Telomere dynamics during hibernation in a tropical primate.

Hibernation is a widespread metabolic strategy among mammals for surviving periods of food scarcity. During hibernation, animals naturally alternate between metabolically depressed torpor bouts and energetically expensive arousals without ill effects. As a result, hibernators are promising models for investigating mechanisms that buffer against cellular stress, including telomere protection and restoration. In non-hibernators, telomeres, the protective structural ends of chromosomes, shorten with age and metabolic stress. In temperate hibernators, however, telomere shortening and elongation can occur in response to changing environmental conditions and associated metabolic state. We investigate telomere dynamics in a tropical hibernating primate, the fat-tailed dwarf lemur (Cheirogaleus medius). In captivity, these lemurs can hibernate when maintained under cold temperatures (11-15 °C) with limited food provisioning. We study telomere dynamics in eight fat-tailed dwarf lemurs at the Duke Lemur Center, USA, from samples collected before, during, and after the hibernation season and assayed via qPCR. Contrary to our predictions, we found that telomeres were maintained or even lengthened during hibernation, but shortened immediately thereafter. During hibernation, telomere lengthening was negatively correlated with time in euthermia. Although preliminary in scope, our findings suggest that there may be a preemptive, compensatory mechanism to maintain telomere integrity in dwarf lemurs during hibernation. Nevertheless, telomere shortening immediately afterward may broadly result in similar outcomes across seasons. Future studies could profitably investigate the mechanisms that offset telomere shortening within and outside of the hibernation season and whether those mechanisms are modulated by energy surplus or crises.

Emotion recognition and eye tracking of static and dynamic facial affect: A comparison of individuals with and without traumatic brain injury.

Diminished social functioning is often seen after traumatic brain injury (TBI). Mechanisms contributing to these deficits are poorly understood but thought to relate to impaired ability to recognize facial expressions. Static stimuli are often used to investigate ability post-TBI, and there is less evidence using more real-life dynamic stimuli. In addition, most studies rely on behavioral responses alone. The present study investigated the performance of a TBI group and matched non-TBI group on static and dynamic tasks using eye-tracking technology alongside behavioral measures. This is the first study to use eye tracking methodology alongside behavioral measures in emotion recognition tasks in people with brain injury. Eighteen individuals with heterogeneous TBI and 18 matched non-TBI participants were recruited. Stimuli representing six core emotions (Anger, Disgust, Fear, Happy, Sad, and Surprise faces) were selected from the Amsterdam Dynamic Facial Expression Set (ADFES). Participants were instructed to identify the emotion displayed correctly whilst eye movement metrics were recorded. RESULTS: Results of analyses showed that TBI patients had First Fixation to nose for all emotion stimuli, shorter Fixation Duration and lower Fixation Count to eyes, were generally slower to classify stimuli, and less accurate than non-TBI group for the static task. Those with TBI were also less accurate at identifying Angry, Disgust, and Fear stimulus faces compared to the non-TBI group during the dynamic unfolding of an emotion. CONCLUSION: In the present study, those with TBI had atypical eye scan patterns during emotion identification in the static emotion recognition task compared to the non-TBI group and were associated with lower identification accuracy on behavioral measures in both static and dynamic tasks. Findings suggest potential disruption to oculomotor systems vital for first stage perceptual processing. Arguably, these impairments may contribute to diminished social functioning.

Of fruits and fats: high-sugar diets restore fatty acid profiles in the white adipose tissue of captive dwarf lemurs.

Fat-storing hibernators rely on fatty acids from white adipose tissue (WAT) as an energy source to sustain hibernation. Whereas arctic and temperate hibernators preferentially recruit dietary polyunsaturated fatty acids (PUFAs), tropical hibernators can rely on monounsaturated fatty acids that produce fewer lipid peroxides during oxidation. Nevertheless, compositional data on WAT from tropical hibernators are scant and questions remain regarding fat recruitment and metabolism under different environmental conditions. We analyse fatty acid profiles from the WAT of captive dwarf lemurs (Cheirogaleus medius) subjected to high-sugar or high-fat diets during fattening and cold or warm conditions during hibernation. Dwarf lemurs fed high-sugar (compared to high-fat) diets displayed WAT profiles more comparable to wild lemurs that fatten on fruits and better depleted their fat reserves during hibernation. One PUFA, linoleic acid, remained elevated before hibernation, potentially lingering from the diets provisioned prior to fattening. That dwarf lemurs preferentially recruit the PUFA linoleic acid from diets that are naturally low in availability could explain the discrepancy between captive and wild lemurs' WAT. While demonstrating that minor dietary changes can produce major changes in seasonal fat deposition and depletion, our results highlight the complex role for PUFA metabolism in the ecology of tropical hibernators.

Early Cenozoic Decoupling of Climate and Carbonate Compensation Depth Trends.

Our understanding of the long-term evolution of the Earth system is based on the assumption that terrestrial weathering rates should respond to, and hence help regulate, atmospheric CO2 and climate. Increased terrestrial weathering requires increased carbonate accumulation in marine sediments, which in turn is expected to result in a long-term deepening of the carbonate compensation depth (CCD). Here, we critically assess this long-term relationship between climate and carbon cycling. We generate a record of marine deep-sea carbonate abundance from selected late Paleocene through early Eocene time slices to reconstruct the position of the CCD. Although our data set allows for a modest CCD deepening, we find no statistically significant change in the CCD despite >3 °C global warming, highlighting the need for additional deep-sea constraints on carbonate accumulation. Using an Earth system model, we show that the impact of warming and increased weathering on the CCD can be obscured by the opposing influences of ocean circulation patterns and sedimentary respiration of organic matter. From our data synthesis and modeling, we suggest that observations of warming, declining δ13C and a relatively stable CCD can be broadly reproduced by mid-Paleogene increases in volcanic CO2 outgassing and weathering. However, remaining data-model discrepancies hint at missing processes in our model, most likely involving the preservation and burial of organic carbon. Our finding of a decoupling between the CCD and global marine carbonate burial rates means that considerable care is needed in attempting to use the CCD to directly gauge global carbonate burial rates and hence weathering rates.

Effects of supplemental fat concentration on feeding logistics, animal performance, and nutrient losses of heifers fed finishing diets based on steam-flaked corn and sorghum-based distiller's grains.

The use of distiller's grains (DG) in beef cattle finishing diets is a common practice. However, the effects of supplemental fat on performance and nutrient losses of cattle fed diets containing DG are not known. Therefore, we fed 398 crossbred yearling heifers (initial BW = 373.5 kg) for 106 d to determine the effects of dietary fat concentration and sorghum-based wet distiller's grains with solubles (SWDGS) on performance, carcass characteristics, and nutrient losses of finishing cattle. Treatments included two 92% concentrate, steam-flaked corn (SFC)-based diets with 0% or 3% added fat from yellow grease and 3 SFC-based diets with 15% SWDGS (DM basis) that contained either 0%, 1.5%, or 3% added fat (8 pens per treatment) in a randomized block design. Overall DMI and ADG were 5% to 6% greater (P < 0.01) for heifers fed 15% SWDGS than for those fed 0% SWDGS. Among heifers fed 15% SWDGS, DMI was greatest (P = 0.04; quadratic effect) and ADG tended (P = 0.12; quadratic effect) to be greatest for heifers fed 1.5% fat. The ADG:DMI did not differ between 0% SWDGS with 0% or 3% fat, and was not altered by replacing a portion of SFC with SWDGS (P > 0.36). However, ADG:DMI tended to increase as more fat was added to diets with 15% SWDGS (P = 0.06). Average hot carcass weight (HCW) was 5 kg greater (P = 0.05) when SWDGS was fed, but HCW tended to be greatest for heifers fed 15% SWDGS with 1.5% fat (P = 0.09, quadratic effect). Heifers fed 0% SWDGS with 0% fat tended to have a lower marbling score, less rib fat, lower average yield grade (P < 0.08), and more (P < 0.01) yield grade 1 carcasses than heifers fed 0% SWDGS with 3% fat. Averaged across fat levels, heifers fed 15% SWDGS had more rib fat and a higher yield grade (P < 0.03) than heifers fed 0% SWDGS. Feeding 15% SWDGS did not alter carcass quality grade distribution compared to feeding 0% SWDGS, but 15% SWDGS produced fewer yield grade 3 carcasses (P = 0.03) than 0% SWDGS. The calculated NEg of SWDGS (1.36 Mcal/kg) was 91% of the tabular value for dry rolled corn (1.50 Mcal/kg) and 84% of the tabular value for SFC (1.62 Mcal/kg). Nitrogen intake, and N excretion were greater (P < 0.05) in heifers fed 15% SWDGS than in heifers fed the 0% SWDGS diets, but N loss as a % of N intake was less (P < 0.05). Our results suggest adding 1.5% fat to diets containing 15% SWDGS may improve beef cattle performance; however, feeding logistics need to be considered when pricing wet DG.

Undergraduate use of medical radiation science mobile applications.

INTRODUCTION: Despite the technologically intense nature of the medical radiation science (MRS) profession, literature specifically supporting the adoption of mobile learning in MRS education is scarce. To this aim, we explored student utilization of and influences for choosing MRS applications (apps, a specific type of mobile learning) within the Bachelor of Medical Radiation Science course at Charles Sturt University (CSU), Australia. Secondary objectives briefly investigated content reliability within selected chosen apps and overall student willingness to embrace this methodology prior to mainstream integration. METHODS: A mixed-method census survey was delivered to 415 enrolled students using the software Survey Monkey to compile responses to 28 questions. Inclusion criteria included students who owned a smartphone or tablet and who used any apps listed on the survey. RESULTS: Among the 97 students who completed the survey, 37% (36/97) freely use MRS apps at least weekly (70%, 21/30), of which anatomy atlases were reported as most popular. Peer recommendation influenced 67% (20/30) of students to choose the MRS apps used. Thirty-seven percent (11/30) of students integrated only one method to check the accuracy of app content prior to download. Students who do not use MRS apps (78%, 76/97) stated they were unaware of this resource; however, 91% (80/88) of the respondents indicated they would use MRS apps if incorporated into the curriculum. CONCLUSION: The majority of CSU students agreed that apps offer a convenient way to engage in a variety of interactive content both in the classroom and on-the-go, using apps most pertinent to their specific curriculum and/or for revision. Students preferred to use MRS apps if integrated as supplemental study tools vetted by the lecturer.

Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy.

Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase-based screening method can reduce the hospital stay by one day and reduced costs by ∼$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ∼$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate.

Parish Prevalence Estimates of Obesity, Diabetes and Hypertension in Jamaica: Is It Now Time for More Targeted Public Health Interventions? / Estimados de la Prevalencia de la Obesidad, la Diabetes y la Hipertensión por Parroquia en Jamaica: ¿Es ya Tiempo de Realizar Intervenciones de Salud Pública Más Específicas?

ABSTRACT Objective: Geographic variation in obesity, Diabetes mellitus (DM) and hypertension (HTN) prevalence at the parish level was examined using the Jamaica Health and Lifestyle Survey 2008 (JHLS II). Methods: Total and sex-specific parish age-adjusted prevalence estimates of obesity, DM and HTN were obtained and ranked. Binary logistic regression models were adjusted for age, urbanicity, educational level, physical activity and diet. Results: Parish prevalence ranges were obesity 19.5-37.8% (1.7-31.0% in men versus 27.39-48.30% in women); DM 5.08-37.82% (0-26.45% in men versus 7.11-14.17% in women) and HTN 19.50-36.02% (10.94-48.39% in men versus 18.85-36.61% in women). The highest parish prevalences were St Elizabeth for obesity, Portland for DM and St Mary for HTN. Men residing in St Elizabeth were 16 times more obese compared to those in Portland [(Odds Ratio) OR = 15.84; 95% CI = 2.00, 125.51, p < 0.01], while women in St Elizabeth had twice the odds of being obese compared to those in St Ann [OR = 2.3; 95% CI, 1.007, 5.3). Men in Portland were eight times more likely to have HTN compared to those residing in St Ann (OR = 7.70; 95% CI = 2.34, 25.40, p = 0.001) whilst women in St Mary were three times more likely to be hypertensive compared to those living in St Thomas (OR = 3.05; 95% CI = 1.63, 5.72, p = 0.001). No significant associations were seen with DM. Conclusion: Significant heterogeneity exists at the parish level in obesity, DM and HTN, with important sex differences. Further analyses are needed to understand the determinants and work toward context-specific prevention and intervention programming.

RESUMEN Objetivo: La variación geográfica de la prevalencia de la obesidad, la diabetes mellitus (DM) y la hipertensión (HT) a nivel parroquia, se examinó usando la Encuesta 2008 sobre Salud y Estilo de Vida de Jamaica (JHLS-2). Métodos: Los estimados totales y específicos por género, ajustados por edad y a nivel de parroquia, de la prevalencia de la obesidad, DM y HT, fueron obtenidos y clasificados. Los modelos de regresión logística binaria fueron ajustados por edad, urbanidad, nivel educacional, actividad física, y dieta. Resultados: Los rangos de prevalencia por parroquia fueron como sigue: obesidad 19.5- 37.8% (1.7-31.0% en hombres versus 27.39-48.30% en mujeres); DM 5.08-37.82% (0- 26.45% en hombres versus 7.11-14.17% en mujeres); y HT 19.50-36.02% (10.94-48.39% en hombres versus 18.85-36.61% en mujeres). Las prevalencias más altas por parroquia fueron: Saint Elizabeth en obesidad, Portland en DM, y Saint Mary en HT. Los hombres de Saint Elizabeth eran 16 veces más obesos en comparación con los de Portland [(Odds Ratio) OR = 15.84; 95% IC = 2.00, 125.51, p < 0.01], mientras que las mujeres de Saint Elizabeth tenían el doble de probabilidades de ser obesas en comparación con las de Saint Ann (OR = 2.3; 95% IC, 1.007, 5.3). Los hombres de Portland eran ocho veces más propensos a padecer de HT en comparación con los residentes en Saint Ann (OR = 7.70; 95% IC = 2.34, 25.40, p = 0.001) en tanto que las mujeres de Saint Mary tenían tres veces más probabilidades de ser hipertensas comparadas con las que viven en Saint Thomas (OR = 3.05; 95% IC = 1.63, 5.72, p = 0.001). No se observaron asociaciones significativas con DM. Conclusión: Existe una heterogeneidad significativa a nivel de parroquias en cuanto a obesidad, DM, y HT, con importantes diferencias de género. Se necesitan más análisis para entender las determinantes y trabajar hacia la programación de intervenciones y prevenciones específicas del contexto.

Transient osteoporosis of the hip: review of the literature.

Transient osteoporosis of the hip (TOH) is a temporary clinical condition of unknown etiology which usually resolves with conservative therapy though may be complicated by fracture or progression to avascular necrosis (AVN). TOH may be slightly more prevalent in men but when it occurs in women, it is most often seen in the latter part of pregnancy. Though fracture is a rare complication of TOH when it occurs, it is most often associated with TOH occurring in pregnancy. Magnetic resonance imaging (MRI) is the best method to diagnosis TOH. Low signal intensity on T1-weighted images, high signal intensity on T2-weighted images, and homogenous pattern of edema (the femoral head and/or neck) with normal subchondral area are in favor of TOH. A shortened course to recovery is reported by use of bisphosphonates, calcitonin, or teriparatide. Based on reported cases, core decompression is not superior to medical therapy. Transient osteoporosis of the hip, which often has no known etiology, usually resolves with conservative therapy but may predispose the patient to fracture or avascular necrosis. Diagnostic method of choice is magnetic resonance imaging. Bisphosphonates, calcitonin, or teriparatide are reported as a useful approach to reduce duration of recovery.

meso-Acetoxymethyl BODIPY dyes for photodynamic therapy: improved photostability of singlet oxygen photosensitizers.

We report two BODIPY based photosensitizers (Br2BOAc and I2BOAc) featuring an acetoxymethyl substituent at the meso-position. These photosensitizers show improved photostability against singlet oxygen, when compared to a BODIPY photosensitizer lacking the acetoxymethyl group. Both compounds were evaluated for photodynamic therapy against HeLa cells and photodynamic inactivation against E. coli bacteria. We show that the compounds readily embed in the lipid membranes of HeLa cervical cancer cells and efficiently induced light-dependent apoptosis at nanomolar concentration. Also, both compounds showed a substantial degree of photoinactivation of E. coli bacteria when used at low micromolar concentrations.

Severity of Nasal Inflammatory Disease Questionnaire for Canine Idiopathic Rhinitis Control: Instrument Development and Initial Validity Evidence.

BACKGROUND: Effective treatments are needed for idiopathic chronic rhinitis in dogs, but assessment of efficacy requires a practical, quantifiable method for assessing severity of disease. OBJECTIVES: To develop and perform initial validity and reliability testing of an owner-completed questionnaire for assessing clinical signs and dog and owner quality of life (QOL) in canine chronic rhinitis. ANIMALS: Twenty-two dogs with histopathologically confirmed chronic rhinitis and 72 healthy dogs. METHODS: In this prospective study, an online questionnaire was created based on literature review and feedback from veterinarians, veterinary internists with respiratory expertise, and owners of dogs with rhinitis. Owners of affected dogs completed the questionnaire twice, 1 week apart, to test reliability. Healthy dogs were assessed once. Data were analyzed using the Rasch Rating Scale Model, and results were interpreted using Messick's framework for evaluating construct validity evidence. RESULTS: Initial item generation resulted in 5 domains: nasal signs, paranasal signs, global rhinitis severity, and dog's and owner's QOL. A 25-item questionnaire was developed using 5-point Likert-type scales. No respondent found the questionnaire difficult to complete. Strong psychometric evidence was available to support the substantive, generalizability, content, and structural aspects of construct validity. Statistical differences were found between responses for affected and control dogs for all but 2 items. These items were eliminated, resulting in the 23-item Severity of Nasal Inflammatory Disease (SNIFLD) questionnaire. CONCLUSIONS AND CLINICAL IMPORTANCE: The SNIFLD questionnaire provides a mechanism for repeated assessments of disease severity in dogs with chronic rhinitis.

Pre-clinical evaluation of a novel class of anti-cancer agents, the Pyrrolo-1, 5-benzoxazepines.

Microtubules are currently ranked one of the most validated targets for chemotherapy; with clinical use of microtubule targeting agents (MTAs) extending beyond half a century. Recent research has focused on the development of novel MTAs to combat drug resistance and drug associated toxicities. Of particular interest are compounds structurally different to those currently used within the clinic. The pyrrolo-1, 5-benzoxazepines (PBOXs) are a structurally distinct novel group of anti-cancer agents, some of which target tubulin. Herein, we review the chemistry, mechanism of action, preclinical development of the PBOXs and comparisons with clinically relevant chemotherapeutics. The PBOXs induce a range of cellular responses including; cell cycle arrest, apoptosis, autophagy, anti-vascular and anti-angiogenic effects. The apoptotic potential of the PBOXs extends across a wide spectrum of cancer-derived cell lines, by targeting tubulin and multiple molecular pathways frequently deregulated in human cancers. Extensive experimental data suggest that combining the PBOXs with established chemotherapeutics or radiation is therapeutically advantageous. Pre-clinical highlights of the PBOXs include; cancer specificity and improved therapeutic efficacy as compared to some current first line therapeutics.

Design and construction of a point-contact spectroscopy rig with lateral scanning capability.

The design and realization of a cryogenic rig for point-contact spectroscopy measurements in the needle-anvil configuration is presented. Thanks to the use of two piezoelectric nano-positioners, the tip can move along the vertical (z) and horizontal (x) direction and thus the rig is suitable to probe different regions of a sample in situ. Moreover, it can also form double point-contacts on different facets of a single crystal for achieving, e.g., an interferometer configuration for phase-sensitive measurements. For the later purpose, the sample holder can also host a Helmholtz coil for applying a small transverse magnetic field to the junction. A semi-rigid coaxial cable can be easily added for studying the behavior of Josephson junctions under microwave irradiation. The rig can be detached from the probe and thus used with different cryostats. The performance of this new probe has been tested in a Quantum Design PPMS system by conducting point-contact Andreev reflection measurements on Nb thin films over large areas as a function of temperature and magnetic field.

BILL E. KUNKLE INTERDISCIPLINARY BEEF SYMPOSIUM: Assessing the mineral supplementation needs in pasture-based beef operations in the Southeastern United States.

Macro- and microminerals are required for all physiological processes in beef cattle. When mineral deficiencies occur in pasture-based production systems, a multitude of deficiency symptoms may occur, and most often, these deficiencies result in hidden losses to include reduced production potential, reduced immunity, and reproductive failure. More severe deficiencies will result in specific deficiency symptoms, depending on the specific mineral deficiency. In pasture-based beef operations, specific deficiency symptoms are seldom observed. Forage mineral supply is highly variable and dependent on the forage type, stage of forage growth, and soil fertility. Grazing cattle mineral requirements change throughout the production cycle. With the variability of forage mineral supply and the changing mineral requirements, care must be taken when developing mineral supplementation programs for grazing cattle. The macrominerals function in nerve transmission, bone development, and metabolism and as electrolytes. These are Ca, P, Mg, Na, K, Cl, and S. The microminerals function in various areas of metabolism, immune responsiveness, reproductive efficiency, and many other functions. These minerals are Zn, Cu, Fe, I, Mn, Se, Mo, and Co. Of these macro- and microminerals, those that are important for supplementation to pasture-based cattle include Ca, P, Mg, Na, Cl, Zn, Cu, I, Mn, Se, and Co. However, the amounts to be supplemented will depend on the specific mineral requirements and the forage supply of the minerals. Consequently, the development of free-choice mineral supplementation programs is a moving target. Generally, this entangled mess is sorted by taking one mineral at a time into consideration. However, in doing so, one has to be cognizant of the many interactions that occur when changing intake of just 1 mineral in the supplement with respect to the amount supplied in the base forage. Often times, mineral nutrition problems of one or more minerals are created when trying to correct a deficiency of another mineral. This paper will address specific factors that are important to consider when developing and delivering mineral supplementation programs in pasture-based production systems in the Southeastern United States.

Two-step fabrication technique of gold tips for use in point-contact spectroscopy.

For a successful point-contact spectroscopy (PCS) measurement, metallic tips of proper shape and smoothness are essential to ensure the ballistic nature of a point-contact junction. Until recently, the fabrication of Au tips suitable for use in point-contact spectroscopy has remained more of an art involving a trial and error method rather than an automated scientific process. To address these issues, we have developed a technique with which one can prepare high quality Au tips reproducibly and systematically. It involves an electronic control of the driving voltages used for an electrochemical etching of a gold wire in a HCl-glycerol mixture or a HCl solution. We find that a stopping current, below which the circuit is set to shut off, is a single very important parameter to produce an Au tip of desired shape. We present detailed descriptions for a two-step etching process for Au tips and also test results from PCS measurements using them.

A novel patient-controlled bidirectional palatal lift appliance.

OBJECTIVE: Palatal lift appliances have a role in management of velopharyngeal dysfunction for immobile palates of adequate length where surgery is contraindicated. Conventional appliances involve acrylic/wire work adjustment over successive appointments until they can be tolerated without gagging. A novel appliance has been developed where the lifting plate is incrementally distalized by the patient and vertically adjusted to optimize soft palate positioning. METHOD: The design, construction, and utility of the appliance, which was developed in Dundee Dental Hospital, are described. PARTICIPANTS: The subject was a 12-year-old boy with a variant of Moebius syndrome and velopharyngeal dysfunction. Previous pharyngoplasty had been carried out and further surgery was contraindicated. INTERVENTIONS: The appliance is constructed and fitted and the flexible spring arm is vertically adjusted to lift the soft palate. The screw is turned incrementally at home, extending the lifting plate posteriorly. Videofluoroscopy allows visualization of the appliance and soft palate positioning. MAIN OUTCOME MEASURES/RESULTS: The procedure improved soft palate positioning, as demonstrated by videofluoroscopy, and objective speech outcomes. CONCLUSIONS: The appliance was well tolerated and led to improved speech outcomes for the patient. Adjustments were quick and easy for both clinician and patient. Further studies are needed to definitively determine the efficacy of the appliance.

Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae.

CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at toll-like receptor 4 (TLR4), presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu opioid receptor (MOR)-inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated nuclear factor kappaB (NF-κB), increased tumor necrosis factor-α (TNFα) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E2 (PGE2) from these cells. (-)-Morphine-induced upregulation of TNFα mRNA and PGE2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNFα and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequelae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly.

Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease.

Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.

Lack of anti-factor Xa assay standardization results in significant low molecular weight heparin (enoxaparin) dose variation in neonates and children.

INTRODUCTION: Enoxaparin is a frequently used anticoagulant in children. Unlike in adults, consensus guidelines recommend therapeutic monitoring to a target anti-factor Xa level of 0.5-1 U mL(-1) . Therapeutic ranges are not well correlated with clinical outcomes (e.g. thrombosis or hemorrhage), and assays are not standardized. Owing to limited reagent supplies, our clinical laboratory conducted a validation process and switched anti-FXa assays. Although the assays correlated well with each other, anti-FXa values were, on average, 33% higher with the new assay. The target anti-FXa range was not altered. We evaluated how this change in anti-FXa assays influenced enoxaparin dosing (mg kg(-1) ). METHODS: Enoxaparin dosing and anti-FXa values for all patients started on enoxaparin for the 6 months before and after assay change were retrospectively compiled and analyzed with a Student's t-test. RESULTS: One hundred and nine children were started on enoxaparin before assay change, and 104 after assay change. The mean therapeutic enoxaparin dose (mg kg(-1) ) was significantly lower in subjects aged < 3 months (P = 0.01) and 3 months to 2 years (P < 0.0001), but not in subjects aged > 2 years (P = 0.18), after assay change. The median number of enoxaparin dose changes required to achieve the target range was significantly reduced after assay change, from 1 to 0 (P = 0.004). CONCLUSIONS: The current pediatric practice of dose adjustment to achieve and maintain a target anti-FXa range is vulnerable to assay determination, which may provide false reassurance of efficacy and safety and represent misappropriation of time and resources. These data support a pediatric randomized controlled clinical trial comparing the safety and efficacy of enoxaparin weight-based dosing with or without dose titration based on anti-FXa.

The impact of a school-based water supply and treatment, hygiene, and sanitation programme on pupil diarrhoea: a cluster-randomized trial.

The impact of improved water, sanitation, and hygiene (WASH) access on mitigating illness is well documented, although impact of school-based WASH on school-aged children has not been rigorously explored. We conducted a cluster-randomized trial in Nyanza Province, Kenya to assess the impact of a school-based WASH intervention on diarrhoeal disease in primary-school pupils. Two study populations were used: schools with a nearby dry season water source and those without. Pupils attending 'water-available' schools that received hygiene promotion and water treatment (HP&WT) and sanitation improvements showed no difference in period prevalence or duration of illness compared to pupils attending control schools. Those pupils in schools that received only the HP&WT showed similar results. Pupils in 'water-scarce' schools that received a water-supply improvement, HP&WT and sanitation showed a reduction in diarrhoea incidence and days of illness. Our study revealed mixed results on the impact of improvements to school WASH improvements on pupil diarrhoea.