Biomedical subjects

C A Meyers

Publications and source records attributed to C A Meyers.

At least 19 recordsLinked to original sources

PubMed2000

NGF gene transfer to intrinsic basal forebrain neurons increases cholinergic cell size and protects from age-related, spatial memory deficits in middle-aged rats.

Administration of nerve growth factor (NGF) by intracerebroventricular infusion or transplantation of NGF-secreting cells to the basal forebrain improves spatial memory in aged animals. Using the adeno-associated virus (AAV) vector system, basal forebrain neurons were transduced to produce NGF ectopically for long intervals (at least 9 months). Rats received intraseptal injections of either the control vector, pTR-UF4, or the pTR-NGFmyc at 3 months of age, prior to testing their performance in the Morris water task. An age-related decrease in the acquisition of the hidden platform location was found at 12 months of age in the pTR-UF4 control group, but not in the pTR-NGFmyc group. Further, when compared to 3 month old untreated animals, the control group, but not the pTR-NGFmyc group, was impaired at 12 months of age. Concomitant to preventing age-related memory deficits, the NGF gene transfer increased cholinergic neuron size by 34% in the medial septum. This approach may therefore represent a viable therapy for age-related dementia involving dysfunction in cholinergic activity and memory, such as Alzheimer's disease.

Aging↗

PubMed2000

Neurocognitive effects of therapeutic irradiation for base of skull tumors.

PURPOSE: To determine whether radiation therapy delivered to the paranasal sinuses causes any long-term impairment in neurocognitive function as a result of incidental brain irradiation. METHODS AND MATERIALS: Nineteen patients who received paranasal sinus irradiation at least 20 months and up to 20 years before assessment were given a battery of neuropsychologic tests of cognitive function. Radiation was delivered by a three-field (one anteroposterior and two lateral) technique. The median radiation dose was 60 Gy (range 50-68 Gy) in fractions of 1.8 to 2 Gy. The volume of irradiated brain was calculated from planning computed tomography slices or simulation films. The results of the neuropsychologic tests were compared to normative control values. RESULTS: Memory impairment was found in 80% of the patients, and one-third manifested difficulty with visual-motor speed, frontal lobe executive functions, and fine motor coordination. Two of the patients had frank brain necrosis with resultant dementia and blindness, and three had evidence of brain atrophy. Three of the fourteen patients without documented cerebral atrophy or necrosis were disabled from their normal activities. Three patients also developed pituitary dysfunction. Neurocognitive symptoms were related to the total dose of radiation delivered but not to the volume of brain irradiated, side of radiation boost, or chemotherapy treatment. The pattern of test findings was consistent with radiation injury to subcortical white matter. CONCLUSIONS: Radiation therapy for paranasal sinus cancer may cause delayed neurocognitive side effects. Currently, however, the development of severe adverse effects appears to be decreasing because of improvements in the techniques used to deliver radiation. Lowering the total dose and improving dose distributions should further decrease the incidence of delayed brain injury due to radiation.

Adult↗

PubMed2000

Cognitive function as a predictor of survival in patients with recurrent malignant glioma.

PURPOSE: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors. PATIENTS AND METHODS: A total of 80 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma were seen for baseline evaluations before beginning a phase I or phase II clinical trial. Each patient received a battery of nine brief tests measuring cognitive function, ability to perform activities of daily living (ADLs), and quality of life (QOL). Tests were given monthly after treatment was begun. RESULTS: Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, Karnofsky performance status score, histology, and time since diagnosis. Models incorporating three of nine and all nine tests in the battery accounted for significantly more variance in survival than did the clinical variables alone. Measures of QOL and ADLs (bathing, feeding, and so on) were not independently related to survival, although they provide clinical information that is important for patient care. CONCLUSION: These results indicate that a multifaceted assessment of cognition, QOL, and patient function is practical for brain tumor patients in clinical trials and can provide information regarding the relative risks versus benefits of new treatment regimens that supplements the information from the usual clinical variables.

Activities of Daily Living↗

PubMed2000

Neurocognitive dysfunction in cancer patients.

Many cancer patients experience impairments of neurocognitive function, including memory loss, distractibility, difficulty in performing multiple tasks (multitasking), and a myriad of other symptoms. Patients may also concurrently suffer from mood disturbance and symptoms that compromise their ability to function adequately, including fatigue and pain. The etiologies of these problems are diverse and include the direct effects of cancer within the central nervous system (CNS), indirect effects of certain cancers (e.g., paraneoplastic brain disorders), and both diffuse and highly specific effects of cancer treatments on the brain. In addition to these cancer-related causes, patients may have coexisting neurologic or psychiatric disorders that affect their cognition and mood. Careful assessment of patients complaining of neurocognitive or behavioral problems is essential to providing appropriate interventions and maximizing their ability to carry out usual activities.

Cognition Disorders↗

PubMed1999

Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2.

The signal-inducible phosphorylation of serines 32 and 36 of IkappaB-alpha is the key step in regulating the subsequent ubiquitination and proteolysis of IkappaB-alpha, which then releases NF-kappaB to promote gene transcription. The multisubunit IkappaB kinase (msIKK) responsible for this phosphorylation contains two catalytic subunits, termed IKK-1 and IKK-2. Using recombinant IKK-2, a kinetic pattern consistent with a random, sequential binding mechanism was observed with the use of a peptide corresponding to amino acids 26-42 of IkappaB-alpha. Values of 313 microM, 15.5 microM, and 1.7 min(-1) were obtained for K(peptide), K(ATP), and k(cat), respectively. The value of alpha, a factor by which binding of one substrate changes the dissociation constant for the other substrate, was determined to be 0.2. Interestingly, the recombinant IKK-1 subunit gave similar values for alpha and K(ATP), but values of 1950 microM and 0.016 min(-1) were calculated for K(peptide) and k(cat), respectively. This suggests that the IKK-2 catalytic subunit provides nearly all of the catalytic activity of the msIKK complex with the IKK-1 subunit providing little contribution to catalysis. Using peptides corresponding to different regions of IkappaB-alpha within amino acids 21-47, it was shown that amino acids 31-37 provide most binding interactions (-4.7 kcal/mol of binding free energy) of the full-length IkappaB-alpha (-7.9 kcal/mol) with the IKK-2. This is consistent with the observation that IKK-2 is able to phosphorylate the IkappaB-beta and IkappaB-epsilon proteins, which have consensus phosphorylation sites nearly identical to that of amino acids 31-37 of IkappaB-alpha. A peptide corresponding to amino acids 279-303 in the C-terminal domain of IkappaB-alpha was unable to activate IKK-2 to phosphorylate an N-terminal peptide, which is in contrast to the results observed with the msIKK. Moreover, the IKK-2 catalyzes the phosphorylation of the full-length IkappaB-alpha and the amino acid 26-42 peptide with nearly equal efficiency, while the msIKK catalyzes the phosphorylation of the full-length IkappaB-alpha 25,000 times more efficiently than the 26-42 peptide. Therefore, the C terminus of IkappaB-alpha is important in activating the msIKK through interactions with subunits other than the IKK-2.

Amino Acid Sequence↗

PubMed1999

Mood and cognitive disorders in cancer patients receiving cytokine therapy.

Chronic treatment with cytokines is associated with the development of mood and cognitive changes that suggests frontal-subcortical cerebral dysfunction. There is large individual variability in the type and severity of specific symptoms that are reported. The CNS effects of cytokines can be disassociated from the effects of chronic disease, other treatments and medications, and psychological responses to illness. The length of treatment and dose are both important factors in the development of mood disturbance. The finding that treatment chronicity is important makes long-term follow-up of patients on cytokine therapy all the more vital. Most adverse effects of cytokines improve with appropriate treatment of symptoms, although dose reduction or cessation of therapy may be necessary in individual cases. Future studies will be needed to better identify at-risk individuals, to compare the efficacy of various interventions, including antidepressants, stimulants, and opiate antagonists, and to assess the feasibility of treating at-risk individuals prophylactically.

Brain↗

PubMed1998

The multisubunit IkappaB kinase complex shows random sequential kinetics and is activated by the C-terminal domain of IkappaB alpha.

The multisubunit IkappaB kinase (IKK) catalyzes the signal-inducible phosphorylation of N-terminal serines of IkappaB. This phosphorylation is the key step in regulating the subsequent ubiquitination and proteolysis of IkappaB, which then releases NF-kappaB to promote gene transcription. As measured by 33P incorporation into a GST-IkappaB alpha fusion protein, varying both the concentration of GST-IkappaB alpha and [gamma-33P]ATP resulted in a kinetic pattern consistent with a random, sequential binding mechanism. Values of 55 nM and 7 microM were obtained for the dissociation constants of GST-IkappaB alpha and ATP, respectively. The value of alpha, a factor by which binding of one substrate changes the dissociation constant for the other substrate, was determined to be 0.11. This indicates that the two substrates bind in a cooperative fashion. Peptides corresponding to either amino acids 26-42 (N-terminal peptide) or amino acids 279-303 (C-terminal peptide) of IkappaB alpha inhibited the IKK-catalyzed phosphorylation of GST-IkappaB alpha; the C-terminal peptide, unexpectedly, was more potent. The inhibition by the C-terminal peptide was competitive with respect to GST-IkappaB alpha and mixed with respect to ATP, which verified the sequential binding mechanism. The C-terminal peptide was also a substrate for the enzyme, and a dissociation constant of 2.9-6.2 microM was obtained. Additionally, the N-terminal peptide was a substrate (Km = 140 microM). Competitive inhibition of the IKK-catalyzed phosphorylation of the C-terminal peptide by the N-terminal peptide indicated that the peptides are phosphorylated by the same active site. Surprisingly, the presence of the C-terminal peptide greatly accelerated the rate of phosphorylation of the N-terminal peptide as represented by a 160-fold increase in the apparent second-order rate constant (kcat/Km). These results are consistent with an allosteric site present within IKK that recognizes the C terminus of IkappaB alpha and activates the enzyme. This previously unobserved interaction with the C terminus may represent an important mechanism by which the enzyme recognizes and phosphorylates IkappaB.

Amino Acid Sequence↗

PubMed1998

Phase II study of i.v. CI-980 in patients with advanced platinum refractory epithelial ovarian carcinoma.

CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine site, inhibiting the polymerization of microtubules and arresting cellular division in metaphase. Myelosuppression and neurotoxicity were dose-limiting in phase I studies. Sixteen patients with stage III and IV platinum-refractory ovarian cancer received 4.5 mg/m2/day of CI-980 as a continuous i.v. infusion for 72 h, repeated every 3 weeks. Eleven patients had progression and four patients had stable disease. One patient (6%; 95% CI 0-25%) achieved a partial response after 9 months of treatment which lasted for 27 months. The overall median survival was 7 months. Grade 4 granulocytopenia occurred in five patients, with two episodes of neutropenic fever. Neurological toxicity was mild with 12 episodes of transient subclinical recent memory loss documented in four patients by specialized neuropsychological evaluations. One patient each had hallucinations and mild truncal ataxia, and four patients had mild, reversible neurosensory toxicity. One episode of severe hypoxemia and dyspnea occurred in a patient with chronic obstructive pulmonary disease. CI-980 has minimal activity and is tolerable in a population of heavily pretreated patients with platinum refractory ovarian cancer.

Adult↗

PubMed1998

Neurobehavioral functioning of adults with pituitary disease.

Neurobehavioral disorders are not infrequent in adults with pituitary disease. The disorders can be due to compression of brain structures important for cognitive and emotional function, effects of hormonal imbalance on sensitive structures, post-surgical disruption of connecting pathways, adverse reactions to medical therapy, and adverse delayed effects of radiation therapy. A multidisciplinary team approach to the treatment of pituitary tumors will allow for the early diagnosis of neurobehavioral disorders and the institution of pharmacologic and behavioral interventions.

Adult↗

PubMed1998

Klüver-Bucy syndrome after bilateral selective damage of amygdala and its cortical connections.

Isolated symmetric damage to the amygdala and their cortical connections occurred in an individual following cancer treatment. The lesions were imaged after reversal of hyponatremia. The patient displayed marked behavioral changes including visual agnosia, hypersexuality, hyperorality, a tendency to react to every visual stimulus, and memory deficits. The cluster of neurobehavioral symptoms is similar to previously reported accounts of Klüver-Bucy syndrome and suggests the importance of bilateral amygdala involvement in these behavioral changes.

Adult↗

PubMed1998

Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.

PURPOSE: Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration. PATIENTS AND METHODS: Thirty patients with primary brain tumors underwent neuropsychologic assessment before and during treatment with methylphenidate. Ability to function in activities of daily living and magnetic resonance imaging (MRI) findings were also documented. Patients were assessed on 10, 20, and 30 mg of methylphenidate twice daily. RESULTS: Significant improvements in cognitive function were observed on the 10-mg twice-daily dose. Functional improvements included improved gait, increased stamina and motivation to perform activities, and in one case, increased bladder control. Adverse effects were minimal and immediately resolved when treatment was discontinued. There was no increase in seizure frequency and the majority of patients on glucocorticoid therapy were able to decrease their dose. Gains in cognitive function and ability to perform activities were observed in the setting of progressive neurologic injury documented by MRI in half of the subjects. CONCLUSION: This study demonstrated improved patient function in the setting of a progressive neurologic illness. Methylphenidate should be more widely considered as adjuvant brain tumor therapy.

Adolescent↗

PubMed1998

The hippocampus: normal anatomy and pathology.

The hippocampus is a complex and fascinating region of the brain that has enormous clinical significance. Specifically, small imaging abnormalities may cause major symptoms. We believe that the detection of these lesions will be improved if imaging clinicians have an organized reference that facilitates identification of the cellular zones that comprise the hippocampus.

Adult↗

PubMed1998

Mood and cognitive side effects of interferon-alpha therapy.

The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity.

Cognition Disorders↗

PubMed1997

Efficacy of postacute brain injury rehabilitation for patients with primary malignant brain tumors.

BACKGROUND: Patients with primary malignant brain tumors (PMBT) often have neurobehavioral deficits due to the tumor, subsequent surgery, and therapies that interfere with their ability to live independently or work. Previous studies have shown that such patients generally have a progressive decline in functioning from diagnosis to death. Consequently, PMBT patients have not been considered good candidates for rehabilitation services. The current study is a preliminary, retrospective investigation of the effectiveness of postacute brain injury rehabilitation methods, originally developed for traumatic brain injury survivors, in a sample of patients with PMBT. METHODS: The subjects were 13 patients with a history of surgical resection of PMBT and subsequent radiation and chemotherapy. There were 8 males and 5 females with a mean age of 34.3 +/- 10.0 years and a mean educational level of 15.1 +/- 1.7 years. Mean time from tumor diagnosis to the commencement of rehabilitation was 75.4 +/- 87.9 months. All patients had cognitive deficits documented with neuropsychologic tests. Patients received an average of 2.6 +/- 1.9 months of postacute brain injury rehabilitation. RESULTS: Six patients had increased independence during the time from the start of rehabilitation to discharge, six were unchanged, and one patient had decreased independence. Eight patients had increased productivity during the same time period, four were unchanged, and one had decreased productivity. Treatment gains were maintained at follow-up 8.0 +/- 7.6 months after discharge. CONCLUSIONS: The results of the current study offer preliminary support for the effectiveness of postacute brain injury rehabilitation in the management of PMBT patients. Although additional investigation is needed, such treatment appears to be an attractive, relatively low cost option for these patients.

Adult↗

PubMed1997

Solution structure of the Grb2 N-terminal SH3 domain complexed with a ten-residue peptide derived from SOS: direct refinement against NOEs, J-couplings and 1H and 13C chemical shifts.

Refined ensembles of solution structures have been calculated for the N-terminal SH3 domain of Grb2 (N-SH3) complexed with the ac-VPPPVPPRRR-nh2 peptide derived from residues 1135 to 1144 of the mouse SOS-1 sequence. NMR spectra obtained from different combinations of both 13C-15N-labeled and unlabeled N-SH3 and SOS peptide fragment were used to obtain stereo-assignments for pro-chiral groups of the peptide, angle restraints via heteronuclear coupling constants, and complete 1H, 13C, and 15N resonance assignments for both molecules. One ensemble of structures was calculated using conventional methods while a second ensemble was generated by including additional direct refinements against both 1H and 13C(alpha)/13C(beta) chemical shifts. In both ensembles, the protein:peptide interface is highly resolved, reflecting the inclusion of 110 inter-molecular nuclear Overhauser enhancement (NOE) distance restraints. The first and second peptide-binding sub-sites of N-SH3 interact with structurally well-defined portions of the peptide. These interactions include hydrogen bonds and extensive hydrophobic contacts. In the third highly acidic sub-site, the conformation of the peptide Arg8 side-chain is partially ordered by a set of NOE restraints to the Trp36 ring protons. Overall, several lines of evidence point to dynamical averaging of peptide and N-SH3 side-chain conformations in the third subsite. These conformations are characterized by transient charge stabilized hydrogen bond interactions between the peptide arginine side-chain hydrogen bond donors and either single, or possibly multiple, acceptor(s) in the third peptide-binding sub-site.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Cognitive functioning and quality of life in malignant glioma patients: a review of the literature.

The state of current research in the psychosocial and neurocognitive functioning of primary brain tumor patients, particularly those with gliomas, is reviewed. Specific instruments that have been used to evaluate psychosocial and neurocognitive functioning in this population are reviewed. Suggestions are made, based on the review, of the most appropriate psychosocial and neurocognitive instruments to implement in clinical research. Finally, research pertaining to psychosocial and neurocognitive interventions is reviewed and suggestions for further research are outlined. Few studies have adequately addressed the cognitive and psychosocial functioning of brain tumor patients and have focused primarily on relatively insensitive measures of outcome, including IQ scores, performance status, and neurologic examinations. The use of well-accepted, psychometrically sound quality of life instruments and more specific tests of cognitive functioning need to be included in clinical trials since most current treatments have a limited effect on the length of survival. Thus, the main rationale for selecting a given brain tumor therapy may ultimately be related to its profile of neurotoxic side-effects and impact on quality of life.

Adult↗

PubMed1997

Relationship between quality of life and mood in long-term survivors of breast cancer treated with mastectomy.

This study sought to compare the mood and quality of life (QOL) of breast cancer survivors with those observed in low-risk breast cancer screening patients. A group of long-term stage I-III breast cancer survivors (n = 60) was compared with low-risk breast cancer screening patients (n = 93) on measures of depression, anxiety, and QOL. Patients without a previous psychiatric history were studied. Although the groups differed in age and education, correlations performed between age, education, and the outcome measures showed no association of age and education with the outcome measures. Breast cancer patients with stage III disease showed significantly poorer functioning, in all areas except family than did other breast cancer patients; however, when compared with the breast cancer screening group, they showed higher QOL scores in several domains. Higher mood scores were correlated with poorer scores in all QOL areas except family functioning in the breast cancer group. Only significantly elevated depression scores correlated with poorer QOL areas in the breast cancer screening group. The psychological measures were found to be more robust predictors of QOL than the demographic variables in both the cancer and the screening patients. These results suggest that long-term survivors of breast cancer continue to experience significant stress and emotional distress, as evidenced by increased depression and lower QOL functioning.

Adaptation, Psychological↗

PubMed1997

Manic episodes in two patients treated with interferon alpha.

The authors report the assessment of 2 patients on interferon alpha (IFN-alpha) therapy for chronic myelogenous leukemia who developed manic symptoms long after IFN-alpha therapy had been initiated. These cases suggest that chronic IFN-alpha therapy may be associated with vulnerability for developing overt psychiatric symptoms, particularly in cases where the patient is experiencing psychosocial stress, and that the current definition of persistent adverse effects of IFN-alpha should be broadened to include the occurrence of manic episodes.

Adult↗