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Biomedical subjects

A M Robertson

Publications and source records attributed to A M Robertson.

At least 19 recordsLinked to original sources
PubMed2002

Comparison of a new pmp22 transgenic mouse line with other mouse models and human patients with CMT1A.

Charcot-Marie-Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene. The My41 strain has a severe phenotype consisting of unstable gait and weakness of the hind limbs that becomes obvious during the first 3 weeks of life. My41 mice have a shortened life span and breed poorly. Pathologically, My41 mice have a demyelinating peripheral neuropathy in which 75% of axons do not have a measurable amount of myelin. We compare the peripheral nerve pathology seen in My41 mice, which carry the mouse pmp22 gene, with previously described transgenic mice over-expressing the human PMP22 protein and Trembler-J (TrJ) mice which have a P16L substitution. We also look at the differences between CMT1A duplication patients, patients with the P16L mutation and their appropriate mouse models.

Animals↗
PubMed2000

Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin.

Mucin desulfation is believed to be a rate-limiting step in mucin degradation by colon bacteria. The activities of enzymes hydrolysing nine linkages found in mucin oligosaccharide chains were measured using model substrates, in extracts of two mucin-degrading bacteria, Prevotella strain RS2 and Bacteroides fragilis. Sulfatases desulfating N-acetylglucosamine-6-sulfate, galactose-6-sulfate and galactose-3-sulfate were found. The genomic DNA downstream from the gene encoding the mucin-desulfating sulfatase (N-acetylglucosamine-6-sulfatase) in Prevotella was sequenced, and two putative genes identified which are likely to be coexpressed with this sulfatase, though their activities are unknown. Northern and Western analyses showed that expression of this short operon of three genes is increased during growth on mucin.

Animals↗
PubMed2000

Protein restriction for diabetic renal disease.

OBJECTIVES: To determine whether protein restriction slows or prevents progression of diabetic nephropathy towards renal failure. SEARCH STRATEGY: Computerised databases MEDLINE (1976-1996) and EMBASE (1974-1996) were searched using keywords diabetes mellitus, diabetic nephropathy, dietary proteins, diet, protein restricted and uremia. Recent issues of selected journals (Diabetic Medicine, Diabetologia, Diabetes Care, Kidney International, Nephrology Dialysis and Transplantation) were handsearched for papers not yet in the computerised databases. Reference lists of papers were also checked. SELECTION CRITERIA: This review was not limited to randomised controlled trials. All trials involving people with insulin-dependent diabetes following a lower protein diet for at least 4 months were considered since the straight line nature of progression as reflected by GFR means that patients can act as their own controls in a before and after comparison. DATA COLLECTION AND ANALYSIS: Data were extracted for length of follow up, level of protein restriction, renal function and dietary compliance. No studies of the impact of protein restriction on outcomes such as the need for dialysis or transplantation were found. The trials reported only the effect on short-term indicators such as creatinine clearance. MAIN RESULTS: Overall a protein restricted diet (0.3-0. 8g/kg) does appear to slow the progression of diabetic nephropathy towards renal failure. REVIEWER'S CONCLUSIONS: The results show that reducing protein intake appears to slow progression to renal failure, but some questions remain unanswered. The first is what level of protein restriction we should be used? The trials aimed for a daily intake of between 0.3 to 0.8g/kg of protein. The second concerns compliance in routine care - what level would be acceptable to patients? The third concerns long term outcomes -the present trials use proxy indicators such as creatinine clearance rather than outcomes such as time to dialysis or prevention of ESRF. All trials were carried out in subjects with insulin-dependent diabetes. It remains to be seen if a lower protein intake would slow the progression of nephropathy affecting the non-insulin dependent diabetic population.

Diabetic Nephropathies↗
PubMed2000

Brefeldin A-dependent membrane tubule formation reconstituted in vitro is driven by a cell cycle-regulated microtubule motor.

Treatment of cultured cells with brefeldin A (BFA) induces the formation of extensive membrane tubules from the Golgi apparatus, trans-Golgi network, and early endosomes in a microtubule-dependent manner. We have reconstituted this transport process in vitro using Xenopus egg cytosol and a rat liver Golgi-enriched membrane fraction. The presence of BFA results in the formation of an intricate, interconnected tubular membrane network, a process that, as in vivo, is inhibited by nocodazole, the H1 anti-kinesin monoclonal antibody, and by membrane pretreatment with guanosine 5'-O-(3-thiotriphosphate). Surprisingly, membrane tubule formation is not due to the action of conventional kinesin or any of the other motors implicated in Golgi membrane dynamics. Two candidate motors of approximately 100 and approximately 130 kDa have been identified using the H1 antibody, both of which exhibit motor properties in a biochemical assay. Finally, BFA-induced membrane tubule formation does not occur in metaphase cytosol, and because membrane binding of both candidate motors is not altered after incubation in metaphase compared with interphase cytosol, these results suggest that either the ATPase or microtubule-binding activity of the relevant motor is cell cycle regulated.

Animals↗
PubMed1999

Development of early postnatal peripheral nerve abnormalities in Trembler-J and PMP22 transgenic mice.

Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated with peripheral neuropathy in mice and humans. Although PMP22 is strongly expressed in peripheral nerves and is localised largely to the myelin sheath, a dual role has been suggested as 2 differentially expressed promoters have been found. In this study we compared the initial stages of postnatal development in transgenic mouse models which have, in addition to the murine pmp22 gene, 7 (C22) and 4 (C61) copies of the human PMP22 gene and in homozygous and heterozygous Trembler-J (TrJ) mice, which have a point mutation in the pmp22 gene. The number of axons that were singly ensheathed by Schwann cells was the same in all groups indicating that PMP22 does not function in the initial ensheathment and separation of axons. At both P4 and P12 all mutants had an increased proportion of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating that this step is disrupted in PMP22 mutants. C22 and homozygous TrJ animals could be distinguished by differences in the Schwann cell morphology at the initiation of myelination. In homozygous TrJ animals the Schwann cell cytoplasm had failed to make a full turn around the axon whereas in the C22 strain most fibres had formed a mesaxon. It is concluded that PMP22 functions in the initiation of myelination and probably involves the ensheathment of the axon by the Schwann cell, and the extension of this cell along the axon. Abnormalities may result from a failure of differentiation but more probably from defective interactions between the axon and the Schwann cell.

Animals↗
PubMed1998

Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice.

Charcot-Marie-Tooth disease type 1A is most commonly caused by a duplication of a 1.5 Mb region of chromosome 17 which includes the peripheral myelin protein 22 gene (PMP22). Over-expression of this gene leads to a hypomyelinating/demyelinating neuropathy and to severely reduced nerve conduction velocity. Previous mouse and rat models have had relatively high levels of expression of the mouse or human PMP22 gene leading to severe demyelination. Here we describe five lines of transgenic mice carrying increasing copies of the human PMP22 gene (one to seven) and expressing increasing levels of the transgene. From histological and electrophysiological observations there appears to be a threshold below which expression of PMP22 has virtually no effect; below a ratio of human/mouse mRNA expression of approximately 0.8, little effect is observed. Between a ratio of 0.8 and 1.5, histological and nerve conduction velocity abnormalities are observed, but there are no behavioural signs of neuropathy. An expression ratio >1.5 leads to a severe neuropathy. A second observation concerns the histology of the different lines; the level of expression does not affect the type of demyelination, but influences the severity of involvement.

Animals↗
PubMed1997

Cell cycle regulation of organelle transport.

Microtubule- and actin-based motors play a wide range of vital roles in the organisation and function of cells during both interphase and mitosis, all of which are likely to be under strict control. Here, we describe how one of these roles--the movement of membranes--is regulated through the cell cycle. Organelle movement in many species is greatly reduced in mitosis as compared to interphase, and this change occurs concomitantly with an inhibition of most membrane traffic functions. Data from in vitro studies is shedding light on how microtubule motor regulation may be achieved.

Actins↗
PubMed1997

Abnormal Schwann cell/axon interactions in the Trembler-J mouse.

The Trembler-J (TrJ) mouse has a point mutation in the gene coding for peripheral myelin protein 22 (PMP22). Disturbances in PMP22 are associated with abnormal myelination in a range of inherited peripheral neuropathies both in mice and humans. PMP22 is produced mainly by Schwann cells in the peripheral nervous system where it is localised to compact myelin. The function of PMP22 is unclear but its low abundance (approximately 5% of total myelin protein) means that it is unlikely to play a structural role. Its inclusion in a recently discovered family of proteins suggests a function in cell proliferation/differentiation and possibly in adhesion. Nerves from TrJ and the allelic Trembler (Tr) mouse are characterised by abnormally thin myelin for the size of the axon and an increased number of Schwann cells. We report ultrastructural evidence of abnormal Schwann cell-axon interactions. Schwann cell nuclei have been found adjacent to the nodes of Ranvier whereas in normal animals they are located near the centre of the internodes. In some fibres the terminal myelin loops faced outwards into the extracellular space instead of turning inwards and terminating on the axon. In severely affected nerves many axons were only partially surrounded by Schwann cell cytoplasm. All these features suggest a failure of Schwann cell-axon recognition or interaction. In addition to abnormalities related to abnormal myelination there was significant axonal loss in the dorsal roots.

Animals↗
PubMed1996

The pathology of charcot-marie-tooth disease and related disorders.

Approximately a quarter of a century ago, the disorders originally designated as Charcot-Marie-Tooth disease and Dejerine-Sottas disease were shown by combined clinical, electrophysiological and nerve biopsy studies to be genetically complex. In pathological terms they could be broadly classified into demyelinating neuropathies and axonopathies. Advances in the molecular genetics of these disorders, particularly for those with a demyelinating basis, have recently produced substantial new insights. The identification of mutations in genes for myelin proteins has provided the opportunity for investigating the precise mechanisms of these neuropathies, including the use of spontaneous and genetically engineered animal models.

Animals↗
PubMed1994

Prefrontal cortex and the relative associability of taste and place cues in rats.

The effects of cutting the corticocortical connections between medial and sulcal prefrontal areas on the conditioning of taste and place cues were examined. In Experiment 1, rats were simultaneously exposed to taste and place cues before injection of 0.15 M LiCl. In controls, a significant conditioned taste aversion (CTA) but no conditioned place aversion (CPA) was observed. In contrast, rats with bilateral knife cuts showed a significant CPA but a weaker CTA. To test whether these results could have been due to the effects of simultaneously exposing the rats to taste and place cues during conditioning, rats were trained independently in either CTA or CPA paradigms in Experiment 2. In the CTA test, rats both in operated and control groups showed a CTA when first tested. Rats with bilateral knife cuts, however, showed a weaker CTA than those in the control group. In the CPA test, rats in the control group did not exhibit a CPA, whereas the knife cut group did. Rats with sham lesions tested in Experiment 2 did not differ from control subjects on either the CPA or the CTA test. Thus, bilateral cuts increased the CPA and decreased the CTA even when tested independently. These results indicate that the relative ease of association of place and taste stimuli may be accounted for in part by the organization of the intrinsic connections of the prefrontal cortex in the rat.

Animals↗
PubMed1993

Dichotomous response of whole blood viscosity in streptozotocin-diabetic rats.

Abnormalities of blood rheology may play an important role in the underlying mechanism of the development of diabetic complications. Although streptozotocin (STZ)-induced diabetic rats have been used extensively in the investigation of diabetic complications, blood rheological alterations in this model have not previously been assessed. To assess one aspect of blood rheology, we repeated whole blood viscosity (WBV) measurements at 4, 8, 12 and 16 weeks after the STZ injection in rats. Nine of fifteen diabetic rats showed increased WBV after the induction of diabetes. Although these rats had a higher haematocrit, the increase in WBV was maintained after correction to a standard haematocrit. Percentage changes of WBV were significantly greater in these diabetic rats than in control rats at low shear rates (0.1s-1 and 1.0s-1), but not at high shear rates. In contrast, WBV was lowered at all shear rates after the injection of STZ in the remaining six diabetic rats which had lower haematocrit, severe weight loss and high mortality; no rats survived for 16 weeks post-injection. Animals in this group may be implicated in the high mortality among STZ-diabetic rats. Although there was a clear distinction of rheological and clinical pictures between these two groups of STZ-diabetic rats, blood glucose and HbA1 concentrations did not differ significantly. This study demonstrates a dichotomy in blood viscosity response to STZ-induced diabetes.

Animals↗
PubMed1987

Effects of trimoprostil, a prostaglandin E2 analogue, on human gastric acid secretion and soluble mucin output.

We have studied the effects of Trimoprostil, a prostaglandin E2 analogue, on gastric acid and soluble mucus output using human subjects. This compound caused anti-secretory effects on both basal as well as histamine-stimulated gastric acid secretion in a dose-dependent manner. There was a simultaneous increase in total mucus output. When the secreted mucus was fractionated by Sepharose CL-2B gel chromatography, most of the basal gastric mucin was shown to be in the polymeric form (mol wt 2 X 10(6)), whereas after histamine stimulation the mucin was mostly in the subunit form (mol wt 0.5 X 10(6)). The gastric mucin, after stimulation using low doses of prostaglandin, was mainly in the polymeric form; but after higher doses, the subunit form predominated. These observations are important in the understanding of physiological and pharmacological control of gastric mucus output with regard to its chemical composition and molecular heterogeneity, and provide further insight into the rational clinical use of the prostaglandins for gastroduodenal diseases.

Adult↗
PubMed1983

In vitro thymidine labelling of human pulmonary neoplasms.

The in vitro thymidine labelling indices (TLI) of 58 human lung tumours were assessed using autoradiography. The labelling technique involved incubation of 1 mm3 tumour fragments with 3H-thymidine (5 muCi ml-1) under conditions of hyperbaric oxygenation at a pressure of 3 atmospheres. Only a rim of labelling was achieved along the edges of fragments and the depth of this rim varied from tumour to tumour. A technique for counting TLIs was therefore devised to take this into account. In general, those tumours showing low TLI values of less than 5.0% showed a greater depth of labelling. The common malignant tumours of the bronchus showed a wide range of values (2.2-30.4%) though the adenocarcinomata had a lower average value than the other groups. With the squamous carcinomata a relationship with differentiation was shown. The mean value for small cell carcinomata (16.9%)--a highly aggressive tumour--was no higher than for the other groups. The low grade malignant tumours showed TLIs of less than 3.0% and these values correlate with their less aggressive clinical behaviour. Labelling of stromal cells and inflammatory cells varied greatly from tumour to tumour; however, no correlation was found with the TLIs of tumour cells.

Cell Division↗
PubMed1980

Neurological, psychological and educational sequelae of low birth weight.

In a prospective study of 501 infants of low birth weight (LBW) who mostly weighed 2,041 g (4 1/2 lb) or less, and of 203 control infants of full birth weight (FBW > 2,500 g), 335 LBW and 139 FBW children were followed beyond the age of 6 years and 6 months. The incidence of neurological defects was negatively correlated with birth weight, and the mean "global" IQ of different birth weight groups retained a direct relationship. While the relationship of birth weight to IQ gradually became less marked, the effect of social class was increasingly evident from the age of 2 years and 6 months. The preterm children whose birth weight was appropriate for gestational age (AGA) attained a slightly higher mean IQ and significantly better grade placement in the third school year than the children who were unduly light for their gestational age. Details of the neurological and ophthalmological defects are given, and the predictive significance of neonatal variables is analyzed.

Attention Deficit Disorder with Hyperactivity↗
PubMed1978

Morphological aspects of glucocorticoid-induced cell death in human lymphoblastoid cells.

Morphological aspects of cell death associated with a cytolethal concentration of methylprednisolone sodium succinate (500 micrograms/ml) on the BLA1 lymphoblastoid cell line were studied over a 48-hr incubation period by light, transmission and scanning electron microscopy. Studies revealed two distinctive morphological changes induced by the steroid from 1 hr onwards after treatment. One showed contortion and "blebbing" of the cytoplasm and nucleus accompanied or followed by nuclear pyknosis, resulting in the formation of membrane-bounded bodies containing apparently normal cytoplasmic organelles with or without nuclear fragments. The other showed "rounding up" of the cell with loss of cytoplasmic protrusions and long slender surface processes, aggregation of well-preserved cytoplasmic organelles, accompanied by nuclear pyknosis and fragmentation. In both cases many of the features are typical of apoptosis. The subsequent degeneration of cells and fragments not unexpectedly resembled in vitro autolysis. This in-vitro system is suitable for studying the early biochemical events and intracellular control mechanisms of apoptosis.

Cell Line↗