Myelination of the developing lateral olfactory tract and anterior commissure.

Both the lateral olfactory tract (LOT) and anterior limb of the anterior commissure (AC) carry olfactory information. The LOT forms the projection from the olfactory bulb to the ipsilateral olfactory cortices, while the AC carries odor information across the midline to the contralateral olfactory cortex and bulb. The LOT and AC differ on a number of dimensions, including early development and functional onset. The present work, examining their myelination in mice, reveals additional important differences. For example, the LOT initiates myelination 3-4 days earlier than the AC, evidenced by both an earlier increase in myelin basic protein staining seen with immunohistochemistry and an earlier appearance of myelinated fibers using electron microscopy. While both exhibit a period of rapid myelination, it occurs 4-5 days earlier in the LOT than the AC. The tracts also respond differently to early sensory restriction. Unilateral naris occlusion from the day after birth to postnatal day 30 had no consistent effects on the AC but resulted in significantly thinner myelin sheaths relative to axon caliber in the LOT. Finally, the two tracts differ structurally (the LOT contains larger, more densely packed axons with significantly thicker myelin sheaths resulting in a conduction velocity that is more than twice as fast as the AC). The findings indicate that these two large, accessible tracts provide an important means for studying brain maturation due to basic differences in both the timing of their maturation and general organization.

Dairy cattle in a temperate climate: the effects of weather on milk yield and composition depend on management.

A better understanding of how livestock respond to weather is essential to enable farming to adapt to a changing climate. Climate change is mainly expected to impact dairy cattle through heat stress and an increase in the frequency of extreme weather events. We investigated the effects of weather on milk yield and composition (fat and protein content) in an experimental dairy herd in Scotland over 21 years. Holstein Friesian cows were either housed indoors in winter and grazed over the summer or were continuously housed. Milk yield was measured daily, resulting in 762 786 test day records from 1369 individuals, and fat and protein percentage were sampled once a week, giving 89 331 records from 1220 cows/trait. The relative influence of 11 weather elements, measured from local outdoor weather stations, and two indices of temperature and humidity (THI), indicators of heat stress, were compared using separate maximum likelihood models for each element or index. Models containing a direct measure of temperature (dry bulb, wet bulb, grass or soil temperature) or a THI provided the best fits to milk yield and fat data; wind speed and the number of hours of sunshine were most important in explaining protein content. Weather elements summarised across a week's timescale from the test day usually explained milk yield and fat content better than shorter-scale (3 day, test day, test day -1) metrics. Then, examining a subset of key weather variables using restricted maximum likelihood, we found that THI, wind speed and the number of hours of sunshine influenced milk yield and composition. The shape and magnitude of these effects depended on whether animals were inside or outside on the test day. The milk yield of cows outdoors was lower at the extremes of THI than at average values, and the highest yields were obtained when THI, recorded at 0900 h, was 55 units. Cows indoors decreased milk yield as THI increased. Fat content was lower at higher THIs than at intermediate THIs in both environments. Protein content decreased as THI increased in animals kept indoors and outdoors, and the rate of decrease was greater when animals were outside than when they were inside. Moderate wind speeds appeared to alleviate heat stress. These results show that milk yield and composition are impacted at the upper extreme of THI under conditions currently experienced in Scotland, where animals have so far experienced little pressure to adapt to heat stress.

Prevention of excess weight gain in paediatric primary care: beverages only or multiple lifestyle factors. The Smart Step Study, a cluster-randomized clinical trial.

BACKGROUND: Insufficient evidence exists to support obesity prevention in paediatric primary care. OBJECTIVES: To test a theory-based behaviour modification intervention delivered by trained paediatric primary care providers for obesity prevention. METHODS: Efficacy trial with cluster randomization (practice level) and a 12-session 12-month sweetened beverages decrease intervention or a comprehensive dietary and physical activity intervention, compared with a control intervention among children ages 8-12 years. RESULTS: A low recruitment rate was observed. The increase in body mass index z-score (BMIz) for the 139 subjects (11 practices) randomized to any of the two obesity interventions (combined group) was less than that of the 33 subjects (five practices) randomized to the control intervention (-0.089, 95% confidence interval [CI]: -0.170 to -0.008, P = 0.03) with a -1.44 kg weight difference (95% CI: -2.98 to +0.10 kg, P = 0.095). The incidences of obesity and excess weight gain were lower in the obesity interventions, but the number of subjects was small. Post hoc analyses comparing the beverage only to the control intervention also showed an intervention benefit on BMIz (-0.083, 95% CI: -0.165 to -0.001, P = 0.048). CONCLUSIONS: For participating families, an obesity prevention intervention delivered by paediatric primary care clinicians, who are compensated, trained and continuously supported by behavioural specialists, can impact children's BMIz.

Resting energy expenditure and adiposity accretion among children with Down syndrome: a 3-year prospective study.

BACKGROUND: Children with Down syndrome (DS) have a higher prevalence of obesity than other children. Whether this increased risk for obesity is due to a lower resting energy expenditure (REE) is controversial. Our study assessed whether (1) the REE of children with DS adjusted for fat-free mass (FFM) was lower than that of sibling controls, and (2) the changes in fat mass (FM) over 3 years were associated with FFM-adjusted baseline REE. METHODS: This study used cross-sectional and prospective cohort designs. Four annual measurement visits were conducted with 28 children with DS and 35 sibling controls aged 3-10 years. REE and serum thyroxine (T4) were measured at baseline. Anthropometry, skinfold thickness measures, and, in a subsample, dual-energy x-ray absorptiometry (DXA) were used at each visit to calculate FM. RESULTS: Children with DS had significantly lower REE adjusted for FFM (-78 kcal/day, 95% CI: -133 to -27, P=0.003). The difference remained significant after adjustment for FM, sex and African ancestry (-49 kcal/day, 95% CI: -94 to -4, P=0.03). In the longitudinal analysis, the baseline REE adjusted for baseline FFM was not predictive of FM accretion over time (P=0.8). CONCLUSION: Children with DS have lower REE than sibling controls, but REE was not associated with changes in FM over time. The results suggest that the lower REE of children with DS does not explain their increased risk for obesity.

Identifying the best surface topography parameters for detecting idiopathic scoliosis curve progression.

There is no consensus on which surface topography (ST) parameters may be used to detect scoliosis progression. The sensitivity to change of common ST parameters has not yet been compared. The goal of this study was to determine which ST parameters are most sensitive to scoliosis progression in patients with adolescent idiopathic scoliosis (AIS) receiving conservative treatment. Fifty-eight subjects with AIS were included whose Cobb angle had progressed by at least 5 degrees during a 1 year interval. All had had ST scans and frontal radiographs at a 12 month interval at our clinic. Commonly used back-only ST parameters and contributing scores were derived by one evaluator. Standardized response mean (SRM) and 95% confidence intervals (CI) were calculated using the absolute value of the changes between baseline and follow-up to reflect change in deformity, independent of direction. Decompensation, cosmetic score, Deformity in the Axial Plane Index (DAPI), trunk rotation, Hump Sum, and lordosis angle were highly sensitive to scoliosis progression (SRM>0.8). Cosmetic score, Posterior Trunk Symmetry Index (POTSI), and kyphosis angle had significantly poorer SRM values than the Cobb angle. All other ST parameters had SRM estimates that did not differ significantly from the Cobb angle, suggesting that they have a similar ability to detect progression The ST measures that were most sensitive to detection of scoliosis progression in the frontal, transverse, and sagittal planes were decompensation, trunk rotation, and lordosis angle, respectively. Absolute changes in surface parameters representing either worsening or improvement externally could reflect worsening of the internal deformity. The majority of ST parameters are potentially sensitive to scoliosis progression.

The effects of dietary protein restriction on chorda tympani nerve taste responses and terminal field organization.

Prenatal dietary sodium restriction produces profound developmental effects on rat functional taste responses and formation of neural circuits in the brainstem. Converging evidence indicates that the underlying mechanisms for these effects are related to a compromised nutritional state and not to direct stimulus-receptor interactions. We explored whether early malnourishment produces similar functional and structural effects to those seen following dietary sodium restriction by using a protein deficient, sodium replete diet. To determine if early dietary protein-restriction affects the development of the peripheral gustatory system, multi-fiber neurophysiological recordings were made from the chorda tympani nerve and anterograde track tracing of the chorda tympani nerve into the nucleus of the solitary tract (NTS) was accomplished in rats fed a protein-restricted or a control diet (6% and 20%, respectively). The dietary regimens began on embryonic day 7 and continued until rats were used for neurophysiological recordings (postnatal days (P) 35-50) or for chorda tympani terminal field labeling (P40-50). Responses to a concentration series of NaCl, sodium acetate, KCl, and to 0.50 M sucrose, 0.03 M quinine-HCl, and 0.01 N HCl revealed attenuated responses (30-60%) to sodium-specific stimuli in rats fed the 6% protein diet compared with those fed the 20% protein diet. Responses to all other stimuli were similar between groups. Terminal field volumes were nearly twofold larger in protein-restricted rats compared with controls, with the differences located primarily in the dorsal-caudal zone of the terminal field. These results are similar to the results seen previously in rats fed a sodium-restricted diet throughout pre- and postnatal development, suggesting that dietary sodium- and protein-restriction share similar mechanisms in altering gustatory development.

20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action.

We recently isolated 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol (25-OCH3-PPD), a natural product from Panax notoginseng, and demonstrated its cytotoxicity against a variety of cancer cells. Here we report the effects of this compound in vitro and in vivo on human prostate cancer cells, LNCaP (androgen-dependent) and PC3 (androgen-independent), in comparison with three structurally related ginsenosides, ginsenoside Rh2, ginsenoside Rg3, and 20(S)-protopanaxadiol. Of the four test compounds, 25-OCH3-PPD was most potent. It decreased survival, inhibited proliferation, induced apoptosis, and led to G1 cell cycle arrest in both cell lines. It also decreased the levels of proteins associated with cell proliferation (MDM2, E2F1, cyclin D1, and cdks 2 and 4) and increased or activated pro-apoptotic proteins (cleaved PARP, cleaved caspase-3, -8, and -9). In LNCaP cells, 25-OCH3-PPD inhibited the expression of the androgen receptor and prostate-specific antigen. Moreover, 25-OCH3-PPD inhibited the growth of prostate cancer xenograft tumours. Combining 25-OCH3-PPD with conventional chemotherapeutic agents or with radiation led to potent antitumour effects; tumour regression was almost complete following administration of 25-OCH3-PPD and either taxotere or gemcitabine. 25-OCH3-PPD also demonstrated low toxicity to noncancer cells and no observable toxicity in animals. In conclusion, our preclinical data indicate that 25-OCH3-PPD is a potential therapeutic agent against both androgen-dependent and androgen-independent prostate cancer.

A wireless personal wearable network system to understand the biomechanics of orthotic for the treatment of scoliosis.

The wear tightness of an orthosis for the treatment of scoliosis varies greatly during daily activities. Currently, there is no commercially available product that can monitor force distribution inside the brace and the time that the othosis is worn during daily activities. Subjective feeling is the most commonly used method. To provide an objective measure, a battery-powered wireless personal wearable network system is developed. This system consists of up to 16 wireless force loggers and a USB ZigBee dongle. Each logger contains a force sensor and a wireless unit. The whole system records how much time the orthosis has been used and how loads distribute inside the orthoses. Laboratory tests have been performed; the maximum force measurement error is +/-0.02N and the resolution is 0.1N. The average power consumption of the system is 0.3mW/h and thus a single AAA-sized alkaline battery is able to support the power for 6 months.

Anisotropic wave propagation and apparent conductivity estimation in a fast electrophysiological model: application to XMR interventional imaging.

Cardiac arrhythmias are increasingly being treated using ablation procedures. Development of fast electrophysiological models and estimation of parameters related to conduction pathologies can aid in the investigation of better treatment strategies during Radio-frequency ablations. We present a fast electrophysiological model incorporating anisotropy of the cardiac tissue. A global-local estimation procedure is also outlined to estimate a hidden parameter (apparent electrical conductivity) present in the model. The proposed model is tested on synthetic and real data derived using XMR imaging. We demonstrate a qualitative match between the estimated conductivity parameter and possible pathology locations. This approach opens up possibilities to directly integrate modelling in the intervention room.

Reconstruction of undersampled dynamic images by modeling the motion of object elements.

Dynamic MRI is restricted due to the time required to obtain enough data to reconstruct the image sequence. Several undersampled reconstruction techniques have been proposed to reduce the acquisition time. In most of these techniques the nonacquired data are recovered by modeling the temporal information as varying pixel intensities represented in time or in temporal frequencies. Here we propose a new approach that recovers the missing data through a motion estimation of the object elements ("obels," or pieces of tissue) of the image. This method assumes that an obel displacement through the sequence has lower bandwidth than fluctuations in pixel intensities caused by the motion, and thus it can be modeled with fewer parameters. Preliminary results show that this technique can effectively reconstruct (with root mean square (RMS) errors below 4%) cardiac images and joints with undersampling factors of 8 and 4, respectively. Moreover, in the reconstruction process an approximation of the motion vectors is obtained for each obel, which can be used to quantify dynamic information. In this method the motion need not be confined to a part of the field of view (FOV) or to a portion of the temporal frequency. It is appropriate for dynamic studies in which the obels' motion model has fewer parameters than the number of acquired samples.

Isolation, structural determination, and evaluation of the biological activity of 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol [20(S)-25-OCH3-PPD], a novel natural product from Panax notoginseng.

Ginseng has been used extensively for medicinal purposes, with suggested utility for indications as diverse as diabetes, cardiovascular disease and cancer. Herein we report the discovery and characterization of 20(S)-25-OCH3-PPD, a ginsenoside that inhibits growth and survival of cancer cells. The novel dammarane triterpene sapogenin (C31H56O4; molecular weight 492) was isolated from the total hydrolyzed saponins extracted from the leaves of Panax notoginseng using conventional and reverse-phase silica gel chromatography. Based on physicochemical characteristics and NMR data, the compound was identified as 20(S)-25-OCH3-PPD. The biological activities of 20(S)-25-OCH3-PPD and its known analogs, 20(S)-PPD and Rg3, were evaluated in 12 human cancer cell lines. In all cell lines, the order of cytotoxicity of the test compounds was 20(S)-25-OCH3-PPD >> 20(S)-PPD >> Rg3. 20(S)-25-OCH3-PPD also induced apoptosis and cell cycle arrest in the G1 phase, and inhibited proliferation in breast cancer cell lines, demonstrating its potent biological effects. In regard to cytotoxicity, the IC50 values of 20(S)-25-OCH3-PPD for most cell lines were in the lower microM range, a 5-15-fold greater cytotoxicity relative to 20(S)-PPD and a 10-100-fold increase over Rg3. These findings suggest a structure-activity relationship among dammarane-type sapogenins. The data presented here may provide a basis for the future development of 20(S)-25-OCH3-PPD as a novel anti-cancer agent.

Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function.

As a major negative regulator of p53, the MDM2 oncogene plays an important role in carcinogenesis and tumor progression. MDM2 promotes p53 proteasomal degradation and negatively regulates p53 function. The mechanisms by which the MDM2-p53 interaction is regulated are not fully understood, although several MDM2-interacting molecules have recently been identified. To search for novel MDM2-binding partners, we screened a human prostate cDNA library by the yeast two-hybrid assay using full-length MDM2 protein as the bait. Among the candidate proteins, ribosomal protein S7 was identified and confirmed as a novel MDM2-interacting protein. Herein, we demonstrate that S7 binds to MDM2, in vitro and in vivo, and that the interaction between MDM2 and S7 leads to modulation of MDM2-p53 binding by forming a ternary complex among MDM2, p53 and S7. This results in the stabilization of p53 protein through abrogation of MDM2-mediated p53 ubiquitination. Consequently, S7 overexpression increases p53 transactivational activities, induces apoptosis, and inhibits cell proliferation. The identification of S7 as a novel MDM2-interacting partner contributes to elucidation of the complex regulation of the MDM2-p53 interaction and has implications in cancer prevention and therapy.

Cardiac function estimation from MRI using a heart model and data assimilation: advances and difficulties.

In this paper, we present a framework to estimate local ventricular myocardium contractility using clinical MRI, a heart model and data assimilation. First, we build a generic anatomical model of the ventricles including muscle fibre orientations and anatomical subdivisions. Then, this model is deformed to fit a clinical MRI, using a semi-automatic fuzzy segmentation, an affine registration method and a local deformable biomechanical model. An electromechanical model of the heart is then presented and simulated. Finally, a data assimilation procedure is described, and applied to this model. Data assimilation makes it possible to estimate local contractility from given displacements. Presented results on fitting to patient-specific anatomy and assimilation with simulated data are very promising. Current work on model calibration and estimation of patient parameters opens up possibilities to apply this framework in a clinical environment.

Quantification of the shape of fiber tracts.

The fiber tracts generated using diffusion MRI are usually simply displayed and assessed visually for a specific clinical or medical research purpose. This paper proposes computational techniques that can be used to study the shape of the tracts and make interindividual comparisons. These methods make use of fundamental geometric invariants, such as curvatures and torsions, or Fourier descriptors, together with the link of a pair of curves. Intersubject comparisons only require that the starting and ending points of the tracts can be defined and do not require point-by-point correspondences such as obtained using image registration. Principal component analysis-based shape analysis is also investigated. The invariants are tested on simulations and in vivo datasets, and the scale dependence and noise sensitivity of the measures are assessed. The potential for these techniques to be used in neuroscience research and clinical applications is demonstrated.

Age-related decrease of the chorda tympani nerve terminal field in the nucleus of the solitary tract is prevented by dietary sodium restriction during development.

Institution of a low-NaCl diet beginning at embryonic day 3 and continued throughout pre- and postnatal development has widespread effects on the neuroanatomical organization of the first gustatory relay in the nucleus of the solitary tract. To determine when these effects are expressed postnatally, the terminal field of the chorda tympani nerve was compared between sodium-restricted and sodium-replete rats at postnatal days 15-17, postnatal days 25-27, postnatal days 35-37, and adults. Total terminal fields were significantly larger in postnatal days 35-37 and adult sodium-restricted rats compared with aged-matched controls. The group-related differences appear related more to a remodeling of the terminal field in the dorsal zone of the terminal field in controls. Specifically, the terminal field volume in the dorsal zone in controls decreased dramatically from postnatal days 25-27 to postnatal days 35-37 and then again from postnatal days 35-37 to adulthood. In contrast, the fields did not change during development in sodium-restricted rats. These findings suggest that remodeling of the chorda tympani field occurs in controls at about the developmental period of taste response maturation. The lack of remodeling in sodium-restricted rats may be explained by a corresponding lack of functional response development to sodium salts. These results also illustrate the specificity and extent of how early dietary manipulations shape the developing brainstem.

Smart garment to help children improve posture.

Many of the aches and pains of adults are the result not of injuries, but of the long-term effects of distortions in posture or alignment. Postural kyphosis in adolescence may be one of the effects of poor standing and sitting habits. Kyphosis is an excessive rounding of the upper spine. A smart garment that can monitor and provide vibration feedback to children has been developed to investigate an alternative treatment possibility. Laboratory tests verified that the accuracy of the system was +/-2 degrees within the full 180 degrees range. A clinical trial has been conducted and it showed that the system can aid subjects to improve by 20% the proportion of time in a more balanced posture. The long term effect is still under investigation.

Matrix description of general motion correction applied to multishot images.

Motion of an object degrades MR images, as the acquisition is time-dependent, and thus k-space is inconsistently sampled. This causes ghosts. Current motion correction methods make restrictive assumptions on the type of motions, for example, that it is a translation or rotation, and use special properties of k-space for these transformations. Such methods, however, cannot be generalized easily to nonrigid types of motions, and even rotations in multiple shots can be a problem. Here, a method is presented that can handle general nonrigid motion models. A general matrix equation gives the corrupted image from the ideal object. Thus, inversion of this system allows us to get the ideal image from the corrupted one. This inversion is possible by efficient methods mixing Fourier transforms with the conjugate gradient method. A faster but empirical inversion is discussed as well as methods to determine the motion. Simulated three-dimensional affine data and two-dimensional pulsation data and in vivo nonrigid data are used for demonstration. All examples are multishot images where the object moves between shots. The results indicate that it is now possible to correct for nonrigid types of motion that are representative of many types of patient motion, although computation times remain an issue.

Simulation of cardiac pathologies using an electromechanical biventricular model and XMR interventional imaging.

Simulating cardiac electromechanical activity is of great interest for a better understanding of pathologies and for therapy planning. Design and validation of such models is difficult due to the lack of clinical data. XMR systems are a new type of interventional facility in which patients can be rapidly transferred between X-ray and MR systems. Our goal is to design and validate an electromechanical model of the myocardium using XMR imaging. The proposed model is computationally fast and uses clinically observable parameters. We present the integration of anatomy, electrophysiology, and motion from patient data. Pathologies are introduced in the model and simulations are compared to measured data. Initial qualitative comparison on the two clinical cases presented is encouraging. Once fully validated, these models will make it possible to simulate different interventional strategies.

Tissue deformation and shape models in image-guided interventions: a discussion paper.

This paper promotes the concept of active models in image-guided interventions. We outline the limitations of the rigid body assumption in image-guided interventions and describe how intraoperative imaging provides a rich source of information on spatial location of anatomical structures and therapy devices, allowing a preoperative plan to be updated during an intervention. Soft tissue deformation and variation from an atlas to a particular individual can both be determined using non-rigid registration. Established methods using free-form deformations have a very large number of degrees of freedom. Three examples of deformable models--motion models, biomechanical models and statistical shape models--are used to illustrate how prior information can be used to restrict the number of degrees of freedom of the registration algorithm and thus provide active models for image-guided interventions. We provide preliminary results from applications for each type of model.