympatric species of tephritid fruit fly reproductively isolated by mating time.
Two sibling species of tephritid fruit fly, Bactrocera tryoni and B. neohumeralis, occur sympatrically throughout the range of B. neohumeralis in Australia. Isolation between the two species appears to be maintained by a difference in mating time: B. tryoni mates at dusk, whereas B. neohumeralis mates during the middle of the day. A morphological difference in humeral callus color also distinguishes the two species. Despite clear phenotypic evidence that B. tryoni and B. neohumeralis are distinct species, genetic differentiation as measured by four markers--nuclear DNA sequences from the white gene and the ribosomal internal transcribed spacer (ITS2), and mitochondrial DNA sequences from the cytochrome b (cytb) and cytochrome oxidase subunit II (COII) genes--is very small. Minor fixed differences occur in the ITS2 sequence, however, in all other cases the two species exhibit a high level of shared polymorphic variation. The close genetic similarity suggests either that speciation has occurred very rapidly and recently in the absence of any mitochondrial DNA sorting or that the sharing of polymorphisms is due to hybridization or introgression. A third species within the tryoni complex, B. aquilonis, is geographically isolated. Bactrocera aquilonis is also genetically very similar, but in this case there is clear differentiation for the mitochondrial loci. The three species form a group of considerable interest for investigation of speciation mechanisms.
Amino Acid Sequence↗
Single amino acid (arginine) restriction: growth and death of cultured HeLa and human diploid fibroblasts.
Requirements for arginine are different from leucine for the growth of HeLa cells in monolayer and suspension culture. Cells grow increasingly more slowly as arginine levels fall below millimolar. Most cells died at 10(-5) M in static cultures, but could be sustained in perfused cultures, but at 10(-6) M neither perfusion nor increased volume in static cultures compensated. Cell died within 3-4 days in 10(-6) M in the same manner as those in complete arginine deprivation, i.e. considerably faster than with leucine deprivation. Arginine restriction produced by arginase or arginine decarboxylase addition to culture medium gave similar results. Citrulline substituted for arginine, but ornithine and polyamines did not. Arginine was depleted 3-4 times faster from the medium than other amino acids, <5% being consumed in protein synthesis, and arginine released by protein turnover was less efficiently reutilised than leucine. Deprivation reduced protein and DNA syntheses, greatly extended S-phase and protracted the cell cycle in HeLa cells for more than leucine deprivation. The inability of the cells avoid reinitiation of S-phase resulted in their proliferative impetus driving them into an late cycle (premitotic) death. In contrast, normal human diploid fibroblasts reached quiescence with little delay and survived for >11 days. Arginine deprivation is discussed as a selectively means of tumour cell destruction.
Arginine↗
Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308.
Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the gamma-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4-methylenedioxybenzene)-beta-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-beta-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.
Administration, Oral↗
Activation of calcium channels by cAMP in STC-1 cells is dependent upon Ca2+ calmodulin-dependent protein kinase II.
Activation of L-type calcium channels in the neuroendocrine, cholecytstokinin-secreting cell line, STC-1, is vital for secretion of CCK. In the present study, the regulation of L-type Ca2+ channels by cAMP and Ca2+ calmodulin dependent protein kinase II (CaM-KII) in STC-1 cells was investigated. Exposure to 3-isobutyl-1-methylxanthine (IBMX) increased intracellular cAMP levels, whole cell Ca2+ currents and activated Ca2+ channels in cell-attached membrane patches. Furthermore, in Fura-2AM loaded cells, cytosolic Ca2+ levels increased upon exposure to IBMX. By contrast, pretreatment of cells with the CaM-KII inhibitor KN-62, prevented IBMX activation of Ca2+ channels in cell-attached patches or increases in cytosolic Ca2+ levels. Inclusion of the synthetic peptide fragment 290-309 of CaM-KII, a CaM-KII antagonist, in the pipette solution, blocked the activation of whole cell Ca2+ currents upon addition of IBMX. These results indicate a unique mechanism of L-type Ca2+ channel activation involving two phosphorylation events.
1-Methyl-3-isobutylxanthine↗
The challenge of pollen analysis in palaeoenvironmental studies of hominid beds: the record from Sterkfontein caves.
The search for pollen in carbonate-rich sediments from the hominid site Sterkfontein has been justified because previous investigations suggested that although pollen contamination is a problem, speleothems (e.g. travertines and stalagmites) are most likely to contain reliable assemblages. The new results confirm that, although they have some potential, most sediment types from the site, even speleothems, are usually not suitable for analysis and that they contain very low concentrations of pollen, if any. The extraction of pollen from them is complicated by the problem of contamination from the modern environment. Such contamination has shown up in many previous investigations at this and similar sites and judging from published literature, its significance has not been fully appreciated. Cave palynology can be a very valuable tool in palaeoenvironmental research but the caveats associated with palynology of different sediment types especially carbonate impregnated sediments must be emphasized.
Animals↗
Microvolume fluorimetry for the determination of absolute CD4 and CD8 lymphocyte counts in patients with HIV: a comparative evaluation.
This study compared CD4 and CD8 lymphocyte counts obtained by microvolume fluorimetry (MVF) with those derived by flow cytometry (FC). Samples from 192 patients with known or suspected HIV were analysed, and the distribution of CD4 counts for these samples ranged from 0 and 1,279/microl, with 142/192 (74%) of the samples having CD4 values of less than 400/microl. Good agreement between FC and MVF CD4 counts was found (MVF = 0.98 x FC + 7.30) although there was a minor constant inter-method bias of approximately +7 cells/microl for the MVF data. For CD8 counts there was a constant bias between the two methods of approximately +23 cells/microl for FC. Most outliers were associated with higher FC CD8 counts. Supplementary analyses showed a high level of agreement between FC and MVF methods for the CD4:CD8 ratios (MVF = 0.98 x FC). This suggests that observed discrepancies between FC and MVF methods were almost certainly a result of the influence of the absolute lymphocyte counts obtained from the haematology analyser. The results confirm that the IMAGN 2000 microvolume fluorimeter system can be used as an alternative to conventional flow cytometry for the enumeration of CD4 and CD8 counts.
CD4 Lymphocyte Count↗
The nature and structure of supervision in health visiting with victims of child sexual abuse.
RATIONALE: Part of a higher research degree to explore professional practice. AIM: To explore how health visitors work with victims of child sexual abuse and the supervision systems to support them. OBJECTIVE: To seek the views and experiences of practising health visitors relating to complex care in order to consider the nature and structure of supervision. METHODOLOGY: The research reported in this paper used a qualitative method of research and semi-structured interviews with practising health visitors of varying levels of experience in venues around England. Qualitative research enabled the exploration of experiences. OUTCOMES: Identification of the need for regular, structured, accountable opportunities in a 'private setting' to discuss whole caseload work and current practice issues. RESULTS: Supervision requires a structured, formalized process, in both regularity and content, as a means to explore and acknowledge work with increasingly complex care, to enable full discussion of whole caseloads. Supervision is demonstrated as a vehicle to enable the sharing of good practices and for weak practices to be identified and managed appropriately. Supervision seeks to fulfil the above whilst promoting a stimulating, learning experience, accommodating the notion that individuals learn at their own pace and bring a wealth of human experience to the service. STUDY LIMITATIONS: The size of the study was dictated by the amount of time available within which to complete a research master's degree course primarily in the author's own time, over a 2-year period. The majority of participants volunteered their accounts in their own time. For others I obtained permission from their employers for them to participate once they approached me with an interest in being interviewed. CONCLUSIONS: This research provides a model of supervision based on practitioner views and experiences. The article highlights the value of research and evidence-based information to enhance practice accountability and the quality of care. Proactive risk management can safeguard the health and safety of the public, the practitioner and the organization.
Child↗
Compartmentalisation of the developing trigeminal ganglion into maxillary and mandibular divisions does not depend on target contact.
During development axons contact their target tissues with phenomenal accuracy but the mechanisms that control this homing behaviour remain largely elusive. A prerequisite to the study of the factors involved in hard-wiring the nervous system during neurogenesis is an accurate calendar of developmental events. We have studied the maxillary and mandibular components of the trigeminal system to determine the stages during embryogenesis when a gross somatotopic order is first established within the trigeminal ganglion and the axons projecting to the brainstem. The retrograde transganglionic fluorescent tracers DiO and DiI were injected into the maxillary and mandibular arches or their derivatives in fixed mouse embryos staged between 13 and 40 somites (E9-E11). After 1-4 wk, the distribution of the 2 tracers was determined using confocal laser scanning microscopy. The first maxillary nerve cell bodies and their developing axons were labelled at the 30 somite stage (E10). This was 2 somite stages earlier than the mesencephalic nucleus and the ganglion cell bodies of the mandibular nerve. The gross somatotopic division of cells within the trigeminal ganglion projecting to the maxillary and mandibular targets was established by the 32 somite stage (E10). This arrangement was evident as 2 groups of cell bodies occupying adjacent but separate regions of the trigeminal ganglion. The central branches of the maxillary and mandibular cell bodies entered the metencephalon as 2 distinct bundles at the same stage. The trigeminal motor nucleus was first detected at the 38 somite stage (E10.5). Gross somatotopy in the major divisions of the trigeminal ganglion is established before outgrowing axons have contacted their peripheral target tissue at E10.5. This suggests that target tissues do not induce somatotopy.
Animals↗