Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Ocular Component Development during Infancy and Early Childhood.

SIGNIFICANCE: The study fills an important gap by providing a longitudinal description of development of the major structural and optical components of the human eye from 3 months to nearly 7 years of age. Normative development data may provide insights into mechanisms for emmetropization and guidance on intraocular lens power calculation. PURPOSE: The purpose of this study was to describe the pattern of development of refractive error and the ocular components from infancy through early childhood. METHODS: Cycloplegic retinoscopy (cyclopentolate 1%), keratophakometry, and ultrasonography were performed longitudinally on between 162 and 293 normal birth weight infants at 0.25, 0.75, 1.5, 3, 4.5, and 6.5 years of age. RESULTS: Refractive error and most ocular components displayed an early exponential phase of rapid development during the first 1 to 2 years of life followed by a slower quadratic phase. Anterior and vitreous chamber depths, axial length, and crystalline lens radii increased at every visit. The crystalline lens thinned throughout the ages studied. The power of the cornea showed an early decrease, then stabilized, whereas the crystalline lens showed more robust decreases in power. The crystalline lens refractive index followed a polynomial growth and decay model, with an early increase followed by a decrease starting at 1 to 2 years of age. Refractive error became less hyperopic and then was relatively stable after 1 to 2 years of age. Axial lengths increased by 3.35 ± 0.64 mm between ages 0.25 and 6.5 years, showed uniform rates of growth across the range of initial values, and were correlated with initial axial lengths (r = 0.44, P < .001). CONCLUSIONS: Early ocular optical and structural development appears to be biphasic, with emmetropization occurring within the first 2 years of infancy during a rapid exponential phase. A more stable refractive error follows during a slower quadratic phase of growth when axial elongation is compensated primarily by changes in crystalline lens power.

Pharmacologic management of adolescent catatonia: A dual-case series.

Introduction: Catatonia is a syndrome characterized by psychomotor and behavioral disturbances and is associated with a substantially increased mortality risk in adolescent patients. There is a dearth of published literature describing treatment strategies for pediatric patients with catatonia. This dual-case series will describe the treatment course of 2 adolescent patients with catatonia at our pediatric inpatient psychiatric facility. Case Series: This case series presents 2 adolescent patients (a 17-year-old male and a 16-year-old female) who initially presented with worsening agitation and paranoia, later developing catatonia. Both patients required long durations of hospitalization and were treated with high-dose lorazepam before requiring the addition of electroconvulsive therapy (ECT). Discussion: Treatment of pediatric patients with catatonia creates a significant burden on patients, families, and the healthcare system. Treatment with high-dose benzodiazepines is high risk, while ECT is both difficult to access and comes with its own risks. Both patients discussed are transitional age, meaning they will soon be young adults who will continue to require high-level psychiatric care. Psychiatric pharmacists have a large role to play in ensuring safe medication management for these complex patients. Conclusions: This case series of 2 adolescent patients with catatonia demonstrates marginal reduction in symptoms with high-dose lorazepam in conjunction with ECT, with minimal side effects. This case series adds to the limited available literature regarding treatment of catatonia in pediatric patients and highlights the need for further study into effective treatment alternatives.

The Ratio of Key Metabolic Transcripts Is a Predictive Biomarker of Breast Cancer Metastasis to the Lung.

Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. Although feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in patients with breast cancer. SIGNIFICANCE: Lung-homing metastatic breast cancer cells express an elevated ratio of lactate dehydrogenase to pyruvate dehydrogenase, indicating that ratios of specific metabolic gene transcripts have potential as metabolic biomarkers for predicting organ-specific metastasis.

Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency.

Lipoprotein lipase deficiency (LPLD) results from mutations within the lipoprotein lipase (LPL) gene that lead to a complete lack of catalytically active LPL protein. Glybera was one of the first adeno-associated virus (AAV) gene replacement therapy to receive European Medicines Agency regulatory approval for the treatment of LPLD. However, Glybera is no longer marketed potentially due to a combination of economical, manufacturing, and vector-related issues. The aim of this study was to develop a more efficacious AAV gene therapy vector for LPLD. Following preclinical biodistribution, efficacy and non-Good Laboratory Practice toxicity studies with novel AAV1 and AAV8-based vectors in mice, we identified AAV8 pVR59. AAV8 pVR59 delivered a codon-optimized, human gain-of-function hLPLS447X transgene driven by a CAG promoter in an AAV8 capsid. AAV8 pVR59 was significantly more efficacious, at 10- to 100-fold lower doses, compared with an AAV1 vector based on Glybera, when delivered intramuscularly or intravenously, respectively, in mice with LPLD. Efficient gene transfer was observed within the injected skeletal muscle and liver following delivery of AAV8 pVR59, with long-term correction of LPLD phenotypes, including normalization of plasma triglycerides and lipid tolerance, for up to 6 months post-treatment. While intramuscular delivery of AAV8 pVR59 was well tolerated, intravenous administration augmented liver pathology. These results highlight the feasibility of developing a superior AAV vector for the treatment of LPLD and provide critical insight for initiating studies in larger animal models. The identification of an AAV gene therapy vector that is more efficacious at lower doses, when paired with recent advances in production and manufacturing technologies, will ultimately translate to increased safety and accessibility for patients.

Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.

The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test.

Molecular Dynamics Insight into the Role of Water Molecules in Ionic Liquid Mixtures of 1-Butyl-3-methylimidazolium Iodide and Ethylammonium Nitrate.

Imidazolium-based ionic liquids are well known for their versatility as solvents for various applications such as dye-sensitized solar cells, fuel cells, and lithium-ion batteries; however, their complex interactions continue to be investigated to further improve upon their design. Ionic liquids (ILs) are commonly mixed with co-solvents such as water, organic solvents, or other ionic liquids to tailor their physiochemical properties. To better predict these properties and fundamentally understand the molecular interactions within the electrolyte mixtures, molecular dynamics (MD) simulations are often employed. In this study, MD simulations are performed on ternary solutions containing ionic liquids of 1-butyl-3-methylimidazolium iodide ([BMIM][I]) and ethylammonium nitrate ([EA][NO3]) with increasing concentration of water. As previously reported, these ternary solutions displayed a wide temperature window of thermal stability and electrochemical conductivity. Utilizing MD simulations, the complex intermolecular interactions are identified, and the role of water as a co-solvent is disclosed to correlate with changes in their bulk properties. The MD results, including simulation box snapshots, radial distribution functions, and self-diffusion coefficients, reveal the formation of heterogeneous regimes with increasing water concentration, hydrogen bonding between iodide-water, iodide-[EA]+, and a change in IL ordering when in mixtures containing water. The simulations also display the formation of water aggregates and networks at high water concentrations, which can contribute to the thermal behavior of the respective mixtures. As the design of IL-based electrolytes grows in demand with increasing complexity, this work demonstrates the capability of MD simulations containing multiple constituents and their necessity in material development through identification of microscopic structure-property relationships.

GMP Manufacturing and IND-Enabling Studies of a Recombinant Hyperimmune Globulin Targeting SARS-CoV-2.

Conventionally, hyperimmune globulin drugs manufactured from pooled immunoglobulins from vaccinated or convalescent donors have been used in treating infections where no treatment is available. This is especially important where multi-epitope neutralization is required to prevent the development of immune-evading viral mutants that can emerge upon treatment with monoclonal antibodies. Using microfluidics, flow sorting, and a targeted integration cell line, a first-in-class recombinant hyperimmune globulin therapeutic against SARS-CoV-2 (GIGA-2050) was generated. Using processes similar to conventional monoclonal antibody manufacturing, GIGA-2050, comprising 12,500 antibodies, was scaled-up for clinical manufacturing and multiple development/tox lots were assessed for consistency. Antibody sequence diversity, cell growth, productivity, and product quality were assessed across different manufacturing sites and production scales. GIGA-2050 was purified and tested for good laboratory procedures (GLP) toxicology, pharmacokinetics, and in vivo efficacy against natural SARS-CoV-2 infection in mice. The GIGA-2050 master cell bank was highly stable, producing material at consistent yield and product quality up to >70 generations. Good manufacturing practices (GMP) and development batches of GIGA-2050 showed consistent product quality, impurity clearance, potency, and protection in an in vivo efficacy model. Nonhuman primate toxicology and pharmacokinetics studies suggest that GIGA-2050 is safe and has a half-life similar to other recombinant human IgG1 antibodies. These results supported a successful investigational new drug application for GIGA-2050. This study demonstrates that a new class of drugs, recombinant hyperimmune globulins, can be manufactured consistently at the clinical scale and presents a new approach to treating infectious diseases that targets multiple epitopes of a virus.

Listening in on the conversation between the human gut microbiome and its host.

The gut microbiome is an ecosystem. Natural selection favored microbes fit for the gut, which can utilize and convert molecules produced by the host for their own benefit. But natural selection also favored the host's mechanisms to sense and respond to the microbial ecosystem for its own benefit. We can listen in on the host-microbiome 'conversation' in the simultaneous responses of the microbiome and the host to strong perturbations. In laboratory animals a perturbation can be done for research; in human patients a perturbation can be caused by disease or therapy. Advances in metagenomics, metabolomics and computation amplify our means to listen in on the conversation between the gut microbiome and its host.

Detection and quantification of trace organic contaminants in water using the FT-IR-attenuated total reflectance technique.

The Fourier transform infrared-attenuated total reflectance (FT-IR-ATR) technique has been used to detect and quantify the following volatile organic compounds (VOCs) in water: 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, styrene, and tetrachloroethylene, among which the first three compounds were investigated at parts per million levels for the first time. Enhancement of the detection was made by (1) coating the ATR crystal with a hydrophobic polymer membrane, (2) optimizing the flow rate of the sample solution, (3) varying polymer membrane thickness, and (4) increasing the number of reflection bounces within the ATR crystal. Our flow rate optimization confirmed a previous finding that turbulent flow is more favorable than laminar flow in detecting the VOCs in water. However, decreases of ATR signal intensity were observed at very high turbulency due to analytes flowing too quickly through and exiting the ATR cell to be adsorbed onto the polymer membrane. The optimal membrane thickness was found to be associated with the maximum overlap between the IR evanescent wave penetration depth and the analyte diffusion depth. Consequently, there is no universal optimal flow rate and optimal polymer membrane thickness for detection of all VOCs. Doubling the number of IR reflection bounces within the ATR crystal enhanced both detection and sensitivity by about a factor of 2. Finally, it was observed that the detection limit concentrations decrease with the water solubility of the VOCs.

Validation of cell density and viability assays using Cedex automated cell counter.

A method using Cedex automatic cell counter (Innovatis) to determine the cell density and viability of a whole cell-based immunotherapy product has been developed and validated for the assay performance characteristics including specificity, accuracy, precision, linearity, range, and robustness. Instrument-to-instrument variation due to intrinsic differences in handmade flow cells was also evaluated. For cell density, Cedex demonstrated acceptable specificity, accuracy and precision for cell densities ranging from 3.13x10(5) to approximately 1.0x10(7)cells/mL, with intermediate precision of about 5% relative standard deviation (RSD). However, a marked difference was observed between the two instruments studied and they therefore could not be used interchangeably without additional calibration procedures that went beyond the manufacturer's recommendation. For viability, mixing known numbers of non-viable cells with highly viable cells allowed evaluation of the specificity, accuracy and linearity of the viability determination. Acceptable levels of accuracy (95.3-106.4% recovery) and precision (RSD<5%) were demonstrated for the viability range from 50 to 100%. The instrument-to-instrument difference was less than 4.6%. The assays for both cell density and viability were sufficiently robust for assay parameters. However, the effect of certain parameters was cell line-dependent, suggesting that Cedex performance should be verified for each cell line of interest.

Mammary tumors with diverse immunological phenotypes show differing sensitivity to adoptively transferred CD8+ T cells lacking the Cbl-b gene.

We tested the efficacy of CD8+ T cells lacking the Cbl-b gene against a panel of mammary tumor lines with different intrinsic sensitivities to T cells. Mice bearing established tumors expressing an ovalbumin-tagged version of HER-2/neu underwent adoptive transfer with Cbl-b-replete or -null CD8+ T cells from OT-I T cell receptor transgenic donor mice. In general, Cbl-b-null OT-I cells showed enhanced expansion, persistence, and capacity for tumor infiltration. This resulted in markedly enhanced efficacy against two tumor lines that normally demonstrate complete (NOP21) or partial (NOP23) regression. Moreover, a third tumor line (NOP6) that normally demonstrates progressive disease underwent complete regression in response to Cbl-b-null OT-I cells. However, a fourth tumor line (NOP18) was resistant to Cbl-b-null OT-I cells owing to a profound barrier to lymphocyte infiltration. Thus, Cbl-b-null CD8+ T cells are generally more efficacious but are nonetheless unable to mediate curative responses against all tumor phenotypes.

Accommodation, acuity, and their relationship to emmetropization in infants.

PURPOSE: To evaluate the relationship between accommodation, visual acuity, and emmetropization in human infancy. METHODS: Defocus at distance and near (57 cm) was assessed using Mohindra and dynamic retinoscopy, respectively, in 262 normal birthweight infants at 3, 9, and 18 months of age. Preferential looking provided acuity data at the same ages. The spherical equivalent refractive error was measured by cycloplegic retinoscopy (cyclopentolate 1%). RESULTS: Univariate linear regression analyses showed no associations between the change in refractive error and defocus at distance or near. Change in refractive error was linearly related to the accommodative response at distance (R = 0.17, p < 0.0001) and near (R = 0.13, p < 0.0001). The ten subjects with the poorest emmetropization relative to the change predicted by the linear effects of their refractive error had higher average levels of hyperopic defocus at distance and near (p < 0.043). Logistic regression showed a decrease in the odds of reaching +2.00 diopter or less hyperopia by 18 months with increasing levels of hyperopia at 3 months, or if Mohindra retinoscopy was myopic combined with acuity better than the median level of 1.25 logMAR [area under the receiver operating characteristic curve = 0.78 (95% CI = 0.68 to 0.88)]. CONCLUSIONS: The level of cycloplegic refractive error was the best single factor for predicting emmetropization by 18 months of age, with smaller contributions from visual acuity and Mohindra retinoscopy. The lack of correlation between defocus and change in refractive error does not support a simple model of emmetropization in response to the level of hyperopic defocus. Infants were capable of maintaining accurate average levels of accommodation across a range of moderate hyperopic refractive errors at 3 months of age. The association between the change in refractive error and accommodative response suggests that accommodation is a plausible visual signal for emmetropization.

Tailoring intermolecular interactions to develop a low-temperature electrolyte system consisting of 1-butyl-3-methylimidazolium iodide and organic solvents.

Ionic liquids (ILs) exhibit remarkable properties and great tunability, which make them an attractive class of electrolyte materials for a variety of electrochemical applications. However, despite the promising progress for operating conditions at high temperatures, the development of their low-temperature viability as electrolytes is still limited due to the constrains from thermal and ion transport issues with a drastic decrease in temperature. In this study, we present a liquid electrolyte system based on a mixture of 1-butyl-3-methylimidazolium iodide ([BMIM][I]), γ-butyrolactone (GBL), propylene carbonate (PC), and lithium iodide (LiI) and utilize its molecular interactions to tailor its properties for extremely low-temperature sensing applications. In particular, the carbonyl group on both PC and GBL can form hydrogen bonds with the imidazolium cation, as indicated by Fourier transform infrared spectroscopy (FTIR), and the extent of these interactions between ions and molecules was also characterized and quantified via proton nuclear magnetic resonance (1H NMR) spectroscopy. More importantly, at the optimal ratio, the organic solvents do not have excess content to form aggregates, which may cause undesired crystallization before the glass transition. The microscopic evolutions of the systems are correlated with their bulk behaviors, leading to improvements in their thermal and transport properties. The optimized formulation of [BMIM][I]/PC/GBL/LiI showed a low glass transition temperature (T g) of -120 °C and an effectively reduced viscosity of 0.31 Pa s at -75 °C. The electrochemical stability of the electrolyte was also validated to support the targeted iodide/triiodide redox reactions without interference.

Marine fog inputs appear to increase methylmercury bioaccumulation in a coastal terrestrial food web.

Coastal marine atmospheric fog has recently been implicated as a potential source of ocean-derived monomethylmercury (MMHg) to coastal terrestrial ecosystems through the process of sea-to-land advection of foggy air masses followed by wet deposition. This study examined whether pumas (Puma concolor) in coastal central California, USA, and their associated food web, have elevated concentrations of MMHg, which could be indicative of their habitat being in a region that is regularly inundated with marine fog. We found that adult puma fur and fur-normalized whiskers in our marine fog-influenced study region had a mean (±SE) total Hg (THg) (a convenient surrogate for MMHg) concentration of 1544 ± 151 ng g-1 (N = 94), which was three times higher (P < 0.01) than mean THg in comparable samples from inland areas of California (492 ± 119 ng g-1, N = 18). Pumas in California eat primarily black-tailed and/or mule deer (Odocoileus hemionus), and THg in deer fur from the two regions was also significantly different (coastal 28.1 ± 2.9, N = 55, vs. inland 15.5 ± 1.5 ng g-1, N = 40). We suggest that atmospheric deposition of MMHg through fog may be contributing to this pattern, as we also observed significantly higher MMHg concentrations in lace lichen (Ramalina menziesii), a deer food and a bioindicator of atmospheric deposition, at sites with the highest fog frequencies. At these ocean-facing sites, deer samples had significantly higher THg concentrations compared to those from more inland bay-facing sites. Our results suggest that fog-borne MMHg, while likely a small fraction of Hg in all atmospheric deposition, may contribute, disproportionately, to the bioaccumulation of Hg to levels that approach toxicological thresholds in at least one apex predator. As global mercury levels increase, coastal food webs may be at risk to the toxicological effects of increased methylmercury burdens.

A Dual Ionic Liquid-Based Low-Temperature Electrolyte System.

Ionic liquids (ILs) show a promising future as electrolytes in electrochemical devices. In particular, IL-based electrolytes bring operations at extreme temperatures to realization that conventional electrolytes fail to accomplish. Although IL electrolytes demonstrate considerable progress in high-temperature applications, their breakthroughs in devices operating at low temperatures are still very limited due to undesirable phase transitions and unsatisfying transport properties. In this study, we present an approach where, by tuning molecular interactions in the system, the designed electrolyte of an IL-based mixture can reach a lower operating temperature with improved transport properties. We have discovered that the incorporation of the IL, ethylammonium nitrate ([EA][N]), can contribute to reforming the molecular interactions within the system, which effectively resolve the crystallization accompanied with the excess of water and retain a low glass transition temperature. The reported liquid electrolyte systems based on a mixture of 1-butyl-3-methylimidazolium iodide ([BMIM][I]), [EA][N], water, and lithium iodide exhibit a glass transition temperature below -105 °C. Furthermore, the optimized electrolyte system shows significant viscosity reduction and ionic conductivity enhancement from 25 to -75 °C. The influence is also noticeable on the increased ionicity, which made the developed electrolyte comparable with other good ILs under the Walden rule. The electrochemical stability of the electrolyte system is revealed by a steady and reproducible profile of iodide/triiodide redox reactions at room temperature over a proper potential window via cyclic voltammetry. The results from this work not only provide a potential solution to applications of the iodide/triiodide redox couple-based electrochemical devices at low temperatures but also show a practical approach to obtain tailored properties of a mixture system via modifying molecular interactions.

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care.

Atrial fibrillation (AF) is a common cardiac arrhythmia with significant clinical outcomes, and is associated with high medical and social costs. AF is complicated for patients because of its specialised terminology, long-term adherence, symptom monitoring, referral to specialty care, array of potential interventions and potential for adversity. Health literacy is a frequently under-recognised, yet fundamental, component towards successful care in AF. Health literacy is defined as the capacity to obtain, process and understand health information, and has had markedly limited study in AF. However, health literacy could contribute to how patients interpret symptoms, navigate care, and participate in treatment evaluation and decision-making. This review aims to summarise the clinical importance and essential relevance of health literacy in AF. We focus here on central aspects of AF care that are most related to self-care, including understanding the symptoms of AF, shared decision-making, adherence and anticoagulation for stroke prevention. We discuss opportunities to enhance AF care based on findings from the literature on health literacy, and identify important gaps. Our overall objective is to articulate the importance and relevance of integrating health literacy in the care of individuals with AF.

Axial growth and changes in lenticular and corneal power during emmetropization in infants.

PURPOSE: To evaluate the contribution made by the ocular components to the emmetropization of spherical equivalent refractive error in human infants between 3 and 9 months of age. METHODS: Keratophakometry in two meridians was performed on 222 normal-birthweight infant subjects at 3 and 9 months of age. The spherical equivalent refractive error was measured by cycloplegic retinoscopy (cyclopentolate 1%). Anterior chamber depth, lens thickness, and vitreous chamber depth were measured by A-scan ultrasonography over the closed eyelid. RESULTS: Both the mean and SD for spherical equivalent refractive error decreased between 3 and 9 months of age (+2.16 +/- 1.30 D at 3 months; +1.36 +/- 1.06 D at 9 months; P < 0.0001, for the change in both mean and SD). Average ocular component change was characterized by increases in axial length, thinning, and flattening of the crystalline lens, increases in lens equivalent refractive index, and decreases in lens and corneal power. Initial refractive error was associated in a nonlinear manner with the change in refractive error (R(2) = 0.41; P < 0.0001) and with axial growth (R(2) = 0.082; P = 0.0005). Reduction in hyperopia correlated significantly with increases in axial length (R(2) = 0.16; P < 0.0001), but not with changes in corneal and lenticular power. Decreases in lenticular and corneal power were associated with axial elongation (R(2) = 0.40, R(2) = 0.12, respectively; both P < 0.0001). CONCLUSIONS: Modulation in the amount of axial growth in relation to initial refractive error appeared to be the most influential factor in emmetropization of spherical equivalent refractive error. The associations between initial refractive error, subsequent axial growth, and change in refractive error were consistent with a visual basis for emmetropization. The cornea and crystalline lens lost substantial amounts of dioptric power in this phase of growth, but neither appeared to play a significant role in emmetropization.

Mobility-assistive technology in progressive neuromuscular disease.

Mobility-assistive technologies allow patients with neuromuscular disease to interact with peers and the community. In children, they also serve to facilitate development. Lack of access to appropriate assistive technology, especially in regards to mobility, can have adverse developmental consequences. There are multiple options for mobility devices and methods for their control. These devices can be integrated with other electronics to facilitate the control of a variety of devices in the environment. The clinician should assess which devices are best based on the patient's, caregivers', and medical team's goals.

A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation.

Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression.