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Biomedical subjects

J Kessler

Publications and source records attributed to J Kessler.

At least 109 records · Page 6Linked to original sources
PubMed1994

X-ray structures of fragments from binding and nonbinding versions of a humanized anti-CD18 antibody: structural indications of the key role of VH residues 59 to 65.

X-ray crystal structures of fragments from two different humanized anti-CD18 antibodies are reported. The Fv fragment of the nonbinding version has been refined in space group C2 with a = 64.2 A, b = 61.3 A, c = 51.8 A, and beta = 99 degrees to an R-value of 18.0% at 1.9 A, and the Fab fragment of the tight-binding version has been refined in space group P3 with a = 101. A and c = 45.5 A to an R-value of 17.8% at 3.0 A resolution. The very large difference in their binding affinity (> 1000-fold) is attributed to large and local structural differences in the C-terminal part of CDR-H2, and from this we conclude there is direct contact between this region and antigen when they combine. X-ray structures of antibody-antigen complexes available in the literature have yet to show this part of CDR-H2 in contact with antigen, despite its hypervariable sequence. Implications of this result for antibody humanization are discussed.

Amino Acid Sequence↗
PubMed1994

HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusion and metabolic pattern.

Positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) and single-photon emission tomography (SPET) of 99mTc-hexamethylpropylene amine oxime (HMPAO) were performed under identical resting conditions within 3 h in 20 patients with probable Alzheimer's disease (AD), 12 patients with vascular dementia (VD) and 13 normal persons. In the temporoparietal association cortex similar impairment of relative regional cerebral glucose metabolism (rCMRGl) and relative HMPAO uptake (rCBF) was found. In addition PET showed hypometabolism in the occipital association cortex. The functional pattern was condensed to a ratio of regional values of association areas divided by regional values of structures that are typically less affected by AD. In normals this ratio was significantly related to age for PET metabolic data (r = -0.66, P = 0.01). The ratio was significantly lower in AD than in VD and controls for both rCMRGl and rCBF. In AD only, the metabolic ratio was related to severity of dementia (r = 0.54, P = 0.003) and age (r = 0.64, P = 0.003). Metabolic differences between normals and AD patients were less obvious in old age. In contrast, there were no significant correlations between the perfusion ratio and severity of dementia or age. Comparing the metabolic and perfusion ratio by receiver operating characteristic curves, PET differentiated AD from normals only marginally better than SPET. Differentiation between AD and VD was much better achieved by PET. Our results suggest that both PET and SPET can distinguish AD patients from controls, whereas for differentiation between AD and VD SPET is of little value.

Aged↗
PubMed1994

Difference of regional cerebral metabolic pattern between presenile and senile dementia of the Alzheimer type: a factor analytic study.

Positron emission tomographic studies using metabolic ratios to represent the contrast between certain brain regions have shown differences of cerebral glucose metabolism between presenile and senile dementia of Alzheimer type (DAT). In this study, factors for regional variance of cerebral metabolism in 61 patients with probable Alzheimer's disease were obtained using principal component analysis (PCA). The difference between two age groups of DAT patients according to age at onset < or = 65 years (n = 30) and > 65 years (n = 31) were investigated. A PCA using nine pairs of cerebral regions normalized to cerebellum for reduction of intersubject variability identified five regional factors for cerebral metabolism: one each for the left and right temporo-parietal cortex, and the other three for frontal cortex, primary visual and sensorimotor cortex, and mesial temporal sensorimotor cortex, and mesial temporal cortex. The age groups differed significantly only in the factor for the right temporo-parietal cortex, with a more prominent metabolic reduction in presenile than senile DAT. Severity of dementia was correlated with the factors for the right and left temporo-parietal cortex. The effect of age at onset on glucose metabolism of the right temporo-parietal cortex was independent from that of dementia severity in DAT.

Age Factors↗
PubMed1994

PET and functional testing in temporal lobe epilepsy.

Thirty-seven patients with severe temporal lobe epilepsy were studied interictally with [18F]fluorodeoxyglucose-PET in each of three conditions: resting, during emotional speech, and while performing a visual recognition task. In the resting state, each patient exhibited regional hypometabolism in agreement with his epileptic EEG focus, but that area was typically very large. The zone of maximum dysfunction was significantly better demarcated on activated scans showing an increase in whole-brain metabolism averaging 18%. Concurrently, the midtemporal-focus metabolic contrast was improved by 27%. This effect was more consistently produced by the speech paradigm that also induced significant amygdala recruitment and revealed the individual hemispheric speech dominance. Psychological trait factors played a role only for unspecific global activation.

Adolescent↗
PubMed1994

Left hemispheric neuronal heterotopia: a PET, MRI, EEG, and neuropsychological investigation of a university student.

A 21-year-old left-handed medical student had a prominent unilateral cerebral cortical malformation due to an ontogenetic migration disorder. We performed neuropsychological studies, EEG, T1- and T2-weighted and proton-density MRI, and positron emission tomography (PET) (under both the resting condition and neuropsychological activation). Neuropsychological testing revealed normal intelligence and generally normal memory functioning but selective deficits in tests of verbal fluency and spatial-figural relationships. Proton-density and T2-weighted MRI revealed extensive left cortical heterotopia that included parts of the Wernicke area. PET under the resting condition revealed a small interhemispheric difference with slightly reduced glucose metabolism in the left temporoparietal cortical zone. An activation PET (with the patient performing a verbal fluency test) resulted in a normal overall increase in metabolism but marked deviations in cortical areas. The highest activity changes were in the Broca and Wernicke areas of the right hemisphere, and there was very little activation in those regions of the left hemisphere that were expected to respond well to the activation--the temporal, parietal, and temporo-occipital cortical zones. We conclude that there can be large compensations for unilateral heterotopia.

Adult↗
PubMed1994

Visual evoked potentials in Alzheimer's disease: investigations in a PET-defined collective.

Intravital diagnosis of Alzheimer's disease (AD) based clinical and neuropsychological findings alone does not allow sufficient differentiation from other disorders such as vascular dementia. Positron emission tomography (PET) secures intravital diagnosis with high accuracy by determination of a typical metabolic pattern. Numerous publications have proposed visual evoked potentials (VEP) for the detection of AD. In a collective of 15 patients with probable AD according to NINCDS/ADRDA criteria and the typical metabolic pattern of AD, we examined pattern reversal and flash VEPs. The results were compared to those of an age-matched collective of patients without impairment of memory. Neither pattern reversal nor flash VEP were correlated to severity of dementia as determined by the mini-mental status examination (MMSE). The positive results of other investigators are probably due to different patient selection criteria which do not include findings of cerebral glucose metabolism in the definition of AD.

Aged↗
PubMed1993

Activation PET as an instrument to determine therapeutic efficacy in Alzheimer's disease.

Forty patients with probable Alzheimer's disease (AD) were selected from a pool of 80 patients and assigned to 4 groups. Each received either social support, cognitive training only, or cognitive training in combination with pyritinol or phosphatidylserine. Treatment duration was 6 months. Before and after treatment the patients underwent neuropsychological testing as well as measurement of the regional cerebral metabolic rate for glucose using positron emission tomography (PET) and 2[18F]-fluoro-2-deoxy-D-glucose (FDG). Before treatment, the groups were comparable in respect to resting and activated glucose pattern achieved by a visual recognition task. They did not differ in scores of a neuropsychological test battery. After the treatment period the group with cognitive training + phosphatidylserine showed a significant glucose enhancement during the stimulation tasks in various brain regions, and an improvement in cognitive functioning compared to the other groups. The group with cognitive training + pyritinol had better stimulation effect as that of the social support group indicating that a combination of cognitive training + pharmacological intervention was superior than that of cognitive training alone.

Alzheimer Disease↗
PubMed1993

Cerebral glucose metabolism as a predictor of recovery from aphasia in ischemic stroke.

OBJECTIVE: The recovery of language function seen in poststroke aphasia is significantly related to the severity of the initial neurologic deficit. However, a great deal of variability still remains in the improvement that is actually achieved. To detect predictors that will help in explaining this variability, positron emission tomography (PET) and fluorodeoxyglucose F 18 (18-F-fluorodeoxyglucose) were used and the results were analyzed by stepwise regression. DESIGN: Using PET imaging after injection of fluorodeoxyglucose F 18, the regional changes in glucose metabolism in 26 patients at a period of 12 to 18 days following an ischemic stroke involving the left middle cerebral artery were examined. A second PET examination was performed on 17 of our 26 patients who were able to perform speech activation exercises. All patients received an initial and a 4-month follow-up evaluation of language performance. SETTING: During the two PET studies and the first language assessment, the patients were hospitalized in a neurologic clinic. The follow-up evaluation of language performance was performed when the patients were ambulatory. PATIENTS: Twenty-six patients (10 women, 16 men; aged 38 to 77 years; mean +/- SD, 60 +/- 9.2 years) were selected in the study. Their aphasias were of various types and of varying severity ranging from mild impairment to severe global aphasia. MAIN OUTCOME MEASURES: For the stepwise regression analysis of variables, the following variables were analyzed in resting and activation PET to explain residual variance from the first to the second Token Test: regional cerebral metabolic rate for glucose of infarct and mirror region, left and right cerebral and cerebellar hemispheres, left and right Broca's area, left and right Wernicke's area, and left and right temporoparietal cortex. RESULTS: As was expected, early and late Token Tests exhibit a high correlation (.85). The stepwise regression analysis shows that only the left cerebral hemisphere glucose value of the resting PET had significant effect on the residual variance of the Token Test regression. Regional metabolic rates during speech activation had the largest contribution to a significant recovery from aphasia. The infarct area and its corresponding mirror region, the left Broca's area, and the entire left cerebral hemisphere accounted for 80% of the residual variance. CONCLUSIONS: These results emphasize not only the application of PET activation studies in the prediction of a tissue's potential reserve capacity but also the importance of left hemisphere integrity in the recovery of functional language.

Adult↗
PubMed1993

Sensory neuropathy associated with Dursban (chlorpyrifos) exposure.

Chlorpyrifos (Dursban) is an organophosphate insecticide with extensive domestic and agricultural applications. It is regarded as safe for these purposes; one report of neurotoxicity is attributed to massive ingestion in a suicide attempt. We report eight people who developed peripheral neuropathy after exposure to exterminator-applied commercial Dursban; five also experienced memory loss and cognitive slowing. Evaluation failed to reveal other causes of neurologic dysfunction; symptoms recurred in one patient following accidental reexposure. We conclude that environmental contact with chlorpyrifos can cause sensory neuropathy and CNS dysfunction and that this agent should be used with caution.

Adult↗
PubMed1993

Cortical blindness and seizures possibly related to cisplatin, vinblastine, and bleomycin treatment of ovarian dysgerminoma.

Ovarian dysgerminoma is the most common ovarian malignancy in young women. Conservative treatment is indicated in the reproductive-age woman who wishes to preserve childbearing capacity. This case report describes a patient with ovarian dysgerminoma who underwent chemotherapy with a cisplatin-vinblastine-bleomycin regimen that resulted in serious toxic complications--including cortical blindness and seizures--that were transient in nature. Although current chemotherapy regimens have dramatically improved the overall survival of women with germ-cell tumors, there are toxic complications such as those demonstrated in this report, and toxicity must be balanced against presumed benefit.

Adult↗
PubMed1992

Severity of vascular dementia is related to volume of metabolically impaired tissue.

The relation between dementia severity and regional cerebral metabolic rate of glucose was studied in 28 patients with vascular dementia (VD) in comparison with 20 age-matched patients who were suffering from Alzheimer's disease (AD) and 24 normal subjects by using positron emission tomography with fludeoxyglucose F 18. Similar metabolic impairment was found in the temporoparietal and frontal association cortex in patients with VD and in those with AD. Metabolism of the basal ganglia, thalamus, and cerebellum was reduced significantly in patients with VD only. The total volume of regions with metabolism below the 95% confidence interval of control values was significantly related to the severity of dementia but did not differ between patients with VD and those with AD. A metabolic ratio of regional cerebral glucose metabolism of association areas divided by regional cerebral glucose metabolism of structures that were typically not affected by AD was significantly lower in patients with AD than in those with VD. This ratio was also related to dementia severity in both types of dementia.

Aged↗
PubMed1992

Subcortical damage and cortical dysfunction in progressive supranuclear palsy demonstrated by positron emission tomography.

Regional cerebral glucose metabolism was studied in nine patients with progressive supranuclear palsy (PSP). (18F)-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) revealed general cerebral hypometabolism in all PSP patients in comparison with an age-matched reference group. When comparing the degree of regional metabolic deterioration, a consistent pattern of the most affected brain regions became obvious: the strongest significant alteration of cerebral glucose metabolism was observed in subcortical regions, e.g. in caudate nucleus, lentiform nucleus and upper mid-brain, which showed nerve cell loss in previous pathological studies. Less severe, but still significant hypometabolism was observed in frontal cortex. This pattern of hypometabolism was distinctly different from that typically seen in dementias of Alzheimer's type. The present data show that PET findings agree with histopathological studies: PSP is a primarily subcortical disease with secondary inactivation of cortical, especially of frontal brain regions.

Aged↗
PubMed1992

Quantitative EEG mapping and PET in Alzheimer's disease.

Quantitative analysis of topographical EEG was studied in comparison with measurement of regional glucose metabolism by PET in 42 patients with clinical diagnosis of probable dementia of Alzheimer type (AD) and in 15 age-matched normal controls. Measures analyzed included global and regional data from areas typically affected and not affected by AD pathology. While disturbance of metabolism followed a typical regional pattern, relative alpha, theta and delta power were more globally altered without selectivity for specific regions. Separation between AD and age matched controls by relative theta power was correct in 86% and was close to that by temporo-parietal glucose metabolism (correct classification 87%). Relative theta power as well as temporo-parietal glucose metabolism were significantly correlated (tau B = 0.54 and -0.53, respectively) to severity of AD assessed by the global deterioration scale. These results indicate that EEG measures may be used with an accuracy close to metabolic values from PET for the assessment of severity of AD.

Aged↗
PubMed1992

PET correlates of normal and impaired memory functions.

To date, positron emission tomography (PET) has been the only technology for the quantitative imaging of the changes of regional cerebral glucose (rCMRGl) or oxygen metabolism and blood flow (rCBF) associated with psychophysical stimulation and with the performance of mental tasks. So far, the majority of studies performed in healthy subjects demonstrated activation patterns involving not only certain limbic structures, most of all hippocampus, amygdala, parahippocampus, and cingulate, but also temporal, parietal, and occipital association cortex, depending on the applied paradigm. Indeed, the closest correlation between regional metabolism and memory test scores was found in mesiotemporal structures during the performance of memory tasks. Metabolic or CBF studies also seem to indicate that memorizing strategies may differ among individuals. PET was repeatedly used to investigate metabolic and/or blood flow abnormalities in patients with various amnestic syndromes. In cases with uni- or bilateral lesions of mesiotemporal structures, caused by surgery, herpes simplex encephalitis, or permanent ischemic, anoxic, or toxic damage, disturbances of metabolism and blood flow typically extended far beyond the morphological defects detected by computed tomography or magnetic resonance. In acute transient global amnesia, CBF and metabolism were decreased bilaterally in the mesiotemporal lobes, where hypometabolism persisted for some time, while higher values were observed in thalamus and some cortical areas. Diencephalic lesions causing Korsakoff's syndrome were associated with decreased rCMRGl in the hippocampal formation, upper brainstem, cingulate, and thalamus. Discrete thalamic infarcts caused amnesia and metabolic depression in the morphologically intact ipsilateral thalamus and in various projection areas of the infarcted nuclei. In ischemic forebrain lesions, amnestic deficits could be related to involvement of the anterior cingulate and of basal cholinergic nuclei. A large number of pathologies are diffusely spread out in the brain and affect partially or predominantly structures in memory processing. This holds true especially in the various dementias where memory disturbances are a consistent and often leading feature. Notably, Alzheimer's disease can be distinguished from other dementias by its characteristic pattern of metabolic dysfunction, with the most prominent changes occurring in parietotemporal and frontal association cortex whose residual metabolism is related to the severity of the disease. Therefore, activation studies using paradigms involving memory functions enhance that typical pattern. Only in the activated state is metabolism of mesiotemporal structures significantly correlated with the performance in memory tests. Other dementias also affect some of the distributed memory networks, with Huntington's disease suggesting a role of the striatum in memory processing.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Cultured astrocytes release proenkephalin.

Astrocytes as well as neurons express the mRNA encoding the opioid peptide precursor, proenkephalin. In neurons proenkephalin is cleaved intracellularly to yield smaller, bioactive peptides such as Met-enkephalin and Leu-enkephalin. By contrast, utilizing a combination of radioimmunoassay and chromatographic analysis, we report here that astrocytes cultured from neonatal rat brain contain primarily unprocessed proenkephalin and only small amounts of Met-enkephalin. Further, similar experiments with and without the inclusion of several peptidase inhibitors indicate that cultured astrocytes release proenkephalin itself into the medium where it may be subsequently cleaved to smaller peptide products. The release of intact proenkephalin by astrocytes suggests that the glial propeptide subserves a different function than neuronal proenkephalin and that opioid peptides may play novel roles in the central nervous system.

Animals↗
PubMed1991

Positron emission tomography in the differential diagnosis of organic dementias.

At present, PET is the only technology affording the quantitative, three-dimensional imaging of various aspects of brain function. Since function and metabolism are coupled, and since glucose is the dominant substrate of the brain's energy metabolism, studies of glucose metabolism by PET of 2(18F)-fluoro-2-deoxy-D-glucose (FDG) are widely applied for investigating the participation of various brain systems in simple or complex stimulations and tasks. In focal or diffuse disorders of the brain, functional impairment of affected or inactivated brain regions is a reproducible finding. While glucose metabolism is decreased slightly with age in a regionally different degree, in most types of dementia severe changes of glucose metabolism are observed. Degenerative dementia of the Alzheimer type is characterized by a metabolic disturbance most prominent in the parieto-occipito-temporal association cortex and later in the frontal lobe, while primary cortical areas, basal ganglia, thalamus, and cerebellum are not affected. By this typical pattern Alzheimer disease can be differentiated from other dementia syndromes, as e.g., Pick's disease (with the metabolic depression most prominent in the frontal and temporal lobe), multi infarct dementia (with multiple focal metabolic defects), and Huntington's chorea (with metabolic disturbance in the neostriatum). In demented patients PET studies can also be applied to the quantification of treatment effects on disturbed metabolism.

Alzheimer Disease↗