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Biomedical subjects

J Vaughan

Publications and source records attributed to J Vaughan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype.

A recent study showed significant association of sporadic Parkinson's disease with a polymorphism within the alpha-synuclein gene and closely linked DNA markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha-synuclein/APOE-epsilon4 genotype increased the relative risk of developing Parkinson's disease 12-fold. We failed to confirm this association in a much larger sample of histopathologically proven cases of Parkinson's disease and controls.

Alleles↗
PubMed2001

Occupational health surveillance strategies for an ethnically diverse Asian employee population.

1. Implementation of a medical/health surveillance program can prevent the damaging effects of lead toxicity. Lead toxicity may be a result of acute or chronic exposure and can affect the hematopoietic, nervous, renal, and reproductive systems. 2. Minority groups tend to be overrepresented in lead industries. Further, an increase in high lead levels can be compounded by cultural influences. Education must be geared toward the specific employee populations. 3. Successful programs require assistance from all team members--occupational health nurse, safety engineer, industrial hygienist, and environmental engineer. Occupational health nurses play an important role in implementation of medical/health surveillance programs by scheduling regular blood testing, monitoring results, and educating employees.

Asia↗
PubMed2000

Association between early-onset Parkinson's disease and mutations in the parkin gene.

BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.

Adolescent↗
PubMed1999

Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors.

Histochemical and axonal transport methods were used to clarify the central organization of cells and fibers that express urocortin (UCN), a recently discovered corticotropin-releasing factor (CRF)-related neuropeptide, which has been proposed as an endogenous ligand for type 2 CRF receptors (CRF-R2). Neurons that display both UCN mRNA and peptide expression were found to be centered in the Edinger-Westphal (EW), lateral superior olivary (LSO), and supraoptic nuclei; lower levels of expression are seen in certain cranial nerve and spinal motoneurons and in small populations of neurons in the forebrain. Additional sites of UCN mRNA and peptide expression detected only in colchicine-treated rats are considered to be minor ones. UCN-immunoreactive projections in brain are predominantly descending and largely consistent with central projections attributed to the EW and LSO, targeting principally accessory optic, precerebellar, and auditory structures, as well as the spinal intermediate gray. Although neither the EW nor LSO are known to project to the forebrain, UCN-ir neurons in the EW were identified that project to the lateral septal nucleus, which houses a prominent UCN-ir terminal field. Although substantial UCN-ir projections were observed to several brainstem cell groups that express CRF-R2, including the dorsal raphe and interpeduncular nuclei and the nucleus of the solitary tract (NTS), most prominent seats of CRF-R2 expression were found to contain inputs immunopositive for piscine urotensin I, but not rat UCN. The results define a central UCN system whose organization suggests a principal involvement in motor control and sensorimotor integration; its participation in stress-related mechanisms would appear to derive principally by virtue of projections to the spinal intermediolateral column, the NTS, and the paraventricular nucleus. Several observations, including the lack of a pervasive relationship of UCN-ir projections with CRF-R2-expressing targets, support the existence of still additional CRF-related peptides in mammalian brain.

Amino Acid Sequence↗
PubMed1999

Mutations in the gene encoding human persyn are not associated with amyotrophic lateral sclerosis or familial Parkinson's disease.

The synucleins are a family of small proteins expressed in nervous tissue, which have been implicated in neurodegeneration. Using single strand conformation polymorphism analysis we screened for polymorphisms and mutations in the gene encoding human persyn, a recently discovered member of the synuclein family, in controls, patients with sporadic or familial amyotrophic lateral sclerosis (ALS) or familial Parkinson's disease (PD). Six polymorphisms in the genomic sequence of persyn were detected; A590C (5' untranslated region), G1943C (exon 3), G2049A (intron 3), T4502C (intron 3), T4552A (exon 4) and C5019T (3' untranslated region). However no associations with disease state were found in our sample group.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.

A coding substitution (I93M) in the ubiquitin carboxy-terminal L1 (UCH-L1) gene has recently been identified in a German family with Parkinson's disease. We have sequenced the entire coding region of the gene in 11 families who have a pattern of disease consistent with autosomal dominant inheritance. We found a polymorphism (S18Y) in exon 3, two polymorphisms in the 5' non-coding region, upstream of the transcription start, and an insertion/deletion polymorphism in intron 4. The S18Y allele is present on approximately 20% of chromosomes in a Caucasian population. These changes are, therefore, unlikely to be pathogenic. We conclude that the I93M variant must either be a rare cause of disease or a harmless substitution whose occurrence in the family reflects a chance co-occurrence.

Adult↗
PubMed1999

Remembered positions: stored locations or stored postures?

Many recent studies indicate that memory for final position is superior to memory for movement. There is ambiguity about what is meant by the term final position, however. Is it final spatial location or final posture? According to a recently proposed theory by Rosenbaum et al., which maintains that stored postures form the basis for movement planning, when people try to return to recently reached positions, they should try to adopt the postures they just occupied. An alternative view, which holds that movements are primarily planned with respect to spatial locations, predicts that subjects should tend to return to places in external space. We describe an experiment that tested these opposing predictions. The experiment relied on the notion that if people store and use postures, they should "copy" the posture adopted with one arm to the other arm when possible. The results support this hypothesis. In this article, we review previous work that bears on the question of what is learned when people move repeatedly to a given position. Then we present two theoretical perspectives which make diverging predictions about what should be learned in repositioning tasks. One perspective predicts that final positions are remembered as postures; the other predicts that final positions are remembered as locations. We describe an experiment designed to distinguish between these two predictions. The experiment indicates that final postures are remembered and are "copied" from one arm to the other when subjects try to reach repeatedly to the same location in the midsagittal plane with alternating arms or when subjects try to reach repeatedly to the same location anywhere in the workspace with the same arm. In the last section of the article, we discuss the implications of our findings.

Adult↗
PubMed1999

Coordination of reaching and grasping by capitalizing on obstacle avoidance and other constraints.

Reaching and grasping an object can be viewed as the solution of a multiple-constraint satisfaction problem. The constraints include contact with the object with the appropriate effectors in the correct positions as well as generation of a collision-free trajectory. We have developed a computational model that simulates reaching and grasping based on these notions. The model, rendered as an animation program, reproduces many basic features of the kinematics of human reaching and grasping behavior. The core assumptions of the model are: (1) tasks are defined by flexibly organized constraint hierarchies; (2) manual positioning acts, including prehension acts, are first specified with respect to goal postures and then are specified with respect to movements towards those goal postures; (3) goal postures are found by identifying the stored posture that is most promising for the task, as determined by the constraint hierarchy, and then by generating postures that are more and more dissimilar to the most-promising stored posture until a deadline is reached, at which time the best posture that was found during the search is defined as the goal posture; (4) depending on when the best posture was encountered in the search, the deadline for the search in the next trial is either increased or decreased; (5) specification of a movement to the goal posture begins with straight-line interpolation in joint space between the starting posture and goal posture; (6) if an internal simulation of this default movement suggests that it will result in collision with an obstacle, the movement can be reshaped until an acceptable movement is found or until time runs out; (7) movement reshaping occurs by identifying a via posture that serves as a body position to which the actor moves from the starting posture and then back to the starting posture, while simultaneously making the main movement from the starting posture to the goal posture; (8) the via posture is identified using the same posture-generating algorithm as used to identify the goal posture. These processes are used both for arm positioning and, with some elaboration, for prehension. The model solves a number of problems with an earlier model, although it leaves some other problems unresolved.

Avoidance Learning↗
PubMed1999

Transgene expression and repression in transgenic rats bearing the phosphoenolpyruvate carboxykinase-simian virus 40 T antigen or the phosphoenolpyruvate carboxykinase-transforming growth factor-alpha constructs.

Transgenic Sprague-Dawley rats expressing either human transforming growth factor-alpha (TGFalpha) or simian virus 40 large and small T antigen (TAg), each under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, were developed as an approach to the study of the promotion of hepatocarcinogenesis in the presence of a transgene regulatable by diet and/or hormones. Five lines of PEPCK-TGFalpha transgenic rats were established, each genetic line containing from one to several copies of the transgene per haploid genome. Two PEPCK-TAg transgenic founder rats were obtained, each with multiple copies of the transgene. Expression of the transgene was undetectable in the TGFalpha transgenic rats and could not be induced when the animals were placed on a high-protein, low-carbohydrate diet. The transgene was found to be highly methylated in all of these lines. No pathological alterations in the liver and intestine were observed at any time (up to 2 years) during the lives of these rats. One line of transgenic rats expressing the PEPCK-TAg transgene developed pancreatic islet cell hyperplasias and carcinomas, with few normal islets evident in the pancreas. This transgene is integrated as a hypomethylated tandem array of 10 to 12 copies on chromosome 8q11. Expression of large T antigen is highest in pancreatic neoplasms, but is also detectable in the normal brain, kidney, and liver. Mortality is most rapid in males, starting at 5 months of age and reaching 100% by 8 months. Morphologically, islet cell differentiation in the tumors ranges from poor to well differentiated, with regions of necrosis and fibrosis. Spontaneous metastasis of TAg-positive tumor cells to regional lymph nodes was observed. These studies indicate the importance of DNA methylation in the repression of specific transgenes in the rat. However, the expression of the PEPCK-TAg induces neoplastic transformation in islet cells, probably late in neuroendocrine cell differentiation. T antigen expression during neoplastic development may result in a pervasive change in the islet cell growth properties with selection of a transformed phenotype as a possible requirement for cell viability.

Animals↗
PubMed1999

Spinal cord dose is higher than expected in head and neck radiation.

Myelopathy is a feared consequence of radiation therapy. Risk factors are multifocal; therefore, total dose calculation is crucial. We evaluated the contribution of scatter radiation to obtain an accurate cumulative spinal cord dose. Twenty patients undergoing three field head and neck radiation by Cobalt or 6 MV Linac had a total cord dose calculated from direct and scatter radiation. The cord was removed from the radiation field at tumor doses no higher than 4,400 cGy. Total tumor dose ranged from 5,400-7,400 cGy (mean 6060). All patients achieved the prescribed dose and none were lost to follow up (mean 36 months). It was found that scatter radiation can contribute as much as 20% extra dose to the spinal cord. Mean extra dose was 9% (range 1%-20%). This additional dose ranged from 52-810 cGy (mean 339 cGy). No apparent difference was seen with Cobalt or Linac source. Our conclusion was that significant additional dose is delivered to the spinal cord by scatter radiation and that scatter may contribute more to the development of myelopathy than previously believed.

Cobalt Radioisotopes↗
PubMed1999

Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats.

Determining both the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) acts as a tumor promoter and the shape of the dose-response curve at low doses remains an important goal of risk-assessment-directed research. In this report, we extend previous mechanistic and descriptive work done on the effect of TCDD on promotion in the two-stage model of hepatocarcinogenesis, to include lower, more clinically relevant doses. After initiation [PH + 10 mg diethylnitrosamine (DEN)/kg], groups of female Sprague-Dawley rats were administered TCDD in one of four doses: 0.01, 0.1, 1.0, or 10 ng/kg/day for 1, 3, or 6 months. Early increases in liver weight (19-69%) due to hepatocyte hypertrophy were resolved after 3- or 6-months exposures to TCDD, and were not associated with the effects of TCDD on promotion. Non-focal cell proliferation in DEN-treated groups was significantly reduced after 1 or 3 months of exposure to 0.1 ng/kg/day TCDD, leading to U-shaped dose-response curves. TCDD effects on non-focal cell proliferation were not associated with effects on promotion. GSTP-positive AHF represented approximately 97% of the total AHF. Significant increases in both the volume fraction and the number of altered hepatic foci (AHF) were observed at the highest dose (10 ng/kg/day) for GSTP-positive AHF in DEN-treated groups. Increases in the number of G6Pase- and ATPase-deficient AHF/cm3 were observed at TCDD doses as low as 0.01 ng/kg/day. This is the lowest tumor-promoting dose of TCDD reported to date. This study represents an unusually complete data set for further dose-response analysis and simulation or mathematical modeling of TCDD-mediated promotion in the rat liver.

Alkylating Agents↗
PubMed1999

Short-term fasting and the reversal of the stage of promotion in rat hepatocarcinogenesis: role of cell replication, apoptosis, and gene expression.

Studies of the multistage nature of hepatocarcinogenesis in the rat have led to the development of models having significant potential application to carcinogenesis in other tissues as well as other species. Whereas the initial and final stages of carcinogenesis-initiation and progression-involve genetic changes and are operationally irreversible, the intermediate stage of promotion is operationally reversible and can be modulated by a variety of environmental factors. Numerous investigations have demonstrated that chronic caloric restriction modifies neoplastic development, primarily during the stage of promotion, so that fewer lesions develop. Short-term fasting of rats, initiated with a nonnecrogenic dose of diethylnitrosamine (DEN) and promoted with 0.05% phenobarbital (PB) for 4 weeks, results in loss of virtually all of the measurable altered hepatic foci (AHF) after two 5-day periods of fasting with an intermediate 2-day period of feeding. This change was accompanied by a marked decrease in bromodeoxyuridine (BrdU) labeling of hepatocytes within AHF together with a significant increase in apoptosis of such cells measured by nick end-labeling. Similar but lesser effects were noted in surrounding, nonfocal hepatocytes. On refeeding, both the numbers and volume percentage of AHF returned within 2 weeks to values seen in nonfasted controls. Administration of PB during the fasting period did not alter these results, although AHF reappeared more rapidly in such animals on refeeding. Nuclear DNA fragmentation was evident in samples of whole liver from fasted animals. During this same period the expression of c-myc mRNA increased 3- to 9-fold, while levels of albumin and insulin-like growth factor I mRNAs decreased significantly. This study demonstrates a model system in which the reversibility of the effects of promoting agents may be rapidly determined and the effects of chemopreventive inhibitors of promotion may be rapidly evaluated.

Animals↗
PubMed1999

Approaching grasping from different perspectives.

The hypothesis introduced by Smeets and Brenner concerning the perpendicular approach of the thumb and index finger during grasping has heuristic value, but it also has limitations. Among the limitations are the following: (a) the approach parameter is not directly testable and it is unclear how the values of deceleration at contact and movement time are set theoretically; (b) it is questionable that motion of the thumb and index finger are independent; (c) reliance on the minimum-jerk account ignores critiques of that account; and (d) the model begs the question of how the effectors proximal to the index finger and thumb are controlled. We briefly review an alternative model that can handle these challenges.

Biomechanical Phenomena↗
PubMed1999

Urocortin is not a significant regulator of intermittent electrofootshock-induced adrenocorticotropin secretion in the intact male rat.

Urocortin (Ucn) is a newly identified mammalian member of the CRF family of peptides. Ucn activates CRF receptors (both CRF-R1 and CRF-R2) with greater potency than CRF itself, suggesting that Ucn may play an endogenous role in eliciting (at least some) CRF receptor-mediated events. Because the most characterized physiological function of CRF receptors is the activation of pituitary ACTH secretion, we have compared the effects and potential endogenous roles of CRF and Ucn in regulating plasma ACTH concentrations in intact male rats. Synthetic rat Ucn injected i.v. (0.09-9.0 nmol/kg) elicited ACTH secretion in a dose-dependent manner, causing greater ACTH secretion than CRF at each dose tested. The increases in plasma ACTH concentrations produced by CRF or Ucn were virtually abolished by pretreatment with the CRF receptor antagonist, astressin (3 mg/kg), and were partially attenuated (by 27-37%) by an antiarginine vasopressin serum. These data indicate that both Ucn and CRF elicit ACTH secretion via CRF receptor-dependent mechanisms, and that the ACTH-releasing activities of both CRF and Ucn are potentiated by endogenous arginine vasopressin. Intravenous administration of rabbit anti-Ucn serum, which inhibited ACTH secretion produced by Ucn, but not CRF, had no statistically significant effect on either resting (midday) plasma ACTH concentrations or the rise in ACTH levels elicited by 30 min of intermittent electrofootshocks. By contrast, treatment with a rabbit anti-CRF serum that specifically inhibited the ACTH response to CRF lowered plasma concentrations in control unstressed rats and largely prevented the plasma ACTH response to electrofootshocks. These data indicate that although Ucn is a more potent ACTH secretagogue than CRF in the intact male rat, it is not a major endogenous regulator of pituitary ACTH secretion under basal (midday) conditions or during acute footshock stress.

Adrenocorticotropic Hormone↗
PubMed1999

A Web-accessible tutorial for PsyScope based on classic experiments in human cognition.

PsyScope is a graphically oriented, script-based program for the control of experiments on Macintosh computers that has been made freely available to the psychology community by its developers (Cohen, MacWhinney, Flatt, & Provost, 1993) at Carnegie Mellon University. We describe a graduated tutorial that was written for new users of PsyScope (instructors or students); the text and scripts can be retrieved from a website at Hamilton College (http:/(/)cogito.hamilton.edu/tutorial/). The tutorial examples may be used as classroom demonstrations or as pedagogical aids in teaching students how to use PsyScope in their own research projects. The four examples include a Stroop test, simple and choice reaction time, and a sentence-verification task.

Cognition↗