Cognitive effects of testosterone supplementation.
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Climacteric↗
Biomedical subjects
M J Smith
Publications and source records attributed to M J Smith.
Localization of the VIP2 receptor protein on GnRH neurons in the female rat.
In mammals, the timing and occurrence of the preovulatory LH surge critically depends on the proper functioning of the suprachiasmatic nucleus (SCN). Recent evidence suggests that vasoactive intestinal polypeptide (VIP) conveys time of day information from the SCN to GnRH neurons. However, it is not completely clear whether this action is exerted directly at the level of the GnRH neuron. To determine if GnRH neurons are direct targets for VIP, triple-label immunofluorescence was utilized to simultaneously localize GnRH, VIP and VIP2 receptor protein. The present results demonstrate that about 40% of all GnRH neurons analyzed contain VIP2 receptor immunoreactivity and that VIP-containing processes were seen in close apposition to a significant number of VIP2 receptor-positive GnRH neurons. GnRH neurons that exhibit immunoreactivity for the VIP2 receptor are located predominantly in the OVLT region and the rostral preoptic area. In the median eminence, where the majority of GnRH neurons terminate, VIP2 receptor immunoreactivity was absent. In summary, these findings indicate that VIP can communicate directly with GnRH neurons.
Animals↗
Ergonomic guidelines for using notebook personal computers. Technical Committee on Human-Computer Interaction, International Ergonomics Association.
In the 1980's, the visual display terminal (VDT) was introduced in workplaces of many countries. Soon thereafter, an upsurge in reported cases of related health problems, such as musculoskeletal disorders and eyestrain, was seen. Recently, the flat panel display or notebook personal computer (PC) became the most remarkable feature in modern workplaces with VDTs and even in homes. A proactive approach must be taken to avert foreseeable ergonomic and occupational health problems from the use of this new technology. Because of its distinct physical and optical characteristics, the ergonomic requirements for notebook PCs in terms of machine layout, workstation design, lighting conditions, among others, should be different from the CRT-based computers. The Japan Ergonomics Society (JES) technical committee came up with a set of guidelines for notebook PC use following exploratory discussions that dwelt on its ergonomic aspects. To keep in stride with this development, the Technical Committee on Human-Computer Interaction under the auspices of the International Ergonomics Association worked towards the international issuance of the guidelines. This paper unveils the result of this collaborative effort.
Equipment Design↗
A comparative evaluation of aflatoxin B1 genotoxicity in fish models using the Comet assay.
Aflatoxin B1 (AFB1) is classified as a Group I hepatocarcinogen in humans by the International Agency for Research on Cancer (IARC). The alkaline Comet assay is a simple and rapid method by which DNA damage can be demonstrated as a function of tail moment. The present work is the first to evaluate the genotoxicity of AFB1 in fish using the Comet assay. Two different species of fish were selected as models due to previously established sensitivity to AFB1: rainbow trout (sensitive) and channel catfish (resistant). Fish were i.p. injected with 0.5 mg AFB1/1 ml DMSO/1 kg body weight. The Comet assay was performed after 4 and 24 h on whole blood, liver, and kidney cells of both species. Trout blood and kidney tissue tested displayed significant (p < 0.05) and extensive DNA damage (shown by increased tail moment) after 4 h which then decreased by 24 h. In liver cells, damage progressively increased over time. Conversely, similarly treated catfish showed no elevation in DNA damage over controls at the same doses. These results suggest that the Comet assay is a useful tool for monitoring the genotoxicity of mycotoxins such as AFB1 and for evaluating organ specific effects of these agents in different species.
Aflatoxin B1↗
Menstrual cycle effects on cortical excitability.
OBJECTIVE: To determine whether there are menstrual cycle-related effects on cortical excitability in normal women. BACKGROUND: Ovarian steroid hormones affect neurotransmission in the brain. Data from animal experiments have shown that progesterone metabolites enhance the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cortex, producing benzodiazepine-like (e.g., diazepam and lorazepam) physiologic and behavioral effects. Estradiol has excitatory effects on measures of neuronal excitability, possibly acting through the glutamate system. These effects have been difficult to detect in women using conventional techniques. However, recently, paired transcranial magnetic stimulation (TMS) has been used to detect the effects of GABAergic and glutamatergic drugs in humans. We used this method to measure the effects of the menstrual cycle in normal women. METHODS: We tested 13 healthy women during the follicular (low-progesterone) and luteal (high-progesterone) phases of the menstrual cycle using paired TMS. The effect of a subthreshold conditioning pulse on the cortex was tested by measuring the response to a second suprathreshold test pulse and comparing it with the response elicited by the test pulse administered alone. RESULTS: Conditioning TMS produced more inhibition in the luteal phase than in the follicular phase (p = 0.01), of similar magnitude to the reported effect of benzodiazepine drugs. CONCLUSIONS: This study provides the first direct evidence of changes in the excitability of a cortical network with the menstrual cycle. The results also show a potential confound for studies using transcranial magnetic stimulation in populations that include menstruating women.
Adult↗
Opposite links of positive and negative symptomatology with memory errors in schizophrenia.
We wished to confirm and extend a previous correlational study of our group, suggesting that positive symptoms in schizophrenia were linked to an increase in certain types of memory errors, and negative symptoms to a decrease in other types of errors. A post-hoc analysis was conducted in 33 schizophrenic patients and 40 normal control subjects on memory errors collected in a free recall task and two types of recognition tasks. The memory errors were intrusions and list errors in free recall, and decision bias towards false alarms in recognition, all assumed to reflect a source-monitoring failure. In a first analysis, the patient sample was split along the median for positive symptoms as rated by the Scale for the Assessment of Positive Symptoms (SAPS). In a second analysis, it was split along the median for negative symptoms as rated by the Scale for the Assessment of Negative Symptoms (SANS). Patients with high ratings of positive symptoms made more memory errors (intrusions, list errors, false alarms) than those with low ratings, supporting the hypothesis of a link between positive symptomatology and source-monitoring failure. On the other hand, patients with high ratings of negative symptoms made fewer of these errors than the other patients. Fewer errors were specifically associated with more affective flattening, alogia and anhedonia, whereas avolition was entirely unrelated to them.
Adult↗
Peptide ligands that bind IgM antibodies and block interaction with antigen.
We have selected a peptide-display phage library on IgM Abs and identified a panel of phage-expressing peptides that bind to IgM Abs in general, but not to Abs of other classes. A synthetic peptide corresponding to one of the displayed peptide sequences also binds to IgM Abs. The peptides bind to both soluble pentameric Abs and to monomeric cell-surface IgM. The phage-displayed and synthetic peptides inhibit the binding of IgM Abs to Ag. These peptides may create confounding artifacts when IgM Abs are used for epitope mapping studies. Nonetheless, the peptides may have both experimental and therapeutic utility.
Animals↗
Gene expression during gonadogenesis in the chicken embryo.
Genes implicated in vertebrate sex determination and differentiation were studied in embryonic chicken gonads using reverse transcription and the polymerase chain reaction (RT-PCR). Expression profiles were obtained during gonadal sex differentiation for AMH, SOX9, SOX3, the Wilm's Tumour gene, WT1, and the orphan nuclear receptor genes, SF1 and DAX1. Some of these genes showed sexually dimorphic expression profiles during gonadal development, whereas others were expressed at similar levels in both sexes. The gene encoding Anti-Müllerian hormone (AMH) was expressed in both sexes prior to and during sexual differentiation of the gonads, with levels of expression consistently higher in males than in females. SOX9 expression was male-specific, and was up-regulated after the detection of AMH transcripts. SOX3 expression was observed prior to clear SOX9 expression and was up-regulated in both sexes at the onset of gonadal sex differentiation (but declined later in development). The WT1 gene was highly expressed in both sexes, whereas SF1 expression was clearly higher in developing ovaries compared to testes. DAX1 transcripts were observed in both sexes at all stages examined, but expression appeared somewhat higher in developing ovaries. These expression profiles are analysed in terms of current theories of vertebrate sex determination.
Actins↗
Structure of tau exon 10 splicing regulatory element RNA and destabilization by mutations of frontotemporal dementia and parkinsonism linked to chromosome 17.
Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Intronic mutations and some missense mutations increase splicing in of exon 10, leading to an increased ratio of four-repeat to three-repeat tau isoforms. Secondary structure predictions have led to the proposal that intronic mutations and one missense mutation destabilize a putative RNA stem-loop structure located close to the splice-donor site of the intron after exon 10. We have determined the three-dimensional structure of this tau exon 10 splicing regulatory element RNA by NMR spectroscopy. We show that it forms a stable, folded stem-loop structure whose thermodynamic stability is reduced by frontotemporal dementia and parkinsonism linked to chromosome 17 mutations and increased by compensatory mutations. By exon trapping, the reduction in thermodynamic stability is correlated with increased splicing in of exon 10.
Base Sequence↗
Fate of phenanthrene, pyrene and benzo[a]pyrene during biodegradation of crude oil added to two soils.
The release of 14CO2 from 9-[14C]phenanthrene, 4,5,9,10-[14C]pyrene and 7-[14C]benzo[a]pyrene, added to Brent/Fortes crude oil and mixed into a pristine sand soil (0.40% organic C) and a pristine organic soil (22.9% organic C), was determined. After 244 days at 25 degrees C, 11.1 +/- 3.5% (sand) and 17.1 +/- 0.30% (organic) phenanthrene-14C and 9.77 +/- 2.8% (sand) and 5.86 +/- 1.4% (organic) benzo[a]pyrene-14C was released. After 210 days, 3.65 +/- 0.5% (sand) and 4.43 +/- 0.33% (organic) pyrene-14C was released. Inoculation of these two soils with DC1 and PD2 (bacteria capable of accelerating the phenanthrene and pyrene mineralisation in soil in the absence of crude oil) either at day 0 or after release as 14CO2 by indigenous degraders had ceased, failed to increase or initiate further mineralisation. Thus, aged PAH residues were non-bioavailable to these metabolically competent degrading microorganisms. At the end of the first period of incubation (210 days or 244 days), the total aromatic hydrocarbons recovered using Soxhlet extraction was 0.18% (sand) and 42.8% (organic) compared with approximately 100% from bio-inhibited soils. This confirmed that the indigenous microbiological activity not only caused a limited amount of PAH mineralisation but also reduced the extractability of residues, possibly due to the generation of metabolites which were chemisorbed and bound (and non extractable) in 'aged' soils.
Benzopyrenes↗
Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene.
Mutations in the presenilin 1 (PS1) gene are responsible for approximately 50% of early onset autosomal-dominant Alzheimer's disease cases. A PCR based mutation detection method, chemical cleavage of mismatch, was used to detect a novel PS1 mutation in the coding sequence of the PS1 gene. Sequencing confirmed a T to C transition altering a leucine to proline at codon 219 of the PS1 gene. This is a novel mutation in exon 7 of the PS1 gene occurring outside the transmembrane regions of IV and V.
Age of Onset↗
FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10.
Missense mutations and intronic mutations in the tau gene cause frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known missense mutations reduce the ability of tau to promote microtubule assembly. Intronic mutations lead to increased mRNA splicing of the alternatively spliced exon 10, resulting in an overproduction of tau isoforms with four microtubule-binding repeats. We show here that the recently identified FTDP-17 missense mutations N279K and S305N do not reduce the ability of tau to promote microtubule assembly. Instead they lead to increased splicing of exon 10, like the intronic mutations. The N279K and S305N mutations define a class of missense mutations in tau whose primary effects are at the RNA level.
Alternative Splicing↗
Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.
Aged↗
Expression of chicken steroidogenic factor-1 during gonadal sex differentiation.
The orphan nuclear receptor, steroidogenic factor-1 (SF-1), regulates steroidogenic enzyme expression and is essential for gonadal and adrenal development in mammals. We have examined expression of the chicken homologue, cSF-1, during gonadal sex differentiation using whole mount in situ hybridisation and RNase protection assays (RPA). In the youngest embryos examined (day 3.5; stages 21-22), cSF-1 transcripts were already detectable by in situ hybridisation in the undifferentiated genital ridge of both sexes. Expression continued in the gonads of both sexes at the time of sexual differentiation (days 5.5-6.5; stages 28-30). Expression then became higher in developing ovaries compared to testes at days 6.5-8. 5 (stages 30-35). At day 13.5 (stage 40), when the gonads are well differentiated, both ovaries and testes showed cSF-1 expression, with higher levels of expression in the left ovary compared to the right (regressing) gonad in females and compared to testes. RPA analysis of isolated gonads confirmed higher expression of SF-1 in differentiating ovaries relative to testes. Expression of cSF-1 in the developing adrenal gland was similar for both sexes at all stages examined. In tissue sections of day 8.5 whole mount gonads, cSF-1 expression was localised in the medulla of the ovary and was weakly detectable in the testis. These observations indicate that SF-1 has a conserved role in early gonadal and adrenal development in vertebrates. However, upregulation of cSF-1 expression during ovarian differentiation is opposite to the pattern seen in mammals, in which SF-1 is downregulated in females. This difference between the birds and mammals may reflect differences in steroidogenic activity of the embryonic ovary versus the testis in the two groups.
Animals↗
A direct comparison of selectin-mediated transient, adhesive events using high temporal resolution.
Leukocyte capture and rolling on the vascular endothelium is mediated principally by the selectin family of cell adhesion receptors. In a parallel plate flow chamber, neutrophil rolling on purified selectins or a selectin-ligand substrate was resolved by high speed videomicroscopy as a series of ratchet-like steps with a characteristic time constant (Kaplanski, G., C. Farnarier, O. Tissot, A. Pierres, A.-M. Benoliel, M. C. Alessi, S. Kaplanski, and P. Bongrand. 1993. Biophys. J. 64:1922-1933; Alon, R., D. A. Hammer, and T. A. Springer. 1995. Nature (Lond.). 374:539-542). Under shear, neutrophil arrests due to bond formation events were as brief as 4 ms. Pause time distributions for neutrophils tethering on P-, E-, L-selectin, or peripheral node addressin (PNAd) were compared at estimated single bond forces ranging from 37 to 250 pN. Distributions of selectin mediated pause times were fit to a first order exponential, resulting in a molecular dissociation constant (k(off)) for the respective selectin as a function of force. At estimated single bond forces of 125 pN and below, all three selectin dissociation constants fit the Bell and Hookean spring models of force-driven bond breakage equivalently. Unstressed k(off) values based on the Bell model were 2.4, 2.6, 2.8, 3.8 s(-1) for P-selectin, E-selectin, L-selectin, and PNAd, respectively. Bond separation distances (reactive compliance) were 0.39, 0.18, 1.11, 0.59 A for P-selectin, E-selectin, L-selectin, and PNAd, respectively. Dissociation constants for L-selectin and P-selectin at single bond forces above 125 pN were considerably lower than either Bell or Hookean spring model predictions, suggesting the existence of two regimes of reactive compliance. Additionally, interactions between L-selectin and its leukocyte ligand(s) were more labile in the presence of flow than the L-selectin endothelial ligand, PNAd, suggesting that L-selectin ligands may have different molecular and mechanical properties. Both types of L-selectin bonds had a higher reactive compliance than P-selectin or E-selectin bonds.
Biophysical Phenomena↗
Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation.
OBJECTIVE: Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. METHODS: In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. RESULTS: Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. CONCLUSIONS: The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit.
Antibodies, Monoclonal↗
Analysis of Texas & New Mexico Hospice Organization's new Code of Ethics.
Unique among professional codes of ethics is the Texas & New Mexico Hospice Organization's Code of Ethics. Where other codes concentrate only on principles-based ethics, this new code identifies five models of bioethics currently used in resolving ethical dilemmas. This report's primary purpose analyzes the code's four precepts in the context of (1) principles-based ethics, (2) casuistic-based ethics, (3) covenant-based ethics, (4) evidence-based ethics and narrative-based ethics. The second purpose is to present the practicality of these often esoteric concepts in the day-to-day work of palliative care providers. Indications are that this code of ethics, because of its broad scope, is more useful than other principles-based-only codes.
Ethics, Institutional↗
Macroergonomics and total quality management: how to improve quality of working life?
In this paper, we present a macroergonomic model of work design that is applied and tested to examine Total Quality Management (TQM) in the public sector. According to the model, TQM can influence different aspects of work design and quality of working life (QWL). Questionnaire data collected in 2 public sector organizations in the USA show that TQM can have both positive and negative impact on work design and QWL. The main positive impact of TQM was found on job content, job control and participation, and social relationships. The main negative impact of TQM was on workload, uncertainty, and clarity of job duties. The impact of TQM on QWL was mixed. Our results show that the impact of TQM on work design and QWL varied very much across the 6 participating departments, as well as within the departments. Further research is warranted to assess the human impact of TQM, in particular research on the linkage between various aspects of TQM, on one hand, and work design and QWL, on the other hand.
Analysis of Variance↗