Comparing non-hierarchical models: Application to non-linear mixed effects modeling

There is no method available to compare the fit of two non-hierarchical non-linear mixed effects models, although the common practice is to select the model with the lower objective function. Bootstrapping the log-likelihood differences (LLDs) of non-hierarchical models and constructing a bootstrap confidence interval on the LLDs is proposed for comparing the goodness-of-fit of such models. This is illustrated with different parameterizations of clearance models for an anti-infective agent in a longitudinal pharmacokinetic study which are compared. Additive and exponential models of creatinine clearance as a predictor of clearance are used as examples.     

Pressure-flow relationships of the canine iliac periphery and systemic hemodynamics: Effects of sodiumnitroprusside and adenosine

It has been reported that sodiumnitroprusside (SNP) decreases mean systemic pressure and simultaneously increases pressure pulse amplification towards the iliac periphery (Kenner and van Zwieten 1982). This unexpected finding was suggested to be due to a decrease in iliac peripheral resistance but an increase in iliac differential resistance. In order to investigate this apparent contradiction, the iliac periphery was hemodynamically isolated from the rest of the circulation and perfused with the dog's own blood by means of a pump. Perfusion pressure (P) and flow (F), femoral venous pressure (P_v), systemic pressure (P_s) and cardiac output (CO) were measured. Steady state pressure-flow relations of the isolated bed were obtained during control and during various i.v. infusion rates of SNP and adenosine (ADS) and were found to be straight (meanr=0.99). Their slope (P/F) was defined as differential resistance (R_d). Peripheral resistance (R_p) of the iliac bed was defined as R_p=(P-P_v)/F, calculated at the flow value where perfusion pressure equalled the prevailing systemic pressure. Total peripheral resistance (TPR) was defined as TPR=P_s/CO. The changes of R_d, R_p, P_s, CO and TPR with respect to control show that during low SNP infusion rates R_d and R_p were both increased while TPR was decreased. During all infusion rates of SNP CO did not change while P_s decreased. During low infusion rates of adenosine CO increased while P_s, R_d and R_p did not change and TPR decreased. During high infusion rates of ADS CO decreased again, R_d, R_p and P_s decreased, and TPR remained constant but at a decreased level.It is concluded that: (1) the suggestion of Kenner and van Zwieten is not supported, since SNP (as well as ADS) affects iliac peripheral and iliac differential resistance in a similar way; (2) SNP (as well as ADS) affects iliac peripheral resistance and total peripheral resistance in a differentiated way, and even in an opposite way during low infusion rates of SNP; (3) it is this opposite effect that explains the paradoxical observations of Kenner and van Zwieten; (4) for comparable reductions of TPR, CO is better maintained during infusion of SNP, while P_s is better maintained during infusion of ADS.     

Evening administration of melatonin and bright light: Interactions on the EEG during sleep and wakefulness

Both the pineal hormone melatonin and light exposure are considered to play a major role in the circadian regulation of sleep. In a placebo- controlled balanced cross-over design, we investigated the acute effects of exogenous melatonin (5 mg p.o. at 20.40 hours) with or without a 3-h bright light exposure (5000 lux from 21.00 hours–24.00 hours) on subjective sleepiness, internal sleep structure and EEG power density during sleep and wakefulness in healthy young men. The acute effects of melatonin, bright light and their interaction were measured on the first day (treatment day), possible circadian phase shifts were assessed on the post-treatment day. On the treatment day, the evening rise in subjective sleepiness was accelerated after melatonin and protracted during bright light exposure. These effects were also reflected in specific changes of EEG power density in the theta/alpha range during wakefulness. Melatonin shortened and bright light increased sleep latency. REMS latency was reduced after melatonin administration but bright light had no effect. Slow-wave sleep and slow-wave activity during the first non-rapid eye movement (NREMS) episode were suppressed after melatonin administration and rebounded in the second NREMS episode, independent of whether light was co-administered or not. Self rated sleep quality was better after melatonin administration whereas the awakening process was rated as more difficult after bright light. On the post-treatment day after evening bright light, the rise in sleepiness and the onset of sleep were delayed, independent of whether melatonin was co-administered or not. Thus, although acute bright light and melatonin administration affected subjective sleepiness, internal sleep structure and EEG power density during sleep and wakefulness in a additive manner, the phase shifting effect of a single evening bright light exposure could not be blocked by exogenous melatonin     

Bell s面瘫对患者的心理影响及其心理健康状况

目的探讨Bell's面瘫对首次发病患者形象、情绪、日常生活及社会活动的影响及发病早期患者的心理健康状况。方法采用自编面瘫对患者形象、情绪及社会活动影响的调查问卷及症状自评量表(SCL-90),对63例首次发病的Bell's面瘫患者进行调查。统计分析采用t检验及相关分析。结果Bell's面瘫对首次发病患者形象、情绪、日常生活及社会活动均有明显影响。Bell's面瘫患者SCL-90的躯体化、强迫、人际关系敏感、焦虑、抑郁、敌对、恐怖、精神病性因子分均高于全国成人常模,其SCL-90总分与自编面瘫影响问卷各条目得分均存在统计学相关关系。结论Bell's面瘫给首次发病患者带来不良心理影响,他们存在广泛的心身症状,这些不良影响与其心身症状有关。     

Calcitonin gene products and the kidney

Summary Calcitonin gene-related peptide (CGRP) is localized in capsaicin-sensitive nerve fibres in the kidney and urogenital tract whereas calcitonin reaches the kidney through the general circulation. Systemic infusion of CGRP and perfusion of isolated rat kidney reduces vascular resistance, and increases renal blood flow and glomerular filtration. CGRP stimulates renin secretion in vivo and in vitro and inhibits contraction of isolated rat mesangial cells by angiotensin II. Calcitonin does not affect vascular resistance, renal blood flow and glomerular filtration, and is less potent in stimulating renin secretion, and does not alter contraction of isolated rat mesangial cells by angiotensin II. CGRP also exerts renal tubular effects brought about probably through interaction with calcitonin receptors. To this end, increased excretion of sodium and chloride, and stimulation of urinary flow are less pronounced with CGRP than with calcitonin. Calcitonin, moreover, stimulates the fractional urinary excretion of calcium and phosphate.     

Hemoglobin oxygen affinity in patients suffering from arterial occlusive disease of the legs

Summary Parameters characterizing the hemoglobin oxygen affinity were determined in blood of 12 male patients suffering from arterial occlusive disease (AOD) of the legs and compared with data obtained earlier from healthy human subjects (controls). Due to a COHb content of 4.8%±2.2% in the cigarette-smoking AOD patients, the standard oxygen dissociation curve (ODC) was left-shifted, the half-saturation pressure (P₅₀) amounted to 24.8±1.7 mmHg (3.30±0.23 kPa), although the 2,3-diphosphoglycerate concentration was increased to 15.3±1.7 µmol/g Hb. Correcting the effects of elevated COHb shifts the P₅₀ to 26.3 mmHg (3.5 kPa) and increases the steepness of the ODC (Hill's n) from 2.79±0.27 to about 2.99, which is significantly different from controls. The Bohr coefficients after acidification of blood with lactic acid (BC_Lac) show high values at low oxygen saturations of hemoglobin (–0.50±0.04 in AOD patients, –0.32±0.04 in controls;P<0.05 at 10% S_O2). The cause of the alterations in hemoglobin oxygen affinity may be a reduced mean erythrocyte age, but also the influence of unknown factors generated, e.g., from anaerobic muscle metabolism in AOD.Abbreviations AOD Arterial occlusive disease of the legs - BC Bohr coefficient - BC_CO2 Bohr coefficient after acidification of blood with CO₂ - BC_Lac Bohr coefficient after acidification of blood with lactic acid - DPG 2,3-Diphosphoglycerate - ODC Oxygen dissociation curve - P₅₀ Oxygen pressure when hemoglobin is half-saturated     

Effects of Crowding on the Thermal Stability of Heterogeneous Protein Solutions

Crowding can substantially affect the transition of a protein between its native (N) and unfolded (U) states via volume exclusion effects. Also, it influences considerably the aggregation (A) of unfolded proteins. To examine the details, we developed an approach for computing the kinetic rates of the process N ↔ U → A in which the concentration of the protein is explicitly taken into account. We then compute the relative change with temperature of the protein denaturation for various fractional volume occupancies and partition of proteins in solution. The analysis indicates that, in protein solutions in which the average distance between proteins is comparable with the radius of gyration of an unfolded protein, steric effects increase the stability of the proteins which are in compact, native states. In heterogeneous protein solutions containing various types of proteins with different thermal stabilities, the unfolding of the most thermolabile proteins will increase the stability of the other proteins. The results shed light on the way proteins change the thermal stability of a cell as they unfold and aggregate. This study may be valuable in questions related to the dynamics of thermal injuries.     

Fertilization and early embryology: Effects of persistent chlorinated hydrocarbons on fertility and embryonic development in the rabbit

The commercial polychlorinated biphenyl (PCB) formulation Aroclor1260 (4 mg/kg body weight), technical grade dichlorodiphenyltrichloroethane(DDT; 3 mg) and Lindane (-hexachlorocyclohexane; 0.8 mg) wereadministered orally, either separately or in combination, tosexually mature female rabbits three times per week for 12–15weeks. Oviductal and uterine luminal fluid, cleavage stage embryos(day 1 post coitum), blastocysts (day 6), fetuses, exocoelicfluid and placentae (day 11) were analysed, firstly for chlorinatedhydrocarbon residues, and secondly for embryonic and fetal development.The doses applied were well tolerated by the treated animals.PCB and DDT accumulated in uterine secretions (day 6) but notin oviductal luminal fluid (day 1). Both chlorinated hydrocarbonswere found in preimplantation blastocysts. Residues in day 11fetuses were 16- (DDT) or 18-fold (PCB) higher than in day 6blastocysts. Significant amounts were also detected in placentaltissue and in exocoelic fluid. A specific accumulation of thehighly chlorinated biphenyl congener no. 180 was noted in fetuses,placentae and exocoelic fluid. The clear accumulation of thechlorinated hydrocarbon compounds in luminal fluid and embryonictissue is contrasted by rather weak effects on fertility. Nostatistically significant differences between treated animalsand controls were observed for fertilization rate and pre- andpost-implantation (up to day 11 post coitum) losses. However,in females exposed to PCB, a 20% higher loss of blastocystswas noticed, as compared with controls (P > 0.05). This effectwas shown on day 6 of embryonic development and may be due tothe embryotoxic activities of PCB.     

Psychological and social effects of orthodontic treatment

Adolescents with commonly occurring forms of malocclusion often are presumed to be at risk for negative self-esteem and social maladjustment. A randomized control group design was used to assess the psychosocial effects of orthodontic treatment for esthetic impairment. Ninety-three participants, 11 to 14 years old, with mild to moderate malocclusions, were randomly assigned to receive orthodontic treatment immediately or after serving as delayed controls. A battery of psychological and social measures was administered before treatment, during treatment, and three times after completion of treatment, the last occurring one year after termination. Repeated measures analyses of variance assessed group differences at the five time points. Parent-, peer-, and self-evaluations of dental-facial attractiveness significantly improved after treatment, but treatment did not affect parent- and self-reported social competency or social goals, nor subjects' self-esteem. In summary, dental-specific evaluations appear to be influenced by treatment, while more general psychosocial responses are not.This research was supported by Grant NIH-NIDR-R01-DE06154 from the National Institute of Dental Research.