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At least 919 records · Page 51Linked to original sources
PubMed2002

Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence.

Physical dependence is a widely known consequence of morphine intake. Although commonly associated with prolonged or repeated morphine administration, withdrawal symptoms can be elicited even after a single prior morphine exposure. What remains contentious is the extent to which physical dependence following acute and chronic morphine treatment is mediated by common physiological substrates and, accordingly, represent distinct syndromes. The genetic relationship between acute and chronic morphine dependence was thus presently studied by comparing mice of 11 inbred strains (129P3, A, AKR, BALB/c, C3H/He, C57BL/6, CBA, DBA/2, LP, SJL, and SWR) for naloxone-precipitated withdrawal jumping responses using three subcutaneous morphine administration paradigms: acute (single injection) or chronic (three daily morphine injections for 4 days) injection, or chronic infusion (7 days via implanted osmotic minipumps). Although there were differences in the magnitude of withdrawal jumping between the three different morphine administration paradigms, large and significant strain differences were observed for each. In addition, the same strains were unusually sensitive or, conversely, altogether refractory to withdrawal jumping across all morphine treatment conditions. Overall, strain jumping means between acute and chronic dependence paradigms displayed a high degree of genetic correlation (r=0.87-0.95). The significant correlation between chronic morphine injection and continuous morphine infusion discounts the possible confounding effect of contextual learning and spontaneous withdrawal between chronic injections on the assessment of naloxone-precipitated withdrawal. Substantial heritability was also observed for acute and both paradigms of chronic dependence, with estimates ranging from h(2)=0.53 to 0.70. The present demonstration of a strong genetic correlation between physical dependence to morphine following acute and chronic treatment implies that genes associated with variable sensitivity in the two traits are the same, and is suggestive of shared physiological substrates. The data also demonstrate that the differential genetic liability to morphine physical dependence begins with, and is predicted by, the first morphine exposure.

Acute Disease↗
PubMed2004

Analysing the contributions of genes and parent-child interaction to childhood behavioural and emotional problems: a model for the children of twins.

BACKGROUND: Despite the demonstrable influence of both genes and the family environment on children's behavioural and emotional development, the mechanisms by which these factors are transmitted from parents to their children are not known. Numerous aspects of the family have long been associated with behavioural and emotional problems in children; it is not clear, however, whether these family variables represent genuine environmental risks or secondary consequences of the underlying genetic liability shared between parents and their children. METHOD: In this study we present a model for analysing the non-genetic contributions of family background to risk for childhood and adolescent depression and conduct disturbance using simulated data on adult MZ and DZ twins, their spouses and children. RESULTS: The twin offspring design provides substantial power to detect remarkably small non-genetic effects on parent-offspring resemblance against the background of genetic transmission. As presented, the model is able to resolve the direction of transmission from both parent to child (passive genotype environment correlation) and child to parent (evocative genotype environment correlation). CONCLUSIONS: Unlike many other genetic studies, a study of twins and their children can sort out which putative family environmental risk factors do actually have a significant environmental impact on the child and which ones only appear to do so because they are associated with genetic mediation.

Child↗
PubMed2004

Synthesis and characterization of a magnetic semiconductor Na(2)RuO(4) containing one-dimensional chains of Ru(6+).

A new ternary ruthenium oxide Na(2)RuO(4) was prepared and shown to crystallize with a new structure type. Single crystal X-ray diffraction measurements reveal that Na(2)RuO(4) consists of RuO(4) chains made up of RuO(5) trigonal bipyramids by sharing axial corners. Na(2)RuO(4) is a magnetic semiconductor with a variable range hopping behavior, and its molar magnetic susceptibility chi(mol) has a broad maximum at approximately 74 K. The derivative d(chi(mol).T)/dT exhibits a peak at 37.7 K which has been confirmed by heat capacity measurement to be due to long-range antiferromagnetic ordering.

Journal Article↗
PubMed2005

Executive self, self-esteem, and negative affectivity: relations at the phenotypic and genotypic level.

Complementary approaches examined the relations among executive self, self-esteem, and negative affectivity. A cross-sectional (N = 4,242) and a longitudinal (N = 158) study established that self-esteem mediated the relation between executive self and negative affectivity. A 3rd study (N = 878 twin pairs) replicated this pattern and examined genetic and environmental influences underlying all 3 phenotypes. Covariation among the 3 phenotypes reflected largely common genetic influences, although unique genetic effects explained variability in both executive self and negative affectivity. Executive self was influenced by shared environmental influences unique from those affecting self-esteem and negative affectivity. Non-shared environmental influences accounted for the majority of variance in each construct and were primarily unique to each. The unique genetic and non-shared environmental influences support the proposition that the executive self, self-esteem, and negative affectivity capture distinct and important differences between people.

Adult↗
PubMed2024

Schizophrenia is associated with altered DNA methylation variance.

Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls. Surprisingly, only a small proportion (0.1%) of the 213 variably methylated positions (VMPs) associated with schizophrenia (Benjamini-Hochberg FDR&#x2009;<&#x2009;0.05) were shared with differentially methylated positions (DMPs; sites with mean changes between cases and controls). These blood-derived VMPs were found to be overrepresented in genes previously associated with schizophrenia and amongst brain-enriched genes, with evidence of concordant changes at VMPs in the cerebellum, hippocampus, prefrontal cortex, or striatum. Epigenetic covariance was also observed with respect to clinically significant metrics including age of onset, cognitive deficits, and symptom severity. We also uncovered a significant VMP in individuals with first-episode psychosis (n&#x2009;=&#x2009;644) from additional cohorts and a non-psychiatric comparison group (n&#x2009;=&#x2009;633). Collectively, these findings suggest schizophrenia is associated with significant changes in DNA methylation variance, which may contribute to individual-to-individual heterogeneity.

Humans↗
PubMed2002

Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.

AIMS: Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian-based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N-dimethyltryptamine (DMT), and beta-carboline alkaloids with MAO-inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self-assessment instruments. In the present study the cerebral bioavailability and time-course of effects of ayahuasca were assessed in humans by means of topographic quantitative-electroencephalography (q-EEG), a noninvasive method measuring drug-induced variations in brain electrical activity. METHODS: Two doses (one low and one high) of encapsulated freeze-dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg(-1) body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double-blind crossover placebo-controlled clinical trial. Nineteen-lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). RESULTS: Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose-dependent increases in all subscales of the HRS, and in significant and dose-dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were -20.20+/-15.23 microV2 and -2.70+/-2.21 microV2 for total power and theta power, respectively. Relative power decreased in the delta (-1.20+/-1.31% after 120 min at P3) and theta (-3.30+/-2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta-3 (1.00+/-0.88% after 90 min at P3) and beta-4 (0.30+/-0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15-30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4-6 h after administration. CONCLUSIONS: The central effects of ayahuasca could be objectively measured by means of q-EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q-EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro-serotonergic and pro-dopaminergic drugs. The q-EEG profile supports the role of 5-HT2 and dopamine D2-receptor agonism in mediating the effects of ayahuasca on the central nervous system.

Adult↗
PubMed2001

The role of diastolic pump flow in centrifugal blood pump hemodynamics.

We tried to verify the hypothesis that increases in pump flow during diastole are matched by decreases in left ventricular (LV) output during systole. A calf (80 kg) was implanted with an implantable centrifugal blood pump (EVAHEART, SunMedical Technology Research Corp., Nagano, Japan) with left ventricle to aorta (LV-Ao) bypass, and parameters were recorded at different pump speeds under general anesthesia. Pump inflow and outflow pressure, arterial pressure, systemic and pulmonary blood flow, and electrocardiogram (ECG) were recorded on the computer every 5 ms. All parameters were separated into systolic and diastolic components and analyzed. The pulmonary flow was the same as the systemic flow during the study (p > 0.1). Systemic flow consisted of pump flow and LV output through the aortic valve. The ratio of systolic pump flow to pulmonary flow (51.3%) did not change significantly at variable pump speeds (p > 0.1). The other portions of the systemic flow were shared by the left ventricular output and the pump flow during diastole. When pump flow increased during diastole, there was a corresponding decrease in the LV output (Y = -1.068X + 51.462; R(insert)(2) = 0.9501). These show that pump diastolic flow may regulate expansion of the left ventricle in diastole.

Analysis of Variance↗
PubMed1994

Identification of T-cell receptor alpha-chain genes in the chicken.

T-cell receptor (TCR) alpha-chain (TCR alpha) and beta-chain (TCR beta) genes are well characterized in mammals, while only TCR beta genes have been identified in other vertebrates. To identify avian TCR alpha genes, we used monoclonal anti-CD3 antibodies to isolate chicken TCR alpha for peptide sequence analysis. Degenerate oligonucleotide probes were then used to isolate a candidate TCR alpha cDNA clone that hybridized with a 1.7-kb mRNA species present only in alpha beta T cells and in tissues populated by these cells. Southern blot analysis revealed gene rearrangement in thymocytes and alpha beta T-cell lines. The TCR alpha cDNA candidate encoded an open reading frame of 275 amino acids, the predicted variable (V)-, joining (J)-, and constant (C)-region amino acid sequences of which shared approximately 40%, 60%, and 25% homology with corresponding mammalian sequences. A single C alpha gene and approximately 25 V alpha genes were identified by using region-specific probes. The V alpha cDNA probe isolated from a V beta 1+ cell line reacted with transcripts from one of five V beta 2+ cell lines, suggesting shared use of V alpha genes by V beta 1+ and V beta 2+ T cells and the existence of other V alpha gene families. A genomic V alpha sequence was flanked by classical recombination signal sequences but, unlike previously defined V genes, the leader and V alpha region were encoded by a single exon. The data indicate evolutionary conservation of the basic TCR alpha gene structure in birds and mammals.

Amino Acid Sequence↗
PubMed1997

Tomographic three-dimensional reconstruction of insect flight muscle partially relaxed by AMPPNP and ethylene glycol.

Rigor insect flight muscle (IFM) can be relaxed without ATP by increasing ethylene glycol concentration in the presence of adenosine 5'-[beta'gamma- imido]triphosphate (AMPPNP). Fibers poised at a critical glycol concentration retain rigor stiffness but support no sustained tension ("glycol-stiff state"). This suggests that many crossbridges are weakly attached to actin, possibly at the beginning of the power stroke. Unaveraged three-dimensional tomograms of "glycol-stiff" sarcomeres show crossbridges large enough to contain only a single myosin head, originating from dense collars every 14.5 nm. Crossbridges with an average 90 degrees axial angle contact actin midway between troponin subunits, which identifies the actin azimuth in each 38.7-nm period, in the same region as the actin target zone of the 45 degrees angled rigor lead bridges. These 90 degrees "target zone" bridges originate from the thick filament and approach actin at azimuthal angles similar to rigor lead bridges. Another class of glycol-PNP crossbridge binds outside the rigor actin target zone. These "nontarget zone" bridges display irregular forms and vary widely in axial and azimuthal attachment angles. Fitting the acto-myosin subfragment 1 atomic structure into the tomogram reveals that 90 degrees target zone bridges share with rigor a similar contact interface with actin, while nontarget crossbridges have variable contact interfaces. This suggests that target zone bridges interact specifically with actin, while nontarget zone bridges may not. Target zone bridges constitute only approximately 25% of the myosin heads, implying that both specific and nonspecific attachments contribute to the high stiffness. The 90 degrees target zone bridges may represent a preforce attachment that produces force by rotation of the motor domain over actin, possibly independent of the regulatory domain movements.

Actins↗
PubMed2001

Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma.

Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.

Adult↗
PubMed1995

Infection with Chlamydia trachomatis lymphogranuloma venereum serovar L1 in homosexual men with proctitis: molecular analysis of an unusual case cluster.

Among 767 rectal isolates of Chlamydia trachomatis obtained from men over the period 1981-1991, 7 were found to be a rare lymphogranuloma venereum serovar, L1. These isolates were from rectal specimens taken from five male patients in 1982-1983. Six of the seven isolates were available for DNA sequencing studies. All six of these isolates shared the same DNA sequence in the major outer membrane protein (MOMP) gene variable domains and had different MOMP sequences than did the prototype L1, L2, and L3 strains, suggesting a point source outbreak. All five patients infected with serovar L-1 were homosexual men who had symptomatic proctitis characterized by rectal pain, discharge, tenesmus, abnormalities seen on anoscopy, and leukocytes seen on gram stains of rectal specimens. We conclude that an unrecognized point source outbreak of the rare chlamydial L1 serovar occurred among homosexual men in Seattle in 1982-1983, and that the clinical manifestations of L1 infection may be less severe than those of L2 infections.

Adult↗
PubMed2003

Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly.

The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huët anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states.

Animals↗
PubMed1997

Detection of clonal T cell populations with closely related T cell receptor junctional sequences in persons at high risk for human immunodeficiency virus (HIV) infection and in patients acutely infected with HIV.

The T cell repertoires were characterized for CD4+ and CD4 lymphocytes derived from 2 patients with acute human immunodeficiency virus (HIV) infection and from 25 HIV-seronegative persons at high risk for acquiring HIV. Oligoclonal expansions of CD4 cells were detected in the HIV-infected patients and in 2 of 3 uninfected high-risk subjects with a reduced number of CD4+ lymphocytes. Furthermore, nucleotide sequencing revealed that some of the T cell receptor (TCR) beta variable segments (TCRBV), which were highly selected in the high-risk subjects, shared closely related junctional sequences, with the TCRBV predominantly expanded in the HIV-infected patients. Since the likelihood that these similarities occurred by chance is extremely low, these data provide direct molecular evidence in support of several cellular and serologic studies suggesting that some persons remain uninfected despite exposure to HIV.

CD4 Lymphocyte Count↗
PubMed2003

Common and country-specific dietary patterns in four European cohort studies.

The association between diet and cancer, predominantly investigated univariately, has often been inconsistent, possibly because of the large number of candidate risk factors and their high intercorrelations. Analysis of dietary patterns is expected to give more insight than analysis of single nutrients or foods. This study aimed to develop and apply a common methodological approach to determine dietary patterns in four cohort studies originating in Finland, the Netherlands, Sweden and Italy. Food items on each of the food frequency questionnaires were aggregated into 51 food groups, defined on the basis of their position in the diet pattern and possible relevance to cancer etiology. Exploratory factor analysis was used to analyze dietary patterns. Using a standardized approach, 3-5 stable dietary patterns were identified, explaining 20-29% of total variance in consumption of the food groups. Two dietary patterns, which explained most of the variance, were consistent across the studies. The first pattern was characterized by high consumption of (salad) vegetables, the second by high consumption of pork, processed meat and potatoes. In addition, a few specifically national food patterns were identified. Sensitivity analyses showed that the identified patterns were robust for number of factors extracted, distribution of input variables and energy adjustment. Our findings suggest that some important eating patterns are shared by the four populations under study, whereas other eating patterns are population specific.

Adult↗
PubMed2002

An insight into the active site of a type I DNA topoisomerase from the kinetoplastid protozoan Leishmania donovani.

DNA topoisomerases are ubiquitous enzymes that govern the topological interconversions of DNA thereby playing a key role in many aspects of nucleic acid metabolism. Recently determined crystal structures of topoisomerase fragments, representing nearly all the known subclasses, have been solved. The type IB enzymes are structurally distinct from other known topoisomerases but are similar to a class of enzymes referred to as tyrosine recombinases. A putative topoisomerase I open reading frame from the kinetoplastid Leishmania donovani was reported which shared a substantial degree of homology with type IB topoisomerases but having a variable C-terminus. Here we present a molecular model of the above parasite gene product, using the human topoisomerase I crystal structure in complex with a 22 bp oligonucleotide as a template. Our studies indicate that the overall structure of the parasite protein is similar to the human enzyme; however, major differences occur in the C-terminal loop, which harbors a serine in place of the usual catalytic tyrosine. Most other structural themes common to type IB topoisomerases, including secondary structural folds, hinged clamps that open and close to bind DNA, nucleophilic attack on the scissile DNA strand and formation of a ternary complex with the topoisomerase I inhibitor camptothecin could be visualized in our homology model. The validity of serine acting as the nucleophile in the case of the parasite protein model was corroborated with our biochemical mapping of the active site with topoisomerase I enzyme purified from L.donovani promastigotes.

Amino Acid Sequence↗
PubMed1993

Nonhuman primate responses to murine and humanized OKT4A.

A nonhuman primate antimurine response (MAMA) has been observed in 17 cynomolgus renal allograft recipients of murine OKT 4A. Neither cyclosporine, nor total-lymphoid irradiation, nor donor bone marrow preparation inhibited this antixenogeneic response. In an attempt to alter the antimurine basis of the response, a humanized chimeric OKT4A (IgG4) containing the entire variable portion of the murine OKT4A and a humanized CDR grafted OKT4A mAb sharing only the Complementarity Determining Region from the murine OKT4A, were administered to 8 cynomolgus allograft recipients. MAMA was detected in each recipient. In contrast to sera from recipients of murine OKT4A, sera from recipients of humanized OKT4A displayed no reactivity to other murine mAbs. MAMA specificity did not assay constant (C) region differences between the murine and humanized mAb; however, C region homology in humans should preclude a human antimouse antibody (HAMA) to the Fc portion of a humanized mAb. Furthermore, cynomolgus recipient serum levels of the humanized OKT4A mAb were maintained (> 1 microgram/ml) for a longer period than following treatment with murine OKT4A (murine < 12 days versus between 12 and 24 days for the humanized). If the HAMA response to humanized mAb in future clinical trials, were to be predictably anti-idiotypic, then the opportunity for treatment with sequential mAbs of differing idiotypes would be retained. Moreover, these current studies also suggest that humanized construction may influence the duration of therapeutic mAb levels. Thus, anti-idiotypic reactivity may not be as consequential to the clinical administration of humanized mAb to allograft recipients.

Animals↗
PubMed2004

Injection risk behaviors among clients of syringe exchange programs with different syringe dispensation policies.

While there have been numerous papers published in the medical, social, and epidemiologic literature about the effectiveness of syringe exchange programs (SEPs), few papers identify operational characteristics of the SEPs they study or assess which of those characteristics are associated with optimal HIV risk reduction among clients. The objective of this study was to examine whether different syringe dispensation policies were associated with client-level injection-related HIV risk. Injection drug users (IDUs) were recruited at 23 SEPs in California in 2001 (n = 531). SEPs were classified by their executive directors as to whether they provided a strict one-for-one syringe exchange, gave a few extra syringes above the one-for-one exchange, or distributed the amount of syringes based upon need as opposed to how many syringes were turned in by the clients. Injection-related risk was compared by SEP program type. In multivariate logistic regression analysis, clients of distribution-based programs had lower odds of reusing syringes (adjusted odds ratio = 0.43; 95% CI = 0.27, 0.71) when adjusting for confounding variables. There were no statistical differences with regards to distributive or receptive syringe sharing by dispensation policy. It is concluded that SEPs that base syringe dispensation policy upon need may facilitate reductions in reuse of syringes.

California↗