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Biomedical subjects

S Vinogradov

Publications and source records attributed to S Vinogradov.

At least 19 recordsLinked to original sources
PubMed2002

Inducing neutrophil recruitment in the liver of ICAM-1-deficient mice using polyethyleneimine grafted with Pluronic P123 as an organ-specific carrier for transgenic ICAM-1.

Coordinated expression of cell adhesion molecules and chemokines on the surface of vascular endothelium is responsible for the homing of immune effector cells to targeted sites. One way to attract non-activated immune cells to targeted organs is to use transgenically expressed adhesion molecules responsible for leukocyte recruitment. We have previously shown that polyethyleneimine (PEI) grafted with non-ionic amphiphilic Pluronic P123 block copolymer (P123PEI) modifies biodistribution of plasmid DNA toward the liver. In the present study, a P123PEI-formulated plasmid carrying the gene encoding for the murine ICAM-1 molecule was injected i.v. into transgenic ICAM-1-deficient mice. The RT-PCR analysis of ICAM-1 mRNA expression showed that P123PEI induced a dose-dependent expression of ICAM-1 in the liver. Furthermore, this expression of ICAM-1 induced neutrophil invasion in the liver, while no such invasion was observed in mice injected with formulated control plasmid or naked DNA. These results suggest that P123PEI allows functional transgene expression in the liver following i.v. injection and that ICAM-1 could be used to enhance immune response locally by attracting immune effector cells.

Animals↗
PubMed2001

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.

Bipolar Disorder↗
PubMed2001

Protein and gene structure of a chlorocruorin chain of Eudistylia vancouverii.

The polychaete annelid, Eudistylia vancouverii, contains as oxygen carrier a hexagonal bilayer (HBL) chlorocruorin. One of the globin chains, chain a1, has 142 amino acids (Mr 16,054.99) and its sequence deviates strongly from other nonvertebrate globin sequences. Unprecedented, it displays a Phe at the distal position E7 as well as at position B10, creating a very hydrophobic heme pocket probably responsible for the low oxygen affinity of the native molecule. Phylogenetic analysis of annelid globin chains clearly proves that globin chain a1 belongs to type I of globin chains having a pattern of 3 cysteine residues essential for the aggregation into a HBL structure. The gene coding for globin chain a1 is interrupted by 2 introns at the conserved positions B12.2 and G7.0. Based on protein and gene structure it can therefore be concluded that the globin chains of chlorocruorins are not fundamentally different from other annelid globin chains.

Amino Acid Sequence↗
PubMed2000

The functional relevance of affect recognition errors in schizophrenia.

To evaluate the clinical and ecological validity of affect recognition (AR) measures in a sample of community-dwelling schizophrenic outpatients (N = 40), we analyzed the relation of facial and vocal AR to intellectual, symptomatic, and quality-of-life criteria. Facial and vocal AR showed virtually identical patterns of association with these criteria, suggesting that both modalities of AR draw on the same underlying heteromodal capacity. Specifically, AR was correlated with a subset of intellectual abilities (verbal-semantic, executive-attentional), but was unrelated to age, education, or neuroleptic dose. In terms of clinical and ecological criteria, AR errors correlated with more severe psychotic symptoms (positive and disorganized) and with lower quality of life (relationships, community participation, and richness of intrapsychic experience). Even after controlling for subjects' intellectual abilities and illness severity, inaccurate AR was associated with bizarre behaviors (involving sociosexual interactions, clothing, appearance) and with impoverished interpersonal relations. Thus, while difficulty identifying basic affective cues is related to general cognitive and illness-severity factors, it appears to have specific functional implications that do not depend on generalized impairment. Assessment of AR may identify a subgroup of schizophrenic patients who have a central defect in the heteromodal monitoring of emotional-social displays, associated with dysregulation of social behaviors and disruption of interpersonal relations.

Adult↗
PubMed1999

Independent frontal-system deficits in schizophrenia: cognitive, clinical, and adaptive implications.

This study examined whether frontal-system impairments in schizophrenia occur independently of one another and whether they have distinct implications for information processing, symptom severity, and adaptive functioning. We assessed 26 medication-free schizophrenic outpatients and 18 normal control subjects on eight frontally mediated tasks, semantic information processing, IQ, the BPRS, and long-term psychosocial adaptation. Schizophrenic subjects showed three types of deficits, which were uncorrelated with one another: (1) Executive dysfunction (inflexible problem solving) was related to decreased use of expectancy during controlled semantic priming, lower intelligence, more severe negative symptoms and stereotyped mannerisms. (2) Disinhibition of responses (to irrelevant stimuli) was associated with increased automatic priming, a trend for more severe hallucinations, and was unrelated to intelligence. (3) Motor dyscoordination (inaccurate, dysfluent motor sequencing) was not related to semantic processing, intelligence, or symptoms. Furthermore, all three impairments were unrelated to generalized slowness, age, sex, illness length, or pre-washout neuroleptic dose. Two deficits accounted for aspects of long-term psychosocial adaptation, even after statistical correction for IQ: Executive dysfunction was associated with younger illness onset, poor purposefulness and planning, impaired social relations, and lower global functioning. Motor dyscoordination was associated with poor treatment outcome and restricted educational advancement. Furthermore, executive and motor deficits interacted significantly; subjects who had both deficits showed the least favorable treatment outcome. These findings are neither consistent with generalized impairment nor with a unitary 'frontal syndrome' in schizophrenia. They provide preliminary evidence for at least three frontal-system deficits (dorsolateral, orbital, and premotor), which are dissociable from one another, can occur without general intellectual impairment, and have distinct implications for long-term adaptive functioning.

Adaptation, Psychological↗
PubMed1999

Reduction of fibronectin expression by intravitreal administration of antisense oligonucleotides.

We have investigated whether antisense oligonucleotides delivered intravitreally could reduce gene expression specifically in the retina. In this study, phosphorothioate antisense oligonucleotides targeted to fibronectin transcripts were coupled to a novel carrier and used to specifically reduce fibronectin (FN) expression in retinal vascular cells. Using confocal microscopy, fluorescence from fluorescein isothio-cyanate-labeled FN-oligonucleotides was detected in retinal vascular cells at 24 h postinjection and persisted until day 6 (the end point of this study). The fibronectin mRNA level was consistently decreased to 86.7% +/- 7.9% of control (p<0.05) at day 2, and 46.7% +/- 4.9% of control (p<0.01) at day 6. In contrast, the beta-actin mRNA level, an internal control, was unaltered in rat retinas that received FN-oligonucleotides. Fibronectin protein level at day 6 was also significantly reduced to 61.4% +/- 16% of control (p<0.01). No toxic effect resulting from the carrier was detected histologically. Thus, intravitreal delivery of antisense oligonucleotides to modulate abnormal gene expression in retinal diseases may be an effective approach for ocular gene therapy.

Animals↗
PubMed1999

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.

Bipolar Disorder↗
PubMed1998

Slower and more variable reaction times in schizophrenia: what do they signify?

Extensive research has demonstrated that schizophrenic subjects are slower than normal comparison subjects on a range of reaction-time tasks. Some investigators have also observed that schizophrenic patients exhibit larger intraindividual variability in reaction times when performing these tasks than do normal comparison subjects. This study, using a lexical decision choice reaction time (CRT) task, explored the relation of mean CRT and it intra-individual variability (CRT-SD) to psychiatric symptoms and to performance on executive-motor tasks in 26 medication-free schizophrenic out-patients and 17 normal comparison subjects. Schizophrenic subjects had both significantly slower and more variable CRTs which were unrelated to general intellectual abilities (IQ). Among schizophrenic subjects, both CRT and CRT-SD were significantly related to severity of psychotic symptoms, failure to maintain cognitive set, and poorer motor coordination and global functioning. After controlling for mean CRT, CRT-SD showed unique covariation with clinical symptoms (positive, disorganized and tension/hostility). Conversely, mean CRT showed unique covariation with the failure to maintain cognitive set and with stereotypic mannerisms, independent of CRT-SD. These results suggest that slower CRT and increased intra-individual variability in CRT, while not fully independent of one another, may reflect separate aspects of symptomatic and cognitive dysfunction in schizophrenia.

Adult↗
PubMed1997

Automatic versus controlled semantic priming in schizophrenia.

Schizophrenic individuals (n = 31), including paranoid and nonparanoid diagnostic subgroups, and normal controls (n = 20) participated in a semantic priming experiment involving a single-choice lexical decision task. For the automatic priming blocks, a 260-ms stimulus onset asynchrony (SOA) was used; for the controlled priming blocks, 1,000-ms SOA was used. The paranoid subgroup showed significantly less priming than did the control group. The nonparanoid subgroup showed a decrease in priming compared with the control group that approached significance. There was an increased priming effect for the controlled compared with the automatic priming condition; this difference was not modulated by participant group. Nonsignificant semantic priming (equal to 0) occurred only for schizophrenic subgroups and only in automatic priming conditions.

Adult↗
PubMed1997

Intravascular oxygen distribution in subcutaneous 9L tumors and radiation sensitivity.

Phosphorescence quenching was evaluated as a technique for measuring PO2 in tumors and for determining the effect of increased PO2 on sensitivity of the tumors to radiation. Suspensions of cultured 9L cells or small pieces of solid tumors from 9L cells were injected subcutaneously on the hindquarter of rats, and tumors were grown to between 0.2 and 1.0 cm in diameter. Oxygen-dependent quenching of the phosphorescence of intravenously injected Pd-meso-tetra-(4-carboxyphenyl) porphine was used to image the in vivo distribution of PO2 in the vasculature of small tumors and surrounding tissue. Maps (512 x 480 pixels) of tissue oxygen distribution showed that the PO2 within 9L tumors was low (2-12 Torr) relative to the surrounding muscle tissue (20-40 Torr). When the rats were given 100% oxygen or carbogen (95% O2-5% CO2) to breathe, the PO2 in the tumors increased significantly. This increase was variable among tumors and was greater with carbogen compared with 100% oxygen. Based on irradiation and regrowth studies, carbogen breathing increased the sensitivity of the tumors to radiation. This is consistent with the measured increase in PO2 in the tumor vasculature. It is concluded that phosphorescence quenching can be used for noninvasive determination of the oxygenation of tumors. This method for oxygen measurements has great potential for clinical application in tumor identification and therapy.

Administration, Inhalation↗
PubMed1997

Clinical and neurocognitive aspects of source monitoring errors in schizophrenia.

OBJECTIVE: Source monitoring, an aspect of memory that involves judgments about the origin of information, has been found to be more prone to errors in schizophrenic subjects than in normal persons. To examine the precise nature of such errors and their relationship to clinical and neurocognitive variables, the authors compared schizophrenic and normal subjects. METHOD: Schizophrenic subjects who had been medication free for 1 week (N = 26) and demographically matched normal subjects (N = 21) performed a source monitoring task and were assessed on current psychiatric symptoms, IQ, and frontal lobe functioning. RESULTS: The schizophrenic subjects had normal recognition memory of target words (recognition hits) and a normal generation effect but made more errors than the comparison subjects in identifying the source of target words. Specifically, the schizophrenic subjects made more errors in remembering the source of new and self-generated items, and they tended to attribute items to an external source. In 11 retested subjects, these errors were stable and independent from medication status after a 2-year interval. Secondary analyses suggested that certain source monitoring errors may be associated with hostility and lower IQ. When the effect of IQ was controlled, correlations with frontal dysfunction were not significant. CONCLUSIONS: Schizophrenic subjects make significantly more source monitoring errors than normal subjects, but not because of problems with recognition memory hits or with the generation effect. This tendency may be trait like and may be related to hostility. Lower IQ in schizophrenia plays a partial role in these errors, but frontal dysfunction does not.

Adult↗
PubMed1997

Decreased left frontal lobe N-acetylaspartate in schizophrenia.

OBJECTIVE: The authors measured N-acetylaspartate (a putative neuronal marker), using in vivo proton magnetic resonance spectroscopic imaging (1H-MRSI), in the frontal lobes of schizophrenic patients and normal subjects. METHOD: Frontal lobe 1H-MRSI was performed bilaterally on 24 medicated schizophrenic patients and 15 healthy comparison subjects. Levels of N-acetylaspartate, creatine, and choline were determined. RESULTS: Relative to the comparison group, the patients with schizophrenia demonstrated significantly lower levels of N-acetylaspartate in the left frontal lobe. There was no association between level of N-acetylaspartate and duration of illness or medication dosage. No differences between groups or lateralized asymmetries in choline or creatine were noted. CONCLUSIONS: This preliminary study provides support for decreased N-acetylaspartate in the left frontal lobe in schizophrenia and neuronal dysfunction in this brain region.

Adult↗
PubMed1996

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees.

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

Bipolar Disorder↗
PubMed1996

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees.

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging from recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals.

Bipolar Disorder↗