Effects of aging on event-related brain potentials and reaction times in an auditory oddball task

Auditory event-related potentials (ERPs) were recorded from 71 healthy individuals between 18 and 82 years of age during performance of a disjunctive reaction time task in an auditory oddball paradigm. The effects of aging on reaction times and on the latencies, amplitudes, and distributions of each of the main ERP components were examined. No significant slowing of the reaction times of the elderly subjects was observed in relation to the younger ones. The peak latencies of both the N1 and P2 components elicited by standard tones were slightly but significantly slowed with age. In the ERPs of target tones, the later, endogenous components (N2, P3, and SW) showed linear increases in latency as a function of age; the later the component, the longer the age-related delay. In general, aging was associated with less negativity (both N2 and SW) and more positivity (P3) over the anterior scalp, together with a smaller P3 and a more pronounced N2 over posterior scalp areas. Most of the effects observed in target ERPs were also evident in the difference waves derived from subtraction of the standard from the target ERPs, although the slope of the age-related latency increase of N2 was shallower and that of the P3 was steeper in the difference ERPs. These findings are discussed in relation to previous accounts of ERP changes with aging.     

Conformational features responsible for the binding of cyclic analogues of enkephalin to opioid receptors

Models of μ- and δ-receptor-bound backbone conformations of enkephalin cyclic analogues containing Phe⁴ were determined by comparing geometrical similarity among the previously found low-energy, backbone structures of -enkephalinamide, -enkephalinamide, -enkephalin and -enkephalin. The present μ-receptor-bound conformation resembles a β-I bend in the peptide backbone centred on the Gly³-Phe⁴ region. Two slightly different models were found for the δ-receptor-bound conformation; both of them are more extended than the μ-receptor-bound conformation and include a γ-turn (or a γ-like turn) on the Gly³ residue. Energetically favourable rotamers of Tyr and Phc side chains were also determined for the μ- and δ-conformations. The present models of μ- and δ-conformations share geometrical similarity with the low-energy structures of Leu-enkephalin and the analogue.     

Reading research critically. I. An introduction to appraisal: designs and objectives

• ? This is the first of two articles providing an introduction to appraising published research critically.
• ? In this paper three styles of research are presented and the basic types of research objectives and designs are briefly described.

     

Developmental Neurotoxicity: Evaluation of Testing Procedures with Methylazoxymethanol and Methylmercury

Testing procedures for identification of potential developmentalneurotoxicants were evaluated using two prototypical developmentalneurotoxicants, methylazoxymethanol (MAM) and methylmercury(MeHg). Evaluation of offspring of LongEvans rats incorporatedassessments of developmental toxicity, neurochemistry, histology,and behavior, with most testing being completed near weaning.A number of endpoints in the testing strategy were sensitiveto the effects of prenatal exposure to MAM [30 mg/kg on GestationDay (GD) 15]: (1) MAM caused reduced neonatal body weights butdid not effect viability or postnatal survivorship; (2) measurementof total and regional brain weight and histological analysisshowed that a number of regions, the cortex and hippocampusin particular, were affected by MAM exposure; (3) an assay forglial fibrillary acidic protein (GFAP) showed that the concentrationof this protein was significantly increased in the cortex andhippocampus of treated offspring; (4) a T-maze delayed-alternationprocedure indicated that MAM-treated pups were slower in theacquisition phase of the task relative to control pups; (5)motor activity testing revealed hyperactivity in treated offspringthat persisted into adulthood; and (6) acoustic startle proceduresrevealed reduced startle amplitudes in preweanlings. Few endpointswere significantly affected by prenatal MeHg exposure (1, 2,or 4 mg/kg on GD 6–15). High fetal and neonatal mortalityand lower neonatal body weights were detected at the highestdose of MeHg. Although minimal effects of MeHg may reflect arelative insensitivity of the test species and/or the test methods,the combined results from both chemicals suggest that some proceduresnot currently required in the developmental neurotoxicity guidelinemay be useful in hazard identification, and further evaluationwith other chemicals, species, strains, and/or exposure paradigmsmay be warranted.     

Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12- dihydroxy-13,14-epoxy- 11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography. The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose- dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.      

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

Effects of Procainamide and Lidocaine on Defibrillation Energy Requirements in Patients Receiving Implantable Cardioverter Defibrillator Devices

Effects of Procainamide and Lidocaine on Defibrillation. intntduction: In acute canine studies, lidocaine. but not prucainamidc, increases defibrillation energy requirements. We evaluated the effects of lidocaine or procainamide on defihrillation energy requirements in 27 patients undergoing intraoperative testing fur implantable cardioverter dcfibrillator device placement.
Methods and Results: Patients were tested off antiarrhythmic drugs and again following either lidocaine (200 to 250 mg loading and 3 mg/min maintenance infusions) or procainamide (1 gm loading and 3 to 4 mg/min maintenance infusions). The defibrillation testing protocol consisted of initial testing at 15 J, followed by higher or lower energies to determine the lowest energy producing three consecutive successful defibrillations. Overall, the mean defibrillation energy increased from 14 ± 5 J to 18 ± 7 J during lidocaine (plasma concentration 5.1 ± 1.6 μ/mL; P < 0.02) but were similar at baseline (12 ± 5 J) and during procainamide infusion (13 ± 6 J) (plasma concentration: procainamide 10.7 ± 7.2 μ/rnl.; N-acetyl procainamide 1.0 ± 0.4 μ/niL). A positive linear correlation was found between lidocaine plasma concentration and percent change in defibrillation energy (lidocaine: r = 0.61; P = 0.01). Procainamide raised the defibrillation energy in three patients, two with supra therapeutic plasma concentrations. The increase in defibrillation energy equaled or exceeded 25 J in four patients after lidocaine and in one patient after procainamide.
Conclusion: The data suggest that at high plasma concentrations, lidocaine and procainamide adversely affect defibrillation energy requirements consistent with an adverse, concentration-dependent effect of sodium channel blockade on defibrillation energy requirements in patients.     

Color Flow Doppler Observations on Mitral Valve Flow in Tamponade

We studied the M-mode and two-dimensional imaging of color Doppler mitral flow in eight patients with pericardial effusion and tamponade, and in ten control subjects. Pulsed-Doppler recordings of mitral flow were also obtained in all. Marked phasic changes (presumably respiratory) were consistently recorded in all patients with tamponade with respect to brightness, hue, width (duration), and length of the M-mode Doppler color stream; in these patients, phasic changes were noted in width, length, and color of the mitral flow stream on the two-dimensionalechocardiographic recording, with reciprocal changes in tricuspid flow. In the normal subjects, only minimal fluctuations in these color Doppler characteristics were present. Phasic differences in flow velocity of mitral flow by pulsed Doppler were found between the tamponade and the control groups. Large phasic fluctuations in various characteristics of color Doppler mitral flow on M-mode and two-dimensional imaging may constitute yet another echocardiographic sign of tamponade. (ECHOCARDIOGRAPHY, Volume 8, September 1991)     

Chemoradiation-induced changes in systemic inflammatory markers and their prognostic significance in oesophageal squamous cell carcinoma

Objective:Chemoradiation (CRT) may induce a change in systemic inflammatory state which could affect clinical outcomes in oesophageal cancer. We aimed to evaluate the changes and prognostic significance of systemic inflammatory markers following definitive CRT in oesophageal squamous cell carcinoma.Methods:A total of 53 patients treated with concurrent CRT were included in this retrospective analysis. We compared neutrophils, lymphocytes, platelets, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) before and after CRT using Wilcoxon signed-rank test. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariable and multivariable survival analysis were performed using Cox regression analysis. Clinical univariable survival prognostic factors with p < 0.1 were included in a multivariable cox regression analysis for backward stepwise model selection.Results:Both NLR (median ∆+2.8 [IQR −0.11, 8.62], p < 001) and PLR (median ∆+227 [81.3–523.5], p < 0.001) increased significantly after CRT. Higher levels of pre-CRT, post-CRT and change (∆) in NLR and PLR were associated with inferior OS and PFS. Post-CRT NLR (HR 1.04, 95% CI 1.02–1.07, p < 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01–1.05, p = 0.005), cT-stage (HR 3.83, 95% CI 1.39–10.60, p = 0.01) and RT dose (HR 0.41, 95% CI 0.21–0.81, p = 0.01) were independent prognostic factors for OS in multivariable analysis. Change in NLR (HR 1.04, 95% CI 1.01–1.06, p = 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01–1.05, p = 0.002), cT-stage (HR 3.98, 95% CI 1.55–10.25, p = 0.004) and RT dose (HR 0.41, 95% CI 0.21–0.80, p = 0.009) were independent prognostic factors for PFS.Conclusion:Both NLR and PLR increased following definitive CRT. Post-CRT NLR and ∆NLR were associated with adverse survival in oesophageal SCC.Advances in knowledge:We showed that CRT increased PLR and NLR, possibly reflecting a systemic inflammatory state which were associated with poor clinical outcomes in oesophageal SCC.