Showing papers by "Veterans Health Administration published in 1994"

Guidelines, Criteria, and Rules of Thumb for Evaluating Normed and Standardized Assessment Instruments in Psychology.

Abstract: In the context of the development of prototypic assessment instruments in the areas of cognition, personality, and adaptive functioning, the issues of standardization, norming procedures, and the important psychometrics of test reliability and validity are evaluated critically. Criteria, guidelines, and simple rules of thumb are provided to assist the clinician faced with the challenge of choosing an appropriate test instrument for a given psychological assessment. Clinicians are often faced with the critical challenge of choosing the most appropriate available test instrument for a given psychological assessment of a child, adolescent, or adult of a particular age, gender, and class of disability. It is the purpose of this report to provide some criteria, guidelines, or simple rules of thumb to aid in this complex scientific decision. As such, it draws upon my experience with issues of test development, standardization, norming procedures, and important psychometrics, namely, test reliability and validity. As I and my colleagues noted in an earlier publication, the major areas of psychological functioning, in the normal development of infants, children, adolescents, adults, and elderly people, include cognitive, academic, personality, and adaptive behaviors (Sparrow, Fletcher, & Cicchetti, 1985). As such, the major examples or applications discussed in this article derive primarily, although not exclusively, from these several areas of human functioning.

The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia

Abstract: We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

Abstract: Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

Low Serum Thyrotropin Concentrations as a Risk Factor for Atrial Fibrillation in Older Persons

Abstract: Background Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation. Methods We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (≤ 0.1 mU per liter; 61 subjects); those with slightly low values (>0.1 to 0.4 mU per liter; 187 subjects); those with normal values (>0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (>5.0 mU per liter; 183 subjects). Results During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with sl...

Risperidone in the treatment of schizophrenia.

Abstract: Objective: The purpose ofthis study was to investigate the safety and efficacy of risperidone in the treatment ofschizophrenic patients and determine its optimal dose Method: This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States Patients were randomly assigned to 8 weeks’ treatment with placebo, one of four doses of risperidone (2, 6, 1 0, or 1 6 mg), or 20 mg ofhaloperidol daily Results: Clinical improvement (20% reduction in totalscores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% ofthe patients receiving 2 mg ofrisperidone, 57% receiving 6 mg, 40% receiving 1 0 mg, and 51 % receiving 1 6 mg; and by 30% receiving haloperidoland 22% receiving placebo Statistically significant differences in clinical improvement were found between 6 and 1 6 mg of risperidone versus placebo and versus haloperidol Positive symptom scores were significantly lower after 6, 10, and 1 6 mg of risperidone and 20 mg ofhaloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 1 6 mg ofrisperidone The incidence of extrapyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 1 6 mg of risperidone or 20 mg of haloperidol than placebo The results indicate that the optimal daily dose ofrisperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 1 6 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo Conclusions: Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia (AmJ Psychiatry 1994; 151:825-835)

Nonmelanoma skin cancer in the United States: Incidence

Abstract: Because death from nonmelanoma skin cancer is uncommon, quantification of its morbidity is particularly important. Although its incidence is increasing rapidly, the most recent nationwide estimates are 16 years old. The purpose of this study was to estimate the 1994 nonmelanoma skin cancer incidence in the United States. We updated the 16-year-old incidence estimates to reflect the growth and changing age distribution of the population and the increases in age-adjusted incidence rates documented in two population-based studies. The projected 1994 incidence of nonmelanoma skin cancer in the United States is 900,000 to 1,200,000 cases, similar in magnitude to the overall incidence of noncutaneous cancers. Nonmelanoma skin cancer imposes an enormous public health burden on the U.S. population. Quantification of its morbidity and its prevention are important priorities.

The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community.

Abstract: Background Despite recommendations for annual vaccination against influenza, more than half of elderly Americans do not receive this vaccine. In a serial cohort study, we assessed the efficacy and cost effectiveness of influenza vaccine administered to older persons living in the community. Methods Using administrative data bases, we studied men and women over 64 years of age who were enrolled in a large health maintenance organization in the Minneapolis-St. Paul area. We examined the rate of vaccination and the occurrence of influenza and its complications in each of three seasons: 1990-1991, 1991-1992, and 1992-1993. Outcomes were adjusted for age, sex, diagnoses indicating a high risk, use of medications, and previous use of health care services. Results Each cohort included more than 25,000 persons 65 years of age or older. Immunization rates ranged from 45 percent to 58 percent. Although the vaccine recipients had more coexisting illnesses at base line than those who did not receive the vaccine, duri...

Analysis of the p16 gene (CDKN2) as a candidate· for the chromosome 9p melanoma susceptibility locus

Abstract: A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4 (CDKN2) MTS1. This gene is homozygously deleted from many tumour cell lines including melanomas, suggesting that CDKN2 is a good candidate for MLM. We have analysed CDKN2 coding sequences in pedigrees segregating 9p melanoma susceptibility and 38 other melanoma-prone families. In only two families were potential predisposing mutations identified. No evidence was found for heterozygous deletions of CDKN2 in the germline of melanoma-prone individuals. The low frequency of potential predisposing mutations detected suggests that either the majority of mutations fall outside the CDKN2 coding sequence or that CDKN2 is not MLM.

Falls in the Nursing Home

Abstract: Objective: To review the epidemiology and causes of falls and fall-related injuries in nursing homes and to provide clinicians with a structured framework to evaluate and treat nursing home residen...

GFAP and Astrogliosis

Abstract: One of the most remarkable characteristics of astrocytes is their vigorous response to diverse neurologic insults, a feature that is well conserved across a variety of different species. The astroglial response occurs rapidly and can be detected within one hour of a focal mechanical trauma (Mucke et al., 1991). Prominent reactive astrogliosis is seen; in AIDS dementia; a variety of other viral infections; prion associated spongiform encephalopathies; inflammatory demyelinating diseases; acute traumatic brain injury; neurodegenerative diseases such as Alzheimer's disease. The prominence of astroglial reactions in various diseases, the rapidity of the astroglial response and the evolutionary conservation of reactive astrogliosis indicate that reactive astrocytes fulfill important functions of the central nervous system (CNS). Yet, the exact role reactive astrocytes play in the injured CNS has so far remained elusive. This chapter summaries the various experimental models and diseases that exhibit astrogliosis and increase in glial fibrillary acidic protein (GFAP). Recent in vitro studies to inhibit GFAP synthesis are also presented.

Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase.

Abstract: Nitric oxide (NO)-induced relaxation is associated with increased levels of cGMP in vascular smooth muscle cells. However, the mechanism by which cGMP causes relaxation is unknown. This study tested the hypothesis that activation of Ca-sensitive K (KCa) channels, mediated by a cGMP-dependent protein kinase, is responsible for the relaxation occurring in response to cGMP. In rat pulmonary artery rings, cGMP-dependent, but not cGMP-independent, relaxation was inhibited by tetraethylammonium, a classical K-channel blocker, and charybdotoxin, an inhibitor of KCa channels. Increasing extracellular K concentration also inhibited cGMP-dependent relaxation, without reducing vascular smooth muscle cGMP levels. In whole-cell patch-clamp experiments, NO and cGMP increased whole-cell K current by activating KCa channels. This effect was mimicked by intracellular administration of (Sp)-guanosine cyclic 3',5'-phosphorothioate, a preferential cGMP-dependent protein kinase activator. Okadaic acid, a phosphatase inhibitor, enhanced whole-cell K current, consistent with an important role for channel phosphorylation in the activation of NO-responsive KCa channels. Thus NO and cGMP relax vascular smooth muscle by a cGMP-dependent protein kinase-dependent activation of K channels. This suggests that the final common pathway shared by NO and the nitrovasodilators is cGMP-dependent K-channel activation.

Low level of response to alcohol as a predictor of future alcoholism.

Abstract: Objective As part of a search for measurable attributes of an individual that might be related to the risk of alcoholism, the author's group previously compared 227 sons of alcoholics and 227 matched comparison subjects at the age of about 20 years. Forty percent of the men at high risk for alcoholism and less than 10% of the comparison subjects demonstrated a low intensity of response to alcohol challenge. This article reports the results of the follow-up of the first half of this study group almost a decade later. Method Of the men who had been tested at about age 20, 223 were about age 30 at this evaluation, which included personal and resource-person interviews, record searches, urine toxicology screens, and blood level markers of drinking. Results A low level of response to alcohol at age 20 was associated with a fourfold greater likelihood of future alcoholism in both the sons of alcoholics and the comparison subjects. Fifty-six percent of the sons of alcoholics with the lesser alcohol response developed alcoholism during the subsequent decade, compared to 14% of the men in this group who had highly sensitive alcohol responses. Neither family history of alcoholism nor response to alcohol predicted any other psychiatric diagnoses over the subsequent decade, and neither was a significant predictor of any other substance use disorder. Conclusions In a heavy-drinking society, a lower sensitivity to modest doses of alcohol is associated with a significant increase in the risk of future alcoholism, perhaps through increasing the chances that a person will drink more heavily and more often.

Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome.

Abstract: Background The Smith-Lemli-Opitz syndrome (frequency, 1:20,000 to 1:40,000) is defined by a constellation of severe birth defects affecting most organ systems. Abnormalities frequently include profound mental retardation, severe failure to thrive, and a high infant-mortality rate. The syndrome has heretofore been diagnosed only from its clinical presentation. Methods Using capillary-column gas chromatography-mass spectrometry, we measured the sterol composition of plasma, erythrocytes, lens, cultured fibroblasts, and feces from five children with the syndrome (three girls and two boys). Results Plasma cholesterol levels were abnormally low (8 to 101 mg per deciliter [0.20 to 2.60 mmol per liter]) in every patient, being well below the 5th percentile for age- and sex-matched controls. Concentrations of the cholesterol precursor 7-dehydrocholesterol (cholest-5,7-dien-3β-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were ...

Frontal-subcortical circuits and neuropsychiatric disorders.

Abstract: Five parallel anatomic circuits link regions of the frontal cortex to the striatum, globus pallidus/substantia nigra, and thalamus. The circuits originate in the supplementary motor area, frontal eye fields, dorsolateral prefrontal region, lateral orbito-frontal area, and anterior cingulate cortex. Open loop structures that provide input to or receive output from specific circuits share functions, cytoarchitectural features, and phylogenetic histories with the relevant circuits. The circuits mediate motor and oculomotor function as well as executive functions, socially responsive behavior, and motivation. Neuropsychiatric disorders of frontal-subcortical circuits include impaired executive function, disinhibition, and apathy; indicative mood disorders include depression, mania, and lability. Transmitters, modulators, receptor subtypes, and second messengers within the circuits provide a chemoarchitecture that can inform pharmacotherapy.

Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis

Abstract: Rasmussen's encephalitis is a progressive childhood disease of unknown cause characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. During efforts to raise antibodies to recombinant glutamate receptors (GluRs), behaviors typical of seizures and histopathologic features mimicking Rasmussen's encephalitis were found in two rabbits immunized with GluR3 protein. A correlation was found between the presence of Rasmussen's encephalitis and serum antibodies to GluR3 detected by protein immunoblot analysis and by immunoreactivity to transfected cells expressing GluR3. Repeated plasma exchanges in one seriously ill child transiently reduced serum titers of GluR3 antibodies, decreased seizure frequency, and improved neurologic function. Thus, GluR3 is an autoantigen in Rasmussen's encephalitis, and an autoimmune process may underlie this disease.

Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis.

Abstract: Angiogenesis is important in the proliferation of inflammatory synovial tissue. Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that is also angiogenic in vivo. We examined the potential role of VEGF in mediating chemotaxis and proliferation of endothelial cells in rheumatoid arthritis (RA) using samples of synovial tissue and synovial fluid from 55 arthritic patients. Synovial fluid VEGF by ELISA was higher in RA synovial fluids (386 +/- 122 ng/ml) (SE) compared with osteoarthritis (OA) synovial fluids (< 0.8 ng/ml) (p < 0.05) or synovial fluids from patients with other arthritides (6.6 +/- 2 ng/ml). In addition to its known mitogenic properties, we found that human rVEGF was chemotactic for HUVECs at concentrations above 0.02 nM. Incubation of RA synovial fluids with neutralizing anti-VEGF resulted in 23 to 66% (mean 53 +/- 4%) inhibition of HUVEC chemotaxis. Conditioned medium from four of five RA synovial tissue explants was mitogenic for bovine adrenal capillary endothelial cells. Anti-VEGF neutralized from 19 to 42% (mean 28 +/- 4%) of this mitogenic activity. To determine the cellular source of VEGF in synovial tissue, we employed immunohistochemistry. VEGF+ cells were rarely (< 1%+) found in normal synovial tissues. In contrast, RA and OA synovial tissues exhibited VEGF+ lining cells (8% and 13%, respectively). A few synovial tissue macrophages were VEGF+ in both RA and OA (5% and 2%, respectively). These results elucidate a newly described function for VEGF as a potent chemotaxin for endothelial cells as well as a role for VEGF in RA-associated endothelial migration and proliferation.

Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue.

Abstract: Vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), is a potent microvascular permeability enhancing cytokine and a selective mitogen for endothelial cells. It has been implicated in tumor angiogenesis and ascites fluid accumulation. Since development of the destructive synovial pannus in rheumatoid arthritis (RA) is associated with changes in vascular permeability (synovial fluid accumulation), synovial cell hyperplasia, and angiogenesis, we examined synovial fluids (SFs) and joint tissue for the expression and local accumulation of VPF/VEGF. VPF/VEGF was detected in all of 21 synovial fluids examined and when measured by an immunofluorimetric assay, ranged from 6.9 to 180.5 pM. These levels are biologically significant, since < 1 pM VPF/VEGF can elicit responses from its target cells, endothelial cells. Levels of VPF/VEGF were highest in rheumatoid arthritis fluids (n = 10), with a mean value (+/- SEM) of 59.1 +/- 18.0 pM, vs. 21.4 +/- 2.3 pM for 11 SFs from patients with other forms of arthritis (p = 0.042). In situ hybridization studies that were performed on joint tissues from patients with active RA revealed that synovial lining macrophages strongly expressed VPF/VEGF mRNA, and that microvascular endothelial cells of nearby blood vessels strongly expressed mRNA for the VPF/VEGF receptors, flt-1 and KDR. Immunohistochemistry performed on inflamed rheumatoid synovial tissue revealed that the VPF/VEGF peptide was localized to macrophages within inflamed synovium, as well as to microvascular endothelium, its putative target in the tissue. Together, these findings indicate that VPF/VEGF may have an important role in the pathogenesis of RA.

The Sleep Disorders Questionnaire I: Creation and Multivariate Structure of SDQ

Abstract: The development of the Sleep Disorders Questionnaire (SDQ) from the Sleep Questionnaire and Assessment of Wakefulness (SQAW) of Stanford University is described in detail. The extraction of the best question items from the SQAW and their subsequent rewording in the SDQ to insure greater completion rates are described. Two item test-retest reliability studies are reported on 71 controls and on 130 sleep-disorder patients, which confirmed adequate reliability. To create multivariate scoring scales, SDQ was then given in a multicenter study to 519 persons, 435 of whom were sleep-disorder patients with full polysomnography. Canonical Discriminant Function Analysis was employed, which resulted in four clinical-diagnostic scales: SA for sleep apnea, NAR for narcolepsy, PSY for psychiatric sleep disorder and PLM for periodic limb movement disorder. Each was adjusted for male and female responses and transformed to a percentile using the observed distribution of raw scores. Using Receiver Operating Characteristics analysis, cutoff points were determined for each scale to maximize its sensitivity and specificity. Positive and negative predictive values were also calculated. The SA and NAR scales proved to be the most discriminating.

Human Extrastriate Visual Cortex and the Perception of Faces, Words, Numbers, and Colors

Abstract: Electrophysiological correlates of the processing of visual information were studied in epileptic patients with electrodes chronically implanted on the surface of striate and extrastriate cortex. In separate experiments patients viewed faces, letter strings (words and non-words), numbers, and control stimuli. A negative potential, N200, was evoked by faces, letter strings, and numbers, but not by the control stimuli. N200 was recorded bilaterally from discrete regions of the fusiform and inferior temporal gyri. These category-specific face, letter-string, and number "modules" vary in location. In most cases there was no overlap in the location of face and letter-string modules, suggesting a mosaic of functionally discrete regions. In some cases letter-string and number N200s were recorded from the same location, suggesting that these modules may be less spatially and functionally discrete. Face N200-like potentials can be recorded from temporal scalp, allowing the possibility of studying early face processing in normal subjects. Longer-latency face-specific potentials were recorded from the inferior surface of the anterior temporal lobe. Potentials evoked by colored checkerboards were recorded from a region of the fusiform gyrus posterior to the fusiform region from which category-specific N200s were recorded. These results suggest that there are several processing streams in inferior extrastriate cortex. In addition to object recognition systems previously proposed for faces and words, our preliminary results suggest a separate system dealing with numbers. Postulated systems dealing with larger manipulable objects and animals have not been detected.

Human Chromosome 3 Corrects Mismatch Repair Deficiency and Microsatellite Instability and Reduces N-Methyl-N′-nitro-N-nitrosoguanidine Tolerance in Colon Tumor Cells with Homozygous hMLH1 Mutation

Abstract: The human colon tumor cell line HCT 116 is known to have a homozygous mutation in the mismatch repair gene hMLH1 on human chromosome 3, to exhibit microsatellite instability, and to be defective in mismatch repair. In order to determine whether the introduction of a normal copy of hMLH1 gene restores mismatch repair activity and corrects microsatellite instability, a single human chromosome 3 from normal fibroblasts was transferred to HCT 116 cells via microcell fusion. As a control, human chromosome 2 was also transferred to HCT 116 cells. Two HCT 116 microcell hybrid clones that received a single copy of chromosome 2 (HCT 116+ch2) and two that received a single copy of chromosome 3 (HCT 116+ch3) were isolated and characterized. A G-G mismatch in M13-derived heteroduplex DNA was efficiently repaired in cell extracts from HCT 116+ch3 cells, but not in those of parent HCT 116 cells or HCT 116+ch2 cells. Microsatellite alterations at the D5S107 locus containing CA repeats were seen in 8 of 80 subclones from HCT 116 cells, and in 13 of 150 subclones from HCT 116+ch2 cells. In contrast, none of the 225 subclones derived from mismatch repair-proficient HCT 116+ch3 cells showed alterations in the microsatellite at the same locus. The effect of introducing chromosome 3 on the sensitivity of HCT 116 cells to N -methyl- N′ -nitro- N -nitrosoguanidine (MNNG) was examined, since enhanced tolerance to MNNG is accompanied by loss of mismatch repair activity in several cell lines. Within 3 days after treatment with 5 µm MNNG, HCT 116+ch3 cells became morphologically flat and stopped growing. Their colony-forming ability, determined 10 days after treatment, was reduced 200-fold when compared to MNNG-treated parental HCT 116 and HCT 116+ch2 cells. These results support the hypothesis that mutations in both alleles of the hMLH1 gene are necessary for the manifestation of defective mismatch repair and microsatellite instability and for enhanced MNNG tolerance. The results also suggest that the mismatch repair system contributes to the process that causes growth arrest in response to DNA damage by alkylating agents.

Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli

Abstract: 1. To identify the forebrain and brain stem structures that are active during the perception of acute heat pain in humans, we performed H2 15O positron emission tomographic (PET) analyses of cerebral blood flow (CBF) on nine normal volunteers while they received repetitive noxious (50 degrees C) and innocuous (40 degrees C) 5 s heat pulses to the forearm (average resting temperature of 31.8 degrees C). Each subject rated the subjective intensity of each stimulation series according to a magnitude estimation procedure in which 0 = no heat sensation, 7 = barely painful, and 10 = barely tolerable. 2. Three scans were performed at each temperature. Mean CBF images were created for each experimental condition and oriented onto standardized stereotaxic coordinates. Subtraction images were created between conditions for each subject and averaged across subjects. Volumes of interest (VOI) were chosen, based on a priori hypotheses and the results of previously published PET studies. In addition, a separate statistical summation analysis of individual voxels was performed. Statistical thresholds were established with corrections for multiple comparisons. 3. Significant CBF increases to 50 degrees C stimuli were found in the contralateral thalamus, cingulate cortex, S2 and S1 cortex, and insula. The ipsilateral S2 cortex and thalamus, and the medial dorsal midbrain and cerebellar vermis also showed significant CBF increases. All subjects rated the 50 degrees C stimuli as painful (average subjective rating = 8.9 +/- 0.9 SD) and the 40 degrees C stimuli as warm, but not painful (average subjective rating = 2.1 +/- 1.0).(ABSTRACT TRUNCATED AT 250 WORDS)

Neural Correlates of Attentive Selection for Color or Luminance in Extrastriate Area V4

Abstract: Rhesus monkeys were trained on a conditional orientation discrimination task in order to assess whether attentive selection for a color or luminance stimulus feature would affect visual processing in extrastriate area V4. The task required monkeys to select a bar stimulus based on its color or luminance and then to discriminate the angular tilt of the selected stimulus. The majority of neurons (74%) were selectively activated when the color or luminance of the stimulus in the receptive field matched the color or luminance of the cue. The activity was attenuated when there was not a match between the stimulus and the cue. The differential activation was based on the presence or absence of the stimulus feature and was independent of spatial location. Across the population of V4 neurons, optimal stimuli that matched the selected color or luminance elicited about twice the activity as stimuli that did not match the selected feature. The feature-selective changes in activity were observed to develop beginning about 200 msec after the stimulus onset and were maintained over the remainder of the behavioral trial. In this task the activity of V4 neurons reflected a selection based on the cued feature and not simply the physical color or luminance of the receptive field stimulus. Under these conditions, the topographic representation of the neural activity in area V4 highlights the potential targets in the visual scene at the expense of background objects. These observations offer a physiological counterpart to psychophysical studies suggesting that stimuli can be preferentially selected in parallel across the visual field on the basis of a unique color or luminance feature.

Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.

Abstract: This study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to measure the fractional extraction of [3H]oleate. Limb indirect calorimetry was used to estimate RQ. Percutaneous muscle biopsy samples of vastus lateralis were analyzed for muscle fiber type distribution, capillary density, and metabolic potential as reflected by measurements of the activity of seven muscle enzyme markers of glycolytic and aerobic-oxidative pathways. During postabsorptive conditions, fractional extraction of oleate across the leg was lower in NIDDM subjects (0.31 +/- 0.08 vs. 0.43 +/- 0.10, P < 0.01), and there was reduced oleate uptake across the leg (66 +/- 8 vs. 82 +/- 13 nmol/min, P < 0.01). Postabsorptive leg RQ was increased in NIDDM (0.85 +/- 0.03 vs. 0.77 +/- 0.02, P < 0.01), and rates of lipid oxidation by skeletal muscle were lower while glucose oxidation was increased (P < 0.05). In subjects with NIDDM, proportions of type I, IIa, and IIb fibers were 37 +/- 2, 37 +/- 6, and 26 +/- 5%, respectively, which did not differ from nondiabetics; and capillary density, glycolytic, and aerobic-oxidative potentials were similar. During 6 h after ingestion of a mixed meal, arterial FFA remained greater in NIDDM subjects. Therefore, despite persistent reduced fractional extraction of oleate across the leg in NIDDM (0.34 +/- 0.04 vs. 0.38 +/- 0.03, P < 0.05), rates of oleate uptake across the leg were greater in NIDDM (54 +/- 7 vs. 45 +/- 8 nmol/min, P < 0.01). In summary, during postabsorptive conditions there is reduced utilization of FFA by muscle, while during postprandial conditions there is impaired suppression of FFA uptake across the leg in NIDDM. During both fasting and postprandial conditions, NIDDM subjects have reduced rates of lipid oxidation by muscle.

Interconnections between the prefrontal cortex and the premotor areas in the frontal lobe

Abstract: We examined interconnections between a portion of the prefrontal cortex and the premotor areas in the frontal lobe to provide insights into the routes by which the prefrontal cortex gains access to the primary motor cortex and the central control of movement. We placed multiple injections of one retrograde tracer in the arm area of the primary motor cortex to define the premotor areas in the frontal lobe. Then, in the same animal, we placed multiple injections of another retrograde tracer in and around the principal sulcus (Walker's area 46). This double labeling strategy enabled us to determine which premotor areas are interconnected with the prefrontal cortex. There are three major results of this study. First, we found that five of the six premotor areas in the frontal lobe are interconnected with the dorsolateral prefrontal cortex. Second, the major site for interactions between the prefrontal cortex and the premotor areas is the ventral premotor area. Third, the prefrontal cortex is interconnected with only a portion of the arm representation in three premotor areas (supplementary motor area, the caudal cingulate motor area on the ventral bank of the cingulate sulcus, and the dorsal premotor area), whereas it is interconnected with the entire arm representation in the ventral premotor area and the rostral cingulate motor area. These observations indicate that the output of the prefrontal cortex targets specific premotor areas and even subregions within individual premotor areas.

Functional magnetic resonance imaging of human prefrontal cortex activation during a spatial working memory task

Abstract: High-speed magnetic resonance (MR) imaging was used to detect activation in the human prefrontal cortex induced by a spatial working memory task modeled on those used to elucidate neuronal circuits in nonhuman primates. Subjects were required to judge whether the location occupied by the current stimulus had been occupied previously over a sequence of 14 or 15 stimuli presented in various locations. Control tasks were similar in all essential respects, except that the subject's task was to detect when one of the stimuli presented was colored red (color detection) or when a dot briefly appeared within the stimulus (dot detection). In all tasks, two to three target events occurred randomly. The MR signal increased in an area of the middle frontal gyrus corresponding to Brodmann's area 46 in all eight subjects performing the spatial working memory task. Right hemisphere activation was greater and more consistent than left. The MR signal change occurred within 6-9 sec of task onset and declined within a similar period after task completion. An increase in MR signal was also noted in the control tasks, but the magnitude of change was less than that recorded in the working memory task. These differences were replicated when testing was repeated in five of the original subjects. The localization of spatial working memory function in humans to a circumscribed area of the middle frontal gyrus supports the compartmentalization of working memory functions in the human prefrontal cortex and the localization of spatial memory processes to comparable areas in humans and nonhuman primates.

Five-component model of schizophrenia: Assessing the factorial invariance of the positive and negative syndrome scale

Abstract: A five-component model of schizophrenia has been presented by Kay and Sevy based upon an analysis of the Positive and Negative Syndrome Scale. Kay and Sevy found factorial validity for negative and positive syndromes, and they identified excitement, depressive, and cognitive components as well. They suggested that subtypes and syndromes can be mapped along dimensions presented in their model. The present study compares the five-component solution for a new sample of 146 subjects to a reanalysis of the Kay and Sevy data. Despite divergent demographic characteristics, the two samples produce similar dimensions. Correlations of component loadings and subject scores as well as confirmatory factor analysis are presented. Discussion focuses on points of agreement and important differences in the symptoms assigned to each component. How the dimensions relate to rationally derived models of positive and negative syndromes is reviewed, and implications for subtyping and other methods of examining the heterogeneity of schizophrenia are considered.

Genetic animal models of alcohol and drug abuse

Abstract: Behavioral and pharmacological responses of selectively bred and inbred rodent lines have been analyzed to elucidate many features of drug sensitivity and the adverse effects of drugs, the underlying mechanisms of drug tolerance and dependence, and the motivational states underlying drug reward and aversion. Genetic mapping of quantitative trait loci (QTLs) has been used to identify provisional chromosomal locations of genes influencing such pharmacological responses. Recent advances in transgenic technology, representational difference analysis, and other molecular methods now make feasible the positional cloning of QTLs that influence sensitivity to drugs of abuse. This marks a new period of synthesis in pharmacogenetic research, in which networks of drug-related behaviors, their underlying pharmacological, physiological, and biochemical mechanisms, and particular genomic regions of interest are being identified.