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Biomedical subjects

R G Mills

Publications and source records attributed to R G Mills.

At least 19 recordsLinked to original sources
PubMed1992

Solution structure of endothelin-3 determined using NMR spectroscopy.

The aqueous solution structure of the 21-residue vasoactive peptide hormone endothelin-3 has been determined using high-resolution NMR spectroscopy. A total of 177 proton-proton distance measurements and 5 chi 1 dihedral angle constraints derived from NMR spectra were used to calculate the structure using a combination of distance geometry and dynamical simulated annealing calculations. The calculations reveal a highly ordered, compact conformation in which a helical region extending from K9 to C15 lies in close apposition with the C-terminal hexapeptide; this interaction seems to be largely driven by hydrophobic interactions. Structure-activity studies are interpreted in terms of the conformational features of the calculated endothelin-3 structure.

Amino Acid Sequence↗
PubMed1992

Prediagnostic malakoplakia presenting as a chronic inflammatory mass in the soft tissues of the neck.

Malakoplakia presenting in the head and neck is very rare. We present a case of an inflammatory mass in the neck, clinically mimicking actinomycosis in a 67-year-old man. Repeated culture of E. coli and histological and electron microscopic examination of biopsy material showed an infiltration of granular macrophages and intracellular gram negative bacilli, but no classical Michaelis-Gutmann bodies. The clinical and pathological findings and criteria for the diagnosis of malakoplakia are discussed.

Aged↗
PubMed1992

Early viral brain invasion in iatrogenic human immunodeficiency virus infection.

We report a 68-year-old man who received an IV inoculation of WBCs for an indium radionuclide scan containing 600 to 700 tissue culture infectious doses of human immunodeficiency virus type 1 (HIV-1) from an HIV-1-infected individual. The recipient immediately received zidovudine, then was switched to dideoxyinosine and interferon-alpha, but died of hepatorenal syndrome and hepatic encephalopathy 15 days later. HIV-1 cultures were positive from the recipient's blood on day 14 but not days 0, 1, and 8. At autopsy, cultures of parietal lobe isolated HIV-1. HIV-1 nucleic acid was present in several brain areas, but not in several other organs, by two independent laboratories using the polymerase chain reaction. The brain showed mild perivascular cuffing and a mild lymphocytic meningitis, but there was no evidence of glial nodules, giant cells, or white matter abnormalities. HIV-1 pg41 viral antigen was seen by immunoperoxidase staining in rare infiltrating cells within perivascular and subpial spaces. Thus, HIV-1 was isolated from brain 15 days after mistaken HIV-1 inoculation and 1 day after virus was first recovered from blood.

Aged↗
PubMed1991

Conformation of sarafotoxin-6b in aqueous solution determined by NMR spectroscopy and distance geometry.

The solution structure of sarafotoxin-6b in water has been determined using high-resolution NMR spectroscopy. 127 proton-proton distance measurements and three phi dihedral angle constraints derived from NMR spectra were used to calculate the solution structure using a combination of distance geometry and restrained molecular dynamics. The major structural feature of the resulting family of five structures was a right-handed alpha-helix extending from K9 to Q17. In contrast, the C-terminal region of the peptide appears not to adopt a preferred conformation in aqueous solution. The present structure is compared with those previously determined for endothelin peptides in non-aqueous solvents.

Amino Acid Sequence↗
PubMed1991

Transport complexes associated with slow axonal flow.

Cytoskeletal proteins--neurofilament polypeptides, tubulin and actin--are transported along axons by slow transport. How or in what form they are transported is not known. One hypothesis is that they are assembled into the cytoskeleton at the cell body and transported as intact polymers down the axon. However, recent radiolabeling and photobleaching studies have shown that tubulin and actin exist in both a mobile phase and a stationary phase in the axon. Consequently, it is more likely that cytoskeletal proteins move along the axon in some form of transport complex and are assembled into a cytoskeleton which is stationary. In this overview we discuss these topics and consider the evidence for the existence of transport complexes associated with slow axonal flow. Such evidence includes the slow transport of particulate complexes containing tubulin and neurofilament polypeptides along reconstituted microtubules in vitro, and the coordinate slow transport of actin with actin-binding proteins in vivo.

Actins↗
PubMed1991

Response to beta-blockers in maternal and fetal rat hearts in vitro.

The effects of beta-blockers on maternal and fetal heart rates have been assessed by comparing isoprenaline concentration-heart rate relationships of hearts isolated from pregnant rats. The normal and maximal heart rates obtained for the maternal and fetal hearts were similar to published data. A slightly but significantly higher concentration of isoprenaline was required to produce 50% of the maximal response of fetal hearts than maternal hearts, suggesting that fetal hearts were less sensitive to isoprenaline than the maternal hearts. The beta-blockers used (propranolol, labetalol, metoprolol and atenolol) all showed a lower affinity to the beta-receptors of fetal hearts than those of maternal hearts, as indicated by significant differences in the pA2 values. Given the similar effects of the beta-blockers in the maternal and fetal hearts it is concluded that pharmacokinetic considerations and beta-blocker selectivity should be used as the basis of choice when treating maternal hypertension during pregnancy.

Adrenergic beta-Antagonists↗
PubMed1991

Inhibition of human immunodeficiency virus type I replication by derivatives of gossypol.

Gossypol (I) and its derivatives gossylic nitrile-1,1'-diacetate (II), gossylic iminolactone (III) and gossylic lactone (IV) inhibit the replication of human immunodeficiency virus type 1 in vitro in the order III greater than I greater than II,IV, indicating that derivatives of gossypol can retain antiviral activities. All of the derivatives are less cytotoxic than gossypol.

Antiviral Agents↗
PubMed1990

Effects of electrical stimulation and tetrodotoxin paralysis on antigenic properties of acetylcholine receptors in rat skeletal muscle.

To examine the role of muscle activity in the expression of fetal- and adult-type acetylcholine receptors (AChRs), we studied the effects of muscle stimulation in cell culture and of tetrodotoxin (TTX)-induced paralysis and denervation in adult rat muscles. The AChR content of these muscles was determined using [125I]alpha-bungarotoxin and the proportion of fetal-type receptors was estimated using a radioimmunoprecipitation assay with a myasthenic serum that was highly specific for fetal-type receptors. We found that both stimulated, aneural muscle cells in vitro and inactive muscles in vivo produced predominantly fetal-type AChRs. However the TTX-paralysed muscles had a lower proportion of fetal-type receptors than the denervated muscles. We conclude that neither muscle activity nor innervation alone, but a combination of both, is required for full regulation of AChR antigenicity.

Animals↗
PubMed1990

Does progeria provide the best model of accelerated ageing in humans?

Studies of the causes of ageing are often obscured by the complexity of this phenomenon, hindering investigations in this area. In particular, the variable characteristics of ageing complicate analysis at a molecular level. It is proposed that to gain insight into ageing, the problem must first be simplified by restricting studies to an aspect of the ageing processes. It is suggested that progeria, which presents a less complicated etiology and phenotype than other accelerated ageing diseases, allows research to focus on a regulation site involved in development and ageing.

Aging↗
PubMed1989

Glucose inhibition of human fibroblast proliferation and response to growth factors is prevented by inhibitors of aldose reductase.

Diabetes mellitus is associated with premature senescence of cultured dermal fibroblasts. The present study investigated the effect of elevated glucose concentrations on cultured human fibroblasts from normal donors. Mean population doubling times, population doublings until senescence, saturation density at confluence (cells/cm2), tritiated thymidine incorporation, and response to platelet-derived growth factor (PDGF) were inhibited with the increasing glucose concentrations (11.0, 22, 44, or 55 mM glucose) (P less than 0.05). Replicative life span was markedly diminished by multiple passages in high glucose medium (5.5 mM glucose: 62.4 +/- 7.9 population doublings; 22 mM glucose: 22.8 +/- 3.4 population doublings: P less than 0.05). Aldose reductase activity was present in the cultured fibroblasts (3.9 +/- 0.5 nmol/min per mg protein), and inhibitors of aldose reductase, including sorbinil (10(-4) M--10(-6) M) and tolrestat (10(-6) M--10(-8) M), completely prevented glucose-mediated inhibition of fibroblast proliferation, restored the response to PDGF, and allowed a normal replicative life span. Myo-inositol (11 microM--5.5 mM) also reversed the adverse effects of glucose. These in vitro data demonstrate that elevated concentrations of glucose inhibit cell growth and promote premature senescence, effects which can be prevented with inhibitors of aldose reductase or supplemental myo-inositol. These aldose reductase-related effects may explain the impaired growth and premature senescence of cultured connective tissue from diabetic patients.

Aldehyde Reductase↗
PubMed1986

Does the precommissural fornix excite neurons in the cat dorsal septum which project to the medial preoptic region?

The possibility that effects of fornix stimulation on units in the medial preoptic region (MPO) may be via an interposed neuron in the dorsal septum was investigated using electrophysiological techniques. We found a reciprocal monosynaptic linkage between the MPO and the dorsal, medial and fimbrial septal nuclei. When recording in the MPO, stimulation of the dorsal septum affected 59% of spontaneously active units. Of all MPO units synaptically excited by stimulation of the dorsal septum 33% also had an input from the fornix. When recording in the dorsal septum during stimulation of the MPO and fornix, units synaptically driven by, or antidromically invaded following MPO stimulation, were found in caudal regions of the DS and units excited by stimulation of the fornix were located in more rostral regions. Units excited by stimulation of the fornix were never antidromically invaded following stimulation in the MPO, so there was no direct pathway for fornix excitation in the dorsal septum to reach the MPO.

Action Potentials↗
PubMed1985

Distribution of osmosensitive cells in the preoptic and adjacent regions of cat brains.

The response of neurons in the preoptic and adjacent regions of the brain to intracarotid injection of hyperosmotic solutions was studied in 22 anesthetized cats. NaCl (0.5 M) caused a brisk acceleration of frequency lasting over 100 s in 120 of 207 units (58%). Glucose (2 M) and sucrose (2 M) had similar but smaller effects, and urea (2 M) was ineffective. Responding units were found in all parts of the preoptic region, the diagonal band of Broca (vertical limb), the lateral septal nucleus, nucleus accumbens and anterior hypothalamus.

Animals↗
PubMed1984

Cellular ions in intact and denervated muscles of the rat.

Tissue composition, membrane potentials and cellular activity of potassium, sodium and chloride have been measured in innervated and denervated rat skeletal muscles incubated in vitro. After denervation for 3 days, tissue water, sodium and chloride were increased but cellular potassium content and measured activity were little affected, despite a decrease of 16 mV in resting membrane potential which would have necessitated a decrease in cellular potassium activity of almost 50% were potassium distributed at electrochemical equilibrium. These findings, therefore, preclude a decreased electrochemical potential gradient for potassium as the cause of the membrane depolarization characteristic of denervated muscle fibers. Analysis of the data excludes an important contribution of rheogenic sodium transport to the resting potential of innervated muscles. These results strongly support the hypothesis that the decreased membrane potential in denervated fibers reflects a relative increase in the membrane permeability to sodium.

Animals↗
PubMed1979

A slow-release technique for inducing prolonged paralysis by tetrodotoxin.

A technique is described for the slow-release of tetrodotoxin in peripheral nerves using a constriction capillary. The capillary, which was implanted under the epineurium of the sciatic nerve, released tetrodotoxin from a 25 micrometer pore. Nerve block was complete after approximately 20 min and lasted 6--9 days. Replacement of the capillary enabled paralysis of the rat hindlimb to be maintained for periods of 21 days and longer. Studies with radioactively labelled compounds demonstrated that the efflux rate from the capillary was dependent on the size of the pore and the relative molecular mass of the compound.

Animals↗
PubMed1979

Responses in the diagonal band of Broca evoked by stimulation of the fornix in the cat.

1. Field potentials were recorded within the boundaries of the septal component of the diagonal band of Broca following stimulation of the fornix. The position of the recording electrode was marked by pressure injection of Alcian blue dye. 2. Stimulation of the medial aspect of the ipsilateral fornix produced a simple field caudally consisting of a short duration, short latency negative wave (N1) and a later small prolonged positive wave (P1). It is suggested that N1 is due to antidromic activation of the cells and P1 to their recurrent inhibition. 3. In the rostral part of the septal component of the diagonal band of Broca the field pattern was more complex, containing, in addition to N1 and P1, further negative waves, N2 and N3. N2 was compounded of antidromically and synaptically evoked components and N3 was associated with monosynaptic excitation of the cells. 4. Stimulation of the lateral margin of the fornix was shown to excite antidromically and synaptically the same cells as were excited by stimulation of the medial aspect of the fornix. 5. Stimulation of the medial and lateral aspects of contralateral fornix generated positive waves of similar character to P1. 6. Intracarotid injection of hyperosmotic saline solution caused behavioural signs of arousal and inhibition of spontaneous discharge in a third of the units tested. Spontaneously discharging units (mean frequency +/- S.E. of mean, 13.4 +/- 1.8, n = 55) were inhibited by stimulation of the medial and lateral ipsilateral and contralateral fornix. It is suggested that inhibitory interneurones receive contra- and ipsilateral input. Units with these characteristics were found. 7. The septal component of the diagonal band of Broca was compared with other septal nuclei and found to resemble them in its rostral portion in that it has a reciprocal relationship with ventral and dorsal hippocampus. The caudal portion is unique in the cells project to dorsal and ventral hippocampus but there is no reciprocal projection.

Animals↗
PubMed1979

The trophic influence of tetrodotoxin-inactive nerves on normal and reinnervated rat skeletal muscles.

1. Nerve impulses in the rat sciatic nerve were blocked for long periods by tetrodotoxin (TTX) released from capillary implants. The TTX capillaries did not block axonal transport, nor did they cause any sign of nerve degeneration. 2. A comparison of the effects of TTX paralysis and denervation was made on both extensor digitorium longus (e.d.l.) and soleus muscles over 21 days, a time when the products of nerve degeneration were unlikely to contribute to the changes associated with denervation. The resting membrane potential of TTX-paralysed muscles was significantly different (P less than 0.005) from that of the denervated muscles at all periods and at 21 days the decrease that can be attributed to inactivity was 61% (e.d.l.) and 49% (soleus) of that which follows denervation. This disparity was even more pronounced for the ACh receptor density where the increase in receptors due to inactivity was only 34% (e.d.l.) and 21% (soleus) of that due to denervation. 3. A similar comparison was made on muscles which had been reinnervated by TTX-inactive nerves. These muscles were found to have a significantly higher resting membrane potential and lower ACh receptor density than the denervated muscles (P less than 0.05). 4. The experiments on reinnervated muscles preclude the possibility that nerve degeneration products are solely responsible for the difference between the TTX-paralysed and denervated muscles and suggest that the difference can be attributed to the trophic influence of the nerve. 5. An observed increase in the m.e.p.p. frequency of the TTX-paralysed muscles indicated that nerve action potentials play a role in regulating the spontaneous release from nerve terminals.

Acetylcholine↗