Biomedical subjects
J O'Brien
Publications and source records attributed to J O'Brien.
Motion processing in autism: evidence for a dorsal stream deficiency.
We report that motion coherence thresholds in children with autism are significantly higher than in matched controls. No corresponding difference in form coherence thresholds was found. We interpret this as a specific deficit in dorsal stream function in autism. To examine the possibility of a neural basis for the perceptual and motor related abnormalities frequently cited in autism we tested 23 children diagnosed with autistic disorder, on two tasks specific to dorsal and ventral cortical stream functions. The results provide evidence that autistic individuals have a specific impairment in dorsal stream functioning. We conclude that autism may have common features with other developmental disorders and with early stages of normal development, perhaps reflecting a greater vulnerability of the dorsal system.
Immune function and vaccine responses in healthy advanced elderly patients.
BACKGROUND: Decline in immune function has been reported to predictably accompany advancing age. However, to our knowledge, few studies have specifically characterized the rapidly expanding advanced elderly population or controlled adequately for concurrent diseases. OBJECTIVE: To assess whether successfully reaching an advanced age in good health is associated with preserved immune function. METHODS: We prospectively compared in vivo with in vitro variables of immune function in 29 healthy, independently living elderly subjects (mean age, 80 years; age range, 75-103 years) and in 21 healthy young control subjects (mean age, 29 years; age range, 25-35 years) in a Veterans Affairs Medical Center. RESULTS: In vivo, among elderly and young subjects, numbers of total white blood cells, monocytes, lymphocytes, and lymphocyte subsets (CD4(+) and CD8(+) T lymphocytes and CD20(+) B cells) were similar, as were levels of total serum IgG and IgM. Only levels of serum IgA were higher in the elderly subjects (3.0 vs 1.7 g/L; P=.001). Functionally, both groups showed vigorous responses to protein (tetanus and diphtheria toxoids) and polysaccharide (23-valent pneumococcal) vaccines. Although levels varied, the fold increases in vaccine antigen-specific IgG were not significantly different in young and elderly subjects, and the avidities of IgG to pneumococcal polysaccharides 14 and 19F were similar before and after vaccination. In vitro, proliferative responses of blood mononuclear cells to T-lymphocyte and B-cell mitogens (pokeweed mitogen, Staphylococcus aureus Cowan strain I, and S aureus Cowan strain I plus interleukin 2), and lipopolysaccharide-induced production of tumor necrosis factor alpha, were comparable in elderly vs young subjects. CONCLUSION: Successful aging, defined by reaching an advanced age with one's overall health intact, may be associated with preserved immune function and adequate responses to vaccines.
End of life treatment decisions in people with dementia: carers' views and the factors which influence them.
OBJECTIVE: Treatment decisions in life threatening situations (TD) are poorly studied in people with dementia. METHOD: The carers of people with dementia were asked four TD questions, pertaining to cardiac resuscitation, intravenous fluids, oral antibiotics and intravenous antibiotics. The impact of key variables (age, dementia severity, psychiatric co-morbidity, physical illness, family relationship of carer) on TD were evaluated. RESULTS: Fifty carers participated, 46% wanted cardiac resuscitation, 60% wanted treatment with intravenous fluids, 52% wanted treatment with intravenous antibiotics and 60% wanted treatment with oral antibiotics. Agreement between questions was high (76 - 89%), suggesting that relatives were either for or against intervention. There was an association between more severe dementia and a reduced wish for intravenous antibiotics. None of the variables significantly influenced other TD. CONCLUSION: The 'global' view of carers, was not influenced greatly by key disease variables. There are potential implications for the way in which carers are used as proxy decision makers.
Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors.
Cholinergic neurons degenerate in Alzheimer's disease, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M1 muscarinic agonists. 5-(3-Ethyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine trifluoroacetic acid (CDD-0102) stimulates M1 muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230-1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonist to M1 receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735-745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M1 receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129-1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M1 receptor affinity, selectivity and activity.
IL-2 promotes the subset restoration of intraepithelial lymphocytes after ischemia/reperfusion injury.
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Anxiety, depression and psychosis in vascular dementia: prevalence and associations.
BACKGROUND: Little is known about psychiatric symptoms in Vascular dementia (VaD). METHOD: 92 patients with VaD, and 92 patients with Alzheimer's disease (AD) are reported. The evaluation included standardised measures of mood and psychosis. RESULTS: 72% of VaD patients and 38% of those with AD had two or more anxiety symptoms. VaD patients with severe dementia (94%) were the most likely to be anxious. Depression was also significantly more common in VaD patients (19% vs. 8%) whereas psychotic symptoms were prevalent in both dementias. CONCLUSION: Psychiatric symptoms are common in VaD, especially in patients with moderate or severe dementia. Rigorous assessment of psychiatric symptoms in VaD should be part of good clinical practice.
Depression in the carers of dementia sufferers: a comparison of the carers of patients suffering from dementia with Lewy bodies and the carers of patients with Alzheimer's disease.
BACKGROUND: Depression has not previously been studied in the carers of patients suffering from dementia with Lewy Bodies (DLB). METHOD: Twenty-five DLB carers were matched with 75 AD carers, according to carer characteristics. A standardised assessment incorporated measures of cognition, depression, psychosis and behavioural disturbance. DLB (consensus criteria), and AD (NINCDS ADRDA criteria) were diagnosed using operationalised clinical criteria. Carer depression was diagnosed using the Research Diagnostic Criteria. RESULTS: The overall frequency of depression was similar in DLB and AD carers (28% vs. 31%). DLB carers were significantly more likely to experience a major depressive disorder (3/25 - 12% vs. 0/75 - 0% chi(2)=9.3, P=0.002, df 1), although the numbers were small. The severity of behavioural disturbance was associated with carer depression in the DLB carers and in the total sample. CONCLUSION: The severity of behavioural disturbance was significantly associated with depression in DLB carers.
A simple and effective separation and purification procedure for DNA fragments using dodecyltrimethylammonium bromide.
In this work we describe a simple two step separation procedure for the separation and purification of short DNA fragments. The first step involves precipitating the DNA using the cationic surfactant dodecyltrimethylammonium bromide. Dodecyltrimethylammonium bromide, unlike cetyltrimethylammonium bromide will not precipitate DNA before complexation is complete thus providing a high purity DNA. The second step involves dissolution of the DNA-dodecyltrimethylammonium complex in 75% ethanol, followed by precipitation of the Sodium-DNA salt, by titrating in a salt solution. This method is particularly suited to purification of short fragments as it does not require high salt concentrations in the ethanol precipitation step, which can be damaging for short DNA. The ability of dodecyltrimethylammonium bromide to remove ethidium bromide from intercalation sites on the DNA is also discussed
The centromeric part of the human NK gene complex: linkage of LOX-1 and LY49L with the CD94/NKG2 region.
The natural killer (NK) gene complex is a genomic region containing lectin-type receptor genes. We have established a contig of PAC and BAC clones comprising about 1 Mb of the centromeric part of the NK gene complex. This region extends from the LOX-1 gene, which encodes a receptor for oxidized LDL and was found within 100 kb telomeric of the STS marker D12S77, contains the CD94 and NKG2 NK receptor genes and reaches beyond D12S852 on the proximal side. In this part we have mapped the human LY49L gene, a homologue of the rodent Ly49 genes, which encode important MHC class I receptors for the regulation of NK cell activity in rodents. The LY49L gene is localized 100 to 200 kb centromeric of the NKG2 gene cluster and 300 to 400 kb telomeric of the STS marker D12S841. Genomic sequencing of the complete gene including promoter and intron sequences confirmed that the structure is similar to the mouse Ly49 genes. Screening of several cDNA libraries did not detect any transcripts of putative additional human LY49 genes. In addition, in the course of these studies several EST sequences were localized in the region, one immediately upstream of the LY49L gene.
Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity.
We show here the identity of Alamar Blue as resazurin. The 'resazurin reduction test' has been used for about 50 years to monitor bacterial and yeast contamination of milk, and also for assessing semen quality. Resazurin (blue and nonfluorescent) is reduced to resorufin (pink and highly fluorescent) which is further reduced to hydroresorufin (uncoloured and nonfluorescent). It is still not known how this reduction occurs, intracellularly via enzyme activity or in the medium as a chemical reaction, although the reduced fluorescent form of Alamar Blue was found in the cytoplasm and of living cells nucleus of dead cells. Recently, the dye has gained popularity as a very simple and versatile way of measuring cell proliferation and cytotoxicity. This dye presents numerous advantages over other cytotoxicity or proliferation tests but we observed several drawbacks to the routine use of Alamar Blue. Tests with several toxicants in different cell lines and rat primary hepatocytes have shown accumulation of the fluorescent product of Alamar Blue in the medium which could lead to an overestimation of cell population. Also, the extensive reduction of Alamar Blue by metabolically active cells led to a final nonfluorescent product, and hence an underestimation of cellular activity.
When texture takes precedence over motion in depth perception.
Both texture and motion can be strong cues to depth, and estimating slant from texture cues can be considered analogous to calculating slant from motion parallax (Malik and Rosenholtz 1994, report UCB/CSD 93/775, University of California, Berkeley, CA). A series of experiments was conducted to determine the relative weight of texture and motion cues in the perception of planar-surface slant when both texture and motion convey similar information. Stimuli were monocularly viewed images of planar surfaces slanted in depth, defined by texture and motion information that could be varied independently. Slant discrimination biases and thresholds were measured by a method of single-stimuli binary-choice procedure. When the motion and texture cues depicted surfaces of identical slants, it was found that the depth-from-motion information neither reduced slant discrimination thresholds, nor altered slant discrimination bias, compared to texture cues presented alone. When there was a difference in the slant depicted by motion and by texture, perceived slant was determined almost entirely by the texture cue. The regularity of the texture pattern did not affect this weighting. Results are discussed in terms of models of cue combination and previous results with different types of texture and motion information.
Information theoretical probe selection for hybridisation experiments.
MOTIVATION: The choice of probes is an important feature of hybridisation experiments. In this paper we present an algorithm that optimises probes with respect to a training set of sequences based on Shannon entropy as a quality criterion. The practical motivation for our algorithm is oligonucleotide fingerprinting, a method for the simultaneous identification of sequences (cDNA or genomic DNA) by their hybridisation tags according to a set of short probes such as octamers, although the algorithm is of course not restricted to that application. RESULTS: We can show that our method is superior to the selection of probes according to their frequencies, which is a widely used strategy, and to randomly chosen probe sets. The quality of probe sets is assessed by a simulation pipeline that entails the set of probes as a simulation parameter. The performance of probe sets trained on sequences from different organisms shows additionally that probes should be chosen with regard to the organism under analysis. Case studies are presented on how constraints (G+C-content, complexity of the individual probes) influence the selection process. AVAILABILITY: A description of the oligonucleotide fingerprinting pipeline is published on our web-page http://www.molgen.mpg.de/ approximately ag_onf/met.htm. An executable of the algorithm and probe lists designed for human and rodents can be downloaded from the ftp-site ftp://ftp.molgen.mpg.de/pub/mpimg/probe_design/.
Breast cancer metastatic to the choroid in a male patient.
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Tissue gene expression analysis using arrayed normalized cDNA libraries.
We have used oligonucleotide-fingerprinting data on 60,000 cDNA clones from two different mouse embryonic stages to establish a normalized cDNA clone set. The normalized set of 5,376 clones represents different clusters and therefore, in almost all cases, different genes. The inserts of the cDNA clones were amplified by PCR and spotted on glass slides. The resulting arrays were hybridized with mRNA probes prepared from six different adult mouse tissues. Expression profiles were analyzed by hierarchical clustering techniques. We have chosen radioactive detection because it combines robustness with sensitivity and allows the comparison of multiple normalized experiments. Sensitive detection combined with highly effective clustering algorithms allowed the identification of tissue-specific expression profiles and the detection of genes specifically expressed in the tissues investigated. The obtained results are publicly available (http://www.rzpd.de) and can be used by other researchers as a digital expression reference.
Nonsteroidal anti-inflammatory drugs in patients with inflammatory bowel disease.
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Neurocardiovascular instability, hypotensive episodes, and MRI lesions in neurodegenerative dementia.
We investigated whether carotid sinus hypersensitivity (CSH) and orthostatic hypotension (OH) were associated with a greater severity of hyperintensities on MRI scan in 30 patients with neurodegenerative dementia (17 dementia with Lewy bodies, 13 Alzheimer's disease), who had a detailed evaluation of OH and CSH during active standing and head-up tilt. Patients also underwent a 1.0 Tesla MRI scan, from which hyperintensities were rated on a standardized scale. A blood pressure (BP) drop > 30 mm Hg during carotid sinus massage or active standing was significantly associated with the severity of MRI hyperintensities in the deep white matter (OR 10.0, 95%; CI 1.8-55.7) and in the basal ganglia (OR 11.0, 95%; CI 1.2-99.5) but not in periventricular areas (OR 1.4, 95%; CI 0.3-1.8). Patients with the cardio-inhibitory form of CSH with the largest BP drops were the most at risk. Further longitudinal studies need to investigate the direction of causality to determine whether CSH or OH predispose to MRI hyperintensities and accelerate cognitive decline.
The association between white matter lesions on magnetic resonance imaging and noncognitive symptoms.
A number of studies have suggested that cerebral changes, particularly deep white matter lesions (WML) visualized on magnetic resonance imaging (MRI), may be involved in the genesis of late life depression. This has been confirmed in a prospective study which also found a relationship between the presence of WML and poor 3-year outcome in elderly depressed subjects. Most studies find these lesions to predominate in frontal lobe and basal ganglia, supporting the hypothesis of "fronto-striatal" dysfunction in depression. To investigate whether WML are associated with mood disturbance in dementia, proton density and T2-weighted images were obtained in 80 subjects with dementia (dementia with Lewy bodies, n = 27; Alzheimer's disease, n = 28; vascular dementia, n = 25) and 26 age-matched normal controls. Periventricular lesions (PVL), white matter lesions (WML), and basal ganglia hyperintensities (BG) were visually rated blind to diagnosis using a semiquantitative scale. Frontal WML were associated with higher depression scores in patients with dementia, implying a common pathophysiology of depression irrespective of diagnosis. Further study of the neurobiological basis of WML is needed. This can best be achieved by serial clinical assessment combined with in vivo and in vitro MRI and neuropathological examination.