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PubMed2001

Relations between the neural bases of dynamic auditory processing and phonological processing: evidence from fMRI.

Functional magnetic resonance imaging (fMRI) was used to examine how the brain responds to temporal compression of speech and to determine whether the same regions are also involved in phonological processes associated with reading. Recorded speech was temporally compressed to varying degrees and presented in a sentence verification task. Regions involved in phonological processing were identified in a separate scan using a rhyming judgment task with pseudowords compared to a lettercase judgment task. The left inferior frontal and left superior temporal regions (Broca's and Wernicke's areas), along with the right inferior frontal cortex, demonstrated a convex response to speech compression; their activity increased as compression increased, but then decreased when speech became incomprehensible. Other regions exhibited linear increases in activity as compression increased, including the middle frontal gyri bilaterally. The auditory cortices exhibited compression-related decreases bilaterally, primarily reflecting a decrease in activity when speech became incomprehensible. Rhyme judgments engaged two left inferior frontal gyrus regions (pars triangularis and pars opercularis), of which only the pars triangularis region exhibited significant compression-related activity. These results directly demonstrate that a subset of the left inferior frontal regions involved in phonological processing is also sensitive to transient acoustic features within the range of comprehensible speech.

Adult↗
PubMed2005

DNA-binding domain mutations in SMAD genes yield dominant-negative proteins or a neomorphic protein that can activate WG target genes in Drosophila.

Mutations in SMAD tumor suppressor genes are involved in approximately 140,000 new cancers in the USA each year. At this time, how the absence of a functional SMAD protein leads to a tumor is unknown. However, clinical and biochemical studies suggest that all SMAD mutations are loss-of-function mutations. One prediction of this hypothesis is that all SMAD mutations cause tumors via a single mechanism. To test this hypothesis, we expressed five tumor-derived alleles of human SMAD genes and five mutant alleles of Drosophila SMAD genes in flies. We found that all of the DNA-binding domain mutations conferred gain-of-function activity, thereby falsifying the hypothesis. Furthermore, two types of gain-of-function mutation were identified - dominant negative and neomorphic. In numerous assays, the neomorphic allele SMAD4(100T) appears to be capable of activating the expression of WG target genes. These results imply that SMAD4(100T) may induce tumor formation by a fundamentally different mechanism from other SMAD mutations, perhaps via the ectopic expression of WNT target genes - an oncogenic mechanism associated with mutations in Adenomatous Polyposis Coli. Our results are likely to have clinical implications, because gain-of-function mutations may cause tumors when heterozygous, and the life expectancy of individuals with SMAD4(100T) is likely to be different from those with other SMAD mutations. From a larger perspective, our study shows that the genetic characterization of missense mutations, particularly in modular proteins, requires experimental verification.

Animals↗
PubMed1996

Human cells and cell cultures: availability, authentication and future prospects.

The availability of well characterized, viable human cells, tissues and cell lines along with pertinent data on the specific patient donors is a prerequisite for much current transplantation and biomedical research. In the USA, institutional and multi-center networks have been established for provision of primary human cells and tissues to qualified clinicians and research scientists. Monetary support derives from government, university, institutional and fee sources. Problems involved include concern for the rights and privacy of tissue donors, cultural reservations relating to tissue provision, the need for safe and expeditious transport, short term survival and limited supply, adequate correlation of patient data with samples provided, presence of infectious viruses and microorganisms, as well as state or government regulations regarding national or international shipping. The use of human cell lines with continuous or even somewhat limited doubling potentials overcomes many of the above difficulties. National cell banks have been established to provide reference lines for use by multiple investigators. Use of such cell lines assures improved research comparability both geographically and with time. Authentication procedures are critically important for all of these programs. Verification of tissue types and conditions is required through histological, biochemical and immunological assays. Tests for microbial and viral contaminants must be applied. In addition to such procedures utilized for tissues, with cell lines the banking agency must also verify species and where possible identity, properties and functions. The literature is replete with descriptions documenting incorrect identifications and infections of proliferating cell strains used for research. The availability of viable tissue through local sources and distribution agencies in the USA is becoming more commonplace even including full family participation and collection of related, detailed histories. Increased support for this developmental activity is needed, coupled with provision of blood and normal cells and cell lines from family members in many disease categories. Modern techniques, new and improved culture ware, serum-free media, reagents such as growth, adherence and transfer factors will permit isolation, propagation and wide spread distribution not only of human tumor cells but also normal and functional human cells of most renewing and expanding tissue types. Hybridization and immortalization techniques are enhancing this capability such that virtually all human cell types should be available for short or longer-term propagation and study in the foreseeable future.

Biological Specimen Banks↗
PubMed2006

[Evaluation of the accuracy of line spread function (LSF) and point spread function (PSF) measured in the computed tomography.].

We propose a method to estimate the accuracy of the line spread function (LSF) in computed tomography (CT). When we assume an object for scanning has a shape and CT-value in the x-y scan-plane that are constant in the z-direction perpendicular to the scan-plane, blurring in the image of the object is predicted with calculation by the LSF measured in the scanner. When using the precise LSF, the calculated image must agree well with the scanned image of the phantom corresponding to the object. Then, verification of LSF is performed by comparing the calculated image with the scanned image. We measured the LSF in our scanner, and scanned a cylindrical phantom with constant diameter and CT-value in which the direction of cylinder was parallel to the z-direction, as mentioned above. Images calculated by using the LSF corresponded well to scanned images, indicating the validity of the LSF. We obtained another LSF by an inappropriate manner, and calculated images using it. Those images showed an apparent difference with scanned images, indicating the inaccuracy of the LSF. Our technique is effective to evaluate the accuracy of LSF, PSF, and also modulation transfer function (MTF) derived from the LSF or PSF.

Phantoms, Imaging↗
PubMed2001

Endocrine responses to space flights.

Simultaneously with human space flights several series of observations were performed by using experimental animals--mainly rats--exposed to space flights on board of special satellites BION-COSMOS or in Shuttle Transportation Systems (STS). The aims of these experiments were to study in more details: the mechanisms of the changes in bones and skeletal muscle, the alterations of the function of immune system, the radiation effects on organism, the mechanism of the changes of endocrine functions, the evaluation of the role of hormones in alteration of metabolic processes in organism. The advantages of these animal experiments were the possibilities to analyze not only the plasma samples, but it was possible to obtain samples of organs or tissues: for morphological and biochemical analysis for studies of the changes in enzyme activities and in gene expressions, for measurement of metabolic processes and for investigation of the hormone production in endocrine glands and estimation of the response of tissues to hormones. It was also possible to compare the endocrine response to spaceflight and to other stress stimuli. These animal studies are interesting for verification of some hypothesis in the mechanism of adaptation of human organism to the changes of gravity. The disadvantage was, however, that the animals in almost all experiments could be examined only after space flight. The actual inflight changes were investigated only in two SLS flights. In this short review it is not possible to evaluate all hormonal data available on the response of endocrine system to the conditions of space flights. Therefore we will concentrate on the response of pituitary adrenocortical system, pituitary thyroid and pituitary gonadal functions.

Animals↗
PubMed2006

Health-related quality of life and psychosocial characteristics of patients with benign essential blepharospasm.

OBJECTIVE: To examine vision-targeted health-related quality of life and psychosocial characteristics in patients with benign essential blepharospasm (BEB) compared with patients with hemifacial spasm (HFS). METHODS: Persons with BEB (n = 159) or HFS (n = 91) were identified based on International Classification of Diseases, Ninth Revision, Clinical Modifications codes with subsequent verification by record abstraction. Information regarding demographics, health characteristics, disease characteristics, and vision-targeted health-related quality of life was obtained through a telephone interview. RESULTS: For patients with BEB and HFS, the composite scores and subscale scores on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) were low. Compared with patients with HFS, patients with BEB reported more depressive symptoms (P = .03), met the criteria for generalized anxiety disorder (P = .007), had lower NEI-VFQ-25 composite scores (P<.001), and had lower NEI-VFQ-25 subscale scores regarding general vision (P = .03), ocular pain (P<.001), distance activities (P = .001), driving (P<.001), and all of the vision-specific subscales addressing psychosocial issues. CONCLUSIONS: Compared with patients with HFS, those with BEB experience a greater reduction in vision-targeted health-related quality of life and are more prone to symptoms of depression and anxiety. This underscores the inadequacy of current treatment options for BEB in light of the fact that these patients had been undergoing standard-of-care treatments for some time.

Aged↗
PubMed1994

Haemorrhagic pituitary tumours.

In a group of 69 patients with pituitary tumours, 12 were found to have evidence of intratumoral haemorrhage on MRI, characterized by high signal intensity on short TR/TE sequences. This was verified in all but 1 patient. The majority of the bleedings occurred in macroadenomas. Five (42%) were prolactinomas and 4 (33%) were non-functioning adenomas. There were 2 GH- and 1 ACTH-secreting tumours. All 5 patients with prolactinomas were on bromocriptine medication. Two of the patients had a clinical picture of pituitary apoplexy. The haemorrhage was not large enough to prompt surgery in any of the patients. However, surgical verification of the diagnosis was obtained in 5 cases, while 6 patients were examined with follow-up MRI.

Adenoma↗
PubMed1997

Prospective multicenter trial of a plate for dorsal fixation of distal radius fractures.

A new plate designed specifically to address complex wrist pathology was used for the internal fixation of 22 complex fractures of the distal radius in 22 patients in a prospective multicenter trial. The majority of fractures were group C2- and C3-type fractures according to the Comprehensive Classification of Fractures. No plate failures, loss of reduction, nonunions, or infections occurred. Within the average follow-up time of 14 months, the functional results (including an average motion of 76% and an average grip strength of 56% of the contralateral side) were comparable to those reported for similar fractures in previous investigations. Five patients had irritation of the tendons in the second dorsal compartment. This trial serves both as a verification of the safety and efficacy of this distal radius plate as well as a demonstration of its utility in the treatment of complex fractures of the distal radius.

Adult↗
PubMed2006

Human genomic deletions mediated by recombination between Alu elements.

Recombination between Alu elements results in genomic deletions associated with many human genetic disorders. Here, we compare the reference human and chimpanzee genomes to determine the magnitude of this recombination process in the human lineage since the human-chimpanzee divergence approximately 6 million years ago. Combining computational data mining and wet-bench experimental verification, we identified 492 human-specific deletions (for a total of approximately 400 kb) attributable to this process, a significant component of the insertion/deletion spectrum of the human genome. The majority of the deletions (295 of 492) coincide with known or predicted genes (including 3 that deleted functional exons, as compared with orthologous chimpanzee genes), which implicates this process in creating a substantial portion of the genomic differences between humans and chimpanzees. Overall, we found that Alu recombination-mediated genomic deletion has had a much higher impact than was inferred from previously identified isolated events and that it continues to contribute to the dynamic nature of the human genome.

Animals↗
PubMed1987

The effects of independently validated strategies on visual hemifield asymmetry.

The study described here employed a sentence-picture verification task in order to examine the effects of different information-processing strategies on hemisphere performance of this task. The original task was slightly modified to allow brief presentation of the picture stimulus to either the left or right visual field. A simple strategies model of hemisphere function would predict an RVF advantage when using a linguistic strategy and an LVF advantage when using a pictorial strategy. Experiment 1 included no explicit instructions on which strategy to employ, thus allowing subjects to use their naturally preferred strategy whilst Expt 2 used explicit instructions to induce the appropriate strategies in two separate experimental blocks. Examination of the data for both experiments strongly supports the claim that the strategies were successfully induced, but in neither case was any clear-cut support for the strategies model of hemisphere function obtained.

Adolescent↗
PubMed1996

Opportunistic oral infections in the immunosuppressed patient: oral hairy leukoplakia and oral candidiasis.

Several opportunistic infections associated with immunosuppression are noted to occur secondary to an altered relationship between host and organism. In relation to diminished host immunologic defenses, associated commensal organisms may evolve to a pathogen state. Candidiasis, a common oral marker disease reflective of immunosuppression, results from dysfunction of complex cellular interactions keyed by depressed T-cell activity or function. Certain viral infections may also serve as probable markers of immunosuppression. One such infection is typified by the development of oral hairy leukoplakia, a condition highly correlated to HIV infection in most, but not all, patients. Detection of Epstein-Barr virus particles and subsequent molecular analytic verification of such and the absence of other potential viral candidates, such as papilloma and human immunodeficiency viruses, have led to a general acceptance of this virus as the cause of this condition.

AIDS-Related Opportunistic Infections↗
PubMed1984

Changing balance: environment and individual.

The role of occupational therapy as a process for changing balance from dysfunction to function is discussed in this paper. The individual as the first level environment to be considered for balance in the occupational therapy process is emphasized. The role of purposeful activity as a change determinant and as a valued treatment modality is recognized as a practice factor that needs verification through research in conjunction with systematic study of the occupational therapy process.

Adaptation, Psychological↗
PubMed2004

Multimodal imaging of somatosensory evoked cortical activity.

Somatosensory evoked cortical activity is well investigated in both fMRI and MEG/EEG. Investigation with functional magnetic resonance spectroscopic (fMRS) imaging is relatively new and provides a means to image the metabolic activity of the brain. We for the first time combined fMRS, fMRI, MEG and EEG. This provides information about the metabolic, hemodynamic and electrical activity of the brain and also the verification of one imaging modality with the other. The dipolar source localized from the EEG/MEG data is in the vicinity of the fMRI activation site and also in the same area where lactate consumption is high as measured with fMRS imaging.

Electroencephalography↗
PubMed1987

Military combat, posttraumatic stress disorder, and criminal behavior in Vietnam veterans.

Although data are inconclusive, popular perception has linked military combat, posttraumatic stress disorder (PTSD), and criminal behavior. This paper discusses the multifactorial elements of this association that include both conscious and unconscious parameters of psychologic functioning. Testimony on combat-related PTSD has been presented in the courtroom to support veterans' claims of not guilty by reason of insanity (NGRI) and diminished capacity and for consideration during judicial sentencing. Because there is a known connection between the degree of combat involvement and PTSD, verification through collateral sources of the veteran's report of combat experiences is an important component of forensic assessment. The DSM-III-defined diagnosis of PTSD and the presence of a dissociative state have particular relevance in NGRI determinations. In other aspects of the judicial process demonstration of the absolute presence or absence of PTSD is often irrelevant and should be replaced by efforts to establish plausible links between provable combat experiences and the circumstances of the crime.

Combat Disorders↗
PubMed1996

A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression.

OBJECTIVE: To assess the use of desipramine for secondary depression in primary alcohol dependence and its effect on abstinence. DESIGN: Randomized, double-blind, placebo-controlled trial, with stratification on the presence of secondary depression. SUBJECTS: Seventy-one volunteer and referred patients with primary alcohol dependence, abstinent a median of 8 days before randomization. A subset of 28 patients had major depression secondary to alcoholism. SETTING: The outpatient psychiatry departments of two urban medical centers. INTERVENTION: Six months of a clinically determined dose of desipramine. MAIN OUTCOME MEASURES: Hamilton Depression Rating Scale, and Time Line Follow Back Interview, with breath alcohol concentrations and collateral verification. RESULTS: Hamilton Depression scores of desipramine-treated depressed alcoholics decreased significantly, controlling for baseline Hamilton Depression scores (P=.04). Overall, patients were abstinent significantly longer when receiving desipramine (P=.03). Rates of relapse of depressed vs nondepressed patients, analyzed separately, were not significant, although the survival function approached significance for the depressed subgroup (P=.09). Desipramine-treated depressed patients were more satisfied and were rated as more improved. CONCLUSIONS: Major depression secondary to alcohol dependence that is diagnosed after at least 1 week of abstinence can remain stable in some placebo-treated alcoholics and can respond to desipramine. Treating depression secondary to alcoholism may reduce risk for drinking relapse in some patients. Use of desipramine to reduce relapse in nondepressed alcoholics is not supported.

Adrenergic Uptake Inhibitors↗
PubMed2004

Catalytic mechanism of type 2 isopentenyl diphosphate:dimethylallyl diphosphate isomerase: verification of a redox role of the flavin cofactor in a reaction with no net redox change.

Type 2 isopentenyl diphosphate:dimethylallyl diphosphate isomerase requires redox co-enzymes, i.e., flavin mononucleotide (FMN) and NAD(P)H, for activity, although it catalyzes a non-redox reaction. Spectrometric studies and enzyme assays under anaerobic conditions indicate that FMN is reduced through the reaction and is sufficient for activity. The sole function of NAD(P)H appears to be the reduction of FMN since it could be replaced by an alternate reducing agent. When the enzyme was reconstructed with a flavin analogue, no activity was detected, suggesting that the isomerase reaction proceeds via a radical transfer mechanism.

Carbon-Carbon Double Bond Isomerases↗
PubMed2005

Vascular smooth muscle cell response on thin films of collagen.

Vascular smooth muscle cells (vSMC) cultured on gels of fibrillar type I collagen or denatured collagen (gelatin) comprise a model system that has been widely used for studying the role of the extracellular matrix in vascular diseases such as hypertension, restenosis and athrosclerosis. Despite the wide use of this model system, there are several disadvantages to using collagen gels for cellular studies. These include poor optical characteristics for microscopy, difficulty in verifying that the properties of the preparations are identical from experiment to experiment, heterogeneity within the gels, and difficulty in handling the gels because they are fragile. Previously, we developed an alternative collagen matrix by forming thin films of native fibrillar collagen or denatured collagen on self-assembled monolayers of alkanethiols [Elliott, J.T., Tona, A., Woodward, J., Jones,P., Plant, A., 2003a. Thin films of collagen affect smooth muscle cell morphology. Langmuir 19, 1506-1514.]. These substrates are robust and can be characterized by surface analytical techniques that allow both verification of the reproducibility of the preparation and high-resolution analysis of collagen structure. In addition, they have excellent optical properties that allow more details of the cell-matrix interactions to be observed by microscopy. In this study, we performed a side-by-side structural and functional comparison of collagen gels with thin films of collagen. Our results indicate that vSMC on thin films of collagen are nearly identical to vSMC on thick gels as determined by morphology, proliferation rate, integrin ligation, tenascin-C expression and intracellular signaling events. These results suggest that the features of collagen gels that direct the observed vSMC responses are adequately reconstituted in the thin films of collagen. These thin films will be useful for elucidating the features of the collagen matrix that regulate vSMC response and may be applicable to high content screening.

Animals↗
PubMed2006

The human stratum corneum as extended, covalently cross-linked biopolymer: mathematics, molecules, and medicine.

A novel mathematical and molecular hypothesis is proposed to account for the peculiar organization of human epidermis. Mathematically, the organization of the interfollicular epidermis is hypothesized to be a tetratomic identity manifesting a gravitational logic in the arrangement of its functional compartments. The squares of the natural numbers; i.e., 1, 4, 9, and 16 are taken, on empirical grounds, to correspond to the number of cell layers in the respective epidermal strata (germinativum, spinosum, granulosum, and corneum). The outer two strata, overlying the Langerhans cells, constitute the 'living' and 'dead' components of the traditional 'epidermal barrier'. Together, these two strata illustrate in their union of 9 + 16 = 25 cells, a way of conceiving the skin surface (the body-environment identity) as both closure and contact. The organization of human epidermis into functional units based on phi, the golden section ratio, builds upon this gravitational logic. Finally, the fact that the extensively cross-linked proteolipid envelope of the cornified epidermal cell is a single multi-gene molecule is deemed scientifically incontrovertible. The molecular hypothesis in need of validation and verification is whether the corneodesmosomal 'rivets' linking one corneocyte to another are covalently bonded structures. If so, the cornified scaffolding of the stratum corneum constitutes a highly organized, extended, multi-gene, polymer molecule strategically located precisely at the shared surface of the body and environment. This hypothesis places the differentiated structure of the epidermis, an ectodermal derivative like the brain, front and center in the translation of molecular biology to clinical bedside care.

Binding Sites↗