Validation of a limited sampling model to determine etoposide area under the curve

STUDY OBJECTIVE: To validate the utility of a previously reported 3-point limited sampling model (LSM) for determining etoposide area under the curve to infinity (AUC(infinity)). DESIGN: Secondary analysis of data from two clinical trials of etoposide. SETTING: University medical center clinical research center. PATIENTS: Thirty-four patients with different malignancies. INTERVENTIONS: Etoposide was administered as a 2-hour infusion to 34 patients. Serial plasma samples were drawn over 24 hours after the infusion and analyzed for etoposide by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: The 3-point LSM AUC was compared with a 14-point actual AUC calculated by the linear trapezoidal rule. Actual and predicted AUC(infinity) by the LSM were highly correlated (r=0.97, p<0.0001). The LSM predictions had a mean absolute error of 10.9% (95% CI -14.1, -5.3) and a mean error of -9.7% (95% CI 6.9, 14.9). Nine patients with poor AUC(infinity) estimations by the LSM (error > 12%) tended to have abnormally low or high peak concentrations. CONCLUSION: Our findings suggest the development of more robust LSM using other techniques, such as pharmacostatistical models, that can accommodate a greater degree of pharmacokinetic variability.     

An extended HLA-DQ-DR haplotype rather than DRB1 alone contributes to RA predisposition

A family with 1 case of retinitis pigmentosa (III-1) and 2 cases of Oguchi's disease (III-2, 3) was examined in terms of electrophysiology as well as molecular biology. The proband (III-3), a 42-year-old female, and 2 older brothers (III-1, 2, aged 52 and 45 years) and 2 unaffected members in the same family participated in this study. Corrected visual acuities of the individuals with Oguchi's disease (III-2, 3) were 1.2. On funduscopy, blood vessels stood out in relief against a metallic-appearing background and a Mizuo-Nakamura phenomenon was evident. Full-field electroretinograms (ERGs) recorded from the proband were indicative of rod dystrophy, but results of other electrophysiological examinations (multifocal ERG, pattern ERG and visual-evoked cortical potential recordings) were within normal limits. Patient III-1 had corrected visual acuities of RE 20 cm/m.m. and LE 30 cm/n.d., severe chorioretinal atrophy in both fundi, and full-field ERG revealed rod-cone dystrophy. Mutation of the arrestin gene (1147de1A) was detected in all 3 patients. Visual function in each patient coincides with that of retinitis pigmentosa or Oguchi's disease, respectively.     

IL-1 beta and TNF alpha modulate delta 9-tetrahydrocannabinol-induced catalepsy in mice

The role of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) in THC-induced catalepsy in mice was examined. Recombinant IL-1 beta (400 ng/mouse, IV) and TNF alpha (500 ng/mouse, IV) were effective in potentiating the cataleptic effect of low-dose THC (10 micrograms/mouse, IV). Recombinant IL-1 alpha and IL-6 did not potentiate catalepsy at any dose tested. Anti-IL-1 beta and anti-TNF alpha antibodies were effective in attenuating high-dose (75 micrograms/mouse) THC-induced catalepsy. Antibodies to IL-1 alpha and IL-6 had no effect on catalepsy. Early onset catalepsy (10 min postinjection) was potentiated by exogenous recombinant IL-1 beta and TNF alpha but only later catalepsy (2 h postinjection) was attenuated by antibodies to endogenous IL-1 beta or TNF alpha. This divergence of the cytokine effect suggests that these substances regulate, by different mechanisms, the early and late THC-induced cataleptic response.     

Life table study of Aedes aegypti (Diptera: Culicidae) in Puerto Rico fed only human blood versus blood plus sugar

Life table studies were performed in 1996 with Aedes aegypti (L.) during the low (cool/dry) and high (hot/rainy) dengue virus transmission seasons in Puerto Rico. Mated adult females from field-collected pupae were placed individually in cages and divided into 2 treatment groups: one was fed only human blood and the other human blood plus a 10% sucrose solution. Survival and number of eggs laid were recorded daily for each female. During both seasons, age specific survivorship was higher for the blood plus sugar group, groups fed only human blood had higher reproductive outputs (mx), and net replacement rates (Ro) for blood only groups were higher than for those fed blood plus sugar. Intrinsic rates of growth (r) were the same for both treatments during the low (cool/dry) transmission season, but higher for the blood-only treatment during the high (hot/rainy) transmission season. Our results indicate that feeding on only human blood provides an evolutionary advantage to Ae. aegypti females in Puerto Rico. These results are similar to those from an earlier study carried out with Ae. aegypti in Thailand; the advantage of feeding on human blood does not seem to be restricted to a particular geographic region. We also found that the benefits associated with human feeding persist through epidemiologically different times of the year. We conclude that feeding on human blood is reproductively beneficial for Ae. aegypti, which may increase their contact with human hosts, and therefore may influence their vectorial capacity for dengue viruses through frequent feeding on blood.     

Cine magnetic resonance imaging of pulsatile cerebrospinal fluid flow using CSPAMM

Spatial modulation of magnetization (SPAMM) is a well established imaging technique which superimposes a tagging pattern on conventional magnetic resonance (MR) images, allowing movement to be visualized. A modification to the SPAMM technique, called complementary spatial modulation of magnetization (CSPAMM), which improves the contrast of the tagging pattern is explained. The application of CSPAMM to the visualization of pulsatile cerebrospinal fluid flow (CSF) using an 8 frame cardiac-gated cine sequence is described. Various combinations of binomial pulses, up to the fifth order, were investigated to see which produces the optimum tagging pattern in the CSPAMM images. The flip angles of the imaging RF pulses were studied to see which would give equal maximum CSF signal intensity in all the cine images. The optimized cine CSPAMM technique was compared in vivo with SPAMM and CSF motion was found to be more easily visualized in the CSPAMM images.     

Failure of Ixodes ticks to inherit Borrelia afzelii infection

To define conditions promoting inherited infection by Lyme disease spirochetes in Ixodes ticks, we variously infected ticks with Borrelia afzelii and examined their progenies by dark-field microscopy, immunofluorescence, PCR, and serial passage. No episode of inherited infection was evident, regardless of instar or gender infected or frequency of exposure. We suggest that these spirochetes rarely, if ever, are inherited by vector ticks.     

Two methods of natural family planning

I read with interest the recent article by Wade and associates, "A randomized prospective study of the use-effectiveness of 2 methods of natural family planning: an interim report" (134: 628, 1979). In reference to the study of the ovulation method, the authors noted that abstinence begins on the 1st day of mucus secretion and continues until the evening of the 4th day beyond the peak or maximal mucus secretion. In the ovulation method, the peak symptom is not the same as maximal mucus secretion as was indicated in the paper. The peak symptom is defined as the last day of the mucus discharge that is clear and/or stretchy and/or lubricative. In the definition of peak symptom, the amount of mucus discharge is not specifically important and may often be misleading. I had the opportunity to do a site visit at this study at the request of the National Institutes of Health while the study was in progress. I analyzed several pregnancies which occurred in users of this ovulation method. Some of the pregnancies occurred as the result of poor teaching of the concept of peak symptom. In the ovulation method, proper understanding and teaching of that concept are essential to the measurement of its effectiveness. Noticeably missing from this interim report was any discussion of the quality control procedures which were utilized to guarantee a high-quality educational service to the people entered into the study. While the authors claim that the methods were taught by professional teachers, these teachers were actually women who had previously used the method and/or had formalized training in teaching the method. Simple use of either of the methods certainly does not qualify an individual to teach natural family planning. For those with formalized teaching, such training should have been outlined since judgment on the effectiveness of the teaching cannot be made; such a judgment is essential to the proper analysis of results. Finally, while the study claims to be a use-effectiveness study, it is rather a modified version of extended use-effectiveness. No objective definition of "user failure" is provided. One cannot ascertain how many pregnancies were related to poor teaching, nor can one tell how many occurred as the result of the couples' last minute exercise of their freedom to use their fertility. The use-effectiveness of the 2 methods under study as a means to achieve a pregnancy have been ignored. In doing so, the investigators have ignored use-effectiveness reality.     

Relationship between a behavioral and several psychometric measures of test anxiety

Behavioral time-sampling was compared with various paper-and-pencil, self-report measures of test anxiety in an examination of the utility of the behavioral measure as an in situo index of test anxiety. The behavioral measure was significantly and positively correlated 0.45 with a paper-and pencil, self-report measure of "facilitative" test anxiety but not with measures of "debilitative" test anxiety (r = -0.15) or general anxiety (r = -0.33) for 12 males and 21 female undergraduates.     

Respiratory symptoms and pulmonary function in coal miners: looking into the effects of simple pneumoconiosis

Most soil quality guidelines do not distinguish among the various forms of metals in soils; insoluble, nonreactive, and nonbioavailable forms are deemed as hazardous as highly soluble, reactive, and toxic forms. The objective of this study was to better understand the long-term effects of copper on microorganisms in relation to its chemical speciation in the soil environment. Carbon mineralization processes and the global structure of different microbial communities (fungi, eubacteria, actinomycetes) are still affected after more than 50 years of copper contamination in 20 soils sampled from two different agricultural sites. The microbial respiration lag period (LP) preceding the beginning of mineralization process increases with the level of soil copper contamination and is not significantly affected by other environmental factors such as soil pH and soil organic matter (SOM) content. The total copper concentration showed the best correlation with the LP when each site is considered separately. However, when considering the whole set of data, soil solution free Cu2+ activity (pCu2+) is the best predictor of Cu toxicity determined by LP (quite likely because pCu2+ integrates the soil physicochemical variability). The maximum mineralization rate (MMR), even if well correlated with the pCu2+, appears not to be a good biomonitor of copper contamination in soils since it is highly sensitive to soil characteristics such as SOM content. This study emphasizes the importance of the physicochemical properties of the environment on soil heavy metal toxicity and on soil toxicological measurements. These properties must be characterized in soil toxicological studies with respect to (1) their interactions with heavy metals, and (2) their direct impact on the selected biological test. The measurement of pCu2+ to characterize the level of soil contamination and of lag period as a bioindicator of metal effects in the soil are recognized as useful tools for the evaluation of the biological quality of soils.     

Lack of TEL/AML1 fusion in pediatric AML: further evidence for lineage specificity of TEL/AML1

The percutaneous cardiopulmonary support system (PCPS) was used in a 64-year-old woman with cardiogenic shock due to sustained ventricular fibrillation (Vf) caused by severe aortic stenosis and regurgitation. The Vf attack was resistant to cardioversion and adrenaline for lack of left ventricular support by PCPS. She was transported to the operation theater with PCPS in situ and emergency aortic valve replacement was performed. Although preoperative cardiac resuscitation time was long (35 minutes), she was discharged from the hospital on foot without any neurological complications on 84th postoperative day. Because PCPS does not decrease left ventricular systolic stress in poorly contracting dilated heart, early surgical treatment is needed in patients with severely damaged heart.