In the absence of prior knowledge about population relations, investigators frequently employ a strategy that uses the data to help them decide whether to adjust for a variable. The authors compared the performance of several such strategies for fitting multiplicative Poisson regression models to cohort data: 1)the ''change-in-estimate'' strategy, in which a variable is controlled if the adjusted and unadjusted estimates differ by some important amount; 2) the ''significance-test-of-the-covariate'' strategy, in which a variable is controlled if its coefficient is significantly different from zero at some predetermined significance level; 3) the ''significance-test-of-the-difference'' strategy, wh ich tests the difference between the adjusted and unadjusted exposure coefficients; 4) the ''equivalence-test-of-the-difference'' strategy, which significance-tests the equivalence of the adjusted and unadjusted exposure coefficients; and 5) a hybrid strategy that takes a weighted average of adjusted and unadjusted estimates. Data were generated from 8,100 population structures at each of several sample sizes. The performance of the different strategies was evaluated by computing bias, mean squared error, and coverage rates of confidence intervals. At least one variation of each strategy that was examined performed acceptably. The change-in-estimate and equivalence-test-of-the-difference strategies performed best when the cut-point for deciding whether crude and adjusted estimates differed by an important amount was set to a low value (10%). The significance test strategies performed best when the alpha level was set to much higher than conventional levels (0.20).
Many different theories have been advanced concerning the biological roles of the oligosaccharide units of individual classes of glycoconjugates. Analysis of the evidence indicates that while all of these theories are correct, exceptions to each can also be found. The biological roles of oligosaccharides appear to span the spectrum from those that are trivial, to those that are crucial for the development, growth, function or survival of an organism. Some general principles emerge. First, it is difficult to predict a priori the functions a given oligosaccharide on a given glycoconjugate might be mediating, or their relative importance to the organism. Second, the same oligosaccharide sequence may mediate different functions at different locations within the same organism, or at different times in its ontogeny or life cycle. Third, the more specific and crucial biological roles of oligosaccharides are often mediated by unusual oligosaccharide sequences, unusual presentations of common terminal sequences, or by further modifications of the sugars themselves. However, such oligosaccharide sequences are also more likely to be targets for recognition by pathogenic toxins and microorganisms. As such, they are subject to more intra- and inter-species variation because of ongoing host-pathogen interactions during evolution. In the final analysis, the only common features of the varied functions of oligosaccharides are that they either mediate 'specific recognition' events or that they provide 'modulation' of biological processes. In so doing, they generate much of the functional diversity required for the development and differentiation of complex organisms, and for their interactions with other organisms in the environment.
In pursuing our work on the organization of human visual cortex, we wanted to specify more accurately the position of the visual motion area (area V5) in relation to the sulcal and gyral pattern of the cerebral cortex. We also wanted to determine the intersubject variation of area V5 in terms of position and extent of blood flow change in it, in response to the same task. We therefore used positron emission tomography (PET) to determine the foci of relative cerebral blood flow increases produced when subjects viewed a moving checkerboard pattern, compared to viewing the same pattern when it was stationary. We coregistered the PET images from each subject with images of the same brain obtained by magnetic resonance imaging, thus relating the position of V5 in all 24 hemispheres examined to the individual gyral configuration of the same brains. This approach also enabled us to examine the extent to which results obtained by pooling the PET data from a small group of individuals (e.g., six), chosen at random, would be representative of a much larger sample in determining the mean location of V5 after transformation into Talairach coordinates. After stereotaxic transformation of each individual brain, we found that the position of area V5 can vary by as much as 27 mm in the left hemisphere and 18 mm in the right for the pixel with the highest significance for blood flow change. There is also an intersubject variability in blood flow change within it in response to the same visual task. V5 nevertheless bears a consistent relationship, within each brain, to the sulcal pattern of the occipital lobe. It is situated ventrolaterally, just posterior to the meeting point of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus. In position it corresponds almost precisely with Flechsig's Feld 16, one of the areas that he found to be myelinated at birth.
It was hypothesized that blood pressure would be inversely related to cognitive functioning, if unconfounded with antihypertensive medication and measured over many occasions prior to neuropsychological testing. For stroke-free Framingham Study participants aged 55-88 years (n = 1,702), blood pressure levels were averaged over five biennial examinations (1956-1964) when few hypertensives were being treated, and examined in relation to neuropsychological tests administered between 1976 and 1978. With age, education, occupation, cigarette smoking, alcohol consumption, and gender controlled, blood pressure levels and chronicity of hypertension were inversely related to the composite score and measures of attention and memory. This was true for the full sample, for a subsample untreated during blood pressure measurement (n = 1,485), and for a subsample untreated throughout the entire study period (n = 1,038). For example, decline per 10 mmHg increment in blood pressure ranged from -0.04 to -0.07 standard score units (z) for the composite score. A negative finding previously was most likely due to blood pressure measurement concurrently with neuropsychological testing, or too few measurements. Hypertension-associated pathogenic processes may cause mild cognitive impairment, but other mechanisms need to be considered.
Apoptotic cell death has recently been suggested to be the underlying mechanism of ovarian follicle atresia. To study the regulation of follicle cell apoptosis by sex steroids, we have analyzed ovarian DNA fragmentation, the hallmark of apoptosis, in rats treated with estrogens and androgens. Immature rats were hypophysectomized and implanted with diethylstilbestrol (DES) capsules. Two days later, DES implants were removed in some animals, followed by treatment with estrogens with or without androgens. The extent of ovarian apoptotic DNA fragmentation was analyzed by autoradiography of size-fractionated DNA labeled at 3'-ends by [P-32]dideoxy-ATP. After DES withdrawal, ovarian weight decreased and DNA fragmentation increased in a time-dependent manner. In granulosa cells, an increase in apoptotic DNA fragmentation was seen 12 h after withdrawal of DES implants, followed by a 25-fold increase at 48 h. In situ analysis of DNA fragmentation on histological sections of ovaries, using a nonisotopic labeling of DNA by digoxigenin-dideoxy-UTP, also demonstrated that apoptosis induced by DES withdrawal is confined to the granulosa cells in early antral and preantral follicles. No increase in DNA breakdown was detected in thecal cells and interstitial tissues or granulosa cells of primordial and primary follicles. In contrast, replacement with DES (0.5 mg twice daily) or estradiol benzoate (3 mg daily) completely prevented the observed ovarian weight loss and increases in granulosa cell apoptosis. Treatment with estradiol benzoate (0.003-3 mg/day) dose dependently suppressed the apoptosis seen 2 days after removal of DES implants. Furthermore, the antiatretogenic effect of estrogen was blocked by treatment with testosterone (0.5 mg twice daily), which increased ovarian apoptotic DNA fragmentation and decreased ovarian weight in DES-treated animals in a time-dependent manner. Also, in situ examination showed that androgen treatment increased apoptosis in the granulosa cells in a subpopulation of early antral and preantral follicles. The specificity of testosterone action was further demonstrated by the lack of effect of progesterone and cortisol on ovarian apoptosis. These data suggest that sex steroids play an important role in the regulation of ovarian apoptotic cell death, with estrogens preventing apoptosis and androgens antagonizing the effect of estrogens. These data provide the basis for future studies on the role of sex steroid hormones in follicular atresia and the regulation of endonuclease activity by steroid hormones.
FORTY-FIVE MEASUREMENTS of diameters of 12 human cerebral arteries were performed during 10 craniotomies under moderate changes in mean blood pressure and end tidal CO2. The mean change in blood pressure was 30 +/- 16 mm Hg (standard deviation) and that of end tidal CO2 was 14 +/- 6 mm Hg (standard deviation). These changes were induced with nitroprusside, phenylephrine, and adjustment of ventilator rate. Measurements were made through the operating microscope focused at the highest power, with meticulous attention to constant angle and distance from the artery. The mean diameter change in the large cerebral arteries (carotid, middle cerebral artery, vertebral artery) was less than 4%, but the smaller arteries (anterior cerebral artery, M2 segment of middle cerebral artery) showed diameter changes as large as 29% and 21% to end tidal CO2 and blood pressure changes, respectively. These data suggest that at the time of craniotomy, diameters of the large cerebral vessels do not significantly change during moderate variations in blood pressure and CO2, but that larger changes may occur in smaller vessels. This constancy of diameter suggests that the transcranial Doppler velocities obtained during intraoperative monitoring of craniotomies may closely reflect blood flow through the insonated artery.
The relationships of the ''primary'' cytoarchitectonic neocortical fields, 17, 41, 3b, and 4 (Brodmann areas), to salient topographic landmarks have been reconstructed from serial histological sections in 20 human cerebral hemispheres (10 brains). Each of these architectonic fields is found to bear a characteristic relationship to a set of enframing anatomic landmarks, in particular, gyri, fissures, and sulci, that can be readily defined by MRI. Two classes of variability were found characteristic, at least to some extent, of each of the fields. Class 1 variability-variability that is not predictable from visible landmarks-was typical of the polar and for the cuneal and lingual extracalcarine distributions of field 17 and the distribution of field 4 upon the paracentral lobule. Class 2 variability-variability that is closely predictable from visible landmarks-is seen in the marked interindividual or interhemispheric variation in size or shape of a field and was found to be prominent for all four fields. Because of the prominence of class 2 variability, direct reference to the landmarks that frame these fields may be expected to be a more reliable basis for functional mapping than reference to a template or stereotactic coordinate-based system of reference to a standard or idealized brain.