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PubMed2003

Optimality of collective choices: a stochastic approach.

Amplifying communication is a characteristic of group-living animals. This study is concerned with food recruitment by chemical means, known to be associated with foraging in most ant colonies but also with defence or nest moving. A stochastic approach of collective choices made by ants faced with different sources is developed to account for the fluctuations inherent to the recruitment process. It has been established that ants are able to optimize their foraging by selecting the most rewarding source. Our results not only confirm that selection is the result of a trail modulation according to food quality but also show the existence of an optimal quantity of laid pheromone for which the selection of a source is at the maximum, whatever the difference between the two sources might be. In terms of colony size, large colonies more easily focus their activity on one source. Moreover, the selection of the rich source is more efficient if many individuals lay small quantities of pheromone, instead of a small group of individuals laying a higher trail amount. These properties due to the stochasticity of the recruitment process can be extended to other social phenomena in which competition between different sources of information occurs.

Animal Communication↗
PubMed1999

The failure of placebo-controlled studies. ECNP Consensus Meeting, September 13, 1997, Vienna. European College of Neuropsychopharmacology.

In recent years an increasing number of clinical trials to test the efficacy of new potential treatments have failed to demonstrate a difference from placebo for either the new treatment or for an established reference drug. A rise in the response rate to placebo observed in a range of psychiatric disorders has not been paralleled by a rise in the response to drug and small effect sizes make it difficult to establish significant differences. A number of factors are thought to contribute to the rising placebo response or the smaller effect sizes. These include differences over time in the populations studied, changes in investigator behaviour, and failures of trial design. The inclusion of a greater number of patients with mild disorder or whose disorder has a fluctuating course is thought likely to increase the placebo response rates. Close attention needs to be paid to patient selection in terms of diagnosis, severity and absence of confounding comorbidity such as alcoholism, personality disorders or brief depression. The rising placebo response is associated with an increasing variability of placebo response seen in some centres. The ability of some centres to select appropriate patients for studies to demonstrate a separation of reference treatment and placebo and the inability of other centres suggests that a more careful selection of investigators is important. Selection should be based on their experience, their record from previous studies, and their aptitude for being trained. The inclusion of a reference treatment arm provides a useful means to judge the performance of individual centres. The exclusion of eccentric centres that fail to reach predetermined performance criteria, such as a failure to separate reference treatment from placebo, may be considered. Trial designs need to qualify adequately the study population and pay sufficient attention to diagnosis, minimum severity and comorbidity at entry. Greater care is needed in excluding concomitant overt or covert psychotherapy and in reducing the unnecessary therapeutic contact that has been increased unwittingly by some protocols. Identifying patients with prior stability of illness, with clear disability, and with a minimum severity at entry is likely to lower the placebo response substantially and increase the effect size and power of the study. The possible influence of comedication should also be considered. The inclusion of a placebo run in period is considered unhelpful and the use of better statistical techniques should be adopted to maximise the sensitivity of the study and increase the chances of testing efficacy.

Controlled Clinical Trials as Topic↗
PubMed1993

Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores.

Stimulated influx of Ca2+ across the plasma membrane of T lymphocytes is an essential triggering signal for T-cell activation by antigen. Regulation of the T-cell Ca2+ conductance is not understood; conflicting evidence supports direct activation by inositol 1,4,5-trisphosphate (IP3) or by a signal generated by the depletion of intracellular Ca2+ stores. We have used the perforated-patch recording technique to compare the biophysical properties of Ca2+ currents activated by T-cell receptor stimulation and by thapsigargin, a Ca(2+)-ATPase inhibitor that depletes intracellular stores without generating IP3. Both currents are blocked by Ni2+, are inwardly rectifying, are highly Ca(2+)-selective, and exhibit voltage-independent gating with a unitary chord conductance of approximately 24 fS in isotonic Ca2+. Fluctuation analysis suggests that the underlying Ca2+ transporter is a channel rather than an iron carrier. Thus, in terms of ion permeation, gating, and unitary conductance, the Ca2+ current activated by thapsigargin is indistinguishable from the elicited by crosslinking of T-cell receptors. Moreover, the unitary Ca2+ conductance is > 100-fold smaller than that of previously described IP3-gated, Ca(2+)-permeable channels in T cells [Kuno, M. & Gardner, P. (1987) Nature (London) 326, 301-304]. These results demonstrate that mitogen-activated Ca2+ influx is controlled by the state of intracellular Ca2+ stores rather than by the direct action of IP3 on Ca2+ channels in the plasma membrane.

Calcium↗
PubMed1995

Urban-rural differentials in infant mortality in Victorian England.

This paper examines the magnitude of urban-rural differentials in infant mortality in England during the nineteenth and early twentieth centuries and also compares the timing of decline for a selection of towns of varying size, and their immediate rural hinterlands. Most towns continued to experience short-term fluctuations in infant mortality until the very end of the nineteenth century; however, in some of the adjacent rural communities--where levels of infant mortality were much lower--conditions were sufficiently favourable to allow a continuous decline in infant mortality from at least the 1860s, if not before. The final part of the paper considers the causes of these patterns and their implications for explanations of infant mortality decline.

History, 19th Century↗
PubMed1998

Narratives of twenty to thirty year outcomes in schizophrenia.

This descriptive study objectively compares three decades in the life histories of women and men with schizophrenia treated continuously at one institution. On the basis of clinical observation, it was hypothesized that the first ten years of illness would be stormier for men, but that women would suffer more than their male counterparts as they began to approach the age of menopause. Eighty active patients with a current diagnosis of DSM-IV schizophrenia were identified. From this group, ten men and ten women, randomly selected, agreed to review and publication of their life stories in slightly altered form. These twenty patients and their current case managers were interviewed. Their medical records were reviewed and the course of selected predictor variables was charted on the Camberwell Assessment of Need (CAN) entry form. The entries on the CAN fluctuated markedly for most of the patients over the two to three decades of illness. Seven of the ten men were, as predicted, globally most severely ill during their first decade of illness and improved thereafter. By contrast, eight of the ten women appeared to suffer a relatively need-free first decade, followed by increasing disability over time. In this small group, which, because of the method of recruitment, excluded best and worst outcomes, factors such as onset age, duration of untreated prodrome, and early course of illness (as assessed by chart review) did not predict long-term outcome. On the other hand, substance abuse, social supports, and a family history of schizophrenia were more closely correlated with 20- to 30-year outcome status. The direct effect of female menopause on illness severity was not possible to gauge in this study, but alterations in hormones may have played a part in responsivity to family and social loss.

Activities of Daily Living↗
PubMed2000

Weak Lensing by Large-Scale Structure: A Dark Matter Halo Approach.

Weak gravitational lensing observations probe the spectrum and evolution of density fluctuations and the cosmological parameters that govern them, but they are currently limited to small fields and subject to selection biases. We show how the expected signal from large-scale structure arises from the contributions from and correlations between individual halos. We determine the convergence power spectrum as a function of the maximum halo mass and so provide the means to interpret results from surveys that lack high-mass halos either through selection criteria or small fields. Since shot noise from rare massive halos is mainly responsible for the sample variance below 10&arcmin;, our method should aid our ability to extract cosmological information from small fields.

Journal Article↗
PubMed1998

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.

The aim of this study was to compare, retrospectively, the value of chronic bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) in patients with young onset Parkinson's disease. We selected 13 consecutive patients with similar characteristics at the time of surgery: age at onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were operated on in the STN and five in the GPi. The Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and off-drug conditions before surgery and 6 months after surgery on stimulation using the chronic electrical parameters found to improve best the motor state of the individual patient, without adverse effects. In off-drug phases, the motor score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi stimulation on average. This difference was statistically significant (P < 0.05). Whereas rigidity and tremor showed good improvement in both groups, the decrease in the akinesia score was more pronounced in the STN group. In the STN group, the improvement of all motor symptoms was very close, or equal, to the best levodopa response. Thus the levodopa test was predictive of outcome. The improvement in off-drug period motor handicap allowed a decrease in the levodopa-equivalent dose only in the STN group (-56%). The voltage, frequency and pulse width used for chronic stimulation were lower in the STN group. In the on-drug phases there was a marked improvement in LID in the GPi group, as measured by the dyskinesias score during an acute levodopa test, whereas there was only a small decrease in the STN group (P < 0.05). However, in the long term, the reduction of levodopa dosage in the STN group led to an indirect reduction of LID similar to that in the GPi group during activities of everyday life. In conclusion, the overall results favour the neurosurgical treatment of Parkinson's disease by stimulating the STN rather than the GPi.

Adult↗
PubMed1991

Stimulation of intrachromosomal homologous recombination in mammalian cells by an inhibitor of poly(ADP-ribosylation).

We determined the effect of 3-methoxybenzamide (3-MB), a competitive inhibitor of poly(ADP-ribose) polymerase (E.C. 2.4.2.30), on intrachromosomal homologous recombination in mouse Ltk- cells. We used a cell line that contained in its genome two defective Herpes thymidine kinase (tk) genes as closely linked direct repeats. Intrachromosomal homologous recombination events were monitored by selecting for tk-positive segregants that arose during propagation of the cells and recombination rates were determined by fluctuation analysis. We found that growth of cells in the continuous presence of 2mM 3-MB increased intrachromosomal recombination between 3 and 4-fold. Growth of cells in the presence of 2mM m-anisic acid, a non-inhibitory analog of 3-MB, had no effect on intrachromosomal recombination rates. Additionally, we found that 3-MB increased both gene conversions and crossovers to similar extents, adding to the evidence that these two types of intrachromosomal rearrangements share a common pathway. These findings contrast with our previous studies [Waldman, B.C. and Waldman, A.S. (1990) Nucleic Acids Res., 18, 5981-5988] in which we determined that 3-MB inhibits illegitimate recombination and has no effect on extrachromosomal homologous recombination in mouse Ltk- cells. An hypothesis is offered that explains the influence of 3-MB on different recombination pathways in mammalian cells in terms of the role that poly(ADP-ribosylation) plays in DNA break-repair.

Animals↗
PubMed1978

Social influences on the prognosis of schizophrenia.

Literature relating to social influences on prognosis of schizophrenia is selectively reviewed. The influence of the care system is considered separately from other social influences such as business cycle fluctuations, community organization and attitudes, social class membership, independent events in the patient's life, and expression of emotion by the patient's family members. Several studies of milieu indicate that milieu can influence course of illness for better, or for worse. One study of group psychotherapy suggests that groups help improve social function of schizophrenics in the community. Studies of individual psychotherapy fail to demonstrate its efficacy. Business cycle fluctuations clearly relate to admission rates of schizophrenics to hospitals; independent life events are associated with onset and relapse. Community attitudes and family emotional expression relate to relapse and rehospitalization. Clearly, social events, especially those occurring outside the care system, do influence the course of illness. There is also evidence for the influence of psychosocial treatment but at the present time is less consistent the evidence for the influence of other social events on the prognosis and course in schizophrenia.

Antipsychotic Agents↗
PubMed1986

Hypothalamic and pituitary enzymatic degradation of luteinizing hormone-releasing hormone during the 4-day estrous cycle of the rat. Assessment by high-performance liquid chromatography.

Luteinizing hormone-releasing hormone (LHRH) degrading activity may be of physiological significance as a mechanism capable of partial regulation of hypothalamic LHRH release as well as LHRH levels at the gonadotroph. The possibility of cyclic fluctuations in LHRH-degrading activity was investigated in female rat hypothalami and pituitaries. These tissues were collected at selected time points during the 4-day estrous cycle, homogenized, and centrifuged at 100,000 g. Supernatants were incubated with synthetic LHRH, the reactions terminated, and the decapeptide and its products separated by high-performance liquid chromatography. Degradation of LHRH incubated with active cytosol was estimated by comparison of integrated LHRH peak area with that from incubations with heat-inactivated cytosol. Hypothalamic LHRH degradation was depressed during the latter hours of diestrus 2, a time during which the LHRH content in the hypothalamus has been reported to be increasing. From diestrus 24.00 h to proestrus 15.00 h, there was a significant increase in degrading activity. This was then followed by a decline from 15.00 to 18.00 h proestrus; at the time of the LH surge, the activity had not undergone significant increase in comparison to 18.00 h. Pituitary LHRH degradation was significantly increased during the 6-hour period preceding the surge, but was significantly depressed at the surge. The hypothalamic reduction in activity associated with diestrus 2 as well as the hypothalamic and pituitary reductions associated with proestrus may represent a permissive effect allowing increased LHRH accumulation in the hypothalamus and its prolonged action in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

An unusual pattern of spontaneous mutations recovered in the halophilic archaeon Haloferax volcanii.

Spontaneous mutations in the orotate:phosphoribosyl transferase (pyrE2) gene of the halophilic archaeon Haloferax volcanii were selected by 5-fluoroorotic acid plus uracil at a rate of approximately 2 x 10(-8)/cell division in fluctuation and null-fraction tests but approximately 6 x 10(-8)/cell division in mutation-accumulation tests. The corresponding genomic mutation rates were substantially lower than those observed for other mesophilic microbial DNA genomes on the basis of similar target genes. The mutational spectrum was dominated by indels adding or deleting multiples of 3 bp. Properties of the organism contributing to this unusual mutational pattern may include phenotypic lag caused by a high chromosomal copy number and efficient promotion of strand misalignments by short direct repeats.

Genes, Archaeal↗
PubMedDate not supplied

Cellular plasma membrane domains.

The plasma membranes of migrating cells differentiate into at least three distinct domains as defined by the laser tweezers and the motile behaviour of particles bound to specific membrane glycoproteins. These domains are important for steps in the cell migration process. First, there is a domain at the leading edge of the lamellipodium where preferential attachment of cross-linked glycoproteins to the cytoskeleton occurs. The second domain at the rear of the cell is differentiated for releasing from substrata and shows decreased support of the membrane by the cytoskeleton. The third domain is the highly curved region(s) of the plasma membrane wherein certain membrane glycoproteins concentrate and is a site for controlling extension and attachment. Using single particle tracking and video analysis we find that the quantitative differences between plasma membrane domains are in the 4-20-fold range at any given time. These values are consistent with the rapid fluctuations seen in cell migration rates and directions. Over a longer time-scale, cells can possibly integrate these selective advantages to give a much higher overall fidelity for cell chemotaxis and neuronal path finding.

Cell Membrane↗
PubMed1980

Preliminary epidemiological survey of schistosomiasis in central and southern Liberia.

Some basic epidemiological data on schistosomiasis in central and southern Liberia were collected. A study of snail density fluctuations was carried out in waterbodies bordering the road between Harbel and Gbarnga. Samples from schoolchildren living in ten selected villages were examined for Schistosoma spp. and other helminths. In the coastal region no snail hosts were found, the prevalence rates in schoolchildren were low and the infections were apparently imported. Inland, the intermediate host of Schistosoma haematobium Bulinus globosus was common and the prevalence of urinary schistosomiasis was high. Further inland, around Gbarnga, both Schistosma mansoni and S. haematobium were endemic. The seasonal patterns of patent cercarial infections in Bulinus globosus and Biomphalaria pfeifferi are described. Both snail densities and cercarial infection rates were markedly reduced by heavy rains. The results of the study may contribute to the planning of future integrated control strategy.

Adolescent↗
PubMed1994

The amygdala's contribution to memory--a study on two patients with Urbach-Wiethe disease.

The consequences of primary amygdaloid damage on memory performance are described in terms of neuropsychological, CT, MRI and PET results of two patients, a brother and a sister. Both had circumscribed, bilaterally symmetrical damage confined to the amygdaloid region, while the hippocampal formation and other brain structures were intact. PET-imaging furthermore revealed an overall decrease in glucose metabolism which was particularly apparent at the cingular and thalamic levels. Although neither patient was amnesic, both showed memory impairments in selective tests. In one patient these impairments were more pronounced and they were accompanied by marked affective-emotional fluctuations. Our results suggest that the amygdaloid region is a bottle-neck structure that confers an affective flavour to memories, thereby enhancing the probability of their long term storage.

Adult↗
PubMed1998

Three-process model of supervisory activity over 24 hours.

OBJECTIVES: This study used endogenous and exogenous factors to develop a model for sampling supervisory activity that implied consulting numerous data on computer systems. METHODS: The study was carried out in an automated workshop of a chemical plant. Five crews worked on a 3x8 hour shift system, with changes at 0400, 1200 and 2000. Each team included 2 experienced controllers who supervised the process from computer systems in a control room. Starting and ending duty at the same time as the operators, the researchers used real time to code of all the screen pages selected on the computers by 8 controllers (from 4 teams) over 18 shifts. RESULTS: The time-of-day fluctuations of the call frequency confirmed the existence of endogenous factors (biological rhythms or fatigue), but they cannot explain all the variations observed. The modeling of the data yielded the following 3 explanatory factors: (i) the cognitive demands of the tasks, as an external factor, mainly concern the impact of shift changeover characterized by a strong peak of information gathering at the beginning of the shift, even at 0400; (ii) the shift duration appears as a "fatigue" factor and reflects a rapid reduction of information gathering over the shift; (iii) circadian rhythms are characterized by a minimum of activity at night and a maximum in the afternoon. CONCLUSION: In other similar work situations, in addition to an essential work analysis, our model could help the design of shift duration or schedules for shift changeover.

Adult↗
PubMed2006

Probing dynamics and conformational change of the GroEL-GroES complex by 13C NMR spectroscopy.

Bacterial chaperonin GroEL with a molecular mass of 800 kDa was studied by (13)C NMR spectroscopy. Carbonyl carbons of GroEL were labeled with (13)C in an amino acid specific manner in order to reduce the number of signals to be observed in the spectrum. Combination of selective labeling and site-directed mutagenesis enabled us to establish the sequence specific assignment of the (13)C resonances from GroEL. ADP-binding induced a chemical shift change of Tyr478 in the equatorial domain and His401 in the intermediate domain, but little of Tyr203 in the apical domain. Upon complex formation with co-chaperonin GroES in the presence of ADP, Tyr478 exhibits two peaks that would originate from the cis and trans rings of the asymmetric GroEL-GroES complex. Comparison between the line width of the GroEL resonances and those from GroES in complex with GroEL revealed broadening disproportionate to the size of GroEL, implying the existence of conformational fluctuations which may be pertinent to the chaperone activity. Based on these results, we concluded that (13)C NMR observation in combination with selective labeling and site-directed mutagenesis can be utilized for probing the conformational change and dynamics of the extremely large molecules that are inaccessible with current NMR methods.

Adenosine Diphosphate↗
PubMed1992

Sensitization, response fluctuation and long-term effect of SKF-82958 and bromocriptine in the hemi-parkinsonian rat.

Rats with a unilateral 6-hydroxydopamine lesion of substantia nigra were treated with the dopamine agonists SKF-82958 (D1 receptor selective) or bromocriptine (D2 receptor-selective) and their circling response recorded. Both of the compounds induced an acute episode of rotation directed away from the lesioned side. Consecutive daily treatments with either compound usually resulted in a significantly increased average response (sensitization) over a 3- to 6-day treatment period. But nearly all animals treated with low doses of either SKF-82958 or bromocriptine exhibited one or more days when they were totally unresponsive to drug treatment. Response fluctuations thus were not exclusively associated with D1 or D2 receptor agonist treatment. When subsequently tested, undrugged, in the drug-associated environment, 2, 4 and 10 weeks after their last drug treatment, rats that had previously been treated with SKF-82958 exhibited rapid contralateral rotation while rats that had previously been treated with bromocriptine showed no such undrugged rotation. This result is consistent with previous findings that the D1 receptor agonist, SKF-38393, but not the D2 receptor agonist, quinpirole, had long-term behavioral effect in nigral rats, and suggests that persistent motor consequences of limited treatment with dopamine receptor agonists are D1 receptor-related.

Animals↗
PubMed1987

Simulating evolution by gene duplication.

By considering the recent finding that unequal crossing over and other molecular interactions are contributing to the evolution of multigene families, a model of the origin of repetitive genes was studied by Monte Carlo simulations. Starting from a single gene copy, how genetic systems evolve was examined under unequal crossing over, random drift and natural selection. Both beneficial and deteriorating mutations were incorporated, and the latter were assumed to occur ten times more frequently than the former. Positive natural selection favors those chromosomes with more beneficial mutations in redundant copies than others in the population, but accumulation of deteriorating mutations (pseudogenes) have no effect on fitness so long as there remains a functional gene. The results imply the following: Positive natural selection is needed in order to acquire gene families with new functions. Without it, too many pseudogenes accumulate before attaining a functional gene family. There is a large fluctuation in the outcome even if parameters are the same. When unequal crossing over occurs more frequently, the system evolves more rapidly. It was also shown, under realistic values of parameters, that the genetic load for acquiring a new gene is not as large as J.B.S. Haldane suggested, but not so small as in a model in which a system for selection started from already redundant genes.

Alleles↗