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Biomedical subjects

Karen E Anderson

Publications and source records attributed to Karen E Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Use of the GRP1 PH domain as a tool to measure the relative levels of PtdIns(3,4,5)P3 through a protein-lipid overlay approach.

We describe a novel approach to the relative quantification of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)] and its application to measure, in neutrophils, the activation of phosphoinositide 3-kinase (PI3K). This protein-lipid overlay-based assay allowed us to confirm and extend the observations, first, that N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation of primed human neutrophils leads to a transient and biphasic increase in PtdIns(3,4,5)P(3) levels and, second, that the ability of fMLP to stimulate PtdIns(3,4,5)P(3) accumulation in neutrophils isolated from mice carrying a Ras-insensitive ('DASAA') knock-in of PI3Kgamma (p110gamma(DASAA/DASAA)) is substantially dependent on the Ras binding domain of PI3Kgamma.

Animals↗
PubMed2006

Subjective report versus objective measurement of activities of daily living in Parkinson's disease.

We compared subjective self-reports with objective performance ratings of activities of daily living (ADLs) and instrumental ADLs (IADLs) in patients with Parkinson's disease (PD) and identified variables associated with discordance of ratings between these two methods. Seventy-six PD patients completed a modified Older Americans Resources and Services scale, assessing ADLs and IADLs. These results were compared with structured performance tests of walking, eating, dressing, money, and medicine management administered in the clinic. Patient performance was rated on a five-point Likert-type scale, ranging from 1 = no difficulty to 5 = completely unable to perform task. Significant differences were found between patients and clinicians' ratings on all tasks except walking. On the other four tasks, paired group t tests showed that patients reported better function compared with the clinician rating of medication management (1.33 vs. 2.80), eating (1.53 vs. 1.76), dressing (1.64 vs. 1.86), and managing money (1.44 vs. 2.06). A discrepancy was found between patients subjective reporting of ADL and IADL function and objective ratings. Patients overestimated their function on four of five tasks. Further study is necessary to identify whether subjective or objective performance ratings are more reflective of actual daily function.

Activities of Daily Living↗
PubMed2006

Psychosis in Parkinson's disease: case studies.

Psychosis is common in patients who have PD and leads to significant disability. Patients often can be managed with non-pharmacologic interventions or with decreasing doses of anti-parkinsonism medications. If these interventions are insufficient, then atypical antipsychotics should be considered. Clozapine is used in more refractory cases and requires stringent monitoring for agranulocytosis.

Aged↗
PubMed2006

Evaluation and diagnosis of psychogenic disorders in neurological patients.

Patients with psychogenic neurological symptoms present a diagnostic challenge. There are certain elements in a history that are indicative of a psychogenic condition. These include sudden onset of symptoms, highly emotional events at the time of symptom onset, paroxysmal nature of symptoms, and migrating or changing complaints. Likewise, some findings on examination are more often seen in psychogenic cases than in organic disorders. Multiple symptoms that do not correspond to any identifiable neuroanatomical abnormality, distractibility, entrainment, and false weakness or sensory complaints, are all possible clues that a condition is emotional rather than organic. However, none of these features is an absolute indication of psychogenicity and each must be taken in the context of the complete clinical picture.

Female↗
PubMed2005

Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils.

It is well established that preexposure of human neutrophils to proinflammatory cytokines markedly augments the production of reactive oxygen species (ROS) to subsequent stimuli. This priming event is thought to be critical for localizing ROS to the vicinity of the inflammation, maximizing their role in the resolution of the inflammation, and minimizing the damage to surrounding tissue. We have used a new generation of isoform-selective phosphoinositide 3-kinase (PI3K) inhibitors to show that ROS production under these circumstances is regulated by temporal control of class I PI3K activity. Stimulation of tumor necrosis factor-alpha (TNF-alpha)-primed human neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP) results in biphasic activation of PI3K; the first phase is largely dependent on PI3Kgamma, and the second phase is largely dependent on PI3Kdelta. The second phase of PI3K activation requires the first phase; it is this second phase that is augmented by TNF-alpha priming and that regulates parallel activation of ROS production. Surprisingly, although TNF-alpha-primed mouse bone marrow-derived neutrophils exhibit superficially similar patterns of PI3K activation and ROS production in response to fMLP, these responses are substantially lower and largely dependent on PI3Kgamma alone. These results start to define which PI3K isoforms are responsible for modulating neutrophil responsiveness to infection and inflammation.

Animals↗
PubMed2005

PI 3-kinase p110beta: a new target for antithrombotic therapy.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

Animals↗
PubMed2005

The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among disorders of mood and affect. Proceedings of a roundtable meeting.

This monograph summarizes the proceedings of a roundtable meeting convened to discuss pseudobulbar affect (PBA). Two didactic lectures were presented followed by a moderated discussion among 11 participants. Post-meeting manuscript development synthesized didactic- and discussion-based content ad incorporated additional material from the neuroscience literature. A conceptual framework with which to distinguish between disorders of mood and affect is presented first, and disorders of affect regulation are then reviewed briefly. A detailed description of the most common of these disorders, PBA, is the focus of the remainder of the monograph. The prevalence, putative neuranatomic and neurochemical bases of PBA are reviewed, and current and emerging methods of evaluation and treatment of persons with PBA are discussed. The material presented in this monograph will help clinicians better recognize, diagnose, and treat PBA, and will form a foundation for understanding and interpreting future studies of this condition.

Diagnosis, Differential↗
PubMed2005

Brain networks associated with cognitive reserve in healthy young and old adults.

In order to understand the brain networks that mediate cognitive reserve, we explored the relationship between subjects' network expression during the performance of a memory test and an index of cognitive reserve. Using H2(15)O positron emission tomography, we imaged 17 healthy older subjects and 20 young adults while they performed a serial recognition memory task for nonsense shapes under two conditions: low demand, with a unique shape presented in each study trial; and titrated demand, with a study list size adjusted so that each subject recognized shapes at 75% accuracy. A factor score that summarized years of education, and scores on the NART and the WAIS-R Vocabulary subtest was used as an index of cognitive reserve. The scaled subprofile model was used to identify a set of functionally connected regions (or topography) that changed in expression across the two task conditions and was differentially expressed by the young and elderly subjects. The regions most active in this topography consisted of right hippocampus, posterior insula, thalamus, and right and left operculum; we found concomitant deactivation in right lingual gyrus, inferior parietal lobe and association cortex, left posterior cingulate, and right and left calcarine cortex. Young subjects with higher cognitive reserve showed increased expression of the topography across the two task conditions. Because this topography, which is responsive to increased task demands, was differentially expressed as a function of reserve level, it may represent a neural manifestation of innate or acquired reserve. In contrast, older subjects with higher cognitive reserve showed decreased expression of the topography across tasks. This suggests some functional reorganization of the network used by the young subjects. Thus, for the old subjects this topography may represent an altered, compensatory network that is used to maintain function in the face of age-related physiological changes.

Adult↗
PubMed2005

H215O PET study of impairment of nonverbal recognition with normal aging.

Little research has been conducted regarding age-related changes in nonverbal memory. Using positron emission tomography (PET), the authors studied 17 elderly volunteers and 20 young volunteers, during nonverbal recognition task performance, to examine differences in brain blood flow. The subjects were asked to recognize a study list size (SLS) of shapes that was adjusted so that each subject performed at approximately 75% accuracy. Positron emission tomography results showed that, relative to younger individuals, elderly subjects engaged different regions, including the insula, during recognition. Elderly subjects did not show the relationship between parahippocampal flow and SLS, which was observed in younger subjects. These differences suggest that age-related functional brain changes partly explain performance deficits.

Adult↗
PubMed2005

A comparison of self-report and caregiver assessment of depression, apathy, and irritability in Huntington's disease.

The natural history of psychiatric syndromes associated with Huntington's disease (HD) remains unclear, and longitudinal studies of symptoms such as depression, apathy, and irritability are required to better understand the progression and role of these syndromes and their effect on disability. Self-administered scales such as the Beck Depression Inventory (BDI) may be useful to document changes in symptoms over time, but the validity of self-report may be questionable with the inevitable progression of cognitive deficits. An alternative to the patient's self-report would be assessments by the caregiver. The authors assessed interrater agreement between patient self-assessment and caregiver assessment of patients status for the presence of depressed mood using the BDI and apathy and irritability using an apathy and irritability scale. Agreement between these scales across strata of cognitive status was also examined. Interrater agreement varied from moderate to good for the BDI, depending on patient cognitive status. Agreement for the apathy scores was low for patients with poor cognition and fair in patients with better cognition. Irritability scale agreement was fair at best and was the worst in patients with the most intact cognition. Caregiver assessment of patients' moods and apathy may be an acceptable alternative to patient self-report as patients' cognitive status worsens.

Adult↗
PubMed2005

Behavioral symptoms associated with Huntington's disease.

In addition to the abnormal movements most commonly associated with HD, cognitive impairment and psychiatric symptoms occur in almost all patients. These behavioral symptoms contribute to morbidity and augment what is often an overwhelming caregiver burden. Behavioral interventions may be useful in managing some HD patients with behavioral symptoms, especially irritability and apathy. Patients should be evaluated for underlying medical illness that might contribute to psychiatric symptoms, especially if onset of behavioral change is rapid. According to clinical observation, HD patients with psychiatric symptoms respond to standard pharmacotherapy. Controlled studies are needed to determine the true efficacy of these agents for use in treating people with HD.

Anxiety↗
PubMed2004

SHIP1 and Lyn Kinase Negatively Regulate Integrin alpha IIb beta 3 signaling in platelets.

Integrin alpha(IIb)beta(3) plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin alpha(IIb)beta(3) signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin alpha(IIb)beta(3)-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P(3) metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P(3) metabolism down-regulates the stability of integrin alpha(IIb)beta(3)-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin alpha(IIb)beta(3) adhesive and signaling function.

Animals↗
PubMed2004

Cognitive reserve-mediated modulation of positron emission tomographic activations during memory tasks in Alzheimer disease.

BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.

Aged↗
PubMed2004

Covariance PET patterns in early Alzheimer's disease and subjects with cognitive impairment but no dementia: utility in group discrimination and correlations with functional performance.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

Aged↗
PubMed2004

Cognitive and neurobiological findings in obsessive-compulsive disorder.

The behavioral disturbances seen in OCD patients likely are related to abnormalities in the frontal striatal systems, with complex involvement of other brain regions. This is suggested by data from various modalities. Executive deficits are seen on neuropsychological assessments, which may contribute to poor performance on tasks designed to test other domains. Studies of neurological illness in which obsessive and compulsive symptoms are seen with increased frequency and results of neuroimaging studies are also indicative of frontal-striatal dysfunction. Some neuroimaging studies specifically implicate the OFC, along with other regions such as the anterior cingulate cortex and caudate nucleus. Data from studies of neurological soft signs are less specific and suggest pathology that may be common to other psychiatric conditions, such as schizophrenia. Although data from these various modalities do not give clear guidance on treatment, future work may show usefulness of adding these assessments to a clinical evaluation,especially with respect to predicting treatment response in subtypes of OCD.

Brain↗
PubMed2004

Oral graft-versus-host disease and programmed cell death: pathogenetic and clinical correlates.

Graft-versus-host disease (GVHD) is an untoward complication of bone marrow transplantation. It is characterized by an immune-mediated attack by donor immune cells against various host cells and tissues, a process which may be associated with significant morbidity in affected patients. Oral lesions are a common sequelae and can serve as a highly predictive index to the presence of systemic GVHD. The oral lesions of GVHD are clinically and histologically lichenoid in nature and can be a challenge in terms of management. Ulcerated and painful mucosal lesions may represent a significant impediment to normal eating habits and nutritional intake, necessitating appropriate diagnosis and treatment. Importantly, recent evidence has indicated that programmed cell death, or apoptosis, is the major constituent in the pathogenesis of GVHD. Apoptosis not only plays a major role in normal growth and ontogeny, but has been shown to contribute to a wide spectrum of both inflammatory and neoplastic disorders. Since knowledge of apoptotic molecular pathways is requisite for understanding GVHD, the purpose of this paper is to provide a fundamental overview of the predominant apoptotic mechanisms implicated in the pathogenesis of GVHD and to relate these findings to the oral complications of the disease. Finally, we will discuss management strategies for diagnosing and treating the oral lesions of GVHD. By explicating the molecular events in the apoptotic pathway, unique therapeutic and pharmacologic strategies for regulating apoptosis may be developed in the future, reducing the morbidity associated with conditions like GVHD.

Apoptosis↗