The Effect of Baseline Performance and Age on Cognitive Training Improvements in Older Adults: A Qualitative Review.

Findings that the brain is capable of plasticity up until old age have led to interest in the use of cognitive training as a potential intervention to delay the onset of dementia. However, individuals participating in training regimens differ greatly with respect to their outcomes, demonstrating the importance of considering individual differences, in particular age and baseline performance in a cognitive domain, when evaluating the effectiveness of cognitive training. In this review, we summarize existing literature on cognitive training in adults across the domains of episodic memory, working memory and the task-switching component of executive functioning to clarify the picture on the impact of age and baseline performance on cognitive training-related improvements. Studies targeting episodic memory induced greater improvements in younger adults with more intact cognitive abilities, explained in part by factors specific to episodic memory training. By contrast, older, lower baseline performance adults improved most in several studies targeting working memory in older individuals as well as in the majority of studies targeting executive functioning, suggesting the preservation of neural plasticity in these domains until very old age. Our findings can have important implications for informing the design of future interventions for enhancing cognitive functions in individuals at the prodromal stage of Alzheimer's Disease and potentially delaying the clinical onset of Alzheimer's Disease. Future research should more clearly stratify individuals according to their baseline cognitive abilities and assign specialized, skill-specific cognitive training regimens in order to directly answer the question of how individual differences impact training effectiveness.

Establishing pragmatic estimated GFR thresholds to guide metformin prescribing.

AIMS: Renal impairment is a contraindication to metformin treatment because of the perceived increased risk of lactic acidosis. Current guidelines define renal impairment according to the serum creatinine of the individual, but this measure is being supplanted by the use of estimated glomerular filtration rate (eGFR) as it gives a closer estimate to true GFR. This study aimed to establish pragmatic eGFR limits for use in patients being considered for metformin treatment. METHODS: Estimated GFR measurements corresponding to currently used metformin creatinine limits of 130 and 150 micromol/l were derived and then applied to 12 482 patients with diabetes in Hull and East Yorkshire. RESULTS: Few patients with a serum creatinine of 130 or 150 micromol/l have an eGFR of < 30 ml/min/1.73 m(2)[chronic kidney disease (CKD) stage 4 or greater], while most are between 30 and 59 ml/min/1.73 m(2) (CKD stage 3). When applied to the 12 482 patients (median age 67 years, interquartile range 56-75), males predominated when using creatinine cut-offs (13.6% of males and 8.3% of females had creatinine > 130 micromol/l; 8.2% males and 5.2% females > 150 micromol/l), but not using eGFR CKD thresholds (3.3% males and 4.7% females < 30 ml/min/1.73 m(2); 20.8% males and 28.1% females eGFR 30-59 ml/min/1.73 m(2)). Similar proportions of patients as currently would have metformin withheld if using eGFR cut-offs between 30 and 49 ml/min/1.73 m(2). CONCLUSIONS: We have proposed pragmatic eGFR limits to guide metformin prescribing in patients with renal impairment. CKD stage 4 or greater should be an absolute contraindication to metformin, while CKD stage 3 should alert clinicians to consider other risk factors before initiating or continuing treatment.

Strict interpretation of vaccination guidelines with computerized algorithms and improper timing of administered doses.

BACKGROUND: Frequently changing immunization recommendations may lead to incorrectly administered doses. OBJECTIVE: To determine the incidence and characteristics of inappropriately timed vaccinations. METHODS: Prospectively collected immunization histories of patients <5 years old from well-child care encounters with pediatric residents in a large urban clinic during a 3-month study period. New patients or those with no immunization history in the medical record were excluded. Paper records were verified before each visit and served as the immunization history. Immunization records were entered into and analyzed by the Massachusetts Immunization Information System with strict interpretation of minimum spacing and age guidelines to identify invalid vaccine doses. Reasons for invalidity were determined by manual review. Invalid doses were cross-referenced with clinic schedule to determine who delivered doses. RESULTS: Inclusion criteria were met by 690 encounters. Charts were available for review before the encounter for 580, containing 6983 total immunizations. Of these 289 (4.1%) administered doses were invalid; 206 of 580 (35.5%) patients had at least one invalid dose. Common invalid doses given were unnecessary poliovirus vaccine around 18 months (n = 66) and second hepatitis B vaccine given too soon after the first (n = 53). All types of providers gave invalid doses; pediatric residents and fellows delivered significantly more (P < 0.01). CONCLUSIONS: By strict interpretation of immunization guidelines, many patients were immunized incorrectly. Clinicians should be aware of common errors in vaccine dosing and national guidelines should be simplified.

Public eyewitness confidence ratings can differ from those held privately.

Despite much research on eyewitness confidence, we know very little about whether confidence ratings given in public might differ from those held privately. This study tested a prediction derived from self-presentation theory that eyewitnesses will give lower confidence ratings in public when there is a possibility of their account being contradicted by other witnesses as compared to when they report their confidence in private. In groups of 3 or 4 people, 96 participants watched a videotape of a simulated robbery and then answered 16 forced-choice questions about details from the videotape. In half of the experimental sessions, the participants shared their answers and confidence ratings aloud with the other participants (public condition), and in the other half, the answers and ratings were not shared (private). As predicted, confidence ratings were significantly lower in the public condition than in the private condition, but the privacy manipulation had no effect on response accuracy. These results are consistent with a self-presentation explanation, and they highlight the need to examine public confidence ratings more thoroughly.

Recognition instructions and recognition practice can alter the confidence--response time relationship.

Three face-recognition experiments examined how instructions for a recognition test (e.g., emphasize speed or emphasize accuracy) can impact the confidence-response time relationship for episodic memory reports. In all 3 experiments, the confidence-response time correlation was smaller when participants were told to speed up their responding rate, which suggests that participants in these conditions relied less on the artificially compressed response times in forming their confidence judgments than they would under "normal" circumstances. Also, recognition practice before the final memory test eliminated the effect of the recognition instruction manipulation. These results support J. S. Shaw's (1996) suggestion that witnesses rely in part on the fluency of their memory reports when generating confidence judgments, and these findings have important implications for understanding the relationships among witness confidence, accuracy, and response time.

Lay Attitudes toward Genetic Testing for Susceptibility to Inherited Diseases.

One of the most important issues facing legal and medical policy makers in the coming years will be whether to employ populationbased testing for genetic markers of inherited diseases. Two hundred and twenty-six randomly selected individuals from Easton, Pennsylvania completed a mail questionnaire that was designed to assess the general public's attitudes toward many of the personal and societal issues surrounding genetic testing for disease susceptibility. Respondents were generally optimistic about the potential benefits of genetic testing, and their attitudes about genetic testing were associated with their personal interest in getting a genetic test. Respondents were more likely to be interested in undergoing genetic testing for disease susceptibility if they might have some control over the targeted disease (i.e. there was a cure) and if the test was highly predictive of their chances of developing the disease. Respondents were wary of granting access to genetic testing results to anyone other than doctors and family members, and they did not want the government, religious leaders, or the courts involved in regulating genetic testing. These results have important implications for psychologists, genetic scientists, bioethicists, and legal scholars who are grappling with the many issues related to population-based genetic testing for inherited diseases.

Impact of an encounter-based prompting system on resident vaccine administration performance and immunization knowledge.

OBJECTIVES: To evaluate an encounter-based immunization prompting system on resident performance in administering vaccines and knowledge of immunization guidelines. DESIGN/METHODS: Prospective randomized, controlled trial. Subjects were first- and second-year pediatric residents in a hospital-based continuity clinic. The intervention group received manual prompts of immunizations due. Postclinic chart review compared immunizations due with those administered. Acceptable and unacceptable reasons for not administering vaccines were assigned. Resident knowledge was measured by a 70-item examination. RESULTS: The intervention group had significantly less missed opportunities/vaccine administration errors (11.4% vs 21.6%). The most common reason for unacceptable errors in the intervention group: vaccine was given too early; in the control group: vaccine was postponed to next visit. Pre- and postintervention knowledge scores were similar: intervention group (75.5% vs 80.7%, control group; 76.5% vs 81.3%). CONCLUSION: An immunization prompting system in a hospital-based pediatric resident continuity clinic reduced missed opportunities/vaccine administration errors without significantly impacting resident knowledge of immunization guidelines.immunization schedule, vaccination, immunization, prompting systems, resident education.

Nail primer cosmetics: correlations between product pH and adequacy of labeling.

BACKGROUND: We have previously reported on injuries suffered by young children exposed to methacrylic acid-containing nail primers and the need for public education efforts concerning this potential household hazard. However, some primers contain alternative ingredients, which may or may not pose the same risk; product labeling information is variable and may be confusing to consumers. OBJECTIVE: To investigate the relationship between pH of different primer products, product contents, and appropriateness of product labeling and packaging. METHODS: Twenty-three commercially available primers were grouped by product contents: (methacrylic acid vs others). Product pH was measured and product labels were scored on 7 warning points: "poison and/or corrosive," a "caution to avoid contact and/or to use a barrier when handling the product," a "skin first aid," and "eye first aid," an "ingestion first aid," a caution to "keep out of reach of children," and a "in emergency, contact a poison center." A summative "global hazard notification score" was calculated for each product. Data were analyzed using correlations and the two-sample t-test. RESULTS: None of 23 products tested were contained in a child-resistant container and none included all 7 label items. Product pH ranged from 1.90-8.55 (mean pH 4.59 +/- 1.99); 20 products had pH < 7.0. Only 1 product advised, in the event of a poisoning, that a poison center be contacted. Of 20 acidic products, only 7 alerted users that the contents could cause burns. The mean global hazard notification score (MAX = 7) was 3.6; global hazard notification score did not correlate with pH. Methacrylic acid-containing products had a lower pH (mean 3.43 +/- 0.78) than those without methacrylic acid (mean 5.34 +/- 2.18), p = 0.008. When the primer bottle was separated from the rest of the packaging which comprised the artificial nail "kit," 50% of products lost all of their warning information. CONCLUSIONS: Most, but not all, artificial nail primers analyzed in this study were highly acidic. Labeling and packaging of many nail primers are inadequate, given the potential of methacrylic acid in these products to cause burns and the toxicity of most nail primers. We agree with the Consumer Product Safety Commission's recently proposed rule to require cosmetic manufacturers to repackage methacrylic acid-containing household products in child-resistant containers. We also urge manufacturers to alert consumers to the hazards of nail primers by better labeling. Manufacturers should also investigate the feasibility of either substituting other chemicals or lowering the concentration of methacrylic acid.

More than suggestion: the effect of interviewing techniques from the McMartin Preschool case.

Child interviewing techniques derived from transcripts of the McMartin Preschool case were found to be substantially more effective than simple suggestive questions at inducing preschool children to make false allegations against a classroom visitor. Thirty-six children interviewed with McMartin techniques made 58% accusations, compared with 17% for 30 children interviewed with suggestive questions. Social influence and reinforcement appeared to be more powerful determinants of children's answers than simple suggestive questions. The SIRR model is proposed to explain how false statements may be elicited from children or adults. Categories identified in the SIRR model are suggestive questions, social influence, reinforcement, and removal from direct experience.

Co-witness information can have immediate effects on eyewitness memory reports.

When questioning a reluctant witness, investigators sometimes encourage the witness by providing information about what other witnesses have said. Three experiments were conducted to test the combined effects of such co-witness information and suggestive questioning on the accuracy of eyewitness memory reports. Experiment 1 was analogous to the experience of a witness who receives information from an interviewer or questioner about what other witnesses have already said, whereas Experiments 2 and 3 simulated the situation in which a witness receives information directly from a co-witness. In all three experiments, when participants received incorrect information about a co-witness's response, they were significantly more likely to give that incorrect response than if they received no co-witness information. This effect persevered in a delayed memory test 48 h after the initial questioning session in Experiment 3. Accuracy rates were lowest of all when incorrect co-witness information was paired with questioning that suggested an incorrect response. These results have implications not only for the immediate effects on the accuracy of witnesses' memory reports, but also for the impact that even one such inaccurate report can have on the manner in which a case is investigated by the police or other authorities.

Retrieval-induced forgetting in an eyewitness-memory paradigm.

The potential impact of repeated questioning of a witness was examined. Subjects were shown slides depicting the aftermath of a theft and subsequently were asked several times to recall selected details of what they saw. Previous experiments employing simple verbal materials have demonstrated that information addressed by questioning becomes more recallable in the future than it would have been without such retrieval practice, but other information, especially that bearing a categorical similarity to the practiced items, becomes less recallable. Such positive and negative effects appeared in subjects' later recall of crime-scene details in the present experiment. These results have an important implication for legal practice: Repeated interrogation of a witness can modify the witness's memory-enhancing the recall of certain details while inducing the forgetting of other details-even when no misinformation is contained or implied in the questioning.

Differential sensitivity of antinociceptive assays to the bradykinin antagonist Hoe 140.

1. The antinociceptive activity of the bradykinin (BK) BK2 receptor antagonist D-Arg-[Hyp3,Thi5D-Tic7,Oic8]BK (Hoe 140) was determined in a range of mouse abdominal constriction assays. 2. Hoe 140 potently inhibited the response induced by i.p. injection of 10 micrograms BK/mouse, and 1 microgram BK/mouse in mice pre-sensitized by i.p. injection of prostaglandin E2 (PGE2). The ED50 values in these assays were 1.9 and 3.7 micrograms kg-1 respectively. This confirms that Hoe 140 is a potent antagonist of BK in vivo. 3. Hoe 140 produced potent, but incomplete inhibition of the responses evoked by i.p. injection of kaolin or 0.25% acetic acid. ED25 values in these assays were 2.7 and 16.1 micrograms kg-1, and the maximum inhibition produced was 60% and 70% respectively. 4. At doses up to 1 mg kg-1, Hoe 140 was completely ineffective against the abdominal constriction response induced by zymosan. In contrast, morphine, ibuprofen and indomethacin had similar potencies against zymosan, kaolin and acetic acid-induced abdominal constriction. 5. Although zymosan, acetic acid and kaolin all produce qualitatively similar responses, it is appears that they achieve this by different mechanisms. The extent to which BK is involved as a mediator differs between the various types of abdominal constriction assay.

Structure/activity studies related to 2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- ethyl]acetamides: a novel series of potent and selective kappa-opioid agonists.

This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides 1, variously substituted at the carbon adjacent to the amide nitrogen (C1), and related analogues, together with their biological evaluation as opioid kappa agonists. In the first part of the study, the variants in N-acyl, N-alkyl, and amino functions were explored when the substituent at C1 was 1-methylethyl and the optimum was found to be exemplified by 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(1-methylethyl)-2- (1-pyrrolidinyl)ethyl]acetamide (13). Subsequently, racemic or chiral amino acids were used to introduce other alkyl and aryl substituents at C1 of the ethyl linking moiety. A series of potent compounds, bearing substituted-aryl groups at C1, were discovered, typified by 2-(3,4-dichloro-phenyl)-N-methyl-N-[(1R,S)-1-(3-aminophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide (48), which was 5-fold more active as the racemate than 13 in vitro and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.04 mg/kg sc) in a mouse abdominal constriction model.

2-(3,4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- ethyl]-acetamides: the use of conformational analysis in the development of a novel series of potent opioid kappa agonists.

This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa agonist N-[2-(1-pyrrolidinyl)cyclohexyl] acetamide U-50488 might possess kappa agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.

The coexistence of adenosine A1 and A2 receptors in guinea-pig aorta.

The effects of adenosine, 5'-(N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CA), N6-cyclohexyladenosine (CHA) and N6(R-2-phenylisopropyl)-adenosine (R-PIA) on the tone of phenylephrine-constricted guinea-pig isolated aorta have been examined. For aortic relaxation the analogues exhibited the following rank order of potency: NECA greater than adenosine greater than 2-CA greater than R-PIA greater than CHA. This is consistent with previous reports that relaxation of this tissue is mediated by the adenosine A2 receptor. An unexpected finding was that R-PIA, 2-CA and CHA all induced contractions at concentrations lower than were required for relaxation, giving a biphasic dose-response curve. Neither NECA nor adenosine contracted the aorta. This is consistent with activation of vascular A1 receptors. An A1-selective concentration of the antagonist 1,3-dipropyl-8-cyclopentyl xanthine abolished the contraction elicited by R-PIA in the guinea-pig aorta. This further suggests that the contraction is mediated by A1 receptors.

The xanthene-9-spiro-4'-piperidine nucleus as a probe for opiate activity.

A series of novel 1'-methylxanthene-9-spiro-4'-piperidines has been prepared in the search for opiate analgesics with improved pharmacological properties. It has been found that introduction of a hydroxyl group into the 4-position of the xanthenespiropiperidine nucleus produces a potent mu-opiate agonist. The structure-activity relationship of the series has been explored by use of isosteric replacements of the phenolic hydroxyl group. Moreover, the effect of altering the conformation of the piperidine ring has been studied. It was interesting to note that, in compounds lacking the phenolic hydroxyl group, opiate activity could be produced by introduction of the (phenylamino)ethyl group instead of methyl at the 1'-position.

ICI 204448: a kappa-opioid agonist with limited access to the CNS.

1. A number of compounds were evaluated in an attempt to identify a kappa-opioid receptor agonist with limited access to the central nervous system. 2. Quaternary derivatives of the kappa-opioid agonists tifluadom, U-50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations. 3. A novel compound - ICI 204448 - is described which produced a potent and naloxone-reversible inhibition of electrically-evoked contraction of the guinea-pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the kappa-opioid ligand [3H]-bremazocine from guinea-pig cerebellum membranes. 4. Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by kappa-agonists such as U-50488H and tifluadom. 5. A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration.

Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists.

1. The antinociceptive activity of a range of opioid agonists and agonist-antagonist analgesics was determined in mice by use of the 55 degrees C hot plate and abdominal constriction assays. 2. Opioid agonists were approximately 10 times more effective in the abdominal constriction assay. 3. The agonist-antagonists produced analgesia only in the abdominal constriction assay, and antagonized the antinociceptive action of opioid agonists in the 55 degrees C hot plate test. 4. These differences were shown to be attributable to the different levels of stimulus employed in the two tests. 5. By comparing the antagonist potencies of the agonist-antagonists in the 55 degrees C hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calculated.

A novel series of potent and selective agonists at the opioid kappa-receptor.

Three novel opioid agonists are described. These compounds were found to bind with high affinity and selectivity to the kappa-opioid receptor. Isolated tissue studies using the field-stimulated mouse vas deferens and guinea-pig ileum preparations confirmed the high agonist potency and naloxone-reversibility of these agents. All three compounds exhibited potent antinociceptive activity in the mouse abdominal constriction model. These compounds should prove useful as tools to investigate kappa-receptor function.

The physiological relevance of low agonist affinity binding at opioid mu-receptors.

1. Inhibition constant (Ki) were determined for a range of opioid standards using two binding assays; [3H]-[D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]-GLYOL) binding to guinea-pig brain membranes in HEPES buffer and [3H]-naloxone binding to rat whole brain membranes in Krebs/HEPES buffer. 2. These values were compared with affinity measurements determined by antagonism of GLYOL on the rat isolated vas deferens preparation and by the receptor occlusion technique of Furchgott on the guinea-pig ileum longitudinal muscle, myenteric plexus preparation. 3. Agonists demonstrated markedly reduced binding affinity in the [3H]-naloxone binding assay where binding was conducted in the presence of sodium. 4. A strong correlation was obtained between Ki values from the [3H]-naloxone binding assay and affinity values determined in both isolated tissue preparations. Ki values obtained from [3H]-GLYOL binding did not correlate well with affinity data determined by isolated tissue techniques. 5. These findings suggest that functionally relevant receptors exhibit low agonist affinity.