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Biomedical subjects

G Miller

Publications and source records attributed to G Miller.

At least 235 records · Page 13Linked to original sources
PubMed1992

Early onset autosomal dominant progressive muscular dystrophy presenting in childhood as a Becker phenotype--the importance of dystrophin and molecular genetic analysis.

We present two cases of autosomal dominant limb girdle muscular dystrophy in a father and son. Both presented in childhood with a classical Becker muscular dystrophy phenotype. The father had initially been informed that he would not have affected children. After the diagnosis of muscular dystrophy in the son, immunoblot analysis was performed on muscle and revealed normal dystrophin. The polymerase chain reaction did not show any deletions in the dystrophin gene, and the father's dystrophin gene was not passed to his son. These cases demonstrate that autosomal dominant muscular dystrophy may present in childhood, and that dystrophin and molecular genetic analyses should be performed when considering the diagnosis of childhood muscular dystrophy, even in the presence of a classical phenotype.

Child↗
PubMed1992

A study of evoked potentials in the 18q-syndrome which includes the absence of the gene locus for myelin basic protein.

We report evoked potential findings in a patient with 18q-syndrome (18q22.3----qter). The deletion included the locus for myelin basic protein (MBP). Clinical manifestations were mild intellectual deficit, involuntary movements and ataxia. MRI of the brain showed diffusely abnormal white matter. Visual evoked responses were normal. Central conduction was prolonged on median somatosensory evoked potentials and no central response was seen with posterior tibial somatosensory potentials. Putative congenital deficiency of MBP does not necessarily cause abnormal visual evoked responses.

Adult↗
PubMed1992

Transcriptional synergy by the Epstein-Barr virus transactivator ZEBRA.

ZEBRA is an Epstein-Barr virus (EBV) transcriptional activator that mediates a genetic switch between the latent and lytic states of the virus by binding to the promoters of genes involved in lytic DNA replication and activating their transcription. A computer survey revealed that 9 of 23 potential or known ZEBRA-responsive EBV genes contained two or more upstream binding sites; this suggested that ZEBRA can stimulate transcription synergistically. By using a series of synthetic promoters bearing one, two, three, five, and seven upstream recognition sites, we showed that ZEBRA activates transcription synergistically when templates bearing multiple sites were compared with a template bearing a single site. This phenomenon was observed in both uninfected and EBV-infected B-lymphoid cells and in vitro in a HeLa cell nuclear extract. DNase I footprinting was used to show that the synergy was not due to cooperative DNA binding mediated by direct contact between ZEBRA dimers. The in vitro experiments revealed two manifestations of synergy. One was seen when the levels of transcription observed with the same amounts of ZEBRA added to templates bearing different numbers of sites were compared. The other was observed when the two lowest concentrations of ZEBRA that stimulated measurable transcription from any given template were compared. On the basis of both the number of sites and the calculated Kd of ZEBRA for a single site, we estimated that the critical concentration of ZEBRA needed to elicit transcriptional synergy corresponds to a site occupancy of two or three bound ZEBRA dimers. Our results have biologic implications for both the EBV lytic cycle and other processes in which the concentration of an activator changes either temporally or spatially.

Base Sequence↗
PubMed1992

Glycogen depletion-induced lactate reductions attenuate reflex responses in exercising humans.

Post leg exercise circulatory arrest (PLE-CA) raises blood pressure (BP) and reduces peak forearm vascular conductance (C). This reflex is evoked by activation of muscle afferents that are often sensitive to lactic acid. We tested the hypothesis that lactic acid reductions induced by muscle glycogen depletion would attenuate the lower-limb metaboreceptor-mediated pressor and forearm vasoconstrictor responses. Eleven subjects had C measured (plethysmography) during post leg exercise circulatory arrest (PLE-CA) (supine bicycle exercise for 9 min, 10 s at 75% VO2max before and after undergoing a glycogen-depletion paradigm (24-h fast followed by 10 min of supine leg exercise at 75% VO2max). In six subjects with lower lactate values, C during PLE-CA was higher after glycogen depletion (0.39 +/- 0.05 vs. 0.21 +/- 0.01 ml.min-1.100 ml-1 x mmHg-1; P < 0.01) and BP was lower (113 +/- 6 vs. 128 +/- 6 mmHg, P < 0.01). In five subjects without attenuated lactate responses, C and BP during PLE-CA were not different. Muscle biopsies (n = 5) demonstrated that the paradigm lowered muscle glycogen concentrations. Thus glycogen depletion-induced reductions in muscle lactate are associated with reduced muscle metaboreceptor-mediated responses.

Adult↗
PubMed1992

Dystrophin in frameshift deletion patients with Becker muscular dystrophy.

In a previous study we identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. We have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases we detected slightly lower-molecular-weight dystrophin in 12%-15% abudance relative to the normal. By sequencing amplified mRNA we have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternative splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame.

Adolescent↗
PubMed1991

Inhibition of growth of HT-29 human colon cancer xenografts in nude mice by treatment with bombesin/gastrin releasing peptide antagonist (RC-3095).

Nude mice bearing xenografts of HT-29 human colon cancer cell line were treated for 4 weeks with a [D-Trp6] agonist of luteinizing hormone releasing hormone (LH-RH), somatostatin analogue (RC-160), and bombesin/gastrin releasing peptide antagonist (RC-3095). Some inhibitory effect of [D-Trp6] LH-RH microcapsules releasing 25 micrograms/day on tumor growth was observed that could be due to sex steroid deprivation, but the inhibition was not statistically significant. Microcapsules of RC-160, releasing 50 micrograms/day, significantly reduced tumor volume after 21 and 24 days of treatment, but at the end of the experiment the inhibition in tumor volume and weight was not significant. Bombesin/gastrin releasing peptide antagonist RC-3095, at a dose of 20 micrograms/day administered by daily s.c. injections or by continuous infusion using Alzet osmotic minipumps, had the greatest inhibitory effect on tumor growth. Tumor volume, percentage change in tumor volume, and tumor weights were significantly decreased in both groups treated with RC-3095. This is the first report on inhibition of human colon cancer growth in vivo by bombesin antagonists.

Animals↗
PubMed1991

Relation between HIV-1 syncytium inhibition antibodies and clinical outcome in children.

Syncytium formation, a feature of HIV-1-induced cytopathology, allows the virus to propagate through cell-to-cell spread. An assay has been developed to measure antibodies (syncytium inhibition, SI) that inhibit this process. Two cell lines were used: the indicator cells, which are not HIV-1 infected, bear CD4 receptors on their surface; the fusogenic HIV-1 infected cells, which do not release virus but are responsible for initiating syncytium formation, are free of CD4 receptors. Co-cultivation of about 10(5) of each of these cells induces the emergence of 70-100 multinucleated giant cells within 48 h. Sera from 34 children born to HIV-1-infected mothers were tested by western blot (WB) and SI assay. SI antibodies were detected in the blood of 15 (65%) of 23 WB-positive children and in none of 11 WB-negative children. There were striking differences in prevalence and titre of SI antibodies in children with lymphocytic interstitial pneumonitis (LIP) compared with those with opportunistic infections (OI). All 8 children with LIP had SI antibodies ranging in titre from 40 to greater than 320. By contrast, only 2 of 7 with OI had SI antibodies, in both of whom the SI titre was 20 (p less than 0.05). No sera from children who had seroreverted contained SI antibodies. The findings point to the need to identify the specific HIV-I peptides or epitopes responsible for syncytium formation since SI antibodies correlate with clinical outcome in children.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Elimination of clonogenic tumor cells from bone marrow using methylprednisolone (MP) and etoposide VP16: an in vitro pharmacologic study.

The ability to eliminate malignant cells from bone marrow (BM) while retaining sufficient numbers of normal progenitors to ensure engraftment, may well establish the future of autologous BM transplantation (ABMT) for hematologic malignancies. In this study, we describe the effects of methylprednisolone (MP) and etoposide (VP16) alone or in combination on 5 tumor cell lines (HL-60, a promyelocytic cell line; Molt-4, a T cell leukemia; Daudi, a Burkitt's lymphoma and R10/8226 and R40/8226, doxorubicin-resistant myeloma cell lines). The tumor cell kill efficiency of the drugs was assayed using the limiting dilution assay. We determined the toxic effect on progenitor cells by assaying granulocyte-macrophage colony-forming units (CFU). With a combination of MP at 10(-3) M and VP16 at 75 microM, we observed the following log reduction in tumor cell clones: HL-60, 4.695 +/- 0.001; Molt-4, 3.626 +/- 0.036; Daudi, 5.633 +/- 0.001; R10/8226, 3.052 +/- 0.544; R40/8226, 3.126 +/- 0.080. CFU recovery was 24% +/- 5%. Mixing tumor cell lines with a 20-fold excess of normal irradiated BM cells did not eliminate the inhibitory effect of the drug combination. We propose that MP and VP16 used in concert produce effective purging of malignant hematopoietic cells from BM while sparing normal progenitors needed for engraftment.

Antineoplastic Agents↗
PubMed1991

Cerebro-ocular dysplasia--muscular dystrophy (Walker Warburg) syndrome. Findings in 20-week-old fetus.

A 20-week fetus affected with cerebro-ocular dysplasia and muscular dystrophy (Walker-Warburg Syndrome) is reported. The central nervous system (CNS) findings were typical of those previously described in this disorder, and were characterized by lissencephaly, hydrocephalus, and cerebral and cerebellar cortical dysplasia with glial and neuronal displacement into the leptomeninges. In addition, severe hypoplasia of pyramidal tracts were noted in the brain stem and spinal cord, as well as malformation of the inferior olivary and dentate nuclei. Skeletal muscle and eyes appeared normal on light microscopy. The genetic defect in this disorder is expressed in the CNS early during the first trimester and causes a marked disorder of cellular migration. Overt changes in muscle occur during a later period. The changes in the CNS are similar to, but more severe than, those found in Fukuyama congenital muscular dystrophy, and both may represent a failure of constraint of neuronal migration. Whether the syndromes characterized by cerebro-ocular dysplasia and muscular dystrophy are genetically heterogeneous or allelic variations is unknown. Molecular genetic analysis should elucidate this question.

Brain↗
PubMed1991

Comparative increases of lead and barium with age in human tooth enamel, rib and ulna.

Lead and Ba in postmortem tooth enamel, rib and ulna of six contemporary people (67-96 years; ave. 80) were shown to exhibit similar accumulations with age in the three different types of osseous tissue: Pb/Ca (wt) = 3.0, 5.2, and 3.9 x 10(-5) in rib, ulna, and tooth enamel; and Ba/Ca (wt) = 2.4, 2.4, and 1.8 x 10(-5) in rib, ulna, and tooth enamel, respectively. Mean concentrations of Pb were 11, 19, and 14 micrograms g-1 in rib (ash), ulna (ash), and enamel (dry), respectively. Means for Ba were 8.7, 8.9, and 6.4 micrograms g-1 in rib (ash), ulna (ash), and enamel (dry), respectively. Comparison of Ba in ulna of our 80-year-old subjects with Ba determined by other investigators in bones of younger contemporary populations indicated that Ba accumulates with age at about half the rate of Pb accumulation in bone. Concentrations of Ba in rib, ulna and enamel were positively correlated and similar within an individual, but varied among subjects in proportion to variations in absorptive uptake in portal blood. Barium may diffuse from a blood-dentine source into enamel, where it replaces Ca and accumulates with age. Because of extreme Pb pollution of our 80-year-old subjects and its variation of intake with age, the correlation of Pb in tooth enamel with Pb in bone was more scattered than for Ba. It is shown by means of stable Pb isotopic tracers that: (i) among the three types of osseous tissue, the residence time of Pb is longest in enamel, where it apparently accumulates with age by diffusion with little loss through exchange; and (ii) the residence time of Pb is longer in compact ulna than in trabecular rib, as it accompanies Ca in its osteoblastic transfer from blood to bone and then in its osteoclastic transfer back to blood from bone.

Aged↗
PubMed1991

Training coaches to observe and remember.

This study tested a video training method that was intended to improve the observational skills of soccer coaches. Three groups of soccer coaches were tested prior to and following a training period. The experimental group was exposed to a video training programme that was designed to highlight certain key elements of soccer team performance. Although both control groups were exposed to the same video excerpts as the experimental group, they were given different orienting activities. The subjects in control group 2 were asked to discuss these excerpts with a colleague and then write a report on what they had seen, while control group 1 members repeated prior test conditions that required them to remember certain events that preceded the scoring of goals. The results indicate that, although all coaches were incapable of remembering more than 40% of pertinent information, the subjects in the experimental group improved their ability to recall all events that surrounded the 'taking of shots'.

Adult↗
PubMed1991

Single-stranded structures are present within plasmids containing the Epstein-Barr virus latent origin of replication.

The Epstein-Barr virus (EBV) latent origin of plasmid replication (oriP) contains two essential regions, a family of repeats with 20 imperfect copies of a 30-bp sequence and a dyad symmetry element with four similar 30-bp repeats. Each of the repeats has an internal palindromic sequence and can bind EBNA 1, a protein that together with oriP constitutes the only viral element necessary for EBV maintenance and replication. Using single-strand-specific nucleases, we have probed plasmids containing oriP-derived sequences for the presence of secondary structural elements. Multiple single-stranded structures were detected within the oriP region. Of the two essential elements of oriP, the family of repeats seemed to extrude these structures at a much higher frequency than did sequences within the dyad symmetry region. Though negative supercoiling was found to stabilize the single-stranded structures, they showed significant stability even after linearization of the oriP plasmids. Two major single-stranded structures detected involved approximately 12 bp of DNA. These loci could be transiently unwound regions that form because of negative supercoiling and the high A + T content of this region of DNA, or they could be cruciform structures extruded within the palindromic sequences of oriP that may be important sites for protein-DNA interactions in the EBV oriP.

Antigens, Viral↗