Neural basis of implicit motor sequence learning: Modulation of cortical power

Implicit sequence learning describes the acquisition of serially ordered movements and sequentially structured cognitive information, that occurs without awareness. Theta, alpha and beta cortical oscillations are present during implicit motor sequence learning, but their role in this process is unclear. The current study addressed this gap in the literature. A total of 50 healthy adults aged between 19 and 37 years participated in the study. Implicit motor sequence learning was examined using the Serial Reaction Time task where participants unknowingly repeat a sequence of finger movements in response to a visual stimulus. Sequence learning was examined by comparing reaction times and oscillatory power between sequence trials and a set of control trials comprising random stimulus presentations. Electroencephalography was recorded as participants completed the task. Analyses of the behavioral data revealed participants learnt the sequence. Analyses of oscillatory activity, using permutation testing, revealed sequence learning was associated with a decrease in theta band (4–7 Hz) power recorded over frontal and central electrode sites. Sequence learning effects were not observed in the alpha (7–12 Hz) or beta bands (12–20 Hz). Even though alpha and beta power modulations have long been associated with executing a motor response, it seems theta power is a correlate of sequence learning in the manual domain. Theta power modulations on the serial reaction time task may reflect disengagement of attentional resources, either promoting or occurring as a consequence of implicit motor sequence learning     

Evaluation of a novel bis-naphthalimide anticancer agent,DMP 840, against human xenografts derived from adult,juvenile, and pediatric cancers

The new bis-naphthalimide antitumor agent (R,R)2,2-[1,2-ethanediylbis[imino(1-methyl-2.1-ethanediyl)]-bis {5-nitro-1H-benz[de]-isoquinoline-1,3-2H) dione} dimethanesulfonate (DMP 840) was evaluated against parental and multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immunedeprived mice. In vitro, KB8-5 cells were 50-fold resistant to vincristine but only 16-fold resistant to DMP 840 as measured by clonogenic survival. For in vivo evaluation, DMP 840 was given by i. v. injection daily for 9 days or for 5 days/week for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resistance of KB cell lines in vitro, both KB3-1 and KB8-5 tumors were highly and equally sensitive to DMP 840; only KB3-1 xenografts demonstrated sensitivity to vincristine, which was consistent with the in vitro results. DMP 840 was also evaluated against a panel of human tumors comprising colon adenocarcinoma and rhabdomyosarcoma xenografts. Against eight lines of colon adenocarcinoma, DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibition of growth in two lines. DMP 840 caused complete regressions in five of six lines of advanced rhabomyosarcomas, demonstrating a broad range of effective dose levels. The pattern of activity against this tumor panel was similar but not identical to that of two inhibitors of topoisomerase I. There was no cross-resistance to DMP 840 in xenografts selected for resistance to vincristine or in a rhabdomyosarcoma selected for resistance to the topoisomerase I inhibitor topotecan. In contrast, a colon tumor selected for topotecan resistance was completely resistant to DMP 840. Slight cross-resistance to DMP 840 was demonstrated in a rhabdomyosarcoma xenograft that was selected for primary resistance to melphalan and was cross-resistant to topoisomerase I inhibitors. The pattern of activity and cross-resistance in these tumors was compared with that shown by two agents that inhibit topoisomerase I: topotecan and CPT-11.This work was supported in part by CA23099, Cancer Center Support (CORE) grant CA21675, The Du Pont Merck Pharmaceutical Company, and by American Lebanese Syrian Associated Charities (ALSAC)     

Oligogenic determination of morphine analgesic magnitude: A genetic analysis of selectively bred mouse lines

Two ongoing selective breeding projects have produced mice that display divergent analgesic responses to morphine. These two projects have selected for similar phenotypes: high and low levorphanol analgesia (HAR/LAR lines; Portland, OR) and high and low swim stress-induced analgesia (HA/LA lines; Jastrzebiec, Poland). Evidence suggests genetic commonalities between mice of the two projects. Using a Mendelian breeding protocol, we have recently found that one or two genetic loci predominantly determine the high morphine analgesia exhibited by HA mice. In the present study we demonstrate that the differential morphine analgesia (5 mg/kg. i.p.) displayed by HAR and LAR mice is similarly oligogenic, predominantly determined by two unlinked loci. A complementation analysis, in which the analgesic responses to morphine of the recessive homozygotes of each project (HAR and HA) were compared to those of their hybrid offspring (HAR x HA), revealed that different genetic loci have been fixed in each project. An intriguing bimodal distribution was observed in the HAR x HA population: Some HAR x HA hybrids displayed greater morphine analgesia than either HAR or HA mice, whereas others displayed minimal analgesia. LAR x LA hybrids displayed less analgesia than either LAR or LA mice. The analgesic responses of HAR x LA and LAR x HA mice were comparable to those of their low-line parents. These findings indicate not only that different loci were responsible for producing high morphine responders in each selection project but that these distinct loci can interact synergistically to produce superhigh and superlow responders.     

Factor analysis of the psychosocial items of the EORTC QLQ-C30 in metastatic breast cancer patients participating in a psychosocial intervention study

The underlying factor structure of a subset of 12 items, which comprise the psychosocial subscales of the EORTC QLQ-C30 was explored in a group of women, all with metastatic breast cancer who were participating in a psychosocial intervention study. Two main factors were identified in this exploratory factor analysis, representing emotional distress and functional ability dimensions. A preliminary assessment of the external validity of the two factor structure was undertaken. The results support the validity of a summative emotional distress and functional ability score in this sample of patients. The functional ability score discriminated well for subgroups defined by clinical status indicators (e.g., performance status, pain, chemotherapy treatment, fatigue). The emotional distress subscale discriminated with respect to suffering, fatigue and sleep disturbance. Both subscales converged with related concepts measured by independent instruments, providing support for convergent validity. Summative index scores may be advantageous for application in particular research situations; applying quality adjustments in health policy analyses; for screening purposes; to monitor populations and make comparisons across broad groups and as stratification variables in clinical trials. Further research to confirm the 2 factor structure is required in other samples before the interpretation can be accepted with confidence.     

A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m²/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m². Both plasma concentrations achieved during infusion (r² = 0.9) and area under the curve (AUC) (r² = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m². Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.     

Intravenous sedation prior to peribulbar anaesthesia for cataract surgery in elderly patients

Purpose

To investigate if pre-block iv sedation using midazolam, alfentanil, or a midazolam-alfentanil combination minimizes pain, reduces pain recall, and attenuates haemodynamic responses to peribulbar block; and to determine other factors influencing oxygen saturation (SpO₂) following iv sedation.

Methods

In a randomized, double-blind, placebo-controlled study, 120 patients, mean age 73 yr, having cataract surgery with peribulbar anaesthesia, were randomized to receive either normal saline, 1 mg midazolam, 500 μg alfentanil, or 0.5 mg midazolam plus 250 μg alfentanil. Blood pressure (BP), heart rate (HR) and pulse oximetry readings were recorded before injection of the study drugs, immediately after completion of the peribulbar block, and 10 min after the block. Pain from the anaesthetic block was assessed immediately after the block and after surgery using a visual analog scale, and recall of pain was assessed by telephone on the day after surgery.

Results

Pain scores were low in all four groups. Midazolamalfentanil reduced pain perception, and all iv sedation used reduced pain recall. Midazolam reduced systolic BP; alfentanil ± midazolam reduced HR. All iv sedation reduced SpO₂ more than did saline, but not usually to a clinically important level. Nine patients had a SpO₂ S 90%; all had received alfentanil with or without midazolam. It was not possible to predicoxygen saturation levels by any factors other than iv sedation and baseline SpO₂ levels.

Conclusion

Intravenous sedation with midazolam or alfentanil or in combination reduced pain perception, pain recall, and haemodynamic responses from peribulbar anaesthesia. Fifteen percent of patients given alfentanil developed clinically important oxygen desaturation. The use of fine gauge needles combined with slow injection of anaesthetic solution causes minimal discomfort, and routine iv sedation may be unnecessary.     

Psychological characteristics of males with secondary erectile failure

This study was designed to obtain objective data on the personality profiles of two groups of males with a primary complaint of erectile failure and compare them to a group of psychiatric patients unselected for sexual dysfunction and to a sexually normal control group. Utilizing the Eysenck Personality Inventory, the Institute of Personality and Ability Testing Anxiety Scale, Symptom Checklist, and the Minnesota Multiphasic Personality Inventory, it was determined that males applying to a university/county hospital sex-dysfunction clinic appeared similar to patients seen in the same clinic who were unselected for sex dysfunction and more psychologically disturbed than patients with the same complaint applying for treatment at a private clinic. All three groups showed more psychopathology than sexually normal males. The implications of these findings are discussed.     

Reading, Demographic, Social and Psychological Factors Related to Pre-adolescent Smoking and Non-smoking Behaviors and Attitudes

The purpose of this study was to examine reading, demographic, social and psychological factors related to pre-adolescent smoking and non-smoking behaviors and attitudes. The school-home humanistic education program was implemented in a large, urban public school system. It stressed responsible decision-making, increased self-esteem and the inter-relationships among the acquisition of knowledge of the consequences of smoking, personal feelings, family relationships and behavior. The results showed that family involvement was necessary to affect smoking attitudes and behaviors. Of all the variables studied, reading had a most pervasive relationship. Peer influence and self-esteem also were related to smoking knowledge, smoking attitude, future smoking intentions and the "purchase" of cigarettes. Two of several conclusions drawn from the results are: 1. Family involvement is necessary to affect attitudes and behaviors. 2. Health education research that does not investigate the relationship between program outcomes and reading achievement may be misleading.     

Hyperglycemia and retinopathy of prematurity in very low birth weight infants.

OBJECTIVE: Retinopathy of prematurity (ROP) remains a leading cause of morbidity in the very low-birth-weight (VLBW) infant. This study investigates a possible association between serum/blood glucose and the development of ROP. METHODS: A retrospective case-control study of all infants born between 1992 and 1997 at the Johns Hopkins Hospital with birth weights less than 1000 g who developed Stage 3 or 4 ROP was conducted. Controls either had Stage 1 ROP or no eye disease and were matched 2:1 with ROP patients for gestational age, birth weight and year of birth. Odds ratios (ORs) of ROP were calculated for multiple exposures over the first month after birth, including oxygen concentration (FiO(2)), blood glucose levels, vitamin E, mean airway pressure and mean blood pressure. RESULTS: In a simple logistic regression analysis, we found an increased ROP risk for: (1) each 10 mg/dl increase of mean glucose (OR 1.96; 95% CI 1.13 to 3.42), (2) each 1% increase of mean FiO(2) (OR 1.06; 95% CI 1.004 to 1.13), (3) history of dopamine infusion (OR 5.4; 95% CI 1.16 to 25.2) and (4) intraventricular hemorrhage Grade 3 or 4 (OR 7.3; 95% CI 1.53 to 34.7). Using a multiple regression model, we found an increased ROP risk for each 10 mg/dl increase of mean glucose (OR 2.7; 95% CI 1.003 to 7.27). Each IU/kg/day of vitamin E supplementation reduced ROP risk (OR 0.37; 95% CI 0.16-0.86). CONCLUSION: In this study, we could demonstrate that glucose levels in the first month of life are associated with the development of ROP. Further studies have to determine if this association is causal or if hyperglycemia is just an expression of severity of illness.     

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.