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Biomedical subjects

L A Howard

Publications and source records attributed to L A Howard.

At least 19 recordsLinked to original sources
PubMed2003

Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality.

Monosomy 1p36 is a relatively common chromosome deletion. Deletion of this chromosome band can be difficult to visualize using routine cytogenetic banding techniques. The use of fluorescence in situ hybridization (FISH) with telomere region-specific probes has aided in the diagnosis of patients. In this study we ascertained 62 patients with deletions of 1p36 from 61 families and collected information regarding previous chromosome analyses, mode of ascertainment, clinical indication, age at diagnosis, and parental ages. The majority of deletions occur on the maternally derived chromosome. We identified terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. We correlated the type of rearrangement with the parental origins. Almost 50% of the patients had at least one chromosome analysis interpreted as normal. Retrospectively, 98% of deletions could be identified by routine chromosome analysis with careful attention to chromosome 1p36. Clinical indications were variable, with developmental delay/mental retardation being the most common. Increased maternal serum alpha fetoprotein (MSAFP) was detected in four of the five prenatally diagnosed cases. Maternal age at the time of birth of the affected child was significantly lower than the general United States population mean. We suggest a multistep approach for the diagnosis and clinical evaluation in cases of monosomy 1p36.

Abnormalities, Multiple↗
PubMed2001

Reaching affects saccade trajectories.

The pre-motor theory suggests that, when attention is oriented to a location, the motor systems that are involved in achieving current behavioural goals are activated. For example, when a task requires accurate reaching, attention to a location activates the motor circuits controlling saccades and manual reaches. These actions involve separate neural systems for the control of eye and hand, but we believe that the selection processes acting on neural population codes within these systems are similar and can affect each other. The attentional effect can be revealed in the subsequent movement. The present study shows that the path the eye takes as it saccades to a target is affected by whether a reach to the target is also produced. This effect is interpreted as the influence of a hand-centred frame used in reaching on the spatial frame of reference required for the saccade.

Adolescent↗
PubMed2001

Vision influences tactile perception at body sites that cannot be viewed directly.

Previous research has demonstrated that vision of a body site, without proprioceptive orienting of eye and head to that site, could affect tactile perception. The body site viewed was the hand, which can be seen directly under normal viewing conditions. The current research asked three further questions: First, can vision similarly affect tactile perception at a body site that cannot normally be viewed directly such as the face or neck? Second, does prior experience of seeing a body site, such as occurs when viewing the face in mirrors, produce larger effects of viewing than body sites rarely seen such as the back of the neck? And third, how quickly can visual information affect tactile target detection? We observe that: detection of tactile targets at these body sites was influenced by whether or not they were viewed, this effect was greater when viewing the more familiar site of the face than that of the neck, and significant effects were observed when the stimulus onset asynchrony between visual display and tactile target was as little as 200 ms.

Adult↗
PubMed2001

Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver.

The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy alcohol users are also smokers. In humans, cigarette smoking significantly enhances CYP2E1 activity, as measured by increased metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and several hepatotoxins. We hypothesized that, like ethanol, nicotine increases CYP2E1 activity. Rats were treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.), or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days. After ethanol or nicotine administration, immunostaining for CYP2E1 was increased in the centrilobular regions of rat liver. Western blot analyses revealed that hepatic CYP2E1 levels were increased by ethanol (1.6-2.4-fold) and nicotine (1.3-1.7-fold). In vitro chlorzoxazone 6-hydroxylation analyses demonstrated elevated Vmax values (compared with saline-treated animals) by using hepatic microsomes from high-dose ethanol (2.27 +/- 0.12 versus 1.18 +/- 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats (2.35 +/- 0.04 versus 1.32 +/- 0.55 nmol/mg/min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microsomes from drug-treated animals is consistent with the observed increase in CYP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis, neuropsychiatric motor disorders).

Animals↗
PubMed2000

The contribution of apraxic speech to working memory deficits in Parkinson's disease.

This article links two formerly separate areas of research associated with Parkinson's disease (PD): speech and memory. It is proposed that speech deficits occur in PD not merely at the level of muscular control, as is commonly termed dysarthria, but also at the level of speech planning and programming, more aptly described as a form of apraxia. It is further argued that PD patient groups exhibit small deficits in verbal span, and the link between apraxic speech and verbal span is elucidated via Baddeley's (1986) model of working memory. An experiment is described in which aspects of speech of 36 PD and 43 healthy control subjects were rated and classified, and measures of span and articulation rate for words of different syllable lengths were taken. Twenty-three PD subjects had dysarthric speech, while 14 of them had apraxic speech, which was associated with lower memory span scores for longer words. It is concluded that apraxic speech can be a source of reduced memory span in PD. In addition to implications for rehabilitation and therapeutic work with PD sufferers, these findings advance our theoretical understanding of the Parkinsonian syndrome.

Adult↗
PubMed1999

Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants.

Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1beta and RANTES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled comparison of these residues in hMIP-1beta and RANTES. Aggregated and disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have equivalent G-protein-coupled receptor-mediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP-1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M- and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.

Amino Acid Sequence↗
PubMed1999

Elevated pain threshold in anorexia nervosa subjects.

BACKGROUND: Conflicting data have been published regarding pain threshold in subjects with anorexia nervosa (AN), with some studies indicating elevated pain threshold and others indicating normal thresholds. Previous research has indicated the presence of elevated pain threshold in eating disorder subjects with binge-eating behavior. METHODS: In this study pressure pain detection thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging and restricting subtypes of AN subjects were compared to control subjects. RESULTS: PDT was elevated in AN compared to control subjects at baseline. There was no difference in PDT between the subgroups of AN subjects. CONCLUSIONS: The etiology of elevated PDT in AN subjects is most likely different from the etiology of elevated PDT in bulimia nervosa subjects.

Adolescent↗
PubMed1999

Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine.

Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.

Animals↗
PubMed1999

Inhibition of return in a selective reaching task: an investigation of reference frames.

Most previous studies of inhibition of return (IOR) have examined reaction time (RT) and accuracy. These effects have been observed via saccades to targets or with key-press responses. In this study the authors examined, for the first time, IOR in components of a selective reaching task in which participants directly reached for and depressed target keys. When the interval between cue and target was 600 ms, robust IOR effects were observed in RT to begin the reach, but no effects were observed in the movement components (movement time to complete the reach and the path of the reach). However, when the cue-target interval was short (200 ms), hand paths deviated toward the cue. The results suggest that although RT measures of IOR appear to reveal perceptual rather than action-based processes, action-based representations may be briefly activated by irrelevant cues, which can be observed via analysis of three-dimensional reach path.

Adolescent↗
PubMed1998

Action-based mechanisms of attention.

Actions, which have effects in the external world, must be spatiotopically represented in the brain. The brain is capable of representing space in many different forms (e.g. retinotopic-, environment-, head- or shoulder-centred), but we maintain that actions are represented in action-centred space, meaning that, at the cellular level, the direction of movement is defined by the activity of cells. In reaching, for example, object location is defined as the direction and distance between the origin of the hand and the target. Most importantly, we argue that more than one task-relevant action can be evoked at any moment in time. Therefore, highly efficient selection processes that accurately link vision and action have had to evolve. Research is reviewed which supports the notion of action-based inhibitory mechanisms that select the target from competing distractors.

Animals↗
PubMed1998

Vision influences tactile perception without proprioceptive orienting.

The perception of tactile stimuli is facilitated when subjects look towards the stimulated body site: this facilitation even takes place when visual information is unavailable, as when orienting in the dark. It is not known whether the facilitation is due entirely to such proprioceptive orienting of eye and head, or whether visual information of the body site can also facilitate touch. An experiment is reported which dissociates vision and proprioception, and demonstrates for the first time that vision of a body part, independent of proprioceptive orienting, can indeed effect somatosensation.

Adult↗
PubMed1997

p53, mutation frequency and apoptosis in the murine small intestine.

Normal function of the p53 gene is integral to the cellular response to genotoxic stress. One prediction arising from this is that p53 deficiency results in an increased mutation frequency. However, limited evidence has been produced in support of this idea. In order to further investigate the in vivo role of p53 in surveillance against mutation, and particularly to address the significance of p53-dependent apoptosis, we scored mutation frequency at the Dlb-1 locus within cells of the intestinal epithelium of animals which were wild type, heterozygous or null for p53 and heterozygous (a/b) at the Dlb-1 locus. Using this assay we have shown that loss of a p53-dependent apoptotic pathway is associated with the detectable acquisition of mutations, but only at high levels of DNA damage. These results question the significance of the immediate 'wave' of p53-dependent apoptosis seen in this tissue, particularly as there was a delayed p53-independent apoptotic pathway. We conclude that loss of p53 function only becomes relevant to the in vivo acquisition of mutations and thus tumorigenesis in certain circumstances.

Animals↗
PubMed1997

Hand deviations away from visual cues: indirect evidence for inhibition.

Previous research has demonstrated that when a stimulus is to be ignored, the path of motion towards a target (saccade or manual reach) deviates away from the to-be-ignored stimulus. Path deviations in saccade and reaching tasks have, however, been observed in very different situations. In the saccade tasks subjects initially attended to a cue, then disengaged attention while saccading to a target. By contrast, in the selective reaching tasks attention was continuously withdrawn from the to-be-ignored stimulus, as this was irrelevant throughout the experiment. In the two experiments reported here, cues similar to those studied in saccade tasks are examined with selective reaching procedures. Experiment 1 shows that when a coloured light-emitting diode cue, upon which subjects engage and then subsequently disengage attention, is close to the responding hand, the hand deviates away from the cue. Experiment 2 confirms this cue avoidance by showing that, compared with central fixation alone, the hand veers away from a central cue. These results confirm that the path deviations observed in saccades can also be obtained in manual reaching movements. Such findings support the notion that eye and hand movements are both affected by inhibitory mechanisms of attention.

Acoustic Stimulation↗
PubMed1994

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a potent mutagen in the mouse small intestine.

Mutations in long lived stem cells are critical events in carcinogenesis. The Dlb-1 assay detects intestinal stem cell mutation at the Dlb-1 locus in Dlb-1a/b heterozygous mice by visualizing mutated clones of epithelial cells in situ which do not bind the lectin Dolichos biflorus agglutinin. We have used this assay to show that the food-derived heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent intestinal mutagen when administered either i.p. or p.o. This contrasts with the inactivity of the structurally related mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the assay which we have described previously. Immunocytochemical localization of the P-450 enzyme CYP1A2, which is responsible for the primary activation of these mutagens, shows that in untreated mice it is present in liver hepatocytes and in occasional villus epithelial cells but is absent from the target intestinal stem cell population. In addition, liver microsomes, unlike intestinal microsomes, were able to convert PhIP to the proximate mutagen N-hydroxy-PhIP. CYP1A2 immunoreactivity in beta-napthoflavone-induced animals was elevated in liver hepatocytes and increased to a lesser extent in duodenal villus epithelial cells. Treatment with beta-napthoflavone produced an unexpected 46% decrease in the number of Dlb-1 mutations in response to PhIP. Following treatment with PhIP, there was no difference in the number of Dlb-1 locus mutations between the proximal and distal ends of the small intestine in uninduced animals, indicating that the bile duct is unlikely to be responsible for transport of mutation inducing metabolites of PhIP to the small intestine. Our results demonstrate that metabolic activation of an indirect acting genotoxic agent can occur at a site other than the target tissue, and absence of the enzymes required for activation of a mutagen does not necessarily protect that tissue from its genotoxic effects.

Animals↗
PubMed1994

How convincing is the evidence for cognitive slowing in Parkinson's disease?

The issue of whether or not Parkinson's disease (PD) patients process information more slowly than normal is unresolved. Across a range of paradigms the evidence for slowing is scant, and many show no slowing. Even the results of a single experimental paradigm can be conflicting; some studies have obtained evidence for slowed memory scanning in subgroups of PD patients whereas others have not. The present study sought the cause of these discrepant results. Old-old (n = 11) and young-old (n = 7) PD subjects and controls (n = 16, n = 9) completed both fixed and varied set versions of the memory scanning task. No evidence for slowing in PD was found. These results indicated that PD did not interact with age or task version in its effects on information processing rates in the memory scanning task. It was concluded that PD patients do not have any cognitive slowing that is detectable with the memory scanning task.

Aged↗
PubMed1994

Comparison of 16S rRNA genes within the T960 and parvo biovars of ureaplasmas isolated from humans.

Two-by-two sequence alignment revealed that the levels of homology between 16S rRNA gene sequences of strains belonging to the two biovars of Ureaplasma urealyticum (class Mollicutes) ranged from 98.5 to 98.9%. Within the biovars, three serovars of the T960 biovar exhibited levels of homology of > or = 99.7%, and the four serovars of the parvo biovar exhibited levels of homology of > or = 99.7%. A dendrogram of the Mycoplasma pneumoniae-Ureaplasma clade of the Mollicutes reflected the distinctiveness of the biovars.

DNA, Bacterial↗