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M J West

Publications and source records attributed to M J West.

At least 37 records · Page 2Linked to original sources
PubMed2000

The CA1 region of the human hippocampus is a hot spot in Alzheimer's disease.

Data from an ongoing study of differences in the total number of neurons in the five major subdivisions of the hippocampal regions of the brains of patients with Alzheimer's disease (AD) and normal age-matched controls confirm an earlier finding from our laboratories of a pronounced loss of CA1 neurons associated with AD. In view of an earlier finding that the CA1 region does not suffer normal age-related neuronal loss, these data support the earlier conclusion that the neuropathologic mechanisms involved in the AD-related losses in CA1 are not related to normal aging and that the study of the cellular and molecular events involved in the AD-related loss of CA1 cells can aid in the identification of the unique pathologic processes associated with AD.

Alzheimer Disease↗
PubMed1999

Oligodendrocyte programmed cell death and central myelination deficiency induced in transgenic mice by synergism between c-Myc and Oct-6.

The basic helix-loop-helix transcription factor c-Myc is a potent trigger of programmed cell death when overexpressed during late oligodendrocyte development in transgenic mice. Here we provide evidence that c-Myc can act synergistically with the Pit, Oct, Unc homeodomain transcription factor Oct-6 to produce myelin disease pathogenesis in transgenic mice. More than 70% of c-myc/Oct-6 bitransgenic mice, obtained from crosses between phenotypically normal heterozygous mice of various My (c-Myc) and Oc (Oct-6) transgenic strains that express c-myc and oct-6 transgenes under transcriptional control of the myelin basic protein gene, developed severe neurological disturbances characterized by action tremors, recurrent seizures, and premature death. Affected bitransgenic mice exhibited multiple hypomyelinated lesions in the white matter that did not stain with myelin-specific antibodies against myelin basic protein, proteolipid protein, CNPase, and myelin-associated glycoprotein. The mice also exhibited a larger number of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling positive cells in the white matter as well as ultrastructural evidence of glial cell death and astrogliosis. These observations indicate that the myelin lesions observed in the c-myc/oct-6 bitransgenic mice result from the untimely programmed cell death of oligodendroglia and that the c-myc and oct-6 transgenes act synergistically in producing the lesions.

Animals↗
PubMed1999

Stimulation of Tat-associated kinase-independent transcriptional elongation from the human immunodeficiency virus type-1 long terminal repeat by a cellular enhancer.

The human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR) initiates transcription efficiently but produces only short transcripts in the absence of the trans-activator protein, Tat. To determine whether a cellular enhancer could provide the signals required to recruit an elongation-competent polymerase to the HIV-1 LTR, the B cell-specific immunoglobulin heavy chain gene enhancer (IgHE) was inserted upstream of the LTR. The enhancer increased transcription in the absence of Tat between 6- and 7-fold in transfected B cells, but the full-length transcripts remained at basal levels in HeLa cells, where the enhancer is inactive. RNase-protection studies showed that initiation levels in the presence and absence of the enhancer were constant, but the enhancer significantly increased the elongation capacity of the polymerases. Tat-stimulated elongation is strongly inhibited by the nucleoside analogue 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), which inhibits the Tat-associated kinase, TAK (CDK9). However, polymerases initiating transcription from LTRs carrying the enhancer were able to efficiently elongate in the presence of DRB. Specific repression of TAK by expression in trans of the CDK9 kinase also inhibited Tat-stimulated elongation but did not inhibit enhancer-dependent transcription significantly. Thus, the activation of polymerase processivity by the IgHE involves a unique mechanism which is independent of TAK.

B-Lymphocytes↗
PubMed1999

Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias.

The emergence of a new generation of stereological techniques for counting objects in histological sections has prompted a debate about whether or not these methods are better than previously available techniques when they are used to make estimates of the total numbers of neurons and synapses in a neural structure. During this debate, the concepts of an unbiased estimate and that of a precise estimate have often been confused. A full understanding of the distinction between these two separate aspects of an estimate is required in order to be able to appreciate the virtues of these new counting methods and to apply them correctly. This review intends to make the fundamental issues of this debate more clear, and describes (1) the fundamental differences between the newer design-based counting techniques and previously available assumption-based techniques, and (2) the distinction between an unbiased estimate and a precise estimate.

Animals↗
PubMed1999

The relationship between oral dyskinesias produced by long-term haloperidol treatment, the density of striatal preproenkephalin messenger RNA and enkephalin peptide, and the number of striatal neurons expressing preproenkephalin messenger RNA in rats.

Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to excitotoxic degeneration within the striatum. Haloperidol treatment for 34 weeks increased the optical density of preproenkephalin messenger RNA in individual striatal neurons and enkephalin peptide in the neuropil, regardless of the level of oral dyskinesia produced. However, using unbiased stereological methods, an increased number of striatal neurons expressing preproenkephalin messenger RNA was observed only in rats that did not develop pronounced oral dyskinesias during haloperidol treatment. Said in another manner, the haloperidol-treated animals that developed pronounced oral dyskinesias, failed to produce an increase in the number of neurons expressing preproenkephalin messenger RNA. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disturbance or even damage to a subpopulation of enkephalinergic neurons in the striatum.

Animals↗
PubMed1999

Consistent responses of human mothers to prelinguistic infants: the effect of prelinguistic repertoire size.

The salience of infants' vocal and visual cues was examined to evaluate the efficacy of prelinguistic vocalizations to guide adult behavior. A videotape, constructed of brief behavioral episodes from 3 infants with different-sized vocal repertoires, was played to 40 mothers of prelinguistic infants. Playback mothers' responses to the episodes were consistent, demonstrating that preverbal behavior elicits comparable reactions across unfamiliar receivers. The audio and video components of the infants' episodes were then recombined. As the vocal repertoire of the stimulus infants increased, changes in the audio component more often led playback mothers to change responses. Thus, playback mothers used vocalizations as cues as the infants' vocal repertoires became larger.

Adult↗
PubMed1998

Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway.

Previous studies on the regulation of c-myc have focused on the transcriptional control of this proto-oncogene. We have investigated the signalling pathways involved under circumstances in which there is a translational upregulation in the levels of c-myc protein. We have demonstrated an up to tenfold serum-dependent increase of c-myc protein levels in Epstein-Barr virus immortalized B-cell lines 2-4 h after disruption of cellular aggregates, which is not accompanied by an equivalent increase in mRNA. Overall protein synthesis rates only increased threefold suggesting that the c-myc message was being selectively translated. We observed increases in the phosphorylation of p70 and p85 S6 kinases and of initiation factor eIF-4E binding protein 1 (4E-BP1) 1-2 h after stimulation, suggesting activation of the FRAP/TOR signalling pathway. The increased phosphorylation of 4E-BP1 led to a decrease in its association with eIF-4E and an increase in its association with the eIF-4G component of the eIF-4F initiation complex. The signalling inhibitors rapamycin and wortmannin blocked the phosphorylation of 4E-BP1 and abolished the translational component of the c-myc response. Our data suggest that dissociation of eIF-4E from 4E-BP1, leading to an increase in the formation of the eIF-4F initiation complex, relieves the translation repression imposed on the c-myc mRNA by its structured 5'UTR.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Failure of central nervous system myelination in MBP/c-myc transgenic mice: evidence for c-myc cytotoxicity.

c-myc is a member of the helix-loop-helix/leucine zipper family of proteins that modulate the transcriptional activity of specific target genes. Although aberrant c-myc expression has been reported to play a role in multistage carcinogenesis in astrocytic gliomas, little is known about the effects of the expression of c-myc on oligodendrocytes. Using transgenic animals expressing a human c-myc oncogene under transcriptional control of the myelin basic protein gene, we investigated the effect of overexpression of this oncogene in oligodendrocytes. The MBP/c-myc transgenic mice developed severe neurological disturbances characterized by action tremors and recurrent seizures, and premature death during postnatal weeks three to five. Affected transgenic mice of various strains had severely hypomyelinated central nervous systems and expressed low levels of c-myc, myelin basic protein (MBP) and proteolipid protein (PLP) mRNAs in the brain. These c-myc transgenic mice also exhibited an increased number of TUNEL positive nuclei, which in most cases were located in cells that expressed c-myc, as judged by double immunohistochemistry. There was no evidence of brain tumors in the c-myc transgenic mice, including heterozygous mice from two strains that had normal lifespans. These observations indicate that the myelin deficiency observed in the MBP/c-myc transgenic animals results from a cytotoxic effect of the c-myc transgene.

Animals↗
PubMed1998

Neurological disturbances, premature lethality, and central myelination deficiency in transgenic mice overexpressing the homeo domain transcription factor Oct-6.

Pit, Oct, Unc (POU) homeo domain transcription factors have been implicated in various developmental processes, including cell division, differentiation, specification, and survival of specific cell types. Although expression of the transcription factor Oct-6 in oligodendroglia is confined to the promyelin stage and is downregulated at the myelin stage of development, the effect of Oct-6 overexpression on oligodendrocyte development has not been established. Here we show that transgenic animals overexpressing Oct-6 at late oligodendrocyte development develop a severe neurologic syndrome characterized by action tremors, recurrent seizures, and premature death. Axons in the central nervous system of Oct-6 transgenics were hypomyelinated, hypermyelinated, or dysmyelinated, and ultrastructural analyses suggested that myelin formation was premature. The vulnerability of developing oligodendroglia to Oct-6 deregulation provides evidence that the POU factor may play a direct role in myelin disease pathogenesis in the mammalian CNS.

Animals↗
PubMed1998

Total number of neurons in the layers of the human entorhinal cortex.

The total number of neurons in the major laminae of the human entorhinal cortex were estimated with a design-based stereological technique, the optical fractionator. Detailed descriptions of the laminar organization and the cortical limits of the region required for the analysis are provided, along with detailed descriptions of the sampling scheme employed. The individual, mean values, and variances for estimates made in layers II, III, V, and VI are presented and discussed in terms of the precision of the estimation procedure and the results of other studies. Neuron numbers were estimated to be about 1 million layer II cells, 5 million layer III cells, 2 million layer V cells, and 4 million layer VI cells, for a total of slightly more that 13 million neurons in the entorhinal cortex. Combined with data from a similar study carried out in the human hippocampus, the data presented represent the first rigorous stereological evidence of the divergence of entorhinal projections to the hippocampus. The data presented also indicate that projections from layer II of the entorhinal cortex to the dentate gyrus and CA2/3 and projections from layer III of the entorhinal cortex to CA1 differ in the degrees of their divergence.

Adult↗
PubMed1998

Combining propofol with morphine in patient-controlled analgesia to prevent postoperative nausea and vomiting.

We have studied the antiemetic effects of propofol when mixed with morphine in a patient-controlled analgesia (PCA) pump after major gynaecological surgery. In a double-blind, randomized, controlled study, 50 women, ASA I or II, received a standardized anaesthetic comprising thiopental, morphine, atracurium, nitrous oxide and oxygen with enflurane, and received postoperative PCA with morphine mixed with either 1% propofol or lvelip. The PCA bolus was morphine 1 mg with propofol 5 mg or lvelip 0.5 ml, with a lockout time of 5 min. Postoperative nausea and vomiting (PONV) were assessed by the nursing staff using a four-point ordinal scale and by the patient using a visual analogue scale for 48 h after surgery. The two groups were similar in the potential factors influencing the incidence of PONV. There were no significant differences between the two groups in any of the study measurements of PONV. There were, no side effects after propofol. Propofol, when mixed with morphine in this dose combination for PCA, did not decrease the incidence of nausea and vomiting in women undergoing major gynaecological surgery.

Adult↗
PubMed1998

Initiation and evaluation of a research-based fall prevention program.

This study evaluated the effectiveness of research-based interventions in preventing falls. The interventions were based on research studies, experts' opinions, and a pilot study. Thirteen units (72%) had reduced fall rates. The fall rate two years before (O = 7.07; SD = 1.7) and two years after (O = 6.33; SD = 1.731) the intervention was significantly different at p < 0.003. Sixteen patients who fell were at risk (fall assessment score = 17.4 +/- 5.3) and had a history of falls. The most common site for falls was at the bedside. Most falls occurred during walking, climbing over the siderails, and accidentally rolling out of bed. Thus, a research-based fall prevention is effective in reducing falls.

Accidental Falls↗
PubMed1997

Neuron numbers in the presubiculum, parasubiculum, and entorhinal area of the rat.

Estimates of neuron numbers have been useful in studies of neurodegenerative disorders, and in their animal models, and in the computational modeling of hippocampal function. Although the retrohippocampal region (presubiculum, parasubiculum, and entorhinal area) is an integral part of the hippocampal circuitry and is affected selectively in a number of disorders, estimates of neuron numbers in the rat retrohippocampal region have yet to be published. Such data are necessary ingredients for computational models of the function of this region and will also facilitate a comparison of this region in rats and primates, which will help to determine how well we may expect rat models to predict function and dysfunction in primate brains. In the present study, we used the optical fractionator to estimate the number of neurons in the rat retrohippocampal region. The following estimates were obtained: 3.3 x 10(5) in presubicular layers II and III, 1.5 x 10(5) in parasubicular layers II and III, 2.2 x 10(5) in the combined pre- and parasubicular layers V and VI, 6.6 x 10(4) in medial entorhinal area (MEA) layer II, 1.3 x 10(5) in MEA layer III, 1.9 x 10(5) in MEA layers V and VI, 4.6 x 10(4) in lateral entorhinal area (LEA) layer II, 1.2 x 10(5) in LEA layer III, and 1.4 x 10(5) in LEA layers V and VI. A surprising finding was the large numbers of neurons in the pre- and parasubiculum, which indicate an important role of these areas in the control of the entorhino-hippocampal projection. A comparison of the numbers of neurons in the hippocampus and entorhinal areas in rats with similar estimates in humans revealed that gross input-output relations are largely conserved. Differences between rats and humans may be accounted for by more prominent entorhino-neocortical projections in primates and consequent increases in the number of neurons in the hippocampus and retrohippocampal region, which are dedicated to these projections.

Animals↗
PubMed1997

A brain of her own: a neural correlate of song assessment in a female songbird.

The song control region in the avian forebrain is a series of discrete, interconnected nuclei mediating song learning and production. It has been studied in males or in species where both sexes sing. Little is known about the neural correlates of song perception in nonsinging females, often the intended recipients of song. We studied cowbirds (Molothrus ater), a species in which only males sing but in which females discriminate between males on the basis of song. We focused on nucleus lMAN because it has been implicated in early song acquisition, a stage relevant to both sexes to choose among competing acoustic models. We found that volume of lMAN was monomorphic in cowbirds. Moreover, the volume and neuronal number of female lMAN were positively correlated with selectivity of copulatory responding. The results provide strong evidence of nonsinging female's use of "song" control nuclei for song perception without the possibility of song production.

Animal Communication↗
PubMed1997

Renin-angiotensin system gene polymorphisms and left ventricular hypertrophy. The case against an association.

There is accumulating evidence for association between genetic polymorphisms of components of the renin angiotensin system (RAS), especially angiotensin-converting enzyme (ACE), and cardiovascular disease. However, there is lack of agreement that the ACE polymorphism is associated with left ventricular hypertrophy (LVH) in hypertension. A possible paradigm for the development of LVH involves the ACE gene polymorphism influencing cardiac mass by an action on plasma and/or tissue levels of angiotensin II. Such a model has experimental support and provides the basis for examining the lack of agreement between studies. The finding of lack of association between RAS gene polymorphism and LVH may be due to methodological problems, differences in genetic background between populations, interactions between genetic variants of RAS components or to the model being inappropriate. Low predictability of ACE genotype markers for LVH together with conflicting reports on the influence of RAS genetic variants on angiotensin II production suggests that the simple RAS paradigm may not apply for hypertension. Further information on the nature of the link between the ACE polymorphism and ACE regulation as well as the relation between the RAS and pathophysiology of LVH is needed. At present there is insufficient evidence to accept ACE gene polymorphism as a susceptibility marker for LVH.

Angiotensin II↗
PubMed1997

Investigation of aberrant translational control of c-myc in cell lines derived from patients with multiple myeloma.

In cell lines derived from patients with multiple myeloma (MM) we have found an elevation in the amount of the c-myc protein which is not accompanied by an increase in the level of mRNA or a change in the half-life of the protein. There is a 3.4 fold enhancement in the degree of association of the c-myc message with polysomes. This is not accompanied by an alteration in polysome size or a change in the transit time of the c-myc mRNA on the polysomes thus suggesting that there is in increase in the degree of mobilisation of the c-myc message. Sequencing of the c-myc 5'UTR has revealed the presence of a mutation in all the MM cell lines studied and we demonstrate that this mutation causes altered binding of cellular proteins to this RNA species.

Base Sequence↗
PubMed1997

Growth factors released into the coronary circulation after vascular injury promote proliferation of human vascular smooth muscle cells in culture.

OBJECTIVES: This study sought to 1) assess in vivo release of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) into the coronary circulation after vascular injury in human subjects; and 2) evaluate mitogenic effects of PDGF and bFGF on the patient's own vascular smooth muscle cells (VSMCs). BACKGROUND: Circumstantial evidence suggests involvement of PDGF and bFGF peptides in the neointimal response to vascular injury. To date, no study has shown biologically active growth factors within the coronary circulation after vascular injury in human subjects. METHODS: In 18 patients, plasma PDGF AB, platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) levels were measured in coronary sinus blood obtained before and up to 30 min after angioplasty. In five patients undergoing atherectomy, coronary sinus serum was added to cultured VSMCs derived from atherectomy tissue to assess the mitogenic potential of the serum. Mitogenicity attributable to PDGF and bFGF was determined using neutralizing antibodies to these factors. PDGF A, PDGF B and bFGF were localized within the atherectomy tissue using immunocytochemical analysis. RESULTS: Before angioplasty, PDGF AB, PF4 and beta-TG levels were elevated threefold in patients scheduled for angioplasty compared with those in control patients (p < 0.01). Within 5 min of angioplasty, PDGF AB levels increased twofold and returned toward preangioplasty levels at 30 min; PF4 and beta-TG levels remained elevated. Serum obtained at 30 min after atherectomy showed a sixfold increase in mitogenicity compared with preatherectomy serum (p = 0.01). This increase in mitogenicity was reduced by 20%, 40% and 65% in the presence of neutralizing antibodies to PDGF, bFGF and PDGF + bFGF, respectively. PDGF A, PDGF B and bFGF were visualized within the intima of the atherectomy tissue. CONCLUSIONS: The change in plasma PDGF level is consistent with first-phase release of PDGF after vascular injury. The increase in mitogenicity of serum suggests that PDGF and bFGF are biologically active.

Adult↗