2D fetal echocardiography (ECHO) can be used for monitoring heart development in utero. This study’s purpose is to empirically model normal fetal heart growth and function changes during development by ECHO and compare these to fetuses diagnosed with and without cardiomyopathy with diabetic mothers. There are existing mathematical models describing fetal heart development but they warrant revalidation and adjustment. 377 normal fetuses with healthy mothers, 98 normal fetuses with diabetic mothers, and 37 fetuses with cardiomyopathy and diabetic mothers had their cardiac structural dimensions, cardiothoracic ratio, valve flow velocities, and heart rates measured by fetal ECHO in a retrospective chart review. Cardiac features were fitted to linear functions, with respect to gestational age, femur length, head circumference, and biparietal diameter and z-scores were created to model normal fetal growth for all parameters. These z-scores were used to assess what metrics had no difference in means between the normal fetuses of both healthy and diabetic mothers but differed from those diagnosed with cardiomyopathy. It was found that functional metrics like mitral and tricuspid E wave and pulmonary velocity could be important predictors for cardiomyopathy when fitted by gestational age, femur length, head circumference, and biparietal diameter. Additionally, aortic and tricuspid annulus diameters when fitted to estimated gestational age showed potential to be predictors for fetal cardiomyopathy. While the metrics overlapped over their full range, combining them together may have the potential for predicting cardiomyopathy in utero. Future directions of this study will explore creating a classifier model that can predict cardiomyopathy using the metrics assessed in this study.

Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm³ to 62 mm³, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.

Background: Carpal tunnel syndrome (CTS) is a compression neuropathy of the median nerve that results in sensorimotor deficits in the hand. Until recently, the effects of CTS on hand function have been studied using mostly two-digit grip tasks. The purpose of this study was to investigate the coordination of multi-digit forces as a function of object center of mass (CM) during whole-hand grasping.

Methods: Fourteen CTS patients and age- and gender-matched controls were instructed to grasp, lift, hold, and release a grip device with five digits for seven consecutive lifts while maintaining its vertical orientation. The object CM was changed by adding a mass at different locations at the base of the object. We measured forces and torques exerted by each digit and object kinematics and analyzed modulation of these variables to object CM at object lift onset and during object hold. Our task requires a modulation of digit forces at and after object lift onset to generate a compensatory moment to counteract the external moment caused by the added mass and to minimize object tilt.

Results: We found that CTS patients learned to generate a compensatory moment and minimized object roll to the same extent as controls. However, controls fully exploited the available degrees of freedom (DoF) in coordinating their multi-digit forces to generate a compensatory moment, i.e., digit normal forces, tangential forces, and the net center of pressure on the finger side of the device at object lift onset and during object hold. In contrast, patients modulated only one of these DoFs (the net center of pressure) to object CM by modulating individual normal forces at object lift onset. During object hold, however, CTS patients were able to modulate digit tangential force distribution to object CM.

Conclusions: Our findings suggest that, although CTS did not affect patients’ ability to perform our manipulation task, it interfered with the modulation of specific grasp control variables. This phenomenon might be indicative of a lower degree of flexibility of the sensorimotor system in CTS to adapt to grasp task conditions.

Carpal tunnel syndrome (CTS) impairs sensation of a subset of digits. Although the effects of CTS on manipulation performed with CTS-affected digits have been studied using precision grip tasks, the extent to which CTS affects multi-digit force coordination has only recently been studied. Whole-hand manipulation studies have shown that CTS patients retain the ability to modulate multi-digit forces to object mass, mass distribution, and texture. However, CTS results in sensorimotor deficits relative to healthy controls, including significantly larger grip force and lower ability to balance the torques generated by the digits. Here we investigated the effects of CTS on multi-digit force modulation to object weight when manipulating an object with a variable number of fingers. We hypothesized that CTS patients would be able to modulate digit forces to object weight. However, as different grip types involve the exclusive use of CTS-affected digits (‘uniform’ grips) or a combination of CTS-affected and non-affected digits (‘mixed’ grips), we addressed the question of whether ‘mixed’ grips would reduce or worsen CTS-induced force coordination deficits. The former scenario would be due to adding digits with intact tactile feedback, whereas the latter scenario might occur due to a potentially greater challenge for the central nervous system of integrating ‘noisy’ and intact tactile feedback. CTS patients learned multi-digit force modulation to object weight regardless of grip type. Although controls exerted the same total grip force across all grip types, patients exerted significantly larger grip force than controls but only for manipulations with four and five digits. Importantly, this effect was due to CTS patients’ inability to change the finger force distribution when adding the ring and little fingers. These findings suggest that CTS primarily challenges sensorimotor integration processes for dexterous manipulation underlying the coordination of CTS-affected and non-affected digits.

The delicate tuning of digit forces to object properties can be disrupted by a number of neurological and musculoskeletal diseases. One such condition is Carpal Tunnel Syndrome (CTS), a compression neuropathy of the median nerve that causes sensory and motor deficits in a subset of digits in the hand. Whereas the effects of CTS on median nerve physiology are well understood, the extent to which it affects whole-hand manipulation remains to be addressed. CTS affects only the lateral three and a half digits, which raises the question of how the central nervous system integrates sensory feedback from affected and unaffected digits to plan and execute whole-hand object manipulation. We addressed this question by asking CTS patients and healthy controls to grasp, lift, and hold a grip device (445, 545, or 745 g) for several consecutive trials. We found that CTS patients were able to successfully adapt grip force to object weight. However, multi-digit force coordination in patients was characterized by lower discrimination of force modulation to lighter object weights, higher across-trial digit force variability, the consistent use of excessively large digit forces across consecutive trials, and a lower ability to minimize net moments on the object. Importantly, the mechanical requirement of attaining equilibrium of forces and torques caused CTS patients to exert excessive forces at both CTS-affected digits and digits with intact sensorimotor capabilities. These findings suggest that CTS-induced deficits in tactile sensitivity interfere with the formation of accurate sensorimotor memories of previous manipulations. Consequently, CTS patients use compensatory strategies to maximize grasp stability at the expense of exerting consistently larger multi-digit forces than controls. These behavioral deficits might be particularly detrimental for tasks that require fine regulation of fingertip forces for manipulating light or fragile objects.

Introduction: The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters metabolism by increasing the level of ketone bodies in the blood. KetoCal® (KC) is a nutritionally complete, commercially available 4∶1 (fat∶ carbohydrate+protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of refractory pediatric epilepsy. Diet-induced ketosis causes changes to brain homeostasis that have potential for the treatment of other neurological diseases such as malignant gliomas.

Methods: We used an intracranial bioluminescent mouse model of malignant glioma. Following implantation animals were maintained on standard diet (SD) or KC. The mice received 2×4 Gy of whole brain radiation and tumor growth was followed by in vivo imaging.

Results: Animals fed KC had elevated levels of β-hydroxybutyrate (p = 0.0173) and an increased median survival of approximately 5 days relative to animals maintained on SD. KC plus radiation treatment were more than additive, and in 9 of 11 irradiated animals maintained on KC the bioluminescent signal from the tumor cells diminished below the level of detection (p<0.0001). Animals were switched to SD 101 days after implantation and no signs of tumor recurrence were seen for over 200 days.

Conclusions: KC significantly enhances the anti-tumor effect of radiation. This suggests that cellular metabolic alterations induced through KC may be useful as an adjuvant to the current standard of care for the treatment of human malignant gliomas.

Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

Background: Malignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low-carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia.

Methods: Here, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet.

Results: Animals received intracranial injections of bioluminescent GL261-luc cells and tumor growth was followed in vivo. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4.

Conclusions: Our data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose.

We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.