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PubMed2004

Dynamics of thyroid-stimulating and -blocking antibodies to the thyrotropin receptor in a murine model of Graves' disease.

Graves' disease is characterized by the presence of autoantibodies to the TSH receptor (TSHR). There are multiple antibodies to the TSHR, with thyroid-stimulating antibodies (TSAbs) and TSH-stimulating blocking antibodies (TSBAbs), which in patients can fluctuate over time, resulting in changes in disease activity. Recently, animal models of Graves' disease have been developed, but it is not known whether the induced TSAbs and TSBAbs change spontaneously with time to influence disease. We used fibroblasts expressing major histocompatability complex (MHC) class II and human TSHR murine model to study anti-TSHR antibody patterns in serial bleeds of 23 animals. Anti-TSHR antibody responses were first detectable after 7-8 wk of first immunization. Moreover, the pattern of the TSAbs or TSBAbs was selected early in the response. The majority of the animals showed anti-TSHR antibodies that were either TSAb or TSBAb responses and were maintained throughout the course of 17-24 wk of the experiment. Remarkably, a proportion of mice (13%) displayed presence of antibodies with both TSAbs and TSBAbs, which appeared to cycle over time and thus mimic the fluctuations described in some hyperthyroid patients. Analyses of the linear epitopes to TSHR by peptide scanning showed that there was no early restricted epitope response. Thus, despite using an inbred strain, the initial response appears to target different regions of the receptor in different animals. Our data show that anti-TSHR antibody epitopes in the model display heterogeneity in TSHR epitopes, which vary in individual animals as well as in their regulation.

Animals↗
PubMed1982

Metastable equilibrium with random local fluctuations: simulations of dynamic receptor pattern generation in a fluid mosaic membrane.

The generation of receptors in the animal cell's membrane was simulated by a model consisting of units in four possible states within a hexagonal area (playboard) of n units of a triangular network. The state of each unit was determined by the previous state of itself and of its six nearest neighbours, as regulated by a set of transition rules, which kept the mean relative frequency (m.r.f.) of each state constant. The transition rules were applied to the system exactly n times, regardless whether this involved selection of a unit on 0, 1, 2 or more occasions (programme "random selection with repeat"; RS-R). Comparison to previous results obtained by other ways of application of the rules has shown that the RS-R programme accounted for the highest m.r.f. of quiet (Q) units and Q clusters (sub-patterns), and also for the longest survival of Q configurations through several generations. Functioning of the model under the RS-R programme simulates an integrated system in metastable equilibrium with random local fluctuations, such as the cytoplasmic membrane is imagined to be in standardized environmental conditions. The formation-persistence-disintegration cycle of the sub-patterns is believed to simulate the dynamic generation of transitory receptor configurations in the cell membrane.

Animals↗
PubMed1987

Isogeneic monoclonal antibodies against anti-alpha(1----3)dextran idiotypes. I. Isotypes, idiotope specificity and representation of idiotopes in antisera from mice of various genetic constitutions.

Eight isogeneic anti-idiotypic hybridomas were raised against BALB/c myeloma protein MOPC 104E and one against J558. Both myelomas react specifically with the alpha(1----3) glucosidic linkage of dextran B1355 fraction S (Dex). Six anti-MOPC 104E proteins were IgG1, one was IgG2b and one IgM. The anti-J558 protein was IgG1. Competitive interactions of the anti-idiotopes and antigen with anti-Dex proteins were measured. Dex itself was effective, but also an alpha(1----3) glucosidic heptasaccharide (N7-CHO). In order to assess the anti-idiotope specificity of hybridoma proteins, three anti-Dex molecules were used: MOPC 104E, J558 and hybridoma protein Hdex14. These differed from each other in VH amino acid positions 54-55, or 100-101, respectively. By their serological reaction pattern our anti-idiotope proteins could be divided into 3 groups: cross-reactive, partially cross-reactive and strictly specific for the immunogen. The latter ones were in the majority, and were called "private", in contrast to the cross-reactive "public" anti-idiotopes. The serological pattern was followed, in general, by the mouse-to-mouse distribution of idiotopes in physiological anti-Dex sera. Public idiotopes were closely correlated in their expression with anti-Dex activity. "Private" idiotopes showed no correlation, and displayed a characteristically high degree of fluctuation from mouse to mouse. Among the different mouse strains that were compared with respect to idiotope expression in anti-Dex sera, two stand out: C57BL-Igha, which carries chromosome 12 of BALB/c, (as selected through allotype) on the C57BL/6 genome, and BALB-Ighb, dex+, a recombinant in chromosome 12 linking the dex+ trait from BALB/c to the CH allotype from C57BL/6. The latter strain expressed significantly more of the private idiotopes than the former. This observation is discussed in terms of the position effect of classical genetics and network concepts.

Amino Acid Sequence↗
PubMed1986

Circadian corticosterone rhythm did not develop in rats seven weeks after destruction with 5,7-dihydroxytryptamine of the serotoninergic nerve terminals in the suprachiasmatic nucleus at the age of 16 days.

In order to study the role of the serotoninergic innervation of the hypothalamic suprachiasmatic nucleus (SCN) in the development of the circadian rhythm of corticosterone 5,7-dihydroxytryptamine (5,7-DHT) selectively destroying the serotoninergic structures was injected into the cell group of 16-day-old male rats prior to the appearance of the corticosterone rhythm. Rats treated with 5,7-DHT did not show circadian fluctuations in plasma corticosterone concentrations 3, 5 and 7 weeks after the injection of the neurotoxin. Their hypothalamo-pituitary-adrenal system responded to ether stress. Immunocytochemistry revealed that only a very few serotonin immunoreactive elements were visible in the SCN of the 5,7-DHT-treated rats. The results indicate that serotoninergic innervation of the SCN is essential for the development of the corticosterone rhythm.

5,7-Dihydroxytryptamine↗
PubMed1993

Deletion between direct repeats in bacteriophage T7 gene 1.2.

Deletion mutagenesis in bacteriophage T7 was studied with an insertion-reversion assay involving phage containing inserts of foreign DNA that form 10-bp direct repeats. The precise deletion of the insert restores the function of the non-essential gene and is easily assayed by growth on selection strains of E. coli. Similar inserts with unique direct repeats were placed in either gene 1.2 (dGTPase Inhibitor) or gene 1.3 (DNA ligase). The deletion rates of the inserts were quantified with Luria and Delbrück fluctuation tests. Deletion rates were similar for inserts in both genes indicating that the rates of deletion were not unique to either specific site, or the sequence of the direct repeats. Deletion was independent of functional T7 ligase at 37 degrees C, while an increase in the rate of deletion was noted in some ligase-deficient phage at 43 degrees C. The effect of E. coli DNA Polymerase I on deletion rate was tested and found to decrease deletion rate 60% with the polA1 mutation and 90% with the polA546ex mutation.

Bacteriophage T7↗
PubMed1984

Occupational asthma due to pepsin.

A 30-year-old atopic worker exposed to pepsin powder, herb, and pollen extracts at work developed an increase in asthmatic symptoms. Monitoring of peak expiratory flow rate revealed more important fluctuations at work. Skin prick tests yielded a large immediate reaction to pepsin. Specific inhalation challenges confirmed the diagnosis; an intense early response was documented after exposure to pepsin. The pepsin IgE RAST was positive and selectively inhibited by pepsin.

Adult↗
PubMed1989

Differences in the response of the microcirculation to hyperthermia in five different tumours.

The response of the microcirculation in five different tumours, growing in 'sandwich' observation chambers in the back of the rat, to hyperthermia was investigated. The tumours investigated encompassed three human xenografted tumours, of which two were carcinomata of the colon and one of the lung, and two isologous rat tumours, the Rhabdomyosarcoma BA1112 and a rat mammary carcinoma. It was concluded (1) that the various tumours required significantly different exposure times for inducing 50% stoppage of the tumour microcirculation (ST50). This seems to indicate that differences in the characteristics of the tumour cells are more important for causing microcirculatory stoppage than is the sensitivity of the cells of the blood vessels. (2) An increase in surface (i.e. volume) was observed in all four tumours examined for this phenomenon. The rate of increase (usually 1-2% per hour at 42.5 degrees C) was, however, significantly different between the various tumours. This rate was higher exposure temperatures (43 and 43.5 degrees C), but this was only investigated for the Rhabdomyosarcoma BA1112. Extensive statistical analysis of this phenomenon of volume increase could not demonstrate a correlation with any of the circulation parameters. (3) The relative velocity of the erythrocytes in selected capillaries in the tumours decreases as a result of the hyperthermic treatment, and is probably related to the tumour-specific ST50. (4) A human colon carcinoma xenograft, one of the tumours investigated, showed strong fluctuations in the parameter 'erythrocyte velocity'. The appearance of such fluctuations did not seem to influence the heat-induced stoppage of the circulation. Probably the phenomenon of fluctuations in the velocities of the erythrocytes in the tumour capillaries is a tumour-specific phenomenon.

Adenocarcinoma↗
PubMed1984

Electrocortical activity patterns during chloral hydrate induced sleep in developing rats.

The neocortical EEG was quantified during sleep, while under light chloral hydrate anaesthesia, in rats ranging from 9 to 20 days of postnatal age. Continuous amplitude modulation at 0.5-1.0 min per cycle, synchronously over all frequency bands, was observed in 9- and in 10-day-old pups. By day 13, the mean amplitude had risen considerably in each of the frequency bands, and a slow fluctuation in delta-wave activity began to be discernible. Sodium glutamate injections induced EEG changes at 10 days which mimicked certain aspects of normal maturation (viz., large stereotyped potentials at irregular intervals, along with a selective increase in delta-wave activity). Natural as well as experimentally induced EEG changes were paralleled by a rise in neocortical amino acid concentrations, including glutamic acid and GABA. Delta wave amplitudes during quiet sleep increased still further between 13 and 14 days, while beta activity remained at a constant level. Between days 14 and 15 a precipitous decline in delta-wave activity was found, attributable to greater inhibition of slow waves during active sleep. No further developmental changes were noted, except for a gradual rise in the time spent in quiet sleep relative to active sleep.

Aging↗
PubMed2006

Maternal transfer of organohalogen contaminants and metabolites to eggs of Arctic-breeding glaucous gulls.

Eggs of seabirds have routinely been used as indicators of environmental pollution in the Arctic. However, the variability in organohalogen concentration and composition associated with the laying sequence, have not been defined. We examined a suite of PCBs, organochlorine (OC) pesticides and by-products, polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs) and methylsulfonyl- (MeSO2) PCBs in complete 3-egg clutches of glaucous gulls (Larus hyperboreus), and plasma samples of the laying females collected from the Norwegian Arctic. SigmaPCB, SigmaOC and SigmaPBDE, but not SigmaMeSO2-PCB, concentrations in eggs were positively associated, with increasing magnitude and significance from the first through the last-laid egg, with concentrations in female plasma. However, the concentrations of these organohalogen classes fluctuated irrespective of the laying order in the clutch. In general, maternal transfer favored low K(ow) and/or less persistent compounds, whereas the recalcitrant and/or higher-halogenated compounds were less readily transferred, and consequently more selectively retained in the mother.

Animals↗
PubMed2000

Breathing pattern in humans: diversity and individuality.

In adult awake human subjects at rest, there exists a diversity in the breathing pattern not only in terms of tidal volume and inspiratory and expiratory duration and derived variables (TTOT, VT/TI and TI/TTOT) but also in the airflow profile. Besides this diversity, in every recording of ventilation at rest in steady-state condition breath-to-breath fluctuations are observed in ventilatory variables. This variability is non random and may be explained either by a central neural mechanism or by instability in the chemical feedback loops. Beyond this variability, each individual appears to select one particular pattern among the infinite number of possible combination of ventilatory variables and airflow profile. This one particular pattern appears to be a relatively stable characteristic of an adult individual being reproducible in several conditions and above all, after a long period of time. Consequences of this individuality of breathing pattern are discussed with regard to the selection of control subjects for a study and also per se: are there physiological situations where differences may be observed solely because of the differences in the pattern of breathing?

Humans↗
PubMed2001

Pinus pollen aerobiology and clinical sensitization in northwest Spain.

BACKGROUND: Pinus pollen allergy has been generally considered to be rare and clinically insignificant. In our geographical area, Pinus pollen constitutes one of the most predominant pollen together with Poaceae and Urticaceae pollen. Pinus pinaster and Pinus radiata are the main species. OBJECTIVE: This work aimed to determine the atmospheric fluctuations and the existence of patients monosensitized to Pinus pollen in our region. METHODS: Patients attending our outpatient clinic in the last 4 years with positive cutaneous tests to Pinus pollen and with respiratory symptoms were selected. They were skin tested with commercial extracts of a battery of inhalants including Pinus pollen. Serologic specific IgE to Pinus pollen was performed by CAP system (Pharmacia & Upjohn, Uppsala, Sweden). Airborne Pinus pollen counts in our city were obtained for a 5-year period (1995 to 1999). RESULTS: We present 10 patients with sensitivity to Pinus pollen and with symptomatology coinciding with Pinus pollen season (February to April). Most of these patients were monosensitizated to Pinus pollen and suffered from seasonal rhinoconjunctivitis. Pinus pollen is present in our area in large amounts from February to April with a peak pollen count in March and April. CONCLUSIONS: Pinus pollen may be an important allergen since by itself can be the only cause of allergic disease. Therefore, we think that it must be taken into account in patients living in areas with high Pinus pollen concentrations and with seasonal respiratory disease.

Adolescent↗
PubMed2002

Genetics of fluctuating asymmetry in pupal traits of the speckled wood butterfly (Pararge aegeria).

Fluctuating asymmetry (FA), small random differences between left and right, has been extensively used as a measure of individual quality, though its usefulness in that respect is controversial. Whether FA is heritable has implications for sexual selection theory and for its usefulness as an indicator of stress. Heritability (h(2)) of FA is, however, difficult to estimate precisely and reliably. Here we report h(2)s of FA for two pupal traits in the speckled wood butterfly (Pararge aegeria). We used a restriction error maximum likelihood (REML) analysis in combination with a jackknife procedure to analyse a large mixed offspring-parent/half-sib/full sib data set. A five-generation selection experiment provided a second set of narrow sense h(2)s. Narrow sense h(2)s were not significant and on average -0.029 (REML-analysis) and 0.031 (selection experiment) for the pupal segment covering the fore leg (LEG) and 0.057 and 0.004 for a SPOT on that segment. Estimated percentage dominance variances were 0.057 (LEG) and 0.027 (SPOT) and not significantly different from 0. The h(2) estimates had been slightly increased by cage effects. Average FA for LEG after five generations of selection were higher in the high lines than in the low lines, and the control lines were in between. No difference in FA between lines was found for SPOT. Although differences between lines were not significant, a slight h(2) (<3%) for LEG could not be excluded. The genetic effect was, however, small compared with the effect of foodplant quality. Larvae grown on foodplants that were not watered enough for good growth showed significantly higher FA for LEG, but not for SPOT, compared with larvae grown on good foodplants.

Animals↗
PubMed2001

An in vivo model for HIV resistance development.

Treatment of human immunodeficiency virus (HIV-1) with drugs targeted to the reverse transcriptase (RT) rapidly selects for drug-resistant virus. It is essential to develop a suitable animal model that allows the study of the emergence and reversal of drug resistance. A monkey model was previously developed on the basis of a hybrid virus (RT-SHIV) of simian immunodeficiency virus (SIV) with its RT exchanged for HIV-1 RT. In the present study cynomolgus monkeys infected with RT-SHIV were treated with varying doses of the non-nucleoside RT inhibitor nevirapine. The drug was administered for 2-3 weeks, in agreement with clinical experience of resistance development during nevirapine monotherapy. This resulted in the selection of mutants with Y181C and K103N changes in RT, which correspond to the HIV-1 mutations in nevirapine-resistant HIV-1 patients. The mutants coexisted at varying levels with wild-type virus and fluctuations in the proportion of mutants could be closely monitored. Low-dose treatment was not more efficient in induction of mutations than a virus-inhibiting dose. Structured therapy interruptions could be performed. The monkey RT-SHIV infection offers an in vivo model to determine effects of therapies on resistance development.

Animals↗
PubMed1993

Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up.

A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b (Betaseron, Berlex Laboratories, Richmond, CA), in patients with relapsing-remitting multiple sclerosis (RRMS). During the initial dose finding period (24 weeks), five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8, 4, 8, or 16 million units (mU) of Betaseron or placebo (WHO Standard). Although some side effects were noted in all groups, a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted. Patients given 16 mU had no exacerbations during the initial dosing period, but associated side effects led to dose reduction or dropout. An 8 mU dose was selected for further study after 24 weeks, and continuous dosing at 8 mU in 15 patients has now exceeded 6 years. Side effects abated over time. Neutralizing antibody developed in most patients, but titers were variable, fluctuated independently of clinical course, and tended to fall with prolonged treatment. A dose-dependent rise in neopterin levels was observed during the initial dosing period. This pilot study has demonstrated responsiveness to Betaseron, shown a stable safety profile over time, and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS.

Adolescent↗
PubMed2000

Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence.

Autoantigen-specific T-lymphocytes are present in patients with autoimmune disease and in normal subjects. Little is currently known about the temporal variation (dynamics) of the immune repertoire of these autoreactive T cells. We analysed the long-term variation of the immune repertoire of T cells specific for myelin basic protein (MBP) in five untreated patients with multiple sclerosis and four normal control subjects over a mean observation period of 6 years. MBP-specific CD4(+) T-cell lines were selected with purified human MBP, and their epitope specificity was mapped with overlapping synthetic peptides. Three distinct patterns of repertoire development were observed. (i) Two patients and three control subjects maintained a broad epitope response with fluctuations over time. (ii) Two patients initially showed a focused response that broadened over the course of 6 years; this finding could be described as intramolecular epitope spreading. (iii) In one patient and one control subject, a strikingly focused response, which was directed to a cluster of nested epitopes in the MBP region 83-102, persisted over time. T-cell receptor Vbeta sequence analysis allowed us to trace individual clones of MBP-specific T cells for up to 7 years in the peripheral circulation in four of the five patients and three of the four controls, suggesting that the long-term persistence of MBP-specific T-cell clones is a common feature of the T-cell repertoire not unique to multiple sclerosis. The persisting MBP-specific T-cell clones were not detectable in the blood of one of the patients by complementarity-determining region (CDR)-3 spectratyping, indicating that their frequency does not exceed 1 in 5000 T cells. The temporal characteristics of the MBP-specific T-cell repertoire described here are relevant to therapeutic strategies targeting autoantigen-specific T cells in multiple sclerosis and other autoimmune diseases.

Adult↗
PubMed2000

Cahn-hilliard theory for unstable granular fluids

A Cahn-Hilliard-type theory for hydrodynamic fluctuations is proposed that gives a quantitative description of the slowly evolving spatial correlations and structures in density and flow fields in the early stages of evolution of freely cooling granular fluids. Two mechanisms for pattern selection and structure formation are identified: unstable modes leading to density clustering (mechanismlike spinodal decomposition, or "uplifting" in structural geology), and selective noise reduction (mechanismlike peneplanation in structural geology) leading to vortex patterns. As time increases, the structure factor for the density field develops a maximum, which shifts to smaller wave numbers. This corresponds to an approximately diffusively growing length scale for density clusters. Analytic expressions are derived for spatial correlation functions and structure factors that agree well with molecular dynamics simulations of a fluid of inelastic hard disks.

Journal Article↗
PubMed2004

[Behavioral impairments in Parkinson's disease].

Behavioral impairments in parkinsonian patients include agitation, hypersexuality, stereotypic movement, pathological gambling, abuse of antiparkinsonian drugs, REM sleep behavioral disorder, and restless legs syndrome. Dementia, psychoses, and emotional disorders, such as depression and anxiety/panic disorder, also impair behavior. Symptoms may be produced by dysfunction of the central nervous system, medication, and/or the psychosocial problems associated with Parkinson's disease. Treatment therefore should be based on the cause of the symptoms seen. In some cases, the reduction or change of antiparkinsonian drugs, or both, may be effective. Treatment of the motor symptoms of Parkinson's disease, including motor fluctuations, may reduce the risk of panic attacks being evoked in the 'off' period. Use of antidepressants, sedatives, and neuroleptics may often be effective. Physicians should identify the causes of the symptoms of behavioral impairment and select appropriate treatments.

Humans↗
PubMed1991

Retroviral gene transfer of human adenosine deaminase in murine hematopoietic cells: effect of selectable marker sequences on long-term expression.

Retroviral-mediated gene transfer of human adenosine deaminase (hADA) provides a model system for the development of somatic gene therapy as a therapy for diseases of bone marrow-derived cells. We have previously demonstrated that hADA can be observed in all hematopoietic lineages in a minority of mice transplanted with bone marrow cells infected with a simplified retroviral vector, ZipPGK-ADA. Here we report a majority of mice (six of eight) demonstrate expression of hADA in the peripheral blood at least 6 months after transplantation with bone marrow infected with this simplified retroviral vector, which contains no selectable marker. The failure to express hADA in two of eight mice was associated with the absence of the recombinant retroviral provirus in DNA prepared from bone marrow cells of these mice apparently due to failure to efficiently infect the reconstituting hematopoietic stem cell. In an effort to preselect bone marrow stem cells containing proviral integrations, we incorporated the selectable marker neo phosphotransferase (NEO) into a retroviral vector encoding hADA, N2/ZipPGK-ADATKNEO, and used G418 selection of infected bone marrow cells before transplantation. In contrast to the simplified retroviral vector, hADA expression in these recipients was short lived (less than 8 weeks), despite the continued presence of intact provirus in DNA prepared from bone marrow of these mice. To determine whether the preselection of bone marrow using G418 was responsible for the lack of sustained hADA expression, we repeated the infection with the N2/ZipPGK-ADATKNEO vector but omitted the G418 selection step. Again, the majority of recipient mice failed to express hADA long term, although the continued presence of provirus in DNA prepared from peripheral blood cell mononuclear cells was clearly demonstrated. Finally, we demonstrate clonal fluctuation of infected stem cells, and observe a temporal correlation between cessation of expression of hADA and the emergence of a dominant stem cell clone between 14 and 20 weeks posttransplantation in one recipient. These data suggest that inclusion of a second transcriptional unit that includes neo phosphotransferase sequences in this simplified vector is associated with decreased expression of the nonselectable ADA sequences.

Adenosine Deaminase↗