Episodic memory in semantic dementia: a computational approach based on the TraceLink model.
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Aphasia↗
Biomedical subjects
K S Graham
Publications and source records attributed to K S Graham.
Episodic memory: new insights from the study of semantic dementia.
The study of patients with semantic dementia, the temporal variant of frontotemporal dementia, has provided new insights into the interaction between episodic and semantic memory, and the different roles played by various structures in the temporal lobe. Recent findings indicate that the syndrome of semantic dementia can inform us about the organisation of long-term memory and the relationship between semantic memory and other cognitive systems.
Dementia↗
Relearning and subsequent forgetting of semantic category exemplars in a case of semantic dementia.
Over 15 months of longitudinal assessment, a patient with semantic dementia, D.M., improved on tests of naming and category fluency for a specific set of items (Experiment 1). The authors attribute this to his home drill with the names of these concepts plus pictures and descriptions of them. In Experiment 2, D.M. produced significantly more exemplars on category fluency for semantic categories that he had been practicing at home than for nonpracticed categories, an effect that cannot be attributed to an inherent difference between the 2 sets because the fluency performance of control participants revealed no significant difference between the 2 sets. In Experiment 3, D.M. rehearsed some of his previously nonpracticed categories daily for a period of 2 weeks: His fluency scores on the experimental categories improved substantially, but they declined once he ceased the daily drill. The results are discussed with respect to current views of long-term memory, particularly new word learning and forgetting, and to current techniques for facilitating word finding in aphasia.
Aphasia↗
Spontaneous mutation frequency and pattern in Big Blue mice fed a vitamin E-supplemented diet.
Endogenous oxidative DNA damage caused by normal cellular processes may play a vital role in carcinogenesis. To directly test the hypothesis that antioxidants will protect DNA from oxidative damage in vivo, Big Blue((R)) mice were fed either a control diet (66 IU vitamin E/kg diet) or a high-dose vitamin E diet containing 1000 IU vitamin E/kg diet of racemic d,l-alpha-tocopherol acetate from conception until 3 months of age. Using the standard Big Blue((R)) protocol, 15.5 million plaque forming units (pfu) were examined from five tissues (heart, liver, adipose tissue, thymus, and testis) of three control and three high-dose vitamin E supplemented male mice generating 433 mutants, which represented 373 independent mutations upon sequencing the lacI transgene. The alpha-tocopherol tissue concentration increased with high-dose vitamin E supplementation. In four of the tissues, individually or combined, mutation frequency changed little if any with vitamin E supplementation. In adipose tissue, which accumulated the highest levels of vitamin E, mutation frequency was significantly reduced with high-dose vitamin E supplementation (P = 0.047). Within the constraints of sample size, the pattern of mutation in adipose tissue was not altered significantly (P = 0.40). When data from all tissues were combined, a reduction in G:C --> T:A transversions was observed (P = 0.044). These results may have implications for cancer chemoprevention and provide insight into the efficacy of vitamin E supplementation in reducing spontaneous oxidative DNA damage in vivo. More dramatic alterations of mutation frequency and pattern may be observed with higher doses of vitamin E and substitution of the racemic supplement with d-alpha-tocopherol acetate.
Animals↗
ERCP in the management of pediatric pancreatitis.
BACKGROUND: Although ERCP is commonly performed in children, the effect of findings at ERCP on the subsequent management of pediatric pancreatitis is unknown. METHODS: We retrospectively reviewed charts to determine the impact of ERCP on the management of recurrent acute or chronic pancreatitis in 17 consecutive children (3 boys and 14 girls, 3 to 16 years, mean 11.2 years) with recurrent acute (n = 13) or chronic pancreatitis (n = 4) who underwent ERCP. Radiographs were reviewed in a blinded manner, and the effect of ERCP findings on subsequent management was determined. RESULTS: In 16 of 17 patients (94%), the pancreatic duct was successfully visualized. Of the 16 studies, 9 (56%) had abnormal findings. A change in therapy occurred in all 9 patients as a result of the findings at ERCP. Of the 7 patients with a prior abnormal CT or ultrasound, 5 (71%) had an abnormal ERCP, all resulting in a change in therapy. Three of the 9 patients (33%) without radiographic abnormalities had an abnormal ERCP that, in each case, resulted in a change in therapy. Overall, findings at ERCP altered therapy in 52% of pediatric patients studied with recurrent acute or chronic pancreatitis. A prior abnormal CT had a high predictive value with respect to ERCP resulting in a change in management (83%). CONCLUSIONS: ERCP is useful in the management of pediatric recurrent acute or chronic pancreatitis; abnormalities are found at a rate similar to those found in adults.
Acute Disease↗
A reversal of the temporal gradient for famous person knowledge in semantic dementia: implications for the neural organisation of long-term memory.
On tests of autobiographical memory, patients with semantic dementia demonstrate significantly better retrieval of episodic events from the recent past compared with the distant past. This reversal of the Ribot effect has been attributed to the relative sparing of the hippocampal complex in the disorder. Current computational models of long-term memory predict a similar time-dependent pattern of impairment on tests of remote semantic memory. Five patients with semantic dementia were tested on recognition (familiarity) and identification (knowledge) of famous names selected from four different time-periods: 1950's, 1980's, 1990-1993 (early 1990's) and 19941996 (current). As expected, it was found that one patient DM (who had focal left temporal lobe atrophy) showed no significant impairment on recognition of famous names, but was significantly better at producing information about people who were currently famous compared to people famous in the other three time-periods. The other four patients (who had bilateral temporal lobe damage) showed better recognition of famous names from the current time-period (and to a lesser extent the 1950's), yet were profoundly impaired on the identification component, producing very little information across all four time-periods. The results are discussed with respect to current views of the neural organisation of person-specific and general semantic memory.
Aphasia, Wernicke↗
Naming in semantic dementia--what matters?
One of the major symptoms of semantic dementia (or progressive fluent aphasia) is profound word-finding difficulties. We present here a cross-sectional study of the factors affecting picture naming in semantic dementia based on data obtained from eight patients, together with a longitudinal analysis of naming in another patient. Various properties and attributes of the objects were entered into a series of regression analyses in order to predict which items the patients could or could not name. The analyses showed that object familiarity, word frequency and age-of-acquisition predicted naming success for the group and, in most cases, for each individual patient, irrespective of lesion site or overall naming success. We propose that the pattern of naming in semantic dementia is best described in terms of reduced semantic activation within a cascading/interactive speech production system. We suggest that object familiarity, and possibly word frequency, reflect the inherent robustness of individual semantic representations to the decay process in terms of both quantity and quality of experience. Age-of-acquisition and word frequency (at a phonological-lexical level) predicts naming success, because frequent, early-acquired words are relatively easy to activate even with reduced semantic "input".
Adult↗
Glutathione-dependent factors and inhibition of rat liver microsomal lipid peroxidation.
The effects of reduced glutathione (GSH) and glutathione disulfide (GSSG) on lipid peroxidation were investigated in rat liver microsomes containing deficient or adequate amounts of alpha-tocopherol (alpha-TH). Rates of formation of thiobarbituric acid reactive substances (TBARS) as well as rates of consumption of alpha-TH and O2 were decreased by GSH and were more pronounced in the NADPH-dependent assay system than in the ascorbate-dependent system. The GSH-dependent inhibition of lipid peroxidation was potentiated by GSSG in the NADPH-dependent assay system, but it had no effect in the nonenzymatic system. Diphenyliodonium chloride, an inhibitor of NADPH cytochrome P-450 reductase, completely prevented lipid peroxidation in the NADPH-dependent assay system whereas it had no effect on the ascorbate-dependent system. This is further evidenced by the fact that purified rat liver microsomal NADPH cytochrome P-450 reductase (EC 1.6.2.4) was inhibited approximately 24% and 52% by 5 mM GSH and 5 mM GSH + 2.5 mM GSSG, respectively. Glutathione disulfide alone had no effect on reductase activity. Similarly, other disulfides such as cystine, cystamine and lipoic acid were without effect on reductase activity. These results clearly delineate different mechanisms underlying the combined effects of GSH and GSSG on microsomal lipid peroxidation in rat liver. One mechanism involves recycling of microsomal alpha-TH by GSH during oxidative stress via a labile protein, ostensibly associated with "free radical reductase" activity. A second glutathione-dependent mechanism appears to be mediated through the inhibition of NADPH cytochrome P-450 reductase. The enhanced inhibition by GSH + GSSG of microsomal lipid peroxidation in the NADPH-dependent assay system suggests suppression of the initiation phase at the level of NADPH cytochrome P-450 reductase which is independent of microsomal alpha-TH.
Animals↗
On the relationship between knowledge and memory for pictures: evidence from the study of patients with semantic dementia and Alzheimer's disease.
Current views of long-term memory presume that both the hippocampal complex and the neocortex play interactive, but separate, roles in the storage of memories. While the neocortex is considered the eventual and permanent store for our memories, the encoding of recently experienced events is thought to be initially dependent upon the hippocampus and closely related structures. Neuropsychological studies have demonstrated that damage to the medial temporal lobe results in a retrograde amnesia extending back in time, with better preservation of older memories. The converse pattern has been shown in patients with semantic dementia, who have focal atrophy of the inferolateral temporal neocortex, but relative sparing of the hippocampal complex (Graham & Hodges, 1997). Here we demonstrate that such patients can show relatively preserved new learning on a forced-choice recognition memory test (based on real and chimeric animals), while patients in the early amnestic phase of Alzheimer's disease show severely impaired learning on the same test. This result provides support for the view that new learning is primarily dependent upon the hippocampus and related structures.
Alzheimer Disease↗
Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13C urea breath test.
OBJECTIVES: To validate the 13C urea breath test for the detection of Helicobacter pylori infection both before and after treatment. METHODS: 13C urea breath tests with 125-mg and 250-mg doses were carried out on each of 60 infected and 60 noninfected subjects. Results were compared with histological examination of gastric biopsies to establish detection limits. The best cut-off point was used in a clinical trial of the efficacy of the breath test in duodenal ulcer patients before and after antimicrobial therapy. The incremental increase (percentage, delta over baseline in U of delta/mil) in respiratory 13CO2 abundance was associated with histological evidence of H.pylori. Outpatient, tertiary care medical center, and secondary and primary care facilities were included. One hundred twenty healthy asymptomatic subjects and 465 patients with duodenal ulcer disease were studied. The test kit assessed repeatability of breath sample collection and storage and stability of stored samples. Test performance was analyzed by comparison of 125-mg and 250-mg 13C urea with measurements at 30 and 40 min postdose. The test was used to diagnose active H.pylori infection and gauge success of antimicrobial therapy. RESULTS: The test kit results were highly reproducible. The cut-off values were higher with 250-mg compared with 125-mg doses of 13C urea and 40 min compared with 30 min. Using a 125-mg 13C urea and test detection limit of 2.4% at 30 min, the accuracy was 94.8 (95% confidence interval = 92-97%) before antimicrobial therapy and 95.4% (95% confidence interval = 91-98%) after. An increase of 2.4% in the abundance of breath 13CO2 measured 30 min after a 125-mg dose of 13C urea reliably indicated the presence of active H.pylori infection either before or after antimicrobial therapy. The 13C urea breath test provides a simple and reliable and noninvasive method of assessing H.pylori status.
Anti-Bacterial Agents↗
Variability with omeprazole-amoxicillin combinations for treatment of Helicobacter pylori infection.
OBJECTIVE: Although omeprazole co-therapy enhances the effectiveness of some antimicrobials for the treatment of Helicobacter pylori infection, results have not been uniform. A meta-analysis suggested that 20 mg of omeprazole b.i.d. and 2 g or more of amoxicillin would yield a > 80% success rate (Gastroenterology 1994; 106: 142A). Our objective in this study was to test that hypothesis. METHODS: Volunteers with H. pylori infection were studied. Anti-H. pylori therapy was administered with meals for 14 days (omeprazole 20 mg b.i.d. plus amoxicillin 1 g t.i.d., or omeprazole 20 mg b.i.d. plus amoxicillin 0.5 g t.i.d.). Endoscopy was performed 4-6 wk after antimicrobial therapy ended, and the presence or absence of H. pylori was determined with biopsy specimens by Genta stain. RESULTS: Fifty-nine volunteers completed the study; 30 were studied twice. The overall success for initial treatment with either combination of amoxicillin and omeprazole was 18 of 59 [30.5%; 95% confidence interval (CI) = 19-44%]. The success rate with 500 mg amoxicillin t.i.d. was 7 of 29 (24%; 95% CI = 10-43%). With 1 g t.i.d. amoxicillin, the cure rate was higher (36.6%) (11 of 30; 95% CI = 20-56%), or intention-to-treat result was 11 of 31 (35.4%), which includes the early dropout. Compliance was > 95% for both therapies. Side effects were experienced by eight patients, two receiving 1.5 g amoxicillin and six receiving 3 g amoxicillin (p > 0.2). German trials suggest that better results might be achieved when amoxicillin is given as suspension while fasting. Thirty treatment failures were re-treated with 1 g amoxicillin suspension t.i.d., given fasting, and omeprazole 20 mg b.i.d. The cure rate was 16.6% (95% CI = 6-35%). CONCLUSION: Amoxicillin/omeprazole combinations for treatment of H. pylori infection do not yield consistent results. The reason is unknown, but the reported high rate of success with 40 mg of omeprazole and 750 mg t.i.d. suggests that almost complete inhibition of acid secretion is necessary to obtain consistent results with this combination.
Adult↗
The relationship between comprehension and oral reading in progressive fluent aphasia.
The role played by comprehension in oral reading was investigated in three patients with progressive fluent aphasia. For patients J.L. and G.C., there was evidence of a deficit in semantic memory affecting both word production and comprehension. F.M., although equally anomic, had significantly better single-word comprehension than either J.L. or G.C. It was predicted that, for J.L. and G.C., success or failure in word comprehension should show item-specific correspondence with success or failure in reading exception words, but not regular words. This predicted pattern was obtained between word-picture matching tests and reading. For F.M., with only minimal comprehension impairment for the items used, a smaller trend in the same direction was observed. The results are discussed with respect to Patterson and Hodges' hypothesis (Neuropsychologia 30, 1025-1040, 1992) regarding the consequences of impaired semantic memory for the integrity of representations in the phonological output lexicon.
Aphasia↗
Relationships between surgical ability ratings and spatial abilities and personality.
Twenty-two trainee surgeons were tested on high level tests of intelligence, a detailed battery of paper-and-pencil and computerized spatial ability tests, and personality tests. They were also rated for operating ability, clinical decision-making ability, and for overall performance by consultant surgeons who knew them well. Ability ratings were high, indicating very little dissatisfaction with the performance of trainee surgeons. There were no significant correlations between surgical ability ratings and intelligence test scores. The only significant correlation between spatial ability and ability ratings was with one subtest, and was in the opposite direction to that expected. Trends in the data suggested that those trainees rated as superior tended to be more introverted and conscientious, and tended to have better stereoscopic depth perception. The discussion questions the necessity for aptitude testing in surgery and points out some statistical pitfalls in the area. It is concluded that little advance may be made with the application of aptitude testing in the selection of surgeons until there are more objective criteria of surgical ability in different surgical specialties.
Adult↗
A role for aptitude testing in surgery?
Recent interest in the selection of surgical trainees has been directed towards the use of aptitude tests. Using mainly senior surgeons' ratings of trainees' surgical ability for comparison, specific areas of objective investigation have included manual dexterity, spatial ability, personality, and decision-making ability. While certain spatial ability tests have been shown to correlate with ratings of surgical skill, tests of manual dexterity have not. Personality variables, specifically, show how surgeons deal with stress and decision-making ability, and are considered to be important within the profession. Although aptitude tests are being used in medical recruitment, there is still widespread disagreement over their inclusion and their validity. It is proposed that the use of aptitude testing in surgery is limited by three principal factors: there are too few well-designed studies investigating the basic psychological and psychomotor abilities considered to be specific to surgical skill; the use of subjective ratings of surgical ability as the independent variable in most studies; and the fact that, as yet, there is no working definition of superior surgical ability.
Aptitude Tests↗
Accumulation of the insoluble PiZ variant of human alpha 1-antitrypsin within the hepatic endoplasmic reticulum does not elevate the steady-state level of grp78/BiP.
Greater than 85% of the transport-impaired PiZ variant of human alpha 1-antitrypsin is retained within cells and subsequently degraded within a pre-Golgi nonlysosomal compartment that is apparently separate from the endoplasmic reticulum (ER) (Le, A., Graham, K. S., and Sifers, R. N. (1990) J. Biol. Chem. 265, 14001-14007). Despite this phenomenon, human patients and PiZ-bearing transgenic mice exhibit an accumulation of the undegraded protein as insoluble aggregates within distended cisternae of the hepatic ER (Carlson, J. A., Rogers, B. B., Sifers, R. N., Finegold, M. J., Clift, S. M., DeMayo, F. J., Bullock, D. W., and Woo, S. L. C. (1989) J. Clin. Invest. 83, 1183-1190). Immunoprecipitation of the PiZ variant from pulse-radiolabeled hepatocytes from the transgenic animals has demonstrated that a minute quantity of the newly synthesized mutant protein is apparently resistant to degradation and accumulates gradually within the particulate fraction of the cell. Although the steady-state level of the resident ER protein grp78/BiP is elevated in response to the accumulation of malfolded proteins within that subcellular compartment, this phenomenon is not elicited by the accumulation of the insoluble PiZ variant. These results indicate that neither the accumulation of this malfolded protein within the ER nor even the distention of that subcellular compartment is sufficient to cause the up-regulation of grp78/BiP levels. The interpretation of these results with regard to the factors that regulate the levels of grp78/BiP in the ER is discussed.
Animals↗
Structural motif of the DNA binding domain of gamma delta-resolvase characterized by affinity cleaving.
The DNA binding domain of gamma delta-resolvase, residues 141-183, is thought to bind DNA by a helix-turn-helix motif based on sequence similarities with other known DNA binding proteins. Incorporation of the DNA cleaving moiety, EDTA Fe, at the NH2 and COOH termini of gamma delta(141-183) allows the positions of these residues relative to the DNA bases at three resolvase binding sites, each consisting of inverted copies of an imperfectly conserved 9-base pair sequence, to be mapped by high resolution gel electrophoresis. The cleavage data for EDTA-gamma delta(141-183) reveals that the NH2 terminus of the DNA binding domain of gamma delta-resolvase is bound proximal to the minor groove of DNA near the center of the resolvase binding sites. Cleavage by EDTA Fe attached to a lysine side chain (Asn183----Lys183) at the COOH terminus of gamma delta(141-183) reveals that the putative recognition helix is in the adjacent major groove on the same face of the helix, oriented toward the center of the inverted repeats.
Amino Acid Sequence↗
Intracellular degradation of the transport-impaired human PiZ alpha 1-antitrypsin variant. Biochemical mapping of the degradative event among compartments of the secretory pathway.
The naturally occurring PiZ and Pi NullHong Kong variants of the human secretory protein alpha 1-antitrypsin (AAT) are retained within an early compartment of the secretory pathway. Intracellular degradation of these transport-impaired secretory proteins is initiated 30-45 min following their synthesis and translocation into the endoplasmic reticulum (ER). Interestingly, the overall rate of degradation of the retained mutant protein is significantly accelerated when all subcellular compartments are buffered at pH 6. In contrast, degradation is virtually abolished when intravesicular compartments are buffered at pH 8. However, despite this pH sensitivity neither lysosomotrophic amines, leupeptin, or leucine methyl ester have an apparent effect on the intracellular removal of the PiZ variant. The inability of a variety of inhibitors of ER-to-Golgi protein trafficking to hinder the degradative process suggests that degradation of the PiZ variant occurs prior to its delivery to the Golgi complex. To biochemically map the subcellular site of the degradation of the retained mutant protein, a recombinant truncated PiZ variant containing the tetrapeptide KDEL at its carboxyl terminus (a signal for sorting luminal proteins from a post-ER compartment back to the ER) was expressed in cells. Attachment of this ER-recycling signal to the recombinant protein prevented its intracellular degradation. These findings indicate that degradation of the PiZ variant occurs following its export from the ER.
Animals↗
Glutathione disulfide enhances the reduced glutathione inhibition of lipid peroxidation in rat liver microsomes.
Experiments were undertaken to examine the effects of reduced (GSH) and oxidized (GSSG) glutathione on lipid peroxidation of rat liver microsomes. Dependence on microsomal alpha-tocopherol was shown for the GSH inhibition of lipid peroxidation. However, when GSH (5 mM) and GSSG (2.5 mM) were combined in the assay system, inhibition of lipid peroxidation was enhanced markedly over that with GSH alone in microsomes containing alpha-tocopherol. Surprisingly, the synergistic inhibitory effect of GSH and GSSG was also observed for microsomes that were deficient in alpha-tocopherol. These data suggest that there may be more than one factor responsible for the glutathione-dependent inhibition of lipid peroxidation. The first is dependent upon microsomal alpha-tocopherol and likely requires GSH for alpha-tocopherol regeneration from the alpha-tocopheroxyl radical during lipid peroxidation. The second factor appears to be independent of alpha-tocopherol and may involve the reduction of lipid hydroperoxides to their corresponding alcohols. One, or possibly both, of these factors may be activated by GSSG through thiol/disulfide exchange with a protein sulfhydryl moiety.
Animals↗