Biomedical subjects

G G Brown

Publications and source records attributed to G G Brown.

At least 37 records · Page 2Linked to original sources

PubMed1997

Chemically synthesized SDF-1alpha analogue, N33A, is a potent chemotactic agent for CXCR4/Fusin/LESTR-expressing human leukocytes.

Stromal cell-derived factor (SDF) 1 is a potent chemoattractant for leukocytes through activation of the receptor CXCR4/Fusin/LESTR, which is a fusion co-factor for the entry of T lymphocytotropic human immunodeficiency virus type 1 (HIV-1). This CXCR4-mediated HIV-1 fusion can be inhibited by SDF-1. Because of its importance in the study of immunity and AIDS, large scale production of SDF-1 is desirable. In addition to recombinant technology, chemical synthesis provides means by which biologically active proteins can be produced not only in large quantity but also with a variety of designed modifications. In this study, we investigated the binding and function of an SDF-1alpha analogue, N33A, synthesized by a newly developed native chemical ligation approach. Radioiodinated N33A showed high affinity binding to human monocytes, T lymphocytes, as well as neutrophils, and competed equally well with native recombinant SDF-1alpha for binding sites on leukocytes. N33A also showed equally potent chemoattractant activity as native recombinant SDF-1alpha for human leukocytes. Further study with CXCR4/Fusin/LESTR transfected HEK 293 cells showed that N33A binds and induces directional migration of these cells in vitro. These results demonstrate that the chemically synthesized SDF-1alpha analogue, N33A, which can be produced rapidly in large quantity, possesses the same capacity as native SDF-1alpha to activate CXCR4-expressing cells and will provide a valuable agent for research on the host immune response and AIDS.

Binding, Competitive↗

PubMed1997

An open reading frame for a protein involved in cytochrome c biogenesis is split into two parts in Brassica mitochondria.

A plant mitochondrial gene with sequence similarity to ccl1, a bacterial gene involved in cytochrome c biogenesis, occurs as a single open reading frame in wheat, Oenothera, carrot and Marchantia mtDNAs. In Brassica napus "Polima" or Brassica campestris mtDNA, however, this open reading frame is split into two segments that are located 60 kb apart on the master-circle form of the genome. Although transcripts of the split ORF are edited in a manner similar to that of a functional gene, transcripts that span both portions of the ORF are not evident in gel-blot hybridization experiments. Low-abundance transcripts that span both portions of the split ORF can be detected by RT-PCR, but these contain an additional 54-bp sequence, inserted between the two segments, that is unrelated to the corresponding sequences of other plants. Since this additional sequence introduces an in-frame stop codon, no transcripts have been found that could be translated to yield a protein product of a size similar to that present in other plant species. An antiserum directed against the product of the corresponding wheat gene detects polypeptides of similar size in wheat and Brassica mitochondria. This antiserum, however, immunoprecipitates a labelled polypeptide from the products of wheat, but not Brassica, in organello protein synthesis. Gel-blot analysis of total Brassica DNA indicates that sequences capable of hybridizing with the ORF are present in the nuclear genome. We suggest that the functional form of the Brassica gene may reside in the nucleus.

Amino Acid Sequence↗

PubMed1997

Brassica nap cytoplasmic male sterility is associated with expression of a mtDNA region containing a chimeric gene similar to the pol CMS-associated orf224 gene.

Two different cytoplasmic male-sterility (CMS) systems, nap and pol, are found in the oilseed rape (canola) species Brassica napus. Physical mapping studies have previously shown that organizational differences between the sterile pol and fertile cam mitochondrial genomes are restricted to a relatively small region immediately upstream of the atp6 gene. An approximately 4.5-kb pol mtDNA segment containing a chimeric open reading frame (orf224) co-transcribed with atp6 is missing from cam mtDNA and located at a different site on nap mtDNA; expression of the orf224/atp6 gene region is highly correlated with the pol CMS trait. Sequence analysis now shows that the transposed nap segment contains an open reading frame (ORF) related to, but distinct from, pol orf224. This open reading frame (orf222) potentially encodes a protein of 222 amino acids possessing 79% sequence similarity to the predicted product of the pol orf224 gene. nap orf222 is co-transcribed with the third exon of the trans-spliced nad5 gene and another ORF. orf222 transcripts are several times more abundant in nap CMS than in fertility restored nap-cytoplasm plants and qualitative transcript differences for the region between CMS and restored plants are found as well. Expression of the orf222/nad5c/orf139 region is specifically correlated with nap CMS: of 21 mitochondrial gene regions examined, including all the sites of rearrangement between the nap and fertile cam mitochondrial genomes and 22 known genes, only the orf222/nad5c/orf139 region detected transcript differences between maintainer cam cytoplasm, nap CMS- and fertility restored nap cytoplasm-plants. Our results suggest that expression of the orf222/nad5c/orf139 region may be associated with nap CMS, and, more generally, that different forms of CMS may be associated with genes encoding structurally similar proteins.

Amino Acid Sequence↗

PubMed1997

The maize mitochondrial plasmid RNA b is associated with protein during synthesis but is not encapsidated.

RNA b is the most abundant member of a family of autonomously replicating single- and double-stranded RNA plasmids found in maize mitochondria. The extent to which this molecule is associated with proteins was investigated by rate zonal and CsCl equilibrium density gradient centrifugation of clarified lysates of S cytoplasm maize mitochondria. A soluble complex of RNA b, responsible for synthesis of the more abundant (+) RNA b strand in mitochondrial lysates, was identified. The complex had a buoyant density of 1.49 g/cm3, indicating a substantial non-nucleic acids content. The sedimentation coefficient of the complex, however, was only slightly larger than that of deproteinized RNA b. Synthesis of RNA b as well as the larger RNA plasmid, RNA a, was resistant to heparin, suggesting that, for both RNAs, preformed complexes between an RNA template and an RNA-dependent RNA polymerase capable of elongating in vivo preinitiated RNA plasmid strands, were present in the lysate. Only a small fraction of RNA b molecules were bound in the complex; the bulk of RNA b sedimented at the same rate as the deproteinized RNA. Thus, after replication, maize mitochondrial plasmids are not associated with nucleoprotein capsids although their synthesis takes place through ribonucleoprotein replication complexes.

Centrifugation, Zonal↗

PubMed1997

Depression and memory in the elderly: a meta-analysis.

A meta-analysis (N = 40) of the effects of depression on memory in the elderly (sample mean age > or = 55 years) examined variables potentially accounting for divergent findings in the literature. The distribution of effects was bimodal and the effect sizes were heterogeneous. Compared to controls, groups containing unipolar subjects only were significantly less impaired than were mixed unipolar-bipolar; five of six studies mixing depression subtype were associated with the more negative mode. Samples containing younger depressed subjects (< 45 years) were significantly more impaired and were associated with the more negative mode. Significant group differences were found between studies matching their comparison groups reasonably well on years of education and those that did not. Thoroughness of dementia screening yielded no group differences. Although correlated observations precluded significance tests, larger effects were found for (1) figural (vs. verbal) memory; (2) delayed (vs. immediate) memory; and (3) recognition (vs. free recall and incidental or cued recall; incidental and cued recall effects were nearly identical). Similar effects were found for composite memory scores versus constituent and for various presentation paradigms (e.g., single presentation, selective reminding). Effect sizes for these categories were in the moderate range. Difficulties synthesizing this literature are discussed as are suggested remedies and directions for future research.

Aged↗

PubMed1997

Gulf War veterans: a neuropsychological examination.

Eighty-two Persian Gulf War veterans seen in clinic were referred for neuropsychological evaluation. Relatedness of neuropsychological and neurological functioning to subjective complaint, exposure, a clinical signs index, and possible interference variables was examined in a subsample of 49 who completed assessment. The subsample was representative of the entire group with respect to symptom severity. Variables representing sustained attention, grip strength, motor coordination, vibratory sense, finger-tip number writing perception, executive functioning, memory functioning, and subjective complaint were considered. Neuropsychological performance appeared to be more related to emotional functioning than demographic variables or variables associated with the war. Individual differences may be contributing to different emotional reactions to illnesses, perceptions of exposure risks and cognitive functioning, and responses to stress.

Adult↗

PubMed1997

Occupational exposures to metals as risk factors for Parkinson's disease.

In a population-based case-control study, we investigated the potential role of occupational exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and controls (n = 464) consisting of men and women > or =50 years of age, frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-control status of subjects, rated occupational exposure to each of the metals of interest. When adjusted for sex, race, age, and smoking status, we found in those with more than 20 years' exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06, 5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association with PD than with any of these metals alone. These findings suggest that chronic exposure to these metals is associated with PD, and that they may act alone or together over time to help produce the disease.

Aged↗

PubMed1996

Psychiatric sequelae of low birth weight at 6 years of age.

The study examined the association between low birth weight (LBW) (< or = 2,500 g) and attention deficit hyperactivity disorder (ADHD) in two socioeconomically disparate populations. LBW and normal birth weight (NBW) children from the 1983 to 1985 newborn lists of an urban and a suburban hospital in Southeast Michigan were randomly selected. A total of 823 children, 473 LBW and 350 NBW, participated. Data were gathered in 1990 to 1992, when the children were 6 to 7 years of age. The National Institute of Mental Health Diagnostic Interview Schedule for children-Parent version (DISC-P) was used to elicit information on DSM-III-R diagnoses of simple phobia, overanxious, separation anxiety, oppositional defiant, and ADHD. Teachers' ratings of behavior problems were obtained. LBW was associated with ADHD but not with childhood anxiety disorders or oppositional defiant disorder. The association was stronger in the urban than in the suburban population. Data from teachers' ratings revealed an association between LBW and attention problems. The prognostic significance of the observed psychopathology at 6 years of age requires follow-up assessment as the children mature.

Attention Deficit Disorder with Hyperactivity↗

PubMed1996

Vascular pathology in three cases of progressive cognitive deterioration.

The clinical condition known as vascular dementia remains poorly defined. Few studies have attempted a correlative link between the clinical syndrome and the structural abnormalities of the brain. Classically the clinical progression of the vascular dementing process is thought to be a multi-step process punctated by repeated episodes of ischemia, that are clinically expressed as strokes. In most instances it has been assumed that the substrate of vascular dementias consists of atherothrombotic infarcts. The objective of this report is to illustrate 3 cases of progressive (rather than stepwise) cognitive deterioration without clinical evidence of stroke, evolving over a period of several years, in which there were prominent vascular lesions. A complete autopsy and detailed neuropathologic examination demonstrated cerebral vascular lesions involving small arterial vessels (< 200 microns in diameter). The lesions consisted of moderate-to-severe arteriolosclerosis in two cases, and mild-to-moderate arteriolosclerosis in a case of Alzheimer's disease with severe cerebral amyloid angiopathy. Parenchymal lesions consisted of small cortical and subcortical infarcts, most of them smaller than 0.1 cm in average diameter, and subcortical leukoencephalopathy severe in two cases and mild-to-moderate in the third case. Severe atherosclerosis not accompanied by large infarcts was also present in one case. Arterial changes affecting small, distal branches causing sometimes small parenchymal lesions in association with diffuse cerebral white matter disease, appear to be the anatomical substrate that accompanies progressive cognitive impairment in some patients who are frequently diagnosed with Alzheimer's disease because in their clinical records there is neither history of strokes nor stepwise progression of symptoms.

Aged↗

PubMed1996

Impaired set-shifting in Parkinson's disease: new evidence from a lexical decision task.

On a lexical decision (LD) task, participants quickly decide whether a target letter string is a word. When a target word (e.g., CARROT) is preceded by a category cue (e.g., VEGETABLE), participants respond more quickly than when the target is preceded by a semantically neutral cue (e.g., BLANK). Previously, Spicer, Brown, and Gorell (1994) reported that patients with PD, when tested with a variation of Neely's (1977) LD task, showed hyperpriming. That is, patients with PD exhibited a larger difference in reaction time between the neutral cue and category prime conditions than did controls. The present study found little evidence that PD hyperpriming was explained by difficulties accessing semantic information. Rather, hyperpriming appeared to be related to a general tendency among a subgroup of patients with PD to perseverate.

Aged↗

PubMed1996

Nuclear genes associated with a single Brassica CMS restorer locus influence transcripts of three different mitochondrial gene regions.

Previous studies have shown that the mitochondrial orf224/atp6 gene region is correlated with the Polima (pol) cytoplasmic male sterility (CMS) of Brassica napus. We now extend this correlation by showing that the effects of nuclear fertility restoration on orf224/atp6 transcripts cosegregate with the pol restorer gene Rfp1 in genetic crosses. We also show, however, that the recessive rfp1 allele, or a very tightly linked gene, acts as a dominant gene, designated Mmt (modifier of mitochondrial transcripts), in controlling the presence of additional smaller transcripts of the nad4 gene and a gene possibly involved in cytochrome c biogenesis. A common sequence, TTGTGG, maps immediately downstream of the 5' termini of both of the transcripts specific to plants with the Mmt gene and may serve as a recognition motif in generation of these transcripts. A similar sequence, TTGTTG, that may be recognized by the product of the alternate allele (or haplotype), Rfp1, is found within orf224 just downstream of the major 5' transcript terminus specific to fertility restored plants. Our results suggest that Rfp1/ Mmt is a novel nuclear genetic locus that affects the expression of multiple mitochondrial gene regions, with different alleles or haplotypes exerting specific effects on different mitochondrial genes.

Base Sequence↗

PubMed1995

Genetic correlation of the orf224/atp6 gene region with Polima CMS in Brassica somatic hybrids.

To identify regions of the mitochondrial genome from the polima or pol male-sterile cytoplasm of Brassica napus that are genetically correlated with cytoplasmic male sterility (CMS) we analyzed mtDNAs of three male-sterile somatic hybrids formed by the fusion of broccoli (B. oleracea L. var. italica) and pol CMS B. napus protoplasts. Fragments characteristic of a 4.5 kb DNA segment that comprises the single organizational difference between sterile pol and fertile cam Brassica mitochondrial genomes were found in all three sterile somatic hybrids. One of these hybrids possessed a mitochondrial genome that was, apart from a limited region around this 4.5 kb CMS-associated segment, collinear with B. oleracea mtDNA. Previous studies have indicated that expression of transcripts spanning the atp6 gene and a chimeric gene, orf24, located on this 4.5 kb DNA segment, is associated with male sterility. The present results indicate that the orf224/atp6 gene region is genetically correlated with male sterility and provide significant additional support for the view that this gene region may be involved in specifying the CMS trait.

Brassica↗

PubMed1995

Neurobehavioral and physiologic effects of trifluoromethane in humans.

Nuclear magnetic resonance (NMR) imaging shows promise in the measurement of human cerebral blood flow (CBF) in that nonradioactive indicators may be used. Our earlier investigations with trifluoromethane (FC-23) gas have shown that this compound can be used to safely and effectively measure CBF in anesthetized animal models. In this Phase I dose-escalation study we set out to determine the maximal tolerated concentration (MTC) of FC-23 in normal healthy male volunteers and to assess its feasibility as an NMR indicator. Five subjects were exposed in a blinded fashion to escalating concentrations of FC-23 between 10% and 60%, randomly interleaved with exposures to both room air and 40% nitrous oxide. On each study day, the subjects breathed the test gas for eight pulses of 3 min each with 2-min clearance periods between the pulses. The subjects underwent intensive physiologic and neurobehavioral monitoring throughout the study period. The first subject experienced an anesthetic response to 60% FC-23, and the second subject experienced "discomfort" and requested discontinuation at the initiation of 40% FC-23. The MTC was subsequently determined to be 30% FC-23 (all subjects tolerated the gas), although a small (37.6 vs. 40.5) but statistically significant retention of carbon dioxide was found (p = .003). When one subject received 30% FC-23 during an NMR imaging study, a pronounced anesthetic effect with intolerable hyperacusis was demonstrated. Human studies of FC-23 have been discontinued in our laboratory.

Administration, Inhalation↗

PubMed1995

Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease.

Elevated iron levels in the substantia nigra (SN) of the brain in Parkinson's disease (PD) may mediate lipid peroxidative reactions, promoting SN neuronal death. To assess SN iron accumulation in living PD patients and its relation to motor performance, we measured, in 13 nondemented PD patients and 10 normal control subjects, simple reaction time (SRT) and simple movement time (SMT), followed by head MRI in a 3-tesla system. We measured T2 and T2* in the right and left SN of all subjects and calculated R2', the relaxation rate due to local magnetic field in-homogeneities, from these values. Asymmetries of 1/T2 (R2), 1/T2* (R2*), or R2' versus asymmetries of SRT and SMT were assessed in eight PD subjects who had not taken anti-PD medication(s) for 12 hours. The average of right and left SN values for R2 was lower, and R2* and R2' were higher, in PD patients than in controls (R2, p = 0.046; R2*, p = 0.001; R2', p < 0.001). R2' best predicted group differences. The asymmetry of SRT performance was highly correlated with asymmetries of SN R2* (0.91; p = 0.001) and R2' (0.72; p = 0.03). These results strongly suggest that the increases in iron levels seen postmortem in the SN in PD are reflected in increased iron-related MRI contrast at 3 tesla in living PD patients. Correlations with motor performance in PD suggest that the clinical severity of PD may be related to SN iron accumulation.

Adult↗

PubMed1994

RNA editing of transcripts of a chimeric mitochondrial gene associated with cytoplasmic male-sterility in Brassica.

The orf224 gene is a chimeric open reading frame associated with the Polima or pol cytoplasmic male sterility of Brassica napus. The first 58 codons and 5' upstream region of orf224 are derived from a conventional mitochondrial gene, orfB, while the origin of the remaining portion of the gene is unknown. Transcripts of the orf224 gene were found to be edited at a single site in the region of the gene that does not correspond to a known sequence. Oligonucleotides corresponding to the edited and unedited forms were shown to hybridize specifically to respective in vitro orf224 transcripts. Analysis of floral mtRNA by this method indicated that virtually all orf224 transcripts of both sterile and fertile, nuclear-restored pol cytoplasm plants are edited. Our results indicate that transcripts of novel, CMS-associated genes may be edited, but that, at least in this case, the degree of editing does not appear to be directly related to the male-sterile phenotype.

Amino Acid Sequence↗

PubMed1994

A gradient relationship between low birth weight and IQ at age 6 years.

OBJECTIVE: To test for a suspected adverse effect of low birth weight (< or = 2500 g) on IQ at age 6 years in two socioeconomically disparate populations. DESIGN: Nonconcurrent prospective study. SETTING: An urban, predominantly disadvantaged population and a suburban middle-class population in southeastern Michigan. PARTICIPANTS: Low-birth-weight (N = 473) and normal-birth-weight (N = 350) subjects, randomly selected from the 1983 through the 1985 newborn lists of two major hospitals, one serving an urban and the other a suburban population. MAIN OUTCOME MEASURES: The Wechsler Intelligence Scale for Children-Revised to measure IQ. RESULTS: The mean full-scale IQ of low-birth-weight children was 4.9 points lower than that of normal-birth-weight children, controlling for population site, maternal IQ, maternal education, and race (95% confidence interval [CI], 3.0 to 6.8). There was no evidence of low-birth-weight interaction with population site, and the same IQ difference was detected in both populations. In the urban population, low birth weight was associated with an increased risk for IQ below 85 (odds ratio, 2.2; 95% CI, 1.3 to 3.7). In the suburban population, low birth weight was associated with an increased risk for IQ below 100 (odds ratio, 2.0; 95% CI, 1.2 to 3.4). A gradient relationship with full-scale IQ was observed, with the largest deficit in those born weighing 1500 g or less, an intermediate deficit in those born weighing 1501 through 2000 g, and the least pronounced deficit in those born weighing 2001 through 2500 g. CONCLUSIONS: The overall effect of low birth weight represents an increase of approximately 10% of low-birth-weight children with an IQ of more than 1 SD below the population's mean. Children born weighing 2000 g or less bore the major burden of the IQ deficits.

Child↗

PubMed1994

Using a computer model to explore impairments of acquisition processes following ingestion of diazepam.

Hypotheses about the information processes impaired in diazepam-induced amnesia were tested by fitting the output from a computer simulation of list learning to observed serial position curves and to overt rehearsal protocols. Twenty-four subjects received an average weight-relative dosage of 0.18 mg/kg oral diazepam; 24 subjects received placebo. Immediate free recall of 16-word lists was examined at 2- and 8-s presentation times. Subjects receiving diazepam recalled significantly fewer words than placebo subjects (diazepam = 6.77 +/- 2.39 words; placebo = 9.29 +/- 1.42 words); their memory impairment was greater at the 8-s than 2-s presentation time. Tests of nonlinear regression models based on computer simulations of list learning performance were consistent with the hypothesis that diazepam reduces rehearsal capacity and disrupts the formation or utilization of contextual and inter-item associations. Among these causes of diazepam-induced amnesia, the disruption of contextual associations appears most important. The results further suggest that quantitative modeling of memory data may complement traditional methods of inferring relationships between brain processes and cognitive dysfunction in amnesic states.

Adult↗

PubMed1994

Lexical decision in Parkinson disease: lack of evidence for generalized bradyphrenia.

Twenty-two nondemented patients with idiopathic Parkinson disease (PD) and 22 controls completed a lexical decision task for which the expected relationship between primes and targets was manipulated. Both reaction times and movement times were measured. PD subjects were as effective as controls in utilizing the priming cues to reduce their reaction times compared with a neutral condition. This facilitation occurred even at the shortest stimulus onset asynchrony employed (300 ms), and was observed in a condition requiring a shift of attention, suggesting that PD patients experience no general cognitive slowing and no difficulty efficiently shifting attention to a specified semantic category. The degree of facilitation was significantly greater in the PD group in several comparisons, indicating hyperpriming. Finally, expectancy primes facilitated movement times in the PD group only. Although the results do not support the existence of generalized bradyphrenia in nondemented Parkinson disease, the hyperpriming effect and correlational analyses involving vocabulary scores and choice reaction time do raise the possibility of a subtle semantic processing deficit or an impairment of strategic decision-making in PD.

Aged↗