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Biomedical subjects

J G Harris

Publications and source records attributed to J G Harris.

At least 19 recordsLinked to original sources
PubMed2001

Magnetization measurements of magnetic two-dimensional electron gases.

We directly measure the magnetization of both the conduction electrons and Mn2+ ions in (Zn,Cd,Mn)Se two-dimensional electron gases (2DEGs) by integrating them into ultrasensitive micromechanical magnetometers. The interplay between spin and orbital energy in these magnetic 2DEGs causes Landau level degeneracies at the Fermi energy. These Landau level crossings result in novel features in the de Haas-van Alphen oscillations, which are quantitatively reproduced by a simple model.

Journal Article↗
PubMed2001

CADASIL: neuropsychological findings in three generations of an affected family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary brain disease with a variety of neurologic and psychiatric manifestations. We studied 3 members of a family who each had leukoencephalopathy on neuroimaging studies and a characteristic mutation for CADASIL in the notch 3 region of chromosome 19q12. In all 3 cases, neurobehavioral impairment dominated the clinical picture, and a pattern of psychiatric dysfunction heralding cognitive decline emerged. Neuropsychological evaluation revealed diverse deficits, but a profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language was evident. These cases provide a cross-sectional study of the evolution of CADASIL, and suggest that, as in other diseases characterized by white matter dementia, psychiatric dysfunction may occur initially, followed by pervasive cognitive dysfunction later in the course of the disease. CADASIL should be considered in young adults with unexplained leukoencephalopathy on neuroimaging studies, and in those with neurobehavioral dysfunction and a suggestive family history.

Adult↗
PubMed2000

Smooth pursuit eye movements in schizophrenia and attentional dysfunction: adults with schizophrenia, ADHD, and a normal comparison group.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are found in schizophrenia. These deficits often are explained in the context of the attentional and inhibitory deficits central to schizophrenia psychopathology. It remains unclear, however, whether these attention-associated eye movement abnormalities are specific to schizophrenia or are a nonspecific expression of attentional deficits found in many psychiatric disorders. Adult attention-deficit/hyperactivity disorder (ADHD) is an alternative disorder with chronic attentional and inhibitory dysfunction. Thus, a comparison of SPEM in adult schizophrenia and adult ADHD will help assess the specificity question. METHODS: SPEM is recorded during a 16.7 degrees per second constant velocity task in 17 adults with ADHD, 49 adults with schizophrenia, and 37 normal adults; all groups included individuals between ages 25-50 years. RESULTS: Smooth pursuit gain and the frequency of anticipatory and leading saccades are worse in schizophrenic subjects, with normal and ADHD subjects showing no differences on these variables. CONCLUSIONS: Many attention-associated SPEM abnormalities are not present in most subjects with ADHD, supporting the specificity of these findings to the attentional deficits seen in schizophrenia.

Adult↗
PubMed2000

Eye movement task measures inhibition and spatial working memory in adults with schizophrenia, ADHD, and a normal comparison group.

Schizophrenia and attention deficit/hyperactivity disorder (ADHD) are both associated with deficits in inhibition and working memory, although in ADHD the working memory deficit is hypothesized to be secondary to the inhibitory deficit. This similarity in cognitive processes has been paralleled by similarities across the two groups in the performance of working memory and inhibition tasks. The delayed oculomotor response task is an alternative task, which may allow greater separation of working memory from inhibitory components, and thus its use may provide additional information on primary vs. secondary deficits in these disorders. Ten young adult ADHD sufferers, 10 schizophrenic subjects, and 10 normal subjects were matched on age, gender, and education. Eye movements were recorded during delayed oculomotor response tasks with 1- and 3-s delays. Both the ADHD and the schizophrenic subjects demonstrated dis-inhibition (an increased percentage of premature saccades); however only schizophrenic subjects demonstrated an impaired working memory (decreased spatial accuracy of the remembered saccade). The results are consistent with the hypothesis that working memory is a primary deficit in schizophrenia, but secondary to the inhibitory deficit in ADHD.

Adult↗
PubMed2000

The P50 auditory event-evoked potential in adult attention-deficit disorder: comparison with schizophrenia.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and schizophrenia are both conceptualized as disorders of attention. Failure to inhibit the P50 auditory event-evoked response, extensively studied in schizophrenia, could also occur in ADHD patients, if these two illnesses have common underlying neurobiological substrates. METHODS: This study examined the inhibition of the P50 auditory event-evoked potential in 16 unmedicated adults with ADHD, 16 schizophrenic outpatients, and 16 normal control subjects. Auditory stimuli were presented in a paired stimulus, conditioning-testing paradigm. RESULTS: The amplitude of initial or conditioning P50 response did not differ between the three groups; however, significant effects of psychiatric diagnosis on the amplitude of the test response and the ratio of the test to the conditioning response amplitudes were observed. Schizophrenic patients' P50 ratios and test amplitudes were higher than both the ADHD and normal groups. CONCLUSIONS: Adults with ADHD do not have the inhibitory deficit seen in patients with schizophrenia, suggesting that the mechanism of attentional disturbance in the two illnesses may be fundamentally different.

Adult↗
PubMed2000

Familial transmission of risk factors in the first-degree relatives of schizophrenic people.

Schizophrenia is a complex illness with multiple pathophysiologic factors that contribute to its psychopathology. One strategy to identify these factors is to observe them in isolation from each other, by characterizing their expression in the relatives of schizophrenic probands. By Mendel's second law, each genetic factor should be independently distributed in a sibship, so that each can be observed by itself, uncomplicated by the general problems of the illness. Such independently distributed phenotypes are obviously useful for genetic analyses; however, they can also be considered together, to model how various brain dysfunctions may combine to produce psychoses. In addition to a sensory gating deficit linked to the alpha 7-nicotinic acetylcholine receptor locus, schizophrenics and their families have a number of other deficits, including decreased hippocampal volume on magnetic resonance images and increased plasma levels of the dopamine metabolite homovanillic acid. Although such research is far from complete, a heuristic model combining a sensory gating deficit, decreased hippocampal neuron capacity, and increased dopaminergic neurotransmission is consonant with current understanding of the neuropsychology of schizophrenia.

Brain↗
PubMed2000

Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.

Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the alpha7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses.

Chromosomes, Human, Pair 15↗
PubMed2000

Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients.

BACKGROUND: Attenuation of airway responses to inhaled allergen is increasingly used to evaluate anti-asthma drugs. Many studies use different allergen challenge methods and the presence of the late asthmatic response can be identified by a screening challenge with inhalation of incremental doses of allergen. Once defined, subsequent challenges are often administered as a constant dose based on the dose from the screening challenge. Previously, constant dose challenges have been employed but never validated. OBJECTIVE: A comparative study of two methods of delivering inhaled allergen by evaluating the responses of an incremental dose allergen challenge and the same cumulative dose administered as a bolus over a single inhalation. METHODS: Thirty-five male patients with mild allergic asthma underwent incremental dose challenge followed 3-6 weeks later by a bolus dose challenge. Bronchoconstrictor responses were expressed as the maximum percentage fall in FEV1 from baseline during the early (0-2 h) and late (4-10 h) asthmatic responses and area under the percentage change in FEV1-time curve (AUC). RESULTS: There were no significant differences between the challenges. The mean +/- SEM fall in FEV1 following incremental and bolus dose challenge was 33.1 +/- 1.8% and 29.9 +/- 2.2% during the early response, and 36.9 +/- 2.4% and 34.0 +/- 3.1% during the late response, respectively. The mean +/- SEM AUC following incremental and bolus dose challenge was 35 +/- 3 and 33 +/- 3 Delta%FEV1/h for the AUC0-2 h, 147 +/- 12 and 139 +/- 16 Delta%FEV1/h for the AUC4-10 h, and 204 +/- 14 and 190 +/- 19 Delta%FEV1/h for the AUC0-10 h, respectively. CONCLUSION: Bolus dose allergen challenge is a safe method to administer inhaled allergen in clinical trials with a valid response when compared with incremental dose allergen challenge.

Administration, Inhalation↗
PubMed1999

The effects of age on a smooth pursuit tracking task in adults with schizophrenia and normal subjects.

BACKGROUND: Performance during a smooth pursuit eye movement (SPEM) task has been proposed as a marker of genetic risk for schizophrenia, although the precise component of SPEM tracking most associated with genetic risk remains undetermined. Normal adult aging is associated with deterioration on SPEM tasks; it remains unclear whether investigations of SPEM abnormalities will allow inclusion of older subjects in genetic studies. This study examines 1) the effect of normal aging on several components of SPEM performance; and 2) whether schizophrenic-normal differences found in young adults continue over a broad adult age span. METHODS: SPEM was recorded during a 16.7 degrees per sec constant velocity task in 64 normal adults, ages 18 to 79 years, and 58 schizophrenic subjects, ages 18 to 70 years. RESULTS: Smooth pursuit gain, the percent of total eye movements due to catch-up saccades, the frequency of large anticipatory saccades, and the frequency of leading saccades all deteriorate with increasing age. After correction for age, schizophrenic to control differences persist on most eye movement variables with the largest effect sizes for leading saccades (1.56) and smooth pursuit gain (1.17). CONCLUSIONS: The tendency to use saccades to anticipate target motion, even in small steps (leading saccades), deserves further attention as a potential marker useful in genetic analyses.

Adolescent↗
PubMed1999

Evidence for bilineal inheritance of physiological indicators of risk in childhood-onset schizophrenia.

Childhood-onset schizophrenia is proposed to be associated with increased genetic loading compared with adult-onset schizophrenia because of its earlier age of onset and generally greater severity of symptoms. Diminished suppression of P50 auditory evoked responses to repeated stimuli and elevated anticipatory saccades during smooth pursuit eye movements are markers of genetic risk that are found in members of families with schizophrenia even in the absence of the full clinical disorder and appear to be transmitted in a single gene autosomal dominant fashion. Adult-onset schizophrenia is generally associated with one parent who demonstrates abnormal P50 sensory gating and elevated anticipatory saccades and one parent who is normal on the physiologic measures (i.e., unilineal inheritance). This study investigates whether childhood-onset schizophrenia is similarly unilineal or is associated with the inheritance of genetic risk factors from both parents (i.e., bilineal inheritance). Ten childhood-onset schizophrenic probands and their parents were studied. Their P50 sensory gating and anticipatory saccades were compared with adult-onset schizophrenic probands and their parents. Bilineality, measured as physiological impairment in both parents, occurred more frequently in childhood-onset probands than in adult-onset probands for both P50 sensory gating deficits (60% versus 13%) and elevated anticipatory saccades (60 versus 0%). Additionally, childhood-onset schizophrenic probands performed more poorly than adult-onset probands on the anticipatory saccade measure. This physiological evidence suggests that childhood-onset schizophrenia may be associated with increased genetic loading because of contributions of genetic risk from both parents.

Adolescent↗
PubMed1998

Anticipatory saccades during smooth pursuit eye movements and familial transmission of schizophrenia.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are a putative marker of genetic risk for schizophrenia. Accurate SPEM performance requires the subject to activate neural systems responsible for smooth pursuit tracking, while simultaneously suppressing activity of neurons responsible for saccadic movements that would move the eye ahead of the target. This study examined whether specific aspects of SPEM dysfunction cosegregate with genetic risk in parents of schizophrenic probands. METHODS: Eighteen probands and their parents had SPEM recorded. Parents with an ancestral history of schizophrenia were hypothesized to be more likely than their spouses without such a history to carry a genetic risk for schizophrenia. RESULTS: Ten families had a single parent with a positive ancestral history for schizophrenia. The frequency of anticipatory saccades, which were mostly small, and the fraction of total eye movement that they represented were the only measures that differentiated the more likely genetic carrier parents in these families from their spouses and age-matched normals. CONCLUSIONS: Failure to suppress saccadic anticipation of target motion during smooth pursuit appears an aspect of SPEM dysfunction related to presumed genetic risk for schizophrenia.

Adult↗
PubMed1998

Familial transmission of two independent saccadic abnormalities in schizophrenia.

Difficulties with inhibiting inappropriate responses, i.e. disinhibition, and problems with spatial memory are both presumed to be a part of the phenotypic expression of the genetic risk for schizophrenia. Schizophrenic probands are impaired on saccadic eye movement tasks which require (a) response inhibition to prepotent stimuli and (b) generation of an accurate response to a remembered or calculated spatial location, but it is unknown how these deficits are inherited. Sixteen schizophrenic probands, their 32 parents, and two normal control groups completed a delayed oculomotor response and an antisaccade task. The parents with a positive ancestral family history for chronic psychosis (n = 8) were presumed to be more likely than their family history-negative spouses to be genetic carriers for schizophrenia. Probands and their positive family history parents had more failures of response inhibition than did normal control groups. However, it was the probands and their negative family history spouses who demonstrated impaired accuracy of the remembered- or antisaccades. Disinhibition may be closely tied to a specific genetic risk for schizophrenia. However, a second familial factor related to the maintenance or manipulation of spatial information may also contribute to the genetic risk of the full clinical disorder.

Adult↗
PubMed1998

Schizophrenia, sensory gating, and nicotinic receptors.

A series of human and animal investigations has suggested that altered expression and function of the alpha7-nicotinic cholinergic receptor may be responsible for the auditory sensory gating deficit characterized in schizophrenia patients and their relatives as diminished suppression of an auditory-evoked response (P50) to repeated stimuli. This finding, in conjunction with evidence for familial transmission of this sensory gating deficit, suggests a pathogenic role of the gene for the alpha7-nicotinic receptor in schizophrenia. This article considers the possible effects of this dysfunction in a broader context. Not only is this dysfunction consistent with difficulties in sensory gating, but it might also predispose patients to problems with learning efficiency and accuracy. Such learning problems could underlie schizophrenia patients' delusional thinking, hallucinations, and social dysfunction. In addition, heavy smoking in many schizophrenia patients is consistent with the high concentration of nicotine necessary to activate the receptor and with the receptor's extremely rapid desensitization. Finally, the receptor's possible role in cell growth and differentiation should be considered in connection with developmental deficits and other cellular abnormalities in schizophrenia.

Animals↗
PubMed1997

Comparison of salmeterol and albuterol-induced bronchoprotection against adenosine monophosphate and histamine in mild asthma.

Short-acting beta(2)-agonists provide greater protection to bronchoconstriction induced by adenosine-5'-monophosphate (AMP) than does methacholine. Because AMP produces bronchoconstriction through release of mediators from mast cells, and methacholine directly constricts airway smooth muscle, this suggests that beta(2)-agonists stabilize mast cells in vivo. This in vivo property has not been demonstrated with long-acting beta(2)-agonists. We undertook two double-blind, randomized, crossover, placebo-controlled studies to investigate the effects of salmeterol and albuterol on airway responsiveness (AR) to AMP and histamine in patients with mild asthma. In the first study, 19 patients attended on four occasions to inhale salmeterol 50 micrograms or placebo 2 h before challenge with AMP or histamine. In the second study 16 patients (13 of whom had participated in the first study) were studied in a similar fashion but inhaled albuterol 400 micrograms or placebo 30 min prior to challenge. Salmeterol reduced AR to AMP and histamine by 3.4 +/- 0.3 and 3.9 +/- 0.3 doubling doses, respectively (NS). In contrast, albuterol demonstrated a greater protective effect on AMP than on histamine, reducing AR by 5.1 +/- 0.3 and 3.8 +/- 0.2 doubling doses, respectively (p < 0.005). Thus, in contrast to albuterol, salmeterol did not demonstrate mast-cell stabilizing properties in vivo at a time corresponding to maximal bronchodilatation. These findings might be explained by the unique pharmacologic profile of salmeterol in combination with the differential beta(2)-adrenoceptor pharmacology of bronchial mast cells and bronchial smooth muscle.

Adenosine Monophosphate↗
PubMed1996

Neuropsychological dysfunction in parents of schizophrenics.

Neuropsychological measures designed to examine aspects of attention, learning efficiency, and memory were investigated in 14 schizophrenic probands, their 28 parents, and 18 normal individuals. Probands performed at levels significantly below normals on measures of attention and of learning efficiency and performed below their parents on a subset of the same measures. Eight families had one parent with a personal or ancestral pedigree history consistent with schizophrenia; the other parent's personal and ancestral history was negative for schizophrenia. In these families, the probands were significantly different from the negative-history parents, but not the positive-history parents on an aggregate index of attention. Schizophrenics were significantly different from both the positive- and negative-history parents on an aggregate index of learning efficiency. These results extend previous findings of specific neuropsychological dysfunction in attention and learning in schizophrenics to show that some of the deficits are present in a subgroup of their parents, those who are likely carriers of genes conveying risk for schizophrenia. The data suggest that a heritable component of the neuropsychological deficit is a primary dysfunction in attention, and that a secondary or additional deficit in learning may be evident in family members who actually express the disorder of schizophrenia.

Adult↗
PubMed1996

Modulation of ICAM-1 levels on U-937 cells and mouse macrophages by interleukin-1 beta and dexamethasone.

Differentiation of U-937 cells with phorbol ester (10 nM) induced a time-dependent (24 h or 48 h) increase of adhesion molecules and lipocortin 1 expression on the cell surface. Stimulation with interleukin-1 beta for a further 16 h increased the levels of intercellular adhesion molecule-1, and this effect was inhibited by co-incubation with 0.1-1 microM dexamethasone. The effect of the glucocorticoid was not modified by addition of a specific anti-lipocortin 1 monoclonal antibody (mAb 1A, 5 micrograms/ml). This opposite modulatory role of interleukin-1 and dexamethasone on intercellular adhesion molecule-1 expression was also, for the first time, observed in vivo using mouse peritoneal macrophages: a four-fold increase in intercellular adhesion molecule-1 expression was measured after local administration of the cytokine (5 micrograms/kg) and this effect was greatly inhibited (> 70%) by co-injection with 1 microgram dexamethasone. In conclusion, modulation of intercellular adhesion molecule-1 expression by glucocorticoids is an effect independent endogenous lipocortin 1, and it is an in vivo feature of these potent anti-inflammatory drugs.

Animals↗
PubMed1996

Relative contribution of the selectins in the neutrophil recruitment caused by the chemokine cytokine-induced neutrophil chemoattractant (CINC).

Rat CINC induced a dose- and time-dependent accumulation of neurophils into murine air-pouches, a response which was inhibited by two selective H1-antagonists, mepyramine and triprolidine (approximately 60%). As pretreatment with fucoidin abolished CINC effect, the relative time-related contribution of selectins on this process was then investigated by using specific monoclonal antibodies (mAb). Anti-CD62L mAb gave a similar degree of inhibition of CINC-induced cell accumulation both at the 2h and 4h time-point (approximately 75%). Anti-CD62P mAb, but not the anti-CD62E mAb, inhibited PMN accumulation at 2h (65%), but only co-administration of these two mAbs inhibited the cell response to CINC at the 4h time-point (90%). Thus endogenous histamine, CD62L, CD62P, and CD62E, though to a different degree, are required for PMN extravasation observed in response to CINC administration.

Animals↗