Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar ...disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F1,41=6.8; P=0.013) and RD (BDE>CONT: F1,41=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t40=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.
Obsessive-compulsive disorder (OCD) is a disabling condition, often associated with a chronic course. Given its role in attentional control, decision-making, and emotional regulation, the anterior ...cingulate cortex is considered to have a key role in the pathophysiology of the disorder. Notably, the cingulum bundle, being the major white matter tract connecting to this region, has been historically a target for the surgical treatment of intractable OCD. In this study, we aimed to identify the extent to which focal-more than diffuse-abnormalities in fiber collinearity of the cingulum bundle could distinguish 48 adults with OCD (mean age SD = 23.3 4.5 years; F/M = 30/18) from 45 age- and sex-matched healthy control adults (CONT; mean age SD = 23.2 3.8 years; F/M = 28/17) and further examine if these abnormalities correlated with symptom severity. Use of tract-profiles rather than a conventional diffusion imaging approach allowed us to characterize white matter microstructural properties along (100 segments), as opposed to averaging these measures across, the entire tract. To account for these 100 different segments of the cingulum bundle, a repeated measures analysis of variance revealed a main effect of group (OCD < CONT; F
= 5.3; P = 0.024) upon fractional anisotropy (FA, a measure of fiber collinearity and/or white matter integrity), in the cingulum bundle, bilaterally. Further analyses revealed that these abnormalities were focal (middle portion) within the left and right cingulum bundle, although did not correlate with symptom severity in OCD. Findings indicate that focal abnormalities in connectivity between the anterior cingulate cortex and other prefrontal cortical regions may represent neural mechanisms of OCD.
Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally salient ...stimuli were related to heterogeneity in lifetime levels of depressive and subthreshold manic symptoms among adults with MDD.
We compared age- and gender-matched adults with MDD (n = 26) with healthy controls (HC, n = 28). While undergoing functional magnetic resonance imaging, participants performed an implicit emotional faces task: they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology.
Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p < 0.05, corrected). Multiple regression analyses revealed that greater right-amygdala activity to the happy condition in adults with MDD was associated with higher levels of subthreshold manic symptoms experienced across the lifespan (p = 0.002).
Among depressed adults with MDD, lifetime features of subthreshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiological processes that overlap with bipolar disorder.
CONTEXT Gastroesophageal reflux (GER) has not previously been widely regarded
as a hereditary disease. A few reports have suggested, however, that a genetic
component may contribute to the incidence ...of GER, especially in its severe
or chronic forms. OBJECTIVE To identify a genetic locus that cosegregates with a severe pediatric
GER phenotype in families with multiple affected members. DESIGN A genome-wide scan of families affected by severe pediatric GER using
polymorphic microsatellite markers spaced at an average of 8 centimorgans
(cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING General US community, with research performed in a university tertiary
care hospital. SUBJECTS Affected and unaffected family members from 5 families having multiple
individuals affected by severe pediatric GER, identified through a patient
support group. MAIN OUTCOME MEASURES Determination of inheritance patterns and linkage of a genetic locus
with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis,
considering a lod score of 3 or greater as evidence of linkage. RESULTS In these families, severe pediatric GER followed an autosomal dominant
hereditary pattern with high penetrance. A gene for severe pediatric GER was
mapped to a 13-cM region on chromosome 13q between microsatellite markers
D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a
maximum multifamily multipoint lod score of 7.15 were obtained for marker
D13S1253 at map position 35 cM when presumptively affected persons were modeled
as unknown (a maximum multipoint score of 4.88 was obtained when presumptively
affected persons were modeled as unaffected). CONCLUSION These data suggest that a gene for severe pediatric GER maps to chromosome
13q14.
Evolvability—the capacity to generate beneficial heritable variation—is a central property of biological systems. However, its origins and modulation by environmental factors have not been examined ...systematically. Here, we analyze the fitness effects of all single mutations in TEM-1 β-lactamase (4,997 variants) under selection for the wild-type function (ampicillin resistance) and for a new function (cefotaxime resistance). Tolerance to mutation in this enzyme is bimodal and dependent on the strength of purifying selection in vivo, a result that derives from a steep non-linear ampicillin-dependent relationship between biochemical activity and fitness. Interestingly, cefotaxime resistance emerges from mutations that are neutral at low levels of ampicillin but deleterious at high levels; thus the capacity to evolve new function also depends on the strength of selection. The key property controlling evolvability is an excess of enzymatic activity relative to the strength of selection, suggesting that fluctuating environments might select for high-activity enzymes.
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•A study of how enzyme robustness and evolvability depend on selection strength.•Fitness effects of all single amino acid mutations for wild-type and new function.•Adaptation to new function is enhanced in a weak selection environment.•A spatially distributed pattern of adaptive mutations in the protein structure.
The origins of evolvability are examined systematically by analyzing single amino acid mutants in an enzyme under selection for a wild-type function (ampicillin resistance) and for a new function (cefotaxime resistance). The findings indicate that fluctuating environments might select for enzymes with excess activity relative to the strength of selection.
IBM 90-nm silicon-on-insulator (SOI) technology was used for the key chips in the System z9(TM) processor chipset. Along with system design, optimization of some critical features of this technology ...enabled the z9(TM) to achieve double the system performance of the previous generation. These technology improvements included logic and SRAM FET optimization, mask fabrication, lithography and wafer processing, and interconnect technology. Reliability improvements such as SRAM optimization and burn-in reliability screen are also described. PUBLICATION ABSTRACT
Vertical loading rates are typically found to be lower in forefoot compared to rearfoot strikers, promoting the idea that forefoot striking is desirable and may reduce running injury risk. However, ...prior work using linear models has shown that foot inclination angle (FIA) at initial contact is a poor predictor of vertical loading rate, suggesting a more complex association exists.
PURPOSETo determine if a nonlinear model superiorly describes the relationship between FIA and average vertical loading rate (AVLR). Secondary analyses assessed the influence of sex and sport on the association between FIA and AVLR.
METHODSWhole body kinematics and vertical ground reaction forces were collected for 170 healthy National Collegiate Athletic Association Division I athletes (97 males; 81 cross-country runners) during treadmill running at 2.68, 3.35, and 4.47 m·s. Foot inclination angle and AVLR were calculated for 15 strides and averaged across strides for each limb. Polynomial mixed effects models assessed linear and nonlinear trends in the relationship between FIA and AVLR across the entire sample and accounting for sex and sport participation.
RESULTSAverage vertical loading rate was lowest at the extremes of FIA (i.e., −15°, 20°), whereas greater AVLR were observed between 5° and 10°. The cubic model resulted in a significantly better fit than the linear model (P < 0.001). Average vertical loading rate was also more variable among FIA associated with rearfoot and midfoot strike than forefoot strike. Adding sex to the model did not influence model fit; though, controlling for sport minimally improved model fit.
CONCLUSIONSThe relationship between FIA and AVLR is best represented by a cubic model. Consequently, FIA should be treated as a continuous variable. Reducing FIA into categories may misrepresent the relationship between FIA and other gait variables.
A narrow base of gait (BOG), the mediolateral distance between the foot and the body's line of gravity at midstance, during running is a suggested cause of injuries such as iliotibial band syndrome ...and tibial stress injury. However, an understanding of modifiable and nonmodifiable factors that influence BOG is lacking, which limits the development of corrective strategies.
To determine if BOG varies by sex and running speed and the influence of running kinematics and anthropometrics on BOG.
Cross-sectional study.
Record review of routinely collected performance data from a National Collegiate Athletic Association Division I intercollegiate athletic program.
A total of 166 Division I collegiate athletes (basketball, cross-country, football, soccer).
Running biomechanics (N = 166) and dual-energy x-ray absorptiometry-derived anthropometric data (n = 68) were extracted. Running variables were BOG, step rate, stride length, foot-inclination angle, center-of-mass vertical displacement, heel-to-center of mass anteroposterior distance, and peak stance-phase angles: hip flexion, hip adduction, pelvic drop, knee flexion, and ankle dorsiflexion. Extracted anthropometric variables were height; leg, femur, and tibia length; and anterior-superior iliac spine, hip-joint, and greater trochanter width. We calculated linear mixed-effects models to assess the influence of sex and running speed on BOG and identify the kinematic and anthropometric variables most associated with BOG.
A significant interaction between sex and running speed on BOG was observed, with males demonstrating a smaller BOG than females at faster speeds and BOG decreasing overall with speed. The kinematic measures most associated with BOG at preferred running speed were foot-inclination angle at initial contact and peak stance-phase hip adduction and ankle dorsiflexion. Anterior-superior iliac spine width was the anthropometric variable most associated with BOG at preferred running speed.
Sex and running speed must be considered when determining the appropriateness of an individual's BOG. Additionally, BOG was associated with several potentially modifiable kinematic parameters.
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