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Biomedical subjects

J D Miller

Publications and source records attributed to J D Miller.

At least 109 records · Page 6Linked to original sources
PubMed1996

Analysis of Fusarium causing dermal toxicosis in marram grass planters.

In the European coastal dunes, marram grass (Ammophila arenaria) is planted in order to control sand erosion. In the years 1986 to 1991, workers on the Wadden islands in the Netherlands planting marram grass showed lesions of skin and mucous membranes, suggesting a toxic reaction. Fusarium culmorum dominated the mycoflora of those marram grass culms that were used for planting. This plant material had been cut and stored for more than one week in the open. The Fusarium toxin deoxynivalenol (DON) was detected in the suspect marram grass culms. Isolated F. culmorum strains were able to produce DON in vitro in liquid culture as well as in experimentally inoculated wheat heads. Pathogenicity tests, toxin test as well as RAPD analysis showed that the F. culmorum strains were not specialized for marram grass but may form part of the West-European F. culmorum population infecting cereals and grasses. Storage on old sand-dunes with plant debris may have led to the high occurrence of F. culmorum and contamination with DON. Marram grass culms should be obtained from young plantings on dunes on the seaward slopes and cut culms should not be stored.

Adult↗
PubMed1996

Inhibition of HIV-1 infectivity by low molecular weight heparin. Results of in vitro studies and a pilot clinical trial in patients with advanced AIDS.

Several sulfated polysaccharides have been shown to have anti-HIV activity in vitro. However, many of these compounds are not suited for use in vivo because they present an increased risk of bleeding or cannot be administered chronically. We tested the anti-HIV effects of low molecular weight heparin (LMW-heparin) (Enoxaparin) in vitro using a model system of HIV infectivity because LMW-heparin can be given to patients on a long-term basis with little risk. In vitro, LMW-heparin was shown to inhibit HIV-1 production from a T cell lymphoma line (H9) and phytohemagglutinin-stimulated lymphoblasts. Inhibition of infectivity was dose dependent at concentrations achievable in vivo. We then performed a pilot clinical trial in 13 patients with advanced AIDS of 6 months of chronic, self-administered Enoxaparin given in standard prophylactic doses. CD4 counts appeared to stabilize or increase in most patients during the first 3 months of treatment, then remained stable or declined after 6 months. There was no appreciable change in serum p24 levels. There was no evidence of drug toxicity and no bleeding episodes. These findings demonstrate that a commercially available, relatively non-toxic form of LMW-heparin is a potent inhibitor of HIV-1 production in cultured cells and that it is feasible to treat patients with AIDS with LMW-heparin on a long-term basis. Definitive clinical trials of LMW-heparins and related compounds as experimental anti-viral agents in patients with HIV infection are indicated.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Monitoring weight drop velocity and foam stiffness as an aid to quality control of a rodent model of impact acceleration neurotrauma.

Since the publication by Marmarou of a new rodent model of head injury, an increasing number of centres are adopting the model for use in a variety of paradigms. We report on two simple methods we have applied which allows us to monitor weight drop velocity and foam stiffness, both of which are critical factors for producing repeatable closed head injury with this model. We hope the application of these methods will assist in the standardisation of this model between centres.

Animals↗
PubMed1996

New insights into the mammalian circadian clock.

The focus of this review is recent studies of the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The anatomy of the SCN and its major afferents from the retina, raphe, and intergeniculate leaflet (IGL) of the thalamus are considered, with a special emphasis on the effects of afferent interaction on the circadian timekeeping system. What is known of the endogenous clock mechanism is reviewed in comparison with known molecular circadian mechanisms in other species. Efferents of the SCN are also discussed with a view toward understanding how circadian information is transmitted to the rest of the central nervous system. Where possible, anatomical, electrophysiological, neuropharmacological, molecular, and behavioral data are integrated in an attempt to illuminate the mechanisms of circadian timekeeping.

Animals↗
PubMed1996

Surgical neurology and clinical neurosciences in Edinburgh, Scotland.

Surgical neurology in Edinburgh started > 70 years ago with Norman Dott, after his apprenticeship with Harvey Cushing. It continued under the chairmanship of John Gillingham, until 1980, and then Douglas Miller, who merged the Departments of Surgical Neurology and Medical Neurology to form the Department of Clinical Neurosciences in 1986. Particular strengths of the Edinburgh program have been the management of intracranial aneurysms, stereotactic and functional neurosurgery, the management of head and spinal injury and stroke, and neuro-oncology.

History, 20th Century↗
PubMed1996

Ocular motor dysfunction in HIV-1-infected subjects: a quantitative oculographic analysis.

We recorded eye and head movements in 13 human immunodeficiency virus type-1 (HIV-1)-infected patients with CD4 counts of less than or equal to 500 cells/mm3 using magnetic search coil oculography. Horizontal and vertical saccades, smooth pursuit, and vestibular smooth eye movements were recorded, as were horizontal antisaccades and vestibular memory-guided saccades. Rightward and leftward and upward and downward responses were analyzed separately. Compared to normal control subjects, HIV-1--infected patients performed the antisaccade test poorly, making the initial antisaccade in the correct direction (away from the target) in only 33% of trials. The mean final gaze position achieved during the vestibular memory-guided saccade task was less accurate for HIV-1-infected patients than for control subjects, and this correlated with inaccuracies on the antisaccade task. Horizontal saccades, horizontal and vertical smooth pursuit, and vestibular smooth eye movements were quantitatively normal. However, smooth pursuit showed directional asymmetries, vertically more than horizontally; horizontal and vertical unpredictable saccades were more inaccurate than predictable saccades; and vertical saccade latencies were prolonged. In patients with HIV-1 infection, abnormalities in vertical eye movements and relative asymmetries in smooth pursuit gains, both horizontally and vertically, are more sensitive and consistent indicators of CNS dysfunction than are horizontal eye movement abnormalities or measurements of absolute smooth pursuit gain and phase.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The regulation of acetylated microtubules during outgrowth from cultured neurons of the snail, Helisoma.

Axonal stumps of cultured Helisoma trivolvis neurons express abundant acetylated microtubules, as a subset of total microtubules. Label completely disappears from the axonal remnants within approximately 1 day, and reappears in newly extended neurites over the course of the next 3-4 days, first in the proximal neurite as short, isolated segments. Acetylated microtubules occur in the neuritic shaft, but never in growth cones or membranous veils. Thus, acetylated microtubules are very labile to the signals generated by axotomy, and their proximodistal re-expression occurs at well separated sites within the neurite as it matures.

Acetylation↗
PubMed1995

An amino-terminal domain containing hydrophobic and hydrophilic sequences binds the signal recognition particle receptor alpha subunit to the beta subunit on the endoplasmic reticulum membrane.

The signal recognition particle receptor consists of two subunits of 72 kDa (SR alpha) and 30 kDa (SR beta). Assembly of SR alpha on the endoplasmic reticulum membrane can occur independent of the signal recognition particle-mediated translocation pathway. To identify the sequences within SR alpha necessary for membrane binding, a series of amino-terminal and internal deletion mutants was constructed and translated in a cell-free system. In addition, nascent SR alpha polypeptides of varying lengths were generated by cycloheximide treatment of translation reactions. Microsome binding assays performed on these polypeptides revealed a membrane binding domain consisting of the amino-terminal 140 residues of SR alpha. This domain includes the two hydrophobic sequences originally proposed to bind to membranes and a highly charged region not previously implicated in membrane assembly. Furthermore, the domain forms a protease-resistant folding unit that after proteolysis can target and anchor onto microsomes. Extraction of microsomal SR alpha at high pH supplemented with 1 M NaSCN suggests that SR alpha and the membrane binding domain are not integrated in the endoplasmic reticulum membrane. The membrane binding domain is also the major site of tight binding with SR beta, suggesting that SR beta plays a role in the membrane assembly of SR alpha.

Amino Acid Sequence↗
PubMed1995

Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer's disease.

Previous studies have demonstrated the immunolocalization of perlecan, a specific heparan sulfate proteoglycan, to the beta-amyloid protein (A beta)-containing amyloid deposits within the walls of blood vessels (i.e., congophilic angiopathy) in Alzheimer's disease (AD) brain. In the present investigation, the differential binding of previously characterized endothelial cell (EC)- and smooth muscle cell (SMC)-derived PGs to A beta was examined to determine whether the accumulation of A beta in cerebrovascular amyloid deposits may be due to its interactions with perlecan. Pretreatment of AA amyloidotic splenic and liver tissue sections with synthetic A beta (1-28) produced strong immunoreactivity with A beta antibodies at tissue sites enriched in perlecan which was partially removed by pretreatment with heparitinase, but not by chondroitin ABC lyase. [35S]-Sulfate labeled proteoglycans (PGs) derived from cultured ECs and SMCs bound to affinity columns containing A beta (1-28) or (1-40), with virtually no binding to A beta (40-1) (reverse peptide), beta-amyloid precursor protein (410-429), or bovine serum albumin. Characterization of EC and SMC PGs bound to A beta (1-28) revealed strong binding by perlecan, weak binding by decorin and biglycan, two dermatan sulfate proteoglycans, and lack of binding by versican/PG-M, a large chondroitin sulfate proteoglycan. Binding of 125I-labeled perlecan to A beta (1-28) was strongly inhibited by isolated perlecan and to a lesser extent by heparin, but not by chondroitin-6-sulfate or unsulfated dextran sulfate. Heparitinase treatment decreased, but did not eliminate the binding of 125I-labeled perlecan to A beta (1-28). Scatchard analysis of the interaction of A beta (1-28)- and EC-derived perlecan in solid-phase assays indicated high-affinity (Kd = 8.3 x 10(-11) M) and lower-affinity (Kd = 4.2 x 10(-8) M) binding sites, with approximately 1 mol of perlecan binding 1.8 mol of A beta. A significant decrease in binding of EC-derived perlecan to A beta (1-28) was observed when a sequence within the putative heparin-binding motif of A beta (His13His14Gln15Lys16) was replaced by the uncharged peptide sequence, Gly13Gly14Gln15Gly16, indicating a perlecan binding site on A beta near the postulated alpha-secretase site (at Lys-16). Overall, the results indicate that specific vascular cell-derived PGs differentially interact with A beta, and that the interactions of highest affinity occur between A beta and binding sites on both the core protein and glycosaminoglycan chains of perlecan.(ABSTRACT TRUNCATED AT 400 WORDS)

Alzheimer Disease↗
PubMed1995

Phytotoxic effect of deoxynivalenol and gibberella ear rot resistance of corn.

The Fusarium graminearum mycotoxin deoxynivalenol was shown to be more phytotoxic to corn genotypes susceptible to gibberella ear rot than resistant genotypes. The toxin caused greater damage to the membranes of the susceptible genotypes, as evidenced by the release of Na and K ions into solution. Isolated protoplasts of ear rot-resistant genotypes were able to bind more radiolabelled deoxynivalenol than those of susceptible genotypes, providing a partial explanation for the membrane tolerance to the toxin. The results are discussed in relation to the role of resistance to this phytotoxin and tolerance to gibberella ear rot.

Binding Sites↗
PubMed1995

Nicotine phase-advances the circadian neuronal activity rhythm in rat suprachiasmatic nuclei explants.

In vivo studies reported that cholinergic agents affect mammalian circadian rhythmicity. To study phase resetting properties of cholinergic compounds more directly, we carried out experiments in rat suprachiasmatic nuclei slices. Compounds were added to the perfusate for 1 h at specific phases of the circadian cycle. On the following day, the time of peak neuronal activity, a measure of the phase of the endogenous circadian pacemaker, was assessed by means of extracellular recording in the suprachiasmatic nuclei. The peak of neuronal activity occurred at circadian time 5.8 +/- 0.7 (mean +/- 95% confidence limits) in the control slice (circadian time 0: lights-on). Ten-micromolar carbachol had no effect on the phase of the circadian rhythm when given at circadian times 6 and 15, while at circadian time 21 a phase advance of one hour was observed. By contrast, 10 microM nicotine significantly phase advanced (> 1 h) the neuronal circadian rhythm at all but one experimental circadian phase. The circadian times of maximal nicotinic phase advances were 15 (+2.6 h) and 21 (+2.8 h). A concentration response curve for nicotine was generated and pharmacological blocking experiments were performed at circadian time 15. The estimated maximum response of nicotine was 3.4 h, and the estimated concentration for half maximal response was 5 microM. The Hill coefficient (= 1.08) indicated that the effects of nicotine may be explained by a single receptor occupancy model. Mecamylamine (20 microM) almost completely antagonized the nicotinic phase-advances, whereas tetrodotoxin (1 microM) or high Mg2+ (10 mM) did not significantly attenuate the nicotinic phase-advances.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Bioactive isocoumarins and related metabolites from conifer endophytes.

Six new [1-4, 7, 9] and two known [6 and 8] metabolites have been isolated from culture filtrates of conifer endophyte strains of Canoplea elegantula. Their structures have been determined by spectroscopic means. Compound 1 was toxic to spruce budworm cells, and both 1 and 3 were toxic to spruce budworm larvae.

Animals↗
PubMed1995

The beta subunit of the signal recognition particle receptor is a transmembrane GTPase that anchors the alpha subunit, a peripheral membrane GTPase, to the endoplasmic reticulum membrane.

The signal recognition particle receptor (SR) is required for the cotranslational targeting of both secretory and membrane proteins to the endoplasmic reticulum (ER) membrane. During targeting, the SR interacts with the signal recognition particle (SRP) which is bound to the signal sequence of the nascent protein chain. This interaction catalyzes the GTP-dependent transfer of the nascent chain from SRP to the protein translocation apparatus in the ER membrane. The SR is a heterodimeric protein comprised of a 69-kD subunit (SR alpha) and a 30-kD subunit (SR beta) which are associated with the ER membrane in an unknown manner. SR alpha and the 54-kD subunits of SRP (SRP54) each contain related GTPase domains which are required for SR and SRP function. Molecular cloning and sequencing of a cDNA encoding SR beta revealed that SR beta is a transmembrane protein and, like SR alpha and SRP54, is a member of the GTPase superfamily. Although SR beta defines its own GTPase subfamily, it is distantly related to ARF and Sar1. Using UV cross-linking, we confirm that SR beta binds GTP specifically. Proteolytic digestion experiments show that SR alpha is required for the interaction of SRP with SR. SR alpha appears to be peripherally associated with the ER membrane, and we suggest that SR beta, as an integral membrane protein, mediates the membrane association of SR alpha. The discovery of its guanine nucleotide-binding domain, however, makes it likely that its role is more complex than that of a passive anchor for SR alpha. These findings suggest that a cascade of three directly interacting GTPases functions during protein targeting to the ER membrane.

Amino Acid Sequence↗
PubMed1995

Middle cerebral artery blood flow velocity in patients with cirrhosis.

BACKGROUND: Brain dysfunction is common in patients with advanced liver disease; it is often manifested as hepatic encephalopathy, but its cause is not clearly understood. METHODOLOGY: Intracranial blood flow velocity parameters, including peak systolic velocity, end diastolic velocity and mean velocity of both middle cerebral arteries were measured by transcranial Doppler ultrasonography in 37 patients with cirrhosis without encephalopathy (16 Child's A, 10 Child's B and 11 Child's C) and 12 normal controls. The cause was alcohol-related in 24 and non-alcohol-related in 13. RESULTS: No significant differences in any of the Doppler parameters were detected in Child's group A when compared with controls. However, a statistically significant decrease in middle cerebral artery blood flow velocity was evident when Child's B and C patients without clinically apparent encephalopathy were compared with controls irrespective of the cause. Our results demonstrate that intracranial blood flow is abnormal in patients with advanced liver disease without clinically apparent encephalopathy.

Analysis of Variance↗