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At least 1,189 records · Page 66Linked to original sources
PubMed2004

Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease.

BACKGROUND: Transcranial ultrasound may be used to detect increased iron levels of the substantia nigra (SN) in patients with Parkinson disease (PD) and in control subjects. It is not known whether iron accumulation in PD is a primary or secondary phenomenon. However, sequence variations in genes involved in iron metabolism have been linked to basal ganglia disorders. One of these is ceruloplasmin (Cp), which is vitally involved in iron transport across the cell membrane. METHODS: One hundred seventy-six patients with PD according to the UK Brain Bank criteria and 180 ethnically matched control subjects, who were previously examined for SN iron signal changes by transcranial ultrasound, were examined for mutations in the Cp gene using denaturing high-performance liquid chromatography and subsequent sequencing for verification of unequivocal signals. Immunohistochemistry of PD midbrains was performed to examine the presence of Cp in Lewy bodies. RESULTS: Five novel missense variations were detected. One of these (I63T) was found in a single PD patient. A known variation (D554E) was significantly associated with PD and the ultrasound marker for increased SN iron levels. Moreover, a third sequence variation (R793H) was found to segregate with the ultrasound marker for increased iron levels in patients and control subjects. Immunohistochemistry demonstrated that Cp co-localizes with Lewy bodies in PD. CONCLUSIONS: Detection of sequence variations in a single Parkinson disease (PD) patient or associated with the ultrasound marker for increased substantia nigra iron levels and the presence of ceruloplasmin (Cp) immunoreactivity in Lewy bodies underline a suspected role for Cp in the pathogenesis of PD. Further functional analyses are warranted to investigate whether these variations are causally linked to the complex pathogenesis of PD in a subset of cases.

Aged↗
PubMed2006

Helping hippocrates: a cross-functional approach to patient identification.

BACKGROUND: The Joint Commission on Accreditation of Healthcare Organizations National Patient Safety Goal 1, which requires the use of at least two patient identifiers, is the foundation for other patient safety goals. St. Francis Hospital involved staff and patients in the "Helping Hippocrates" Project, which used a "game" with staff and patients to ensure the accuracy of information on patients' identification (ID) bands. THE PROJECT: Members of all hospital departments assigned to a specific day were to compare the ID band with the patient census report and identify patients who had no ID band on their wrist and patients who had a band with inaccuracies. They were to also ask patients if the staff had checked the ID band before treatments or procedures. Also, the nurse manager was to select a patient to add to his or her own ID band a special band bearing the name Hippocrates. The department conducting the survey had to find Hippocrates. FINDINGS: Internal data showed that patient identification errors declined from 8.2% to a sustained zero. Patient satisfaction data showed that since the inception of Helping Hippocrates, patients' perceptions of staffs compliance with ID verification showed steady improvement. CONCLUSION: Helping Hippocrates demonstrates the value of using an innovative problem-solving strategy that engages the entire organization.

Humans↗
PubMed2005

Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems.

Withdrawal from nicotine decreases the activity of brain reward systems, measured in rats by elevations of intracranial self-stimulation (ICSS) thresholds. This reward deficit is hypothesized to contribute to the persistence of the tobacco habit in tobacco smokers. Accumulating evidence suggests that aspects of drug withdrawal may become conditioned to previously neutral environmental stimuli via pavlovian conditioning processes. Here we investigated whether hedonically neutral stimuli repeatedly paired with nicotine withdrawal gained "affective valence" such that withdrawal-associated conditioned stimuli alone decreased brain reward function. Nicotine-dependent rats were presented with a light/tone conditioned stimulus and injected with the nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg) for 4 d consecutively; ICSS thresholds were assessed before and immediately after DHbetaE injection. On the test day, the rats were presented with the conditioned stimulus and injected with saline; next, ICSS thresholds were assessed. During conditioning sessions, DHbetaE elevated reward thresholds, and the magnitude by which thresholds were elevated increased during successive conditioning sessions. These data suggest that withdrawal-associated conditioned stimuli potentiated the magnitude of nicotine withdrawal as their motivational significance increased. Most importantly, on the test day, the conditioned stimulus alone elevated reward thresholds. Similarly, in a separate experiment, withdrawal-associated cues elevated reward thresholds in morphine-dependent rats. These data provide the first empirical verification that conditioned nicotine withdrawal may occur after exposure to withdrawal-paired cues. Moreover, these data demonstrate that withdrawal-paired conditioned stimuli attain negative affective valence and can decrease the activity of brain reward systems, mimicking the reward deficit observed during withdrawal from nicotine and other addictive drugs.

Animals↗
PubMed2000

An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.

We assessed whether the efficacy of plant-source derived phosphatydilserine (one of the phospholipids which play an important functional role in membrane-related processes in the brain) for treatment of age related cognitive decline is consistent with previous (placebo controlled) positive findings with bovine derivative of PS (BC-PS). Eighteen healthy elderly volunteers meeting Age Associated Memory Impairment inclusion and exclusion criteria were treated for 12 weeks with plant-source derived phosphatydilserine (PS) (100 mg x 3/day p.o.) and evaluated at base line, after 6 weeks of treatment and at the end of the trial. Fifteen concluded the study. All but two outcome measures elicited a significant drug over time effect. Post-hoc paired t-tests showed that the significant effect was attributable to an improvement from base line to week 6 and that effect was maintained at week 12. These results are encouraging. However, they await double-blind controlled verification in a large sample before suggesting that this may be a viable approach to the treatment of age-related cognitive decline, without exposing the patients to possible hazards involved in the treatment with bovine derivative of PS (BC-PS).

Aged↗
PubMed1999

Experimental observations of non-Gaussian behavior and stringlike cooperative dynamics in concentrated quasi-two-dimensional colloidal liquids.

We report, from direct observation of particle trajectories as a function of time, the presence of stringlike cooperative motion in a quasi-two-dimensional liquid. We have used digital video microscopy to study the equilibrium dynamics of suspensions of sterically stabilized uncharged poly(methylmethacrylate) spheres confined in a thin glass cell. Our experiments reveal the existence, in semidilute and dense liquid states, of a transition in the qualitative dynamical behavior of the system. At short times particles undergo unhindered Brownian motion, at intermediate times they undergo uncorrelated binary collisions, and at long times these one-particle self-diffusive modes are coupled to collective longitudinal acoustic modes of the fluid, the signature of which is local fluctuating domains of enhanced particle mobility. We study the properties of these domains by examining the density dependence of the van Hove self-correlation function and its deviation from Gaussian behavior. We observe that periods of non-Gaussian behavior correlate precisely with the timing of events involved in the relaxation of "caged" particles and their nearest neighbors. In contrast with relaxation processes in supercooled liquids, the lifetime of dynamical heterogeneities in a dissipative colloidal suspension is found to shift towards shorter time scales with increasing particle density. During time periods for which a quasi-two-dimensional system follows Gaussian behavior, we observe that, as predicted by Cichocki and Felderhof [J. Phys. Condens. Matter 6, 7287 (1994)], the time dependence of the evolution of the effective diffusion coefficient from its short time to its long time value has the form (ln t)/t. This last finding is true for all observed particle densities. To our knowledge, these results are the first experimental verification of the existence of microscopic cooperativity and the predicted temporal evolution of the diffusion coefficient for Brownian motion in concentrated quasi-two-dimensional liquids.

Journal Article↗
PubMed2004

Proteomics of protein secretion by Bacillus subtilis: separating the "secrets" of the secretome.

Secretory proteins perform a variety of important "remote-control" functions for bacterial survival in the environment. The availability of complete genome sequences has allowed us to make predictions about the composition of bacterial machinery for protein secretion as well as the extracellular complement of bacterial proteomes. Recently, the power of proteomics was successfully employed to evaluate genome-based models of these so-called secretomes. Progress in this field is well illustrated by the proteomic analysis of protein secretion by the gram-positive bacterium Bacillus subtilis, for which approximately 90 extracellular proteins were identified. Analysis of these proteins disclosed various "secrets of the secretome," such as the residence of cytoplasmic and predicted cell envelope proteins in the extracellular proteome. This showed that genome-based predictions reflect only approximately 50% of the actual composition of the extracellular proteome of B. subtilis. Importantly, proteomics allowed the first verification of the impact of individual secretion machinery components on the total flow of proteins from the cytoplasm to the extracellular environment. In conclusion, proteomics has yielded a variety of novel leads for the analysis of protein traffic in B. subtilis and other gram-positive bacteria. Ultimately, such leads will serve to increase our understanding of virulence factor biogenesis in gram-positive pathogens, which is likely to be of high medical relevance.

Bacillus subtilis↗
PubMed1992

The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension.

The pathophysiology of the frequent association of insulin resistance and hypertension has not been elucidated. The skeletal muscle is the major site of insulin resistance; when stimulated with insulin, the hypertensive skeletal muscles extract less glucose than the normotensive. We postulate that hypertension-related changes in the skeletal muscle microcirculation contribute to the impaired glucose uptake in hypertension. Vascular rarefaction in hypertension impairs the delivery of insulin and glucose to muscle cells. Insulin resistance has been described both in human and experimental hypertension and both conditions are associated with vascular rarefaction. Functional studies (response to whole body or forearm exercise) and anatomic investigations (conjunctival photography, mesenteric and muscle biopsies) show vascular rarefaction in human hypertension. In addition, patients with hypertension are known to have a larger proportion of insulin resistant, poorly vascularized fast twitch muscle fibers. A few interventions can increase or decrease insulin resistance and these effects can be explained on hemodynamic grounds. Beta adrenergic blocking agents aggravate insulin resistance, and their main hemodynamic effect is a decrease of cardiac output. Converting enzyme inhibitors, alpha adrenergic blocking agents and possibly calcium antagonists decrease the insulin resistance, and their major hemodynamic effect is vasodilation. Physical training decreases insulin resistance; a higher capillary density in skeletal muscles is the hallmark of physical training. A hypothesis ought to rest on sufficient supporting data and its validity ought to lend itself to experimental verification. We believe our hypothesis meets both criteria. After outlining the supporting evidence we propose a number of tests to prove or disprove the hypothesis. In addition to the testable hypothesis we also speculate on the possible cause of the frequent association between hypertension and insulin resistance. We propose that both insulin resistance and blood pressure elevation represent a facet of the "defense reaction" which might have offered an early survival advantage and may, over evolutionary times, have fostered natural selection of subjects with both conditions.

Animals↗
PubMed2003

[Coding single nucleotide polymorphism is an ideal marker for detecting gene imprinting by 5' nuclease assay].

OBJECTIVE: To establish a novel approach for quick and high throughput verification of human gene imprinting. METHODS: By use of a pair of dye-labeled probes, 5' nuclease assay was combined with reverse transcriptase-PCR(RT-PCR) to genotype a coding single nucleotide polymorphism (cSNP), rs705(C/T) of a known imprinted gene, small nuclear ribonucleotide protein N (SNRPN), on both genomic DNA and cDNA of human lymphoblast cell lines. RESULTS: Allele discrimination showed a clear monoallelic expression pattern of SNRPN, which was confirmed by RT-PCR based restriction fragment length polymorphisms. Pedigree analysis verified the paternal origin of expressed allele, which is in consistency with previous report. CONCLUSION: Coding SNP is an ideal marker for detecting gene imprinting by 5' nuclease assay. This approach has also a potentiality to discover differential allele expression of non-imprinted genes in order to find gene cis-acting functional polymorphism.

Alleles↗
PubMed1995

Magnetic resonance imaging verification of a multi-compartment perfusion model for a chromatography gel phantom.

A model of MRI signal intensity was developed for chromatography column phantoms containing Sephadex gels, which were used to simulate tissue perfusion and the exchange of protons between extravascular and intravascular tissue compartments. Computer simulations of two-compartment and three-compartment models were compared in experiments that used two chromatography columns. One column contained a Sephadex G-25 gel that had a smaller pore size and a slower rate of exchange between extrabead and intrabead compartments than did a second column, which contained a G-50 gel with a larger pore size. In both columns the beads were of approximately the same size to simulate the same ratio of intrabead volume to extrabead volume. Slice-selective spin-echo experiments were performed with the columns oriented parallel to each other in a 1.5 T imager and parallel to the magnetic field, with water flowing through each column perpendicular to the slice at mean flow velocities ranging between 0 and 0.66 mm/s. The results of the experiments agreed with computer simulations, which showed that the MRI signal intensity in the perfused columns is a function of the rate of exchange between extrabead and intrabead compartments. The exchange process modifies the transit time of protons passing through an excited region. The simulations also showed that both two-compartment and three-compartment models could be used to fit the experimental data. Experiments with chromatography gel columns are a preliminary investigation into the potential of using MRI to measure the exchange between extravascular and intravascular compartments of endogenous protons during blood perfusion of biological tissue.

Body Fluid Compartments↗
PubMed1990

Changes in retention of a visual discrimination task following unilateral and bilateral transections of temporo-entorhinal connections in rats.

In a previous study, it was shown that the lateral entorhinal cortex (LEC) in the left hemisphere contains higher concentration of glutamate than in the right hemisphere. The purpose of the present study was to examine potential relationship between this neurochemical asymmetry and behavior. Rats with either left, right, or bilateral transections of the fiber connections between the temporal cortex and LEC were tested for postoperative retention of a visual discrimination task. Because histological verification of lesions was crucial in this study, analyses of neurochemistry had to be omitted. The results showed that both left and bilateral lesions resulted in impaired retention, but the bilateral group was even more impaired than the left group. The rats with lesions in the right hemisphere, however, used fewer trials to reach the learning criterion than the control group, but they did not make fewer errors than the controls. The results are discussed in terms of lateralization of mnemonic processes.

Analysis of Variance↗
PubMed1991

Morphometric, histochemical and autoradiographic studies on myocardial cells in experimental cardiac hypertrophy and ischemia.

Experimental studies were conducted into 170 adult male Wistar rats for the purpose of analysis of cellular adaptation processes of the myocardium to acute ischemia. One group of the animals were exposed to physical endurance training, i.e. 180 h of swimming exercises, up to 3 h daily. Positive verification of cardiac hypertrophy was considered a measure of accomplished cellular adaptation. Training-induced increase of relative and absolute heart weight was 25 and 30%, respectively. Acute myocardial ischemia had been produced by ligature of the left coronary artery. There were no significant differences between trained and untrained animals for incidence and size of infarction and postoperative lethality, while cardiac decompensation was less often recorded from trained animals. To study cellular adaptation as well as differences between trained and untrained animals, tissue samples were taken from the non-ischemic part of the left ventricle and checked by means of histology, electron microscopy, morphometry, quantitative histochemistry, and histo-autoradiography 1, 2, 4, 7, and 14 days after occlusion of the coronary artery. The studies have shown endurance training to result in unambiguous modification of structural as well as functional response of the nonischemic heart. Included in such structural modification at cellular level are significant changes in mitochondrial membranes, sarcoplasmic reticulum, and T-system. Structural modification was reflected in changes to the oxidative enzymes and DNA metabolism. Different patterns of cellular reaction could be positively verified up to 14 days after myocardial infarction.

Animals↗
PubMed1991

Mica-associated pulmonary interstitial fibrosis.

We present the clinical and biopsy findings of a 63-yr-old white male with interstitial pulmonary fibrosis and a long history of extensive exposure to mica while working in the rubber industry. The patient presented 30 yr after the initial exposure with complaints of progressive shortness of breath and a chronic nonproductive cough. Pulmonary function testing revealed restrictive lung function with a mild reduction in the total lung capacity (80% of predicted) and a moderate-to-severe reduction in the diffusing capacity of carbon monoxide (50% of predicted). The chest radiogram and high-resolution chest CT scan showed diffuse fibrosis and focal honeycombing involving the upper and lower lung zones bilaterally. Bronchoalveolar lavage revealed 20% neutrophils in the lavage fluid with abundant rectangular flaking crystals. Open-lung biopsy exhibited extensive fibrosis and architectural remodeling with abundant sheets and fragments of engulfed polarizable crystalline material. Energy-dispersive spectroscopy and electron diffraction studies confirmed the material to have the features of mica. Asbestos and other silicates were not identified. The documentation of prolonged exposure to mica, the clinical and radiographic features of severe interstitial fibrosis, and the histopathologic delineation of the interstitial lesion, including spectroscopic and crystallographic verification of crystalline mica, support the causal relationship between mica and interstitial fibrosis.

Aged↗
PubMed2006

Vertebrate gene finding from multiple-species alignments using a two-level strategy.

BACKGROUND: One way in which the accuracy of gene structure prediction in vertebrate DNA sequences can be improved is by analyzing alignments with multiple related species, since functional regions of genes tend to be more conserved. RESULTS: We describe DOGFISH, a vertebrate gene finder consisting of a cleanly separated site classifier and structure predictor. The classifier scores potential splice sites and other features, using sequence alignments between multiple vertebrate species, while the structure predictor hypothesizes coding transcripts by combining these scores using a simple model of gene structure. This also identifies and assigns confidence scores to possible additional exons. Performance is assessed on the ENCODE regions. We predict transcripts and exons across the whole human genome, and identify over 10,000 high confidence new coding exons not in the Ensembl gene set. CONCLUSION: We present a practical multiple species gene prediction method. Accuracy improves as additional species, up to at least eight, are introduced. The novel predictions of the whole-genome scan should support efficient experimental verification.

Animals↗
PubMed1988

Dynamics of activation in semantic and episodic memory.

Spreading-activation models for the structure of semantic and episodic memory postulate a network of interconnected nodes in which activation spreads from a source node to recipient nodes. These models account for a broad range of memory-related processes, including word recognition, sentence verification, prose comprehension, and sentence production. A fundamental question regarding this account concerns the nature of activation growth at each node in the network. Two mutually exclusive possibilities are (a) that activation grows in a discrete fashion, making abrupt transitions between two or more distinct states and (b) that activation grows continuously from a resting level to an asymptotic level. In the present article, we characterize this dichotomy with examples from the literature, and we apply an adaptive priming procedure for testing discrete versus continuous activation models. Our procedure involves the presentation of prime stimuli at various moments before a test stimulus; subjects are required to make a lexical (word/nonword) decision about the test stimulus. The duration of the interval between the prime and test stimuli is varied adaptively on the basis of subjects' performance. Reaction times are recorded as a function of this duration. According to discrete activation models, there is a unique reaction-time distribution associated with each possible state of node activation. The distribution of reaction times observed when the test stimulus appears near the moment of transition between discrete states should therefore constitute a finite mixture of the underlying basis distributions associated with the individual discrete activation states. The mixture proportion will depend on the relation between the priming interval and the distribution of state-transition times. Continuous activation models assert instead that activation grows continuously over time and that there is a unique reaction-time distribution associated with any given degree of intermediate priming. Such models predict that no finite mixture distribution will emerge when the priming interval has a fixed intermediate duration. Two experiments with the adaptive priming procedure are reported to test these alternative predictions. In Experiment 1, the prime and test stimuli were semantically associated words (e.g., bread-butter). In Experiment 2, episodic associations between the prime and test stimuli were established through paired associate learning. For both cases, the mixture prediction failed, and two-state discrete activation models were rejected.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2026

Comprehensive adjudication identifies 111 high-confidence loci for Alzheimer's disease and related dementias.

BACKGROUND: The Alzheimer's Disease Sequencing Project Gene Verification Committee developed a systematic framework to adjudicate genetic evidence for AD and related dementias, addressing wide variation in association quality. METHODS: Phase 1 established tiered criteria by evaluating 23 nominated loci across study designs. Phase 2 applied this framework to 29 large-scale genome-wide studies published since 2015, tiering 163 unique loci. RESULTS: Phase 1 yielded 17 high-confidence loci (12 linked to specific genes), and Phase 2 identified 111 high-confidence loci/genes with replicated associations across ancestries and convergent single-variant/variant-set evidence. Prioritized loci highlight APP processing, microglial immunity, and lipid metabolism pathways, including genes not captured by existing resources like Agora or Open Targets. Summarized results can be viewed at https://topgenes.niagads.org/. CONCLUSION: This rigorously adjudicated catalog represents the most comprehensive AD/ADRD genetics resource to date, providing a foundation for functional validation and therapeutic discovery with broad applicability to complex diseases.

Journal Article↗
PubMed1984

Substituent effects on reactivity and spectral parameters of cephalosporins.

The chemical reactivity of a series of cephalosporins is examined as a function of the substituents at positions 3 and 7. In most cases, the nature of the C7 side chain has a minor influence on the beta-lactam reactivity. But in the case of amino-containing C7 substituents, when intramolecular nucleophilic attack may occur, the reactivity may be greatly increased. The spectroscopic and structural characteristics of the beta-lactam linkage do not correlate with the chemical reactivity of studied compounds. The hydrolysis rates are linked neither with the IR frequency or 13C NMR chemical shift of the carbonyl beta-lactam nor with the geometry of the beta-lactam ring. However, a relationship is confirmed between the beta-lactam ring opening rate and the polarity of the C3-C4 double bond, reflected in the different 13C NMR chemical shifts of those atoms. The results are an experimental verification of the theoretical calculations of Boyd et al. on cephalosporin model compounds, which foresee that a C3 substituent could favor the opening of the beta-lactam cycle by stabilizing a transition state involved in alkaline hydrolysis.

Cephalosporins↗
PubMed2003

An evolutionary approach for identifying potential transcription factor binding sites: the renin gene as an example.

Evolutionary pressure has resulted in the conservation of certain nucleotide sequences. These conserved regions are potentially important for certain functions. Here we give an example of a comparison between noncoding sequences combined with other independent database information to shed light onto the regulation of the renin gene, a gene that has great importance for cardiovascular and renal homeostasis. To combine the information regarding conservation and weight matrices of transcription factor (TF) binding sites, an algorithm was developed (TFprofile). Notably, a local peak in the resulting binding profile coincides with a previously experimentally identified regulatory region for the renin gene. The existence of further peaks in the binding profile in the conserved 3.9-kb-long hRENc DNA block upstream of the renin gene suggests additional regions of potential importance for gene regulation. The algorithm TFprofile may be used to integrate information on cross-species evolutionary conservation and aspects of TF binding characteristics to provide putative regulatory DNA regions for experimental verification.

Animals↗
PubMed1987

Corticomotor and somatosensory evoked potential evaluation of acute spinal cord injury in the rat.

Somatosensory evoked potentials (SSEPs) and corticomotor evoked potentials (CMEPs) were utilized to study acute blunt spinal cord trauma. Rats, anesthetized with ketamine hydrochloride, were subjected to a parasagittal craniotomy and a midthoracic laminectomy. SSEPs were cortically recorded and CMEPs were transcortically produced using epidural ball and disc electrodes. SSEPs were elicited and CMEPs were recorded via hindlimb percutaneous needle electrodes. After control records were made, animals were subjected to a 25-, 50-, or 75-g/cm impact to the dorsal cord surface via a modified weight drop procedure. Evaluation of neurological injury was made by SSEP and CMEP analysis as well as by physical testing with noxious stimulation applied to the hindlimb. Neurohistopathological verification of each spinal cord lesion was performed. No significant change in SSEP configuration was identified in animals subjected to a 25-g/cm cord impact; however, a small decrement in CMEP amplitude was consistently observed. Although vocalization to noxious stimulation was present, flexion activity was less than normal. Animals subjected to a 50-g/cm cord impact also showed no change in SSEP wave forms. All components of the CMEP were greatly attenuated with this injury. Either very weak movement or no movement to noxious stimulation was present without vocalization. After a 75-g/cm cord impact, both SSEPs and CMEPs were abolished. There was no movement or vocalization in response to noxious stimulation. Serial sections of the spinal cords revealed incremental destruction with increasing severity of injury. These results support the hypothesis that CMEPs are a more sensitive indicator of residual spinal cord function after injury than are SSEPs.

Afferent Pathways↗