Tacrine in Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
R Levy
Publications and source records attributed to R Levy.
Arachidonic acid increases the activity of the assembled NADPH oxidase in cytoplasmic membranes and endosomes.
The effect of arachidonic acid (AA) on the assembled NADPH oxidase activity in cytoplasmic membranes and in endosomes separated from human neutrophils was studied. These two fractions were separated on a Percoll-sucrose density gradient from PMA-stimulated neutrophils preincubated with fluorescein isothiocyanate-conjugated dextran (FITC-dextran). In both fractions, NADPH oxidase activity could be detected with the addition of NADPH and cytochrome c, indicating the presence of an assembled activated form of the enzyme. Addition of AA at low concentrations (ED50 = 1 microM and 0.1 microM for cytoplasmic membranes and FITC-dextran endosomes, respectively) caused an increase in the activity of the assembled NADPH oxidase found in these fractions. Addition of 10 microM AA to the assembled oxidase in cytoplasmic membranes or endosomes significantly increased the Vmax (1.37 and 1.45 nmol O2/min compared with 2.05 and 2.20 nmol O2/min in the absence of presence of AA, respectively) and lowered the Km for NADPH (35 microM and 40 microM compared with 7.5 microM and 7.2 microM in the absence or presence of AA, respectively). These results suggest that AA increases the activity of the assembled NADPH oxidase by elevating the number of its active forms and increasing its affinity to the substrate.
Arachidonic Acid↗
Complications of intracranial pressure monitoring in fulminant hepatic failure.
In patients with fulminant hepatic failure, brain oedema and the resulting intracranial hypertension often lead to death; intracranial pressure (ICP) monitoring may therefore be valuable. However, there is uncertainty about the hazards of implanting ICP monitoring devices. We carried out a survey of complications associated with ICP monitoring among centres performing liver transplantation in the USA (n = 262 patients). Epidural transducers were the most commonly used devices and had the lowest complication rate (3.8%); subdural bolts and parenchymal monitors (fibreoptic pressure transducers in direct contact with brain parenchyma and intraventricular catheters) were associated with complication rates of 20% and 22%, respectively. Fatal haemorrhage occurred in 1% of patients undergoing epidural ICP monitoring, whereas subdural and intraparenchymal devices had fatal haemorrhage rates of 5% and 4%. Thus, in the setting of fulminant hepatic failure, epidural transducers may be the safest choice for ICP monitoring, even though they are known to be less precise than the other devices.
Adult↗
Beta A4 protein deposition in familial Alzheimer's disease with the mutation in codon 717 of the beta A4 amyloid precursor protein gene and sporadic Alzheimer's disease.
Beta A4 protein immunoreactivity in the neocortex and hippocampus of familial Alzheimer's disease (AD) including the case with the beta A4 amyloid precursor protein (APP) gene mutation in codon 717 (APP717 Val-->Ile) and sporadic cases of AD is described. A semi-automatic image analysis system was used to quantify beta A4 protein load in the isocortex of the frontal and temporal lobes and in subfields of the hippocampus. Immunoreactivity was measured in ten cases of sporadic AD and in five cases of familial AD including one in which the APP717 Val-->Ile mutation was present. Beta A4 protein load, as measured by square microns of immunoreactivity per square millimetre of cortex, was similar in the frontal and temporal isocortex in both sporadic and familial AD. There was greater variation in beta A4 protein load in subfields of the hippocampus but these differences were not significant between sporadic and familial cases. In the case with the APP717 Val-->Ile mutation. Beta A4 protein load in isocortex was greater than the mean for familial and sporadic cases of AD but less than the most severe cases of beta A4 protein deposition which were found in sporadic AD. In addition, the case with the APP717 Val-->Ile mutation has the same cytoskeletal pathology as sporadic cases of AD. The mechanism by which normal and mutant APP is processed to produce amyloidogenic fragments remains to be determined.
Aged↗
A submicroscopic interstitial deletion of chromosome 14 frequently occurs adjacent to the t(14;18) translocation breakpoint in human follicular lymphoma.
The t(14;18) chromosomal translocation characteristic of follicular lymphoma (FL) juxtaposes the immunoglobulin heavy chain locus (IGH) and the BCL2 proto-oncogene. The translocation can be readily detected as a non-germline Notl fragment resolved by pulsed-field gel electrophoresis. A benefit of this approach is that it enables examination of the structure of a large region (+/- 300 kb) surrounding the chromosomal breakpoint. In 40/46 cases the observed translocated Notl fragment was smaller than the 680-690 kb expected from published restriction maps of the involved loci suggesting a deletion in the region of the breakpoint. Analysis of the der(14) allele by molecular hybridization demonstrated that in 35/46 cases the mu constant region (C mu) was deleted. Further molecular dissection of the IGH locus demonstrated that this resulted from an interstitial deletion of the der(14) chromosome within the region defined by the mu switch region (S mu) on the 5' side and the epsilon constant region (C epsilon) on the 3' end. Thus, the deletion resembled a class switch (CS) recombination event. Surprisingly, the CS deletion was as common in FL which was sIGM positive (24/33, 72.7%) as in cases where the productive allele had already undergone CS deletion (11/13, 84.6%) suggesting that the observed non-physiologic CS deletion resulted from a cis effect of the chromosomal translocation. Similar interstitial deletions of the non-productive IGH allele were not seen in B cell lymphocytic lymphomas which do not have the t(14;18) translocation. Mapping of the 3' extent of the deletion by an isotype PCR assay demonstrated frequent involvement (11/12 cases) of the gamma 1 constant region (C gamma 1). Analysis of cases in which the deletion was not evident by Southern blotting but detectable by PCR suggested that the CS deletion had occurred in a small subpopulation of FL cells subsequent to the t(14;18) translocation. The biological role of frequent interstitial deletions of the der(14) chromosome in t(14;18)-carrying lymphomas remains to be elucidated.
Alleles↗
Both mannose and beta-glucan receptors are involved in phagocytosis of unopsonized, heat-killed Saccharomyces cerevisiae by murine macrophages.
We studied the involvement of lectin-like receptors in phagocytosis of unopsonized heat-killed yeast (Saccharomyces cerevisiae) by murine macrophage-like cell lines and murine peritoneal resident macrophages. For this purpose we used a technique that allowed us to discriminate ingested and adsorbed heat-killed yeast. The internalization can be partly inhibited by soluble polyosides such as laminarin (beta-glucan) or alpha-mannan. However, when they were used together (0.4 mg/ml alpha-mannan and 0.4 mg/ml laminarin), almost complete inhibition of phagocytosis was obtained. These observations suggest that phagocytosis of unopsonized heat-killed yeast by murine macrophage-like cell lines as well as murine peritoneal resident macrophages is mediated by both mannose and beta-glucan receptors. The respective activity of these two types of receptors is a function of in vitro cell differentiation. To achieve maximal phagocytosis of unopsonized heat-killed yeast, coexpression of both mannose and beta-glucan receptors is required.
Animals↗
T-cell receptor gamma delta diversity and specificity of intestinal intraepithelial lymphocytes: analysis of IEL-derived hybridomas.
The phenotype, T-cell antigen receptor (TCR) usage and specificity of intestinal intraepithelial lymphocytes (IEL), and hybridomas derived from IEL have been examined. In young conventionally reared mice, approximately 50% of the IEL express TCR alpha beta and 50% express TCR gamma delta, although there is considerable variation between individuals. Here we demonstrate that T-cell hybridomas can be prepared from freshly isolated BALB/c mouse IEL. The expressed TCR of these hybridomas reflects the TCR isotype distribution of the IEL population. Analysis of the gamma delta TCR expressed by the hybridomas demonstrates that IEL express a greater number of TCR V gene segments than has been reported for gamma delta T cells in several other epithelial sites. At least five types of gamma delta TCRs are expressed by a panel of BALB/c IEL hybridomas, although use of the gamma delta TCR V gene repertoire clearly is not random. Some TCR gamma delta cells and gamma delta hybridomas have been reported to recognize purified protein derivative (PPD); however, none of the IEL hybridomas secreted IL-2 in response to PPD. These data suggest that most TCR gamma delta IEL are not likely to be PPD reactive.
Animals↗
Lyme disease presenting as a stroke in the vertebrobasilar territory: MRI.
A 28-year-old female farmer, without vascular risk factors, developed a limited infarct of the pons, associated with a lymphocytic cerebrospinal fluid (CSF) pleocytosis. Titres of specific antibodies against Borrelia burgdorferi were high in serum and CSF. MRI confirmed an infarct in the territory of the medial pontine arteries, but angiography showed no evidence of cerebral angiopathy. Antibiotic therapy rapidly led to a return to normal of CSF cytology and serology. We suggest that Lyme disease is a possible cause of cerebral ischaemia.
Adult↗
Further analysis of the cognitive effects of tetrahydroaminoacridine (THA) in Alzheimer's disease: assessment of attentional and mnemonic function using CANTAB.
Results of a placebo controlled cross-over trial (N = 89) of the anticholinesterase drug THA as a treatment for dementia of the Alzheimer's type (DAT) are reported, with reference to previous trials of the drug and the cholinergic hypothesis of aging and dementia. Using computerised tests sensitive to specific aspects of memory and attention, evidence is found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Although these improvements were significant, they were small and restricted to certain tests of attentional function. Nevertheless, they add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes. The results will be relevant to future investigations into the therapeutic effects of enhancement of the cholinergic system in DAT sufferers.
Aged↗
Neuropathological basis for drawing disability (constructional apraxia) in Alzheimer's disease.
The performance on four drawing tasks was studied in a sample of patients with verified Alzheimer's disease in order to examine the relationship of 'constructional apraxia' to neuropathological changes in the parietal lobe and in other brain areas. Twenty-three patients were able to attempt to copy pentagons, a spiral and a three-dimensional drawing of a house, 22 patients were able to draw a clock-face spontaneously. The results were rank-ordered by two independent raters. The values obtained in the different drawing tasks were correlated significantly with each other, with global estimates of cognitive performance (CAMCOG, Mini-Mental State), with a shorter duration of illness, higher brain weight (in the subsample of female patients), higher counts of large neurons in the parahippocampal gyrus and hippocampus, but not in the parietal lobe. This suggests that there is no specific relationship between 'constructional apraxia' and neuropathological changes in the parietal lobes of patients with advanced Alzheimer's disease, but that there is a correlation between widespread brain changes and several neuropsychological deficits, one of them being drawing disability.
Alzheimer Disease↗
Evaluation of the Coulter STKS five-part differential.
The authors evaluated the Coulter STKS (Coulter Corp., Hialeah, FL) five-part differential in a tertiary-care hospital using samples with a broad range of distributional and morphologic abnormalities. Particular attention was given to the performance of the instrument-generated suspect flags that occur as an aid to identify samples with abnormal leukocytes. A morphologically abnormal, or positive, blood smear was defined by the presence of any blasts, malignant lymphoid cells, grossly dysplastic neutrophils, nucleated red blood cells (nRBC), platelet clumps, or reactive lymphocytes of more than 5%. The presence of any white blood cell-related suspect flag, except for Immature Granulocyte/Bands (i.e., Blasts, Variant Lymph, NRBC, Platelet Clumps, Review Slide, or WBC*R), was considered to be a positive instrument result. The STKS showed excellent quantitative results for the WBC differential compared with the manual differential when these "morphologic abnormalities" were absent in a 400-cell manual differential or low in numbers (< or = 5%). Specificity of these non-immature granulocyte/band suspect flags was good, with a false-positive rate of only 11.7%. Overall sensitivity in 113 samples with morphologic abnormalities was 67.3%. Sensitivity to detection of > or = 1% abnormal WBCs or > or = 1 nRBC/100 WBCs (a subset of 78 samples) was 80.8%. Sensitivity to detection of more than 5% abnormal WBCs or more than 5 nRBC/100 WBCs (a subset of 53 samples) was 84.9%. The primary deficiency was the inability of the STKS to flag samples with lymphoma cells, lymphoid blasts, or more than 5% reactive lymphocytes.
Blood Cells↗
Hodgkin's disease during HIV1 infection: the French registry experience. French Registry of HIV-associated Tumors.
BACKGROUND: The first cases of Hodgkin's disease (HD) associated with HIV infection were reported in 1984. Since then, short series of seropositive patients suffering from HD have been published. In order to identify the characteristics, treatment response and outcome of HIV-associated Hodgkin's disease (HIV-HD), the data of HIV-HD patients recorded between 1987 and 1989 were analysed and compared with those of primary HD patient and with those of HIV-associated non-Hodgkin's lymphoma (HIV-NHL), registered during the same period. PATIENTS AND METHODS: The 45 cases of HD collected by the French registry of HIV-associated tumors between January 1987 and December 1989 were included in this study. All patients were clinically staged according to the Ann Arbor system. To compare HIV-HD characteristics with those of primary HD, we used a cohort of 407 patients with clinical stages (CS) IA to IVB, who were enrolled between September 1981 and August 1988 in a multicentric clinical trial. To identify the relationship between HIV-HD and the course of HIV infection we studied, when available, the routes of infection, initial CD4 cell count at the moment of HD diagnostic as well as the CDC class of HIV infection and compared these data with the same parameters observed in 142 HIV-NHL enrolled in the registry during the same period. RESULTS: HIV-HD is characterized by an increase in mixed-cellularity histology (49%), with a predominance of advanced stages (75%) and B symptoms (80%). A unique observation is made regarding mediastinal involvement, present in only 13% of HIV-HD (71% in primary HD). The HIV-HD/HIV-NHL ratio was significantly higher in intravenous drug abusers than in male homosexuals. Median CD4 cell count was 306/microliters at HIV-HD diagnosis, and only 11% of the cases were preceded by an AIDS manifestation. With standard therapy, 79% of the patients achieved complete remission, but hematological and infectious complications were very frequent. The progression to AIDS rate was 94% at two years and opportunistic infections were the most frequent cause of death. Overall two-year survival was 41% with 71% for patients with initial CD 4 cell counts higher than 300/microliter and 0% for those with CD4 cell counts lower than 300/microliter (P < 0.01). CONCLUSION: HIV-HD has a particular clinico-pathological profile when compared to primary HD, with a predominance of mixed-cellularity type, a high frequency of advanced stages and a high proportion of patients without mediastinal involvement. Moreover, HIV-HD seems to occur preferentially in the group of subjects infected by needle sharing. Standard HD therapy seems to be efficient but excessively toxic.
Adolescent↗
Two-dimensional NMR investigations of the interactions of antibodies with peptide antigens.
To increase our understanding of the molecular basis for antibody specificity and for the cross-reactivity of anti-peptide antibodies with native proteins it is important to study the three-dimensional structure of antibody complexes with their peptide antigens. For this purpose it may not be necessary to solve the structure of the whole antibody complex but rather to concentrate on elucidating the combining site structure, the interactions of the antibody with its antigen and the bound peptide conformation. We have developed an NMR methodology based on two-dimensional difference spectrum measurements which extract the information concerning antibody-peptide interactions and intramolecular interactions in the bound ligand from the crowded and unresolved spectrum of the Fab complex. These measurements yield restraints on interproton distances in the complex which are used to dock the peptide into calculated models for the antibodies' combining sites. Comparison of the interactions of three antibodies against a cholera toxin peptide (CTP3), which differ in their cross-reactivity with the toxin, yields information about the size and conformation of antigenic determinants recognized by antibodies, the structure of their combining sites and relationships between antibodies' primary structure, and their interactions with peptide antigens.
Amino Acid Sequence↗
Transformation of mycosis fungoides: T-cell receptor beta gene analysis demonstrates a common clonal origin for plaque-type mycosis fungoides and CD30+ large-cell lymphoma.
It is well recognized that patients with classical mycosis fungoides (MF) may develop a large-cell lymphoma (LCL), a phenomenon known as "transformation." An unresolved issue regarding the transformation of MF is whether MF and LCL represent two separate lymphomas or whether they are derived from the same T-cell clone. We report the clinicopathologic, immunophenotypic, and immunogenotypic analysis of MF and LCL in a white male. He developed a rash at age 51 that was diagnosed at age 56 as clinical stage IA patch/plaque MF. After topical nitrogen mustard and total skin electron beam therapy for progressive generalized CD3+CD4+ patch/plaque lesions, he developed nodules of Ki-1+ (CD30+) T-LCL at age 72. Southern blot analysis of DNA digested with Bg/II or BamHI and probed with a T-cell receptor (TCR)-beta gene J beta 1/J beta 2 probe showed a single, identical rearranged band in both the MF and LCL skin lesions that had been obtained 4 years apart. V beta gene family--specific gene amplification assays demonstrated dominant V beta 6 PCR products in both types of lesions. These PCR products and lesional cDNA exhibited a monoclonal pattern when amplified with consensus TCR-beta gene VDJ joint primers and electrophoresed under conditions that allowed the resolution of small differences in size. Furthermore, sequence analysis of the V beta 6 PCR products amplified from both the MF and LCL lesions showed an identical nucleotide sequence involving V beta 6.4, D beta 1.1, J beta 1.2, and C beta 1. These findings indicate that both the MF and the LCL in this patient arose from the same T-cell clone and that these diseases developed at a stage in the clone's differentiation subsequent to rearrangement of the TCR-beta gene.
Aged↗
Successful treatment of a patient with recurrent furunculosis by vitamin C: improvement of clinical course and of impaired neutrophil functions.
BACKGROUND: Neutrophils play a critical role in host defense against a variety of microbial pathogens. There is much information to suggest a role for vitamin C in the physiology of neutrophils. Thus, the effects of vitamin C treatment were studied in a patient with a history of recurrent furunculosis who showed altered neutrophil functions. METHODS: Superoxide generation was measured by cytochrome C reduction. Phagocytosis of opsonized zymosan by neutrophils and chemotaxis on agarose plates were determined. RESULTS: Chemotaxis, phagocytosis, and superoxide generation of the patient's neutrophils were significantly lower than those of the matched control. Treatment with vitamin C (500 mg/day) for 30 days caused a dramatic clinical response and a significant improvement of all three neutrophil functions to values similar to those of the controls. CONCLUSIONS: We suggest that the patient described here had a temporary defect in neutrophil functions. The treatment with vitamin C probably prevented neutrophil oxidation, thus contributing to recovery of neutrophil function and arrest of furunculosis.
Adult↗
Beta-endorphin is a potent inhibitor of thymidine incorporation into DNA via mu- and kappa-opioid receptors in fetal rat brain cell aggregates in culture.
Thymidine incorporation into DNA was inhibited dose-dependently by beta-endorphin in rat fetal brain cell aggregate cultures. The inhibition was reversed partially by mu (cyclic D-Phe-Cys-Tyr-D-Trp-Orn-Thr- Pen-Thr amide) or kappa (norbinaltorphimine) antagonists. Complete blockade of the beta-endorphin inhibitory effect was achieved only on concomitant exposure to both antagonists. Eadie-Hofstee analysis revealed that beta-endorphin inhibited thymidine incorporation noncompetitively. In the presence of protease inhibitors, beta-endorphin decreased thymidine incorporation with an IC50 of 0.7 nM. Truncated and N-acetylated beta-endorphin derivatives, which bind with low affinity to opioid receptors, did not affect thymidine incorporation. These findings indicate that beta-endorphin at physiological concentrations can regulate thymidine incorporation in cultured brain cells.
Animals↗
Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase.
A putative endogenous cannabinoid ligand, arachidonylethanolamide (termed "anandamide"), was isolated recently from porcine brain. Here we demonstrate that this compound is a specific cannabinoid agonist and exerts its action directly via the cannabinoid receptors. Anandamide specifically binds to membranes from cells transiently (COS) or stably (Chinese hamster ovary) transfected with an expression plasmid carrying the cannabinoid receptor DNA but not to membranes from control nontransfected cells. Moreover, anandamide inhibited the forskolin-stimulated adenylate cyclase in the transfected cells and in cells that naturally express cannabinoid receptors (N18TG2 neuroblastoma) but not in control nontransfected cells. As with exogenous cannabinoids, the inhibition by anandamide of the forskolin-stimulated adenylate cyclase was blocked by treatment with pertussis toxin. These data indicate that anandamide is an endogenous agonist that may serve as a genuine neurotransmitter for the cannabinoid receptor.
Adenylyl Cyclase Inhibitors↗
Schizophrenic symptoms in late paraphrenia.
The prevalence of most individual schizophrenic symptoms in late paraphrenia is unknown. Previous attempts to characterize the symptoms of late paraphrenia have been retrospective case-note studies, have not used standardized assessment instruments or have only examined small populations of patients. We examined 83 late paraphrenic patients using the Present State Examination. Persecutory delusions occurred in 86.7% of patients and were the most common symptom elicited. Nonverbal (63.8%) and verbal third person (50.6%) auditory hallucinations were common, as were visual hallucinations (30.1%). Earlier authors have claimed that thought insertion and thought withdrawal do not occur in late paraphrenia; we found them in 15.7 and 6.0%, respectively, of our patients.
Age Factors↗