Sequential Bayesian decoding with a population of neurons.
Population coding is a simplified model of distributed information processing in the brain. This study investigates the performance and implementation of a sequential Bayesian decoding (SBD) paradigm in the framework of population coding. In the first step of decoding, when no prior knowledge is available, maximum likelihood inference is used; the result forms the prior knowledge of stimulus for the second step of decoding. Estimates are propagated sequentially to apply maximum a posteriori (MAP) decoding in which prior knowledge for any step is taken from estimates from the previous step. Not only do we analyze the performance of SBD, obtaining the optimal form of prior knowledge that achieves the best estimation result, but we also investigate its possible biological realization, in the sense that all operations are performed by the dynamics of a recurrent network. In order to achieve MAP, a crucial point is to identify a mechanism that propagates prior knowledge. We find that this could be achieved by short-term adaptation of network weights according to the Hebbian learning rule. Simulation results on both constant and time-varying stimulus support the analysis.


Angiotensin peptide synthesis and cyclic nucleotide modulation in sympathetic stellate ganglia.
Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments the activity of peripheral sympathetic nerves through activation of presynaptic angiotensin II receptors, thus contributing to sympathetic over-activity. Although some cells can synthesise angiotensin II locally, it is not known if this machinery is present in neurons closely coupled to the heart. Using a combination of RNA sequencing and quantitative real-time polymerase chain reaction, we demonstrate evidence for a renin-angiotensin synthesis pathway within human and rat sympathetic stellate ganglia, where significant alterations were observed in the spontaneously hypertensive rat stellate ganglia compared with Wistar stellates. We also used Förster Resonance Energy Transfer to demonstrate that administration of angiotensin II and angiotensin 1-7 peptides significantly elevate cyclic guanosine monophosphate in the rat stellate ganglia. Whether the release of angiotensin peptides from the sympathetic stellate ganglia alters neurotransmission and/or exacerbates cardiac dysfunction in states associated with sympathetic over activity remains to be established.


Arterial stiffness and dementia pathology: Atherosclerosis Risk in Communities (ARIC)-PET Study.
Arterial stiffness has been associated with evidence of cerebral small vessel disease (cSVD) and fibrillar β-amyloid (Aβ) deposition in the brain. These complex relationships have not been examined in racially and cognitively diverse cohorts. The Atherosclerosis Risk in Communities (ARIC)-Neurocognitive Study collected detailed cognitive testing for adjudication of dementia and mild cognitive impairment (MCI), brain MRI, and arterial stiffness by pulse wave velocity (PWV, carotid-femoral [cfPWV] and heart-carotid [hcPWV]). The ARIC-PET ancillary study added Aβ imaging using florbetapir ([18F]-AV-45) to obtain standardized uptake volume ratios and defined global Aβ-positivity as standardized uptake volume ratio >1.2. One-SD increase in PWV was related to brain volume, MRI-defined cSVD (e.g., cerebral microbleeds and white matter hyperintensity), and cortical Aβ deposition adjusted for age, body mass index, sex, race, and APOE ε4 status. We examined the cross-sectional relationships including interactions by race, APOE ε4 status, and cognition. Among the 320 ARIC-PET participants (76 [5] years, 45% black, 27% MCI), greater central stiffness (hcPWV) was associated with greater Aβ deposition (odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.01-1.71). Greater central stiffness (cfPWV) was significantly associated with having lower brain volumes in Alzheimer disease-susceptible regions (in mm3, β = -1.5 [0.7 SD], p = 0.03) and high white matter hyperintensity burden (OR = 1.6, 95% CI 1.2-2.1). Furthermore, cfPWV was associated with a higher odds of concomitant high white matter hyperintensity and Aβ-positive scans (OR = 1.4, 95% CI 1.1-2.1). These associations were strongest among individuals with MCI and did not differ by race or APOE ε4 status. Arterial stiffness, measured by PWV, is an emerging risk factor for dementia through its repeated relationships with cognition, cSVD, and Aβ deposition.


Lyophilized Polyvinylpyrrolidone Hydrogel for Culture of Human Oral Mucosa Stem Cells.
This work shows the synthesis of a polyvinylpyrrolidone (PVP) hydrogel by heat-activated polymerization and explores the production of hydrogels with an open porous network by lyophilisation to allow the three-dimensional culture of human oral mucosa stem cells (hOMSCs). The swollen hydrogel showed a storage modulus similar to oral mucosa and elastic solid rheological behaviour without sol transition. A comprehensive characterization of porosity by scanning electron microscopy, mercury intrusion porosimetry and nano-computed tomography (with spatial resolution below 1 μm) showed that lyophilisation resulted in the heterogeneous incorporation of closed oval-like pores in the hydrogel with broad size distribution (5 to 180 μm, d50 = 65 μm). Human oral mucosa biopsies were used to isolate hOMSCs, expressing typical markers of mesenchymal stem cells in more than 95% of the cell population. Direct contact cytotoxicity assay demonstrated that PVP hydrogel have no negative effect on cell metabolic activity, allowing the culture of hOMSCs with normal fusiform morphology. Pore connectivity should be improved in future to allow cell growth in the bulk of the PVP hydrogel.


Current State of Care for Pediatric ACL Ruptures in the Netherlands: A Survey.
The management of anterior cruciate ligament (ACL) injuries in the skeletally immature patient is an area of controversy. The purpose of this survey is to inventory the current state of care for pediatric ACL injuries in the Netherlands. This survey was conveyed by e-mail among all members of the Dutch Arthroscopy Society (Nederlandse Vereniging van Arthroscopie [NVA]) and promoted on the Web site of the NVA. It was developed by the scientific committee of the NVA by a consensus meeting discussing relevant topics in pediatric ACL injuries. All members of the NVA received the survey (n = 540). A total of 158 (29%) members responded to the survey, of which 143 were completed. A total of 126 responses were analyzed after exclusion. The main finding of this survey is that 78% of the respondents tend to treat children with open physes nonoperatively, while 65% tend to treat children with closed physes operatively. The most frequently performed procedure is the transphyseal reconstruction. Many considerations were involved in choosing operative treatment. The postoperative follow-up period varies from less than 1 year (24%) until fully grown (27%). In conclusion, this survey shows that the current state of care for pediatric ACL injuries is variable and a matter of debate in the Netherlands. Although the response rate seems low, this survey provides an overview of the opinions of specialized orthopaedic surgeons in the Netherlands. The results of this survey led to the development of the national registry for pediatric ACL in the Netherlands. The level of evidence for this study is V.


Hearing loss in Union Army veterans from 1862 to 1920.
To examine the prevalence of hearing loss (HL) in Union Army (UA) veterans by year, birth cohort, and occupation, and to compare Civil War pension and contemporary disability programs by examining monthly dollar awards. A retrospective review of medical records for 17,722 UA veteran pension applicants, a subset of some 35,000 soldiers retrieved randomly from the Military Archives. The diagnosis of HL was based on review of medical records, which used gross measurements because of the unavailability of audiometric testing. One third (5,891 or 33%) of pensioners sampled received compensation for HL. The veterans with HL suffered predominantly from left-sided HL (4,091 or 70%), which is consistent with noise-induced HL in a right-handed individual firing a rifle. Comparison of civilian occupations reveals minimal variation in prevalence of HL. Civil War pensions for unilateral HL averaged $134.04 per year, representing nearly one third of the average annual income in 1890. Bilateral HL received nearly twice that amount. Today, military veterans receive $1,248 annually for unilateral loss and $27,288 annually for bilateral loss. Social Security disability benefits are granted only for bilateral HL, with an average 60-year-old individual receiving $11,400 per year. HL was a common disability among UA Civil War veterans, with noise exposure a likely etiology for the HL. The differing levels of compensation for HL may reflect differing perceptions on the incapacitating effects of HL.


A systems biology representation of developmental anatomy.
The formation of any tissue involves differentiation, cell dynamics and interactions with adjacent tissues. This paper suggests that the complexity of the system as a whole can be represented as a mathematical graph, that is, a set of connected triples of the general form [term] <relationship> [term]. Computationally, such graphs are widely used for modeling data; visually, they form hierarchies and networks. For morphogenesis, the triples are of the general structure <noun > <verb > <noun >, where nouns cover tissues, molecules and networks and verbs describe processes such as moves, differentiates, grows and apoptoses. The paper considers the general formalism of graphs, where graphs are already used in biology, and how developmental anatomy may be described using this format. Representing morphogenesis as a visual graph is complicated as the formalism has to incorporate tissue types, molecular signals, networks, dynamic processes and some aspects, at least, of tissue geometry. The formation of a capillary sprout is chosen as an example of how this complexity can be represented graphically, with colour used to distinguish tissues and molecules. There are three key benefits, beyond its compactness, in using the graph formalism of morphogenesis to complement experimentation. First, it emphasizes the distributed nature of causality in morphogenesis. Secondly, producing all the triples for the visual graph requires explicit formalization of each aspect of the process, and this, in turn, often exposes gaps in knowledge and so suggests new experiments. Thirdly, once the graph has been formalized, triples can be annotated with associated information or IDs (e.g. cell types, publications, gene-expression data) that link to external online resources that may be regularly updated. Such annotations allow the graph to be viewed as a self-maintaining review. The graph approach sees dynamic processes as the drivers of developmental momentum and, because the same processes are used many times during development, it seems appropriate to view them as modules and their underlying networks as genomic subroutines.


The nematode worm C. elegans chooses between bacterial foods as if maximizing economic utility.
In value-based decision making, options are selected according to subjective values assigned by the individual to available goods and actions. Despite the importance of this faculty of the mind, the neural mechanisms of value assignments, and how choices are directed by them, remain obscure. To investigate this problem, we used a classic measure of utility maximization, the Generalized Axiom of Revealed Preference, to quantify internal consistency of food preferences in Caenorhabditis elegans, a nematode worm with a nervous system of only 302 neurons. Using a novel combination of microfluidics and electrophysiology, we found that C. elegans food choices fulfill the necessary and sufficient conditions for utility maximization, indicating that nematodes behave as if they maintain, and attempt to maximize, an underlying representation of subjective value. Food choices are well-fit by a utility function widely used to model human consumers. Moreover, as in many other animals, subjective values in C. elegans are learned, a process we find requires intact dopamine signaling. Differential responses of identified chemosensory neurons to foods with distinct growth potentials are amplified by prior consumption of these foods, suggesting that these neurons may be part of a value-assignment system. The demonstration of utility maximization in an organism with a very small nervous system sets a new lower bound on the computational requirements for utility maximization and offers the prospect of an essentially complete explanation of value-based decision making at single neuron resolution in this organism.


Simulating low-cost cameras for augmented reality compositing.
Video see-through Augmented Reality adds computer graphics to the real world in real time by overlaying graphics onto a live video feed. To achieve a realistic integration of the virtual and real imagery, the rendered images should have a similar appearance and quality to those produced by the video camera. This paper describes a compositing method which models the artifacts produced by a small low-cost camera, and adds these effects to an ideal pinhole image produced by conventional rendering methods. We attempt to model and simulate each step of the imaging process, including distortions, chromatic aberrations, blur, Bayer masking, noise, sharpening, and color-space compression, all while requiring only an RGBA image and an estimate of camera velocity as inputs.


Cerebral air embolism following the removal of a central venous catheter in the absence of intracardiac right-to-left shunting: a case report.
Air embolism following central venous catheter (CVC) removal is a relatively uncommon complication. Despite its rare occurrence, an air embolism can lead to serious outcomes. One of the most fatal complications is cerebral air embolism. We report a case of cerebral air embolism that occurred after the removal of a CVC in a patient with an underlying idiopathic pulmonary fibrosis, subcutaneous emphysema, pneumomediastinum, and a possible intrapulmonary shunt. Although the patient had a brief period of recovery, his condition deteriorated again, and retention of carbon dioxide was sustained due to aggravation of pneumonia. Despite full coverage of antibiotics and maximum care with the ventilator, the patient died about 5 weeks after the removal of the CVC. We suggest that strict compliance to protocols is required even while removing the catheter. Furthermore, additional caution to avoid air embolism is demanded in high-risk patients, such as in this case.


Translucency and the perception of shape.
Previous studies have shown that the perceived three-dimensional (3D) shape of objects depends on their material composition. The majority of this work has focused on glossy, flat-matte, or velvety materials. Here, we studied perceived 3D shape of translucent materials. We manipulated the spatial frequency of surface relief perturbations of translucent and opaque objects. Observers indicated which of two surfaces appeared to have more bumps. They also judged local surface orientation using gauge probe figures. We found that translucent surfaces appeared to have fewer bumps than opaque surfaces with the same 3D shape (Experiment 1), particularly when self-occluding contours were hidden from view (Experiment 2). We also found that perceived local curvature was underestimated for translucent objects relative to opaque objects, and that estimates of perceived local surface orientation were similarly correlated with luminance for images of both opaque and translucent objects (Experiment 3). These findings suggest that the perceived mesoscopic shape of completely matte translucent objects can be underestimated due to a decline in the steepness of luminance gradients relative to those of opaque objects.


Local origin of slow EEG waves during sleep.
Neuronal activity mediating EEG slow waves consists of synchronous alternation of intracellular active and silent states. Recent data demonstrate that each active state of a sleep slow wave originates in a particular cortical location and propagate to involve other cortical areas. Preferential sites of origin of these waves are: the frontal cortex in adult humans, the associative cortex in cats and the somatosensory cortex in mice. In the site of origin of these slow waves any neuron can initiate a particular cycle, however there are neuronal groups with high likelihood of triggering a particular cycle. In epileptic patients, these neurons are mostly located in superficial layers, but in healthy experimental animals, populations ofintrinsically bursting neurons with a high probability of triggering spontaneous active states have been found in deeper cortical layers.


Chrysin suppresses LPS-stimulated proinflammatory responses by blocking NF-κB and JNK activations in microglia cells.
Neuroinflammation mediated by microglia has been implicated in neurodegenerative diseases. Suppression of microglial activation may therefore contribute to neuronal cell survival. Chrysin is present in honey and propolis and in low concentrations in fruits, vegetables, and certain beverages. It has been reported that chrysin has potent anti-inflammation, anti-cancer, and anti-oxidation properties. In the present study, we investigated the effects of chrysin on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated microglia. Chrysin significantly inhibited the release of nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were also significantly inhibited by chrysin. Furthermore, chrysin inhibited the activations of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB), which are signaling molecules involved in neuroinflammation. These results suggest that chrysin may act as a potential therapeutic agent for various neurodegenerative diseases involving neuroinflammation.


Causality assessment: A brief insight into practices in pharmaceutical industry.
Healthcare industry is flooded with multitude of drugs, and the list is increasing day by day. Consumption of medications has enormously increased due to life style changes, having safer drugs is the need of the hour. Regulators and other authorities to have a check have put in stringent regulations and pharmacovigilance system in place. Eventhough there has been increase in adverse drug reactions (ADR) reporting in the last decade, causality assessment has been the greater challenge for academicians and even industry. Causality is crucial for risk benefit assessment, particularly when it involves post marketing safety signals. Pharmaceutical companies have put in efforts to have a standardized approach for causality assessment. This article will provide some insight into the approaches for causality assessment from a pharma industry perspective.


Extracellular matrix components in peripheral nerve repair: how to affect neural cellular response and nerve regeneration?
Peripheral nerve injury is a serious problem affecting significantly patients' life. Autografts are the "gold standard" used to repair the injury gap, however, only 50% of patients fully recover from the trauma. Artificial conduits are a valid alternative to repairing peripheral nerve. They aim at confining the nerve environment throughout the regeneration process, and providing guidance to axon outgrowth. Biocompatible materials have been carefully designed to reduce inflammation and scar tissue formation, but modifications of the inner lumen are still required in order to optimise the scaffolds. Biomicking the native neural tissue with extracellular matrix fillers or coatings showed great promises in repairing longer gaps and extending cell survival. In addition, extracellular matrix molecules provide a platform to further bind growth factors that can be released in the system over time. Alternatively, conduit fillers can be used for cell transplantation at the injury site, reducing the lag time required for endogenous Schwann cells to proliferate and take part in the regeneration process. This review provides an overview on the importance of extracellular matrix molecules in peripheral nerve repair.


Adenylate cyclase of human fat cells. Expression of epinephrrine-sensitive activation revealed by 5'guanylyl-imidodiphosphate.
Although catecholamines stimulate lipolysis in human fat cells, activation by epinephrine of adenylate cyclase in human fat cell membranes is not readily observed. The possible role of guanine nucleotides in this reaction has now been examined with human material. Fat cell ghosts were prepared from subcutaneous fat obtained from patients undergoing elective surgery. Adenylate cyclase was assayed with [alpha-32P]ATP as substrate. Fluoride ion stimulated the enzyme 8.3-fold relative to basal levels, but epinephrine activation of cyclase was not statistically significant. GTP did not allow expression of an epinephrine effect. However, the addition of the GTP analogue, 5'-guanylyl-imidodiphosphate [GMP-P(NH)P], along with epinephrine produced 5.7-fold activation of the enzyme (P less than 0.001). GMP-P(NH)P alone was without stimulatory effect. Comparable augmentation by GMP-P (NH) P of adenylate cyclase activity was seen with isoproterenol, norepinephrine, and epinephrine. Propranolol blocked catecholamine-GMP-P (NH) P stimulation of the enzyme, suggesting that the nucleotide-dependent activation of catecholamine-sensitive adenylate cyclase is mediated by beta-receptors. GMP-P(NH)P may prove useful in allowing in vitro demonstration of additional hormone-sensitive adenylate cyclase systems.


Pharmacokinetics of vitamin D toxicity.
Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin.


Cholinergic modulation of spontaneous hypothalamic-pituitary-adrenal activity and its circadian variation in man.
Controversy still exists regarding the role of cholinergic pathways in the regulation of the hypothalamic-pituitary-adrenal axis in man. We studied the effects of the administration of placebo, pyridostigmine (PD); 120 mg, orally), and the combination of PD and pirenzepine (PZP; 100 mg, orally) on ACTH, cortisol, and GH secretion at 0730 and 2230 h in seven normal males. PD induced a clear decrease in ACTH levels at both times of the day compared to treatment with placebo, producing higher suppression in the nocturnal period (34.4 +/- 5.8% vs. 21.8 +/- 10.7%). The combination PD and PZP prevented the inhibitory action of PD on ACTH secretion in the morning, but not in the evening, when ACTH values showed a decrease similar to that seen after giving PD alone (38.1 +/- 5.6% vs. 34.4 +/- 5.8%, respectively). Cortisol values declined only when the association PD plus PZP was given in the evening. GH levels had a significant increase after PD administration in the morning (4.1 +/- 1.2 ng/mL) and in the evening (10.2 +/- 1.6 ng/mL), confirming that cholinergic stimulation was taking place, whereas the addition of PZP to PD induced a significant attenuation of these responses. It is concluded that cholinergic pathways have a inhibitory role in ACTH secretion in man. M1 muscarinic receptors seem to be involved in the diurnal inhibition of PD, whereas our observations are consistent with the mediation of another type of cholinergic receptors as an explanation for the nocturnal effect of PD on ACTH secretion. PD did not alter the circadian variation in the hypothalamic-pituitary-adrenal axis, whereas the association of PD and PZP increased the differences between diurnal and nocturnal ACTH values, suggesting a modulatory effect of the cholinergic system on the circadian rhythm of ACTH secretion.


Inbreeding and purging at the genomic Level: the Chillingham cattle reveal extensive, non-random SNP heterozygosity.
Local breeds of livestock are of conservation significance as components of global biodiversity and as reservoirs of genetic variation relevant to the future sustainability of agriculture. One such rare historic breed, the Chillingham cattle of northern England, has a 350-year history of isolation and inbreeding yet shows no diminution of viability or fertility. The Chillingham cattle have not been subjected to selective breeding. It has been suggested previously that the herd has minimal genetic variation. In this study, high-density SNP genotyping with the 777K SNP chip showed that 9.1% of loci on the chip are polymorphic in the herd, compared with 62-90% seen in commercial cattle breeds. Instead of being homogeneously distributed along the genome, these loci are clustered at specific chromosomal locations. A high proportion of the Chillingham individuals examined were heterozygous at many of these polymorphic loci, suggesting that some loci are under balancing selection. Some of these frequently heterozygous loci have been implicated as sites of recessive lethal mutations in cattle. Linkage disequilibrium equal or close to 100% was found to span up to 1350 kb, and LD was above r(2) = 0.25 up to more than 5000 kb. This strong LD is consistent with the lack of polymorphic loci in the herd. The heterozygous regions in the Chillingham cattle may be the locations of genes relevant to fitness or survival, which may help elucidate the biology of local adaptation in traditional breeds and facilitate selection for such traits in commercial cattle.


Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury.
Blood vessel loss and inflammation cause secondary degeneration following spinal cord injury. Angiopoietin-1 through the Tie2 receptor, and other ligands through alphavbeta3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis. Here, daily intravenous injections with an alphavbeta3-binding peptide named C16 or an angiopoietin-1 mimetic following a spinal cord contusion at thoracic level 9 in mice rescued epicentre blood vessels, white matter and locomotor function, and reduced detrimental inflammation. Preserved vascularity and reduced inflammation correlated with improved outcomes. C16 and angiopoietin-1 reduced leukocyte transmigration in vitro. Growth factor receptors and integrins facilitate each others' function. Therefore, angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. The treatment had lasting effects when started 4 h following injury and terminated after one week. These results identify alphavbeta3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.


Antigen I/II encoded by integrative and conjugative elements of Streptococcus agalactiae and role in biofilm formation.
Streptococcus agalactiae (i.e. Group B streptococcus, GBS) is a major human and animal pathogen. Genes encoding putative surface proteins and in particular an antigen I/II have been identified on Integrative and Conjugative Elements (ICEs) found in GBS. Antigens I/II are multimodal adhesins promoting colonization of the oral cavity by streptococci such as Streptococcus gordonii and Streptococcus mutans. The prevalence and diversity of antigens I/II in GBS were studied by a bioinformatic analysis. It revealed that antigens I/II, which are acquired by horizontal transfer via ICEs, exhibit diversity and are widespread in GBS, in particular in the serotype Ia/ST23 invasive strains. This study aimed at characterizing the impact on GBS biology of proteins encoded by a previously characterized ICE of S. agalactiae (ICE_515_tRNA(Lys)). The production and surface exposition of the antigen I/II encoded by this ICE was examined using RT-PCR and immunoblotting experiments. Surface proteins of ICE_515_tRNA(Lys) were found to contribute to GBS biofilm formation and to fibrinogen binding. Contribution of antigen I/II encoded by SAL_2056 to biofilm formation was also demonstrated. These results highlight the potential for ICEs to spread microbial adhesins between species.


Understanding laterality disorders and the left-right organizer: Insights from zebrafish.
Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry-or laterality-can result in congenital organ malformations. Situs inversus totalis (SIT) is a complete concordant reversal of internal organs that results in a low occurrence of clinical consequences. Situs ambiguous, which gives rise to Heterotaxy syndrome (HTX), is characterized by discordant development and arrangement of organs that is associated with a wide range of birth defects. The leading cause of health problems in HTX patients is a congenital heart malformation. Mutations identified in patients with laterality disorders implicate motile cilia in establishing LR asymmetry. However, the cellular and molecular mechanisms underlying SIT and HTX are not fully understood. In several vertebrates, including mouse, frog and zebrafish, motile cilia located in a "left-right organizer" (LRO) trigger conserved signaling pathways that guide asymmetric organ development. Perturbation of LRO formation and/or function in animal models recapitulates organ malformations observed in SIT and HTX patients. This provides an opportunity to use these models to investigate the embryological origins of laterality disorders. The zebrafish embryo has emerged as an important model for investigating the earliest steps of LRO development. Here, we discuss clinical characteristics of human laterality disorders, and highlight experimental results from zebrafish that provide insights into LRO biology and advance our understanding of human laterality disorders.


Data Mining for Parameters Affecting Polymorph Selection in Contorted Hexabenzocoronene Derivatives.
The macroscopic properties of molecular materials can be drastically influenced by their solid-state packing arrangements, of which there can be many (e.g., polymorphism). Strategies to controllably and predictively access select polymorphs are thus highly desired, but computationally predicting the conditions necessary to access a given polymorph is challenging with the current state of the art. Using derivatives of contorted hexabenzocoronene, cHBC, we employed data mining, rather than first-principles approaches, to find relationships between the crystallizing molecule, postdeposition solvent-vapor annealing conditions that induce polymorphic transformation, and the resulting polymorphs. This analysis yields a correlative function that can be used to successfully predict the appearance of either one of two polymorphs in thin films of cHBC derivatives. Within the postdeposition processing phase space of cHBC derivatives, we have demonstrated an approach to generate guidelines to select crystallization conditions to bias polymorph access. We believe this approach can be applied more broadly to accelerate the predictions of processing conditions to access desired molecular polymorphs, making progress toward one of the grand challenges identified by the Materials Genome Initiative.


Complete amplitude and phase control of light using broadband holographic metasurfaces.
Reconstruction of light profiles with amplitude and phase information, called holography, is an attractive optical technology with various significant applications such as three-dimensional imaging and optical data storage. Subwavelength spatial control of both amplitude and phase of light is an essential requirement for an ideal hologram. However, traditional holographic devices suffer from their restricted capabilities of incomplete modulation in both amplitude and phase of visible light; this results in sacrifice of optical information and undesirable occurrences of critical noises in holographic images. Herein, we have proposed a novel metasurface that is capable of completely controlling both the amplitude and phase profiles of visible light independently with subwavelength spatial resolution. The full, continuous, and broadband control of both amplitude and phase was achieved using X-shaped meta-atoms based on the expanded concept of the Pancharatnam-Berry phase. The first experimental demonstrations of the complete complex-amplitude holograms with subwavelength definition at visible wavelengths were achieved, and excellent performances with a remarkable signal-to-noise ratio as compared to those of traditional phase-only holograms were obtained. Extraordinary control capability with versatile advantages of our metasurface paves a way to an ideal holography, which is expected to be a significant advancement in the field of optical holography and metasurfaces.


Ginkgo biloba extract increases ocular blood flow velocity.
We evaluated a possible therapeutic effect of Ginkgo biloba extract (GBE) on glaucoma patients that may benefit from improvements in ocular blood flow. A Phase I cross-over trial of GBE with placebo control in 11 healthy volunteers (8 women, 3 men: Age; 34 +/- 3 years, mean +/- SE) was performed. Patients were treated with either GBE 40 mg or placebo three times daily orally, for 2 days. Color Doppler imaging (Siemens Quantum 2000) was used to measure ocular blood flow before and after treatment. There was a two week washout period between GBE and placebo treatment. Ginkgo biloba extract significantly increased end diastolic velocity (EDV) in the ophthalmic artery (OA) (baseline vs GBE-treatment; 6.5 +/- 0.5 vs 7.7 +/- 0.5 cm/sec, 23% change, p=0.023), with no change seen in placebo (baseline vs GBE-treatment; 7.2 +/- 0.6 vs 7.1 +/- 0.5 cm/sec, 3% change, p=0.892). No side effects related to GBE were found. Ginkgo biloba extract did not alter arterial blood pressure, heart rate, or IOP. Ginkgo biloba extract significantly increased EDV in the OA and deserves further investigation in ocular blood flow and neuroprotection for possible application to the treatment of glaucomatous optic neuropathy as well as other ischemic ocular diseases.


Microfluidic bead trap as a visual bar for quantitative detection of oligonucleotides.
We demonstrate a microfluidic bead trap capable of forming a dipstick-type bar visible to the naked eye for simple and quantitative detection of oligonucleotides. We use magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) that are connected and form MMPs-targets-PMPs when target oligonucleotides are present, leaving free PMPs with a number inversely proportional to the amount of targets. Using a capillary flow-driven microfluidic circuitry consisting of a magnetic separator to remove the MMPs-targets-PMPs, the free PMPs can be trapped at the narrowing nozzle downstream, forming a visual bar quantifiable based on the length of PMP accumulation. Such a power-free and instrument-free platform enables a limit of detection at 13 fmol (0.65 nM in 20 μl, S/N = 3) of oligonucleotides and is compatible with single-nucleotide polymorphisms and operation in a complex bio-fluid. Moreover, using DNAzyme as the target oligonucleotide that catalyzes a specific hydrolytic cleavage in the presence of lead ions, we demonstrate a model application that detects lead ions with a limit of detection of 12.2 nM (2.5 μg l-1), providing quantitative and visual detection of lead contamination at resource-limited sites.


One-step formulation of nonionic surfactant bicelles (NSBs) by a double-tailed polyglycerol-type nonionic surfactant.
Bicelles are generally formed by phospholipid-based systems and are useful for various applications, such as nanocarriers or membrane protein crystallization. The same disc-like assemblies, nonionic surfactant bicelles (NSBs), can also be formed using nonionic amphiphiles, but this has not been reported extensively. We report a novel NSB system that employs the double-tailed nonionic amphiphile, polyglyceryl dialkyl ether (C12CmGn), which has two alkyl chains and a polyglyceryl group. A symmetric-tail molecule, C12C12G13.8, formed vesicles, whereas an asymmetric-tail molecule, C12C14G15.5, formed NSBs through a simple one-step process using ultrasonication. The 1 wt% aqueous solution of C12C14G15.5 was in a two-phase equilibrium of a lamellar phase and a water phase. Transparent dispersion was obtained through ultrasonication treatment. The size distribution in the dispersion was obtained by dynamic light scattering (DLS), resulting in a narrow distribution of around 20 nm in diameter. A negatively-stained transmission electron microscopy (TEM) image showed oblong and spherical shapes, which are typically observed in bicelle-forming systems. A small angle neutron scattering (SANS) measurement well proved bicelle formation by fitting a core-shell bicelle form factor model. The disc thickness and diameter were in agreement with the values obtained by DLS and TEM, respectively. A larger shell thickness at the rim part than at the flat disc part suggested that NSB aggregates have inhomogeneous molecular distribution. Similar to phospholipid systems, the bicelle-forming C12C14G15.5 system produced a defective lamellar phase formation at high surfactant concentrations, whereas a general lamellar phase was formed in the vesicle-forming C12C12G13.8 system.


An Online Hand Exercise Intervention for Adults With Rheumatoid Arthritis (mySARAH): Design, Development, and Usability Testing.
The Strengthening and Stretching for Rheumatoid Arthritis of the Hand (SARAH) program is a tailored, progressive 12-week exercise program for people with hand problems due to rheumatoid arthritis. The program was shown to be clinically and cost-effective in a large clinical trial and is recommended by the UK National Institute for Health and Care Excellence (NICE) guidelines for rheumatoid arthritis in adults. We have developed an online version of the SARAH program (mySARAH) to make the SARAH program widely accessible to people with rheumatoid arthritis. The purposes of this study were to develop mySARAH and to evaluate and address its usability issues. We developed mySARAH using a three-step process and gaining feedback from patient contributors. After initial development, mySARAH was tested in two iterative usability cycles in nine participants using a simplified think-aloud protocol and self-reported questionnaires. We also evaluated if participants executed the SARAH exercises correctly after watching the exercise videos included on the website. A preliminary version of mySARAH consisting of six sessions over a 12-week period and delivered via text, exercise videos, images, exercise plan form, exercise calendar, and links to additional information on rheumatoid arthritis was developed. Five participants (1 male; 4 females; median age 64 years) and four participants (four females; median age 64.5 years) took part in the first and second usability testing cycles respectively. Usability issues identified from Cycle 1 such as having a navigation tutorial video and individualised feedback on pain levels were addressed prior to Cycle 2. The need for more instructions to complete the mySARAH patient forms was identified in Cycle 2 and was rectified. Self-reports from both cycles indicated that participants found the program useful and easy to use and were confident in performing the SARAH exercises themselves. Eight of the nine participants correctly demonstrated all the exercises. mySARAH is the first online hand exercise intervention for people with rheumatoid arthritis. We actively involved target users in the development and usability evaluation and ensured mySARAH met their needs and preferences.


The relationship between discrimination and memory for spacing and feature changes in houses.
Adults need to discriminate between stimuli and recognize those previously seen. For faces, feature changes (e.g., different eyes) and spacing changes (e.g., distances between eyes) are important cues. In two experiments, we assessed the influence of these on discrimination and recognition of houses, a commonly used control in face studies. In both experiments, discrimination was better for feature than spacing changes. Memory for spacing changes was generally poor but aided by extra learning and intermixing change types. Conversely, memory for features was good, especially when there were few houses, and change type was blocked. Unexpectedly, memory was best for differences that might signal something about occupants (e.g., changes to garden or bins), perhaps akin to hairstyles for faces. Overall, results are consistent with previous work showing poor discrimination of spacing in non-face objects and extends them to show that, unlike for faces, spacing differences are also not well remembered.


Mapping by synthetic peptides of the binding sites for acetylcholine receptor on alpha-bungarotoxin.
A set of seven peptides constituting the various loops and most of the surface areas of alpha-bungarotoxin (BgTX) was synthesized. In appropriate peptides, the cyclical (by a disulfide bond) monomers were prepared. In all cases, the peptides were purified and characterized. The ability of these peptides to bind Torpedo californica acetylcholine receptor (AChR) was studied by radiometric adsorbent titrations. Three regions, represented by peptides 1-16, 26-41, and 45-59, were able to bind 125I-labeled AChR and, conversely, 125I-labeled peptides were bound by AChR. In these regions, residues Ile-1, Val-2, Trp-28, Lys-26 and/or Lys-38, and one or all of the three residues Ala-45, Ala-46, and Thr-47, are essential contact residues in the binding of BgTX to receptor. Other synthetic regions of BgTX showed little or no AChR-binding activity. The specificity of AChR binding to peptides 1-16, 26-41, and 45-59 was confirmed by inhibition with unlabeled BgTX. It is concluded that BgTX has three main AChR-binding regions (loop I with N-terminal extension and loops II and III extended toward the N-terminal by residues 45-47).


Time-resolved, laser initiated detonation of TATP supports the previously predicted non-redox mechanism.
Our previously reported computational study of the decomposition pathways of triacetone triperoxide (TATP), 1, predicted that unlike most energetic materials, which involve self-combustion of fuel and oxidants, 1 decomposes via a thermoneutral, non-redox pathway that involves entropy burst. These predictions are now corroborated by time-resolved monitoring of deflagration or detonation of 1 using a fast video camera following initiation by a short pulse focused laser beam. While a fireball always accompanies the explosion of 1 under air, the formation of a fireball is totally prevented under a nitrogen atmosphere. These observations indicate that combustion of the gaseous primary products occurs as a secondary event only in the presence of exogenous oxygen. The composition of the product mixture was found to depend on the experimental conditions. With long pulse focused laser beam (150 μs at 1064 nm) at either 210 or 110 mJ, the small amounts of charcoal needed for initiation suggest that the energy required to initiate 1 by pulse laser is 4-10 mJ, much smaller than the energy required for initiation by either mechanical stress or electric discharge. This time-resolved study highlights the very unusual properties of the peroxide based explosives.


What enables size-selective trophy hunting of wildlife?
Although rarely considered predators, wildlife hunters can function as important ecological and evolutionary agents. In part, their influence relates to targeting of large reproductive adults within prey populations. Despite known impacts of size-selective harvests, however, we know little about what enables hunters to kill these older, rarer, and presumably more wary individuals. In other mammalian predators, predatory performance varies with knowledge and physical condition, which accumulates and declines, respectively, with age. Moreover, some species evolved camouflage as a physical trait to aid in predatory performance. In this work, we tested whether knowledge-based faculty (use of a hunting guide with accumulated experience in specific areas), physical traits (relative body mass [RBM] and camouflage clothing), and age can predict predatory performance. We measured performance as do many hunters: size of killed cervid prey, using the number of antler tines as a proxy. Examining ∼ 4300 online photographs of hunters posing with carcasses, we found that only the presence of guides increased the odds of killing larger prey. Accounting for this effect, modest evidence suggested that unguided hunters presumably handicapped with the highest RBM actually had greater odds of killing large prey. There was no association with hunter age, perhaps because of our coarse measure (presence of grey hair) and the performance trade-offs between knowledge accumulation and physical deterioration with age. Despite its prevalence among sampled hunters (80%), camouflage had no influence on size of killed prey. Should these patterns be representative of other areas and prey, and our interpretations correct, evolutionarily-enlightened harvest management might benefit from regulatory scrutiny on guided hunting. More broadly, we suggest that by being nutritionally and demographically de-coupled from prey and aided by efficient killing technology and road access, wildlife hunters in the developed world might have overcome many of the physical, but not knowledge-based, challenges of hunting.


3D assessment of void and gap formation in flowable resin composites using optical coherence tomography.
To investigate the effect of composite type and cavity size on gap and void formation using optical coherence tomography (OCT). Class I cavities of two depths (2 mm or 4 mm; 4 mm diameter) were prepared, treated with Tri-S Bond (Kuraray Medical), and bulk filled with either Surefil SDR Flow (SF; Dentsply) or Clearfil Majesty LV (MJ; Kuraray Medical) to form four groups. After 24 h, the specimens were 3D scanned using swept-source OCT (Santec) with 1310 nm laser at a 20 kHz sweep rate. In OCT tomograms, the bonding interface and the bulk of the restorations were evaluated. The percentage values of sealed interfaces (SP) and void volume (VP) for all groups were calculated and statistically analyzed using two- and one-way ANOVA and Tukey's post-hoc test. Selected specimens were cross sectioned and observed using a scanning electron microscope (SEM) and a confocal laser scanning microscope to confirm OCT findings. The following values were obtained for SP and VP, respectively: SF-2mm: 92% and 0.08%; SF-4mm: 66% and 0.13%; MJ-2mm: 86% and 1.79%; MJ-4mm: 33% and 1.96%. Both composites showed a significant increase in gap formation at 4-mm cavity depth (p < 0.001). While SF showed a rather homogeneous bulk compared to MJ, cavity depth did not significantly affect the void volume fraction (p = 0.08). The flowable composite with SDR (stress-decreasing resin) technology performed better than the conventional composite; however, bulk filling a 4-mm-deep cavity will compromise the sealing of the bonding interface regardless of the type of composite. OCT is a unique method of characterizing materials and their behaviors nondestructively and precisely.


Chelated lead and bone lead.
In this study a close correlation [correlation coefficient (r) = 0.86, P less than 0.001] was found between the blood lead level of 20 lead workers and their urinary excretion of lead for 24 h after intravenous infusion with 1 g of the chelating agent calcium disodium edetate. In addition, there were significant associations between lead levels in different bones (tibia/calcaneus: r = 0.93, P less than 0.001; tibia/phalanx: r = 0.67, P less than 0.002; calcaneus/phalanx: r = 0.80, P less than 0.001), as measured by in vivo X-ray fluorescence. Chelation produced no significant change in the lead level in either tibia or calcaneus. There was a significant correlation between chelated lead and bone lead (eg, for calcaneus, r = 0.62) in currently exposed workers. However, there was no significant relationship when a retired worker and an inactive worker were included (r = 0.14). It was concluded that chelatable lead mainly reflects the blood and soft-tissue lead pool, which is only partly dependent upon the skeletal lead content that comprises the biggest share of the total body burden.


Fertility of yearling beef bulls during mating.
Crossbred (Bos taurus) yearling beef bulls were assessed for breeding soundness and physical traits prior to multi-sire natural mating at pasture. Bulls (n = 60) were assigned to six groups of nine or 10 bulls and two bull-groups were rotated on 14-day intervals during a 63-day mating season in each breeding herd (n = 3) of 191-196 cows. The remaining bulls (n = 14) were maintained under similar environmental conditions without mating exposure. Bulls were observed during mating and assessed for breeding soundness and changes following mating. Bulls used for breeding (UFB) lost 77 kg of body weight and declined from body condition scores of 6 to 4.5, whereas bulls not used for breeding (NUB) maintained body condition scores of 6 and gained 27 kg. The UFB bulls incurred a 75% total injury rate with 63% incidence of lameness and 12% incidence of reproductive injuries, resulting in a 22% attrition rate. Only 45% were physically sound at the end of mating. Scrotal circumference declined in UFB bulls (-4.58%) and increased in NUB bulls (2.49%). From the 98% BSE-satisfactory rate (UFB) prior to breeding, only 61% were BSE-satisfactory post-breeding. The NUB bulls declined from 57 to 36% satisfactory. The BSE classification was influenced by significant increases in abnormal spermatozoa (primary and secondary), which was significantly associated with injuries incurred during mating. Group and breed differences in injury rates and BSE-status following mating were evident. Environmental conditions and mating activity influenced bull seminal quality and physical condition. Pregnancy rates in all three breeding herds (91-96%) were similar, with insignificant differences between bull-groups; the effects of physical and reproductive changes on individual bull fertility were immeasurable.


Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2.
Endoplasmic reticulum (ER) aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I molecules and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we determined crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analogue and a peptidic product to 2.5 and 2.7 Å, respectively, and compared them to the apo-form structure determined to 3.0 Å. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analogue extends away from the catalytic center toward the distal end of the internal cavity, making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product, although decreasing electron density toward its C terminus indicated progressive disorder. Enzymatic analysis confirmed that visualized interactions can either positively or negatively impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to determine trimming rates, thus combining substrate permissiveness with sequence bias.


A definitive diagnosis of primary Hodgkin lymphoma on endoscopic biopsy material utilizing in-depth immunohistochemical analysis.
The esophagus and stomach can be primary sites for Hodgkin lymphoma (HL). The pathognomonic feature of HL is the Reed-Sternberg cell. Because these cells can be rare in HL tumours, biopsies obtained via endoscopy are usually inadequate for establishing a definitive diagnosis. A case of a gastroesophageal junction primary HL is presented that was diagnosed on endoscopic biopsy material with the assistance of the immunohistochemical stains PAX5 and MUM1 which verified the presence of Reed-Sternberg cells. The patient was effectively treated for HL and avoided traditional laparotomy or thoracotomy procedures to obtain the diagnosis. This advanced immunohistochemical approach should be the standard in the diagnosis of primary gastrointestinal HL. An endoscopy-based approach should obviate more invasive, open biopsy procedures for establishing HL diagnosis.


The impact of functional dyspepsia on health-related quality of life in Saudi patients.
The purpose of this study was to evaluate the impact of non-ulcer dyspepsia (NUD) on health-related quality of life (HRQOL), which was assessed using the Nepean Dyspepsia Index, the Short Form-12 quality of life (QOL) scale, the general health questionnaire (GHQ-30) and the self-reporting questionnaire (SRQ-20). Validated Arabic versions of the four scales were administered to 158 subjects (54 with NUD, 50 with gastroesophageal reflux disease [GERD] and 54 with no history of gastrointestinal [GI] disease), with a mean age of 46.6 years and SD 10.7. Subjects with NUD showed the poorest scores in all indices of general QOL and HRQOL. The differences between the NUD patients and the health control in all HRQOL indices were statistically significant (P < 0.05 to P < 0.001). Comparison between NUD and GERD patients showed significant differences only in the indices of psychological health related QOL ( P < 0.05) but not in the indices of other components of QOL, including physical health components. The study also showed that the women scored lower than men in HRQOL indices, particularly those of psychological and mental health components (P < 0.05 to P < 0.001). Finally, it was found that severity of symptoms is associated with the degree of impairments in HRQOL - (r = 0.69) was significant at (P < 0.001). Results of our study showed that HRQOL was significantly impaired in the NUD group. Psychological and mental health related quality of life was particularly impaired in this group compared to both normal patients and patients with similar GI disease. This magnitude of effects on HRQOL was also found to be associated with the severity of symptoms. The implications of these findings for the management of NUD are discussed.


Stability and change in screen-based sedentary behaviours and associated factors among Norwegian children in the transition between childhood and adolescence.
In order to inform interventions to prevent sedentariness, more longitudinal studies are needed focusing on stability and change over time in multiple sedentary behaviours. This paper investigates patterns of stability and change in TV/DVD use, computer/electronic game use and total screen time (TST) and factors associated with these patterns among Norwegian children in the transition between childhood and adolescence. The baseline of this longitudinal study took place in September 2007 and included 975 students from 25 control schools of an intervention study, the HEalth In Adolescents (HEIA) study. The first follow-up took place in May 2008 and the second follow-up in May 2009, with 885 students participating at all time points (average age at baseline = 11.2, standard deviation ± 0.3). Time used for/spent on TV/DVD and computer/electronic games was self-reported, and a TST variable (hours/week) was computed. Tracking analyses based on absolute and rank measures, as well as regression analyses to assess factors associated with change in TST and with tracking high TST were conducted. Time spent on all sedentary behaviours investigated increased in both genders. Findings based on absolute and rank measures revealed a fair to moderate level of tracking over the 2 year period. High parental education was inversely related to an increase in TST among females. In males, self-efficacy related to barriers to physical activity and living with married or cohabitating parents were inversely related to an increase in TST. Factors associated with tracking high vs. low TST in the multinomial regression analyses were low self-efficacy and being of an ethnic minority background among females, and low self-efficacy, being overweight/obese and not living with married or cohabitating parents among males. Use of TV/DVD and computer/electronic games increased with age and tracked over time in this group of 11-13 year old Norwegian children. Interventions targeting these sedentary behaviours should thus be introduced early. The identified modifiable and non-modifiable factors associated with change in TST and tracking of high TST should be taken into consideration when planning such interventions.


Accuracy of the Subchondral Smile and Surface Referencing Techniques in Reverse Shoulder Arthroplasty.
Inferior glenoid baseplate tilt relative to the coronal axis of the scapular body has been associated with improved results and fewer postoperative complications in reverse shoulder arthroplasty. However, the native glenoid surface is not always a reliable reference for the true scapular axis. Digital preoperative planning software and advanced imaging now allow surgeons to more precisely determine optimal glenoid placement. The purpose of this study was to evaluate the accuracy of the subchondral smile and cannulated surface guide techniques in achieving inferior glenoid baseplate tilt by using 3-dimensional preoperative planning software. Virtual glenoid baseplate preparation and implantation was performed using computed tomography scans of 16 shoulders with rotator cuff deficiency. Two techniques were used: a subchondral smile technique that preferentially reams the interior glenoid, resulting in the appearance of a smile, and a cannulated surface guide technique that references the native glenoid face to place the baseplate in 10° of inferior tilt. Using the subchondral smile technique, the glenoid baseplate was implanted at a mean of 8.9° of superior tilt relative to the transverse scapular axis. Using the surface guide technique, the glenoid baseplate was implanted at a mean of 2.8° of superior tilt. Neither the subchondral smile technique nor the 10° cannulated surface guide technique is a reliable method to produce inferior glenoid tilt relative to the transverse axis of the scapula. Three-dimensional preoperative planning software is a useful tool when attempting to achieve optimal glenoid baseplate positioning in reverse shoulder arthroplasty. [Orthopedics. 2016; 39(4):e615-e620.].


The basic residue cluster (55)KKWVR(59) in CCL5 is required for in vivo biologic function.
Chemokine function in vivo depends on the presentation by structures of the extracellular matrix or on endothelial surfaces. CCL5 contains two clusters of basic amino acid residues ((44)RKNR(47) and (55)KKWVR(59)) implicated in presentation of the protein. While (44)RKNR(47) has been shown to moderate CCL5 binding to glycosaminoglycans (GAGs), no direct role for the basic residues in the so called 50s loop ((55)KKWVR(59)) as a presentation structure has been published to date. In ex vivo studies both regions were found to be necessary for direct tissue binding suggesting a role for (55)KKWVR(59). In vitroT lymphocyte and monocyte induced firm adhesion under flow, as well as leukocyte recruitment to the peritoneal cavity in vivo was reduced in the 50s mutant. The binding of the 50s mutant to endothelial cells was significantly reduced as compared to the wild type protein demonstrated by ELISA. The 50s mutant had little impact on GAG binding in vitro. These data suggest that functional CCL5 presentation is mediated through both the 40s as well as the 50s loop with differential functions of the two loops of clusters of basic residues.


Updating diabetic retinopathy screening lists using automatic extraction from GP patient records.
Diabetic Retinopathy screening services aim to reduce the risk of sight loss amongst patients with diabetes. The rising incidence of diabetes in England and the operational need to ensure the accuracy and timeliness of screening lists led to a pilot study of electronic extraction of data from primary care. This study aimed to evaluate the effectiveness of updating the single collated list of patients eligible for diabetic eye screening using extracts from electronic patient records in primary care. The Gloucestershire Diabetic Eye Screening Programme (GDESP) provides screening for 85 General Practices in the county. Of these, 54 using Egton Medical Information Systems (EMIS) practice management system software agreed to participate in this study. The screening list held in 2009 by the Gloucestershire DESP of 14,209 patients known to have diabetes was audited against a list created with automatic extraction from General Practice records of patients marked with the diabetes Read Code C10. Those subsequently screened and referred to the Hospital Eye service were followed up. The Gloucestershire DESP manual list covering the 54 EMIS practices comprised 14,771 people with diabetes. The audit process identified an additional 709 (4.8%) patients coded C10, including 23 diagnosed more than 5 years ago, and 20 patients under the age of 20 who were diagnosed more than a year ago. Automatic extraction of data from General Practice identified 709 patients coded as having diabetes not previously known to the Gloucestershire DESP.


Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia.
DNA analysis was performed on 30 unrelated patients with hereditary nonspherocytic hemolytic anemia (HNSHA) who had been found to be pyruvate kinase (PK) deficient by enzyme assay. 19 different mutations were identified among 58 of the 60 alleles at risk. 13 of these were missense mutations that caused single amino acid changes. Included were the following nucleotide substitutions: 401A, 464C, 993A, 1022C, 1076A, 1178G, 1179A, 1373A, 1378A, 1456T, 1484T, 1493A, 1529A. The remaining six mutations were as follows: two nonsense mutations, 721T and 808T; a nucleotide deletion, 307C; a nucleotide insertion, 1089GG; a three nucleotide in frame deletion, 391-392-393 and a deletion of 1149 bp from the PKLR gene that resulted in the loss of exon 11. All the patients were studied for two polymorphic sites, nucleotide (nt) 1705 A/C and a microsatellite in intron 11, to better understand the origin of the mutations. The 1529A mutation, which is the most common mutation in the European population, was found in 25 alleles. With a single exception this mutation was in linkage disequilibrium with both of the polymorphic markers, i.e., found with 1705C and 14 repeats in the microsatellite. This finding is consistent with a single origin of this common mutation. Other mutations occurring more than once were of much lower frequency than the 1529A mutation.


Intra-operative touch preparation cytology; does it have a role in re-excision lumpectomy?
Breast carcinoma is the most frequently diagnosed malignancy in women of North America. The combination of breast conservation surgery and radiotherapy has become a standard of treatment for the majority of breast cancers. It is critical to obtain clear margins to minimize local recurrence. However, avoiding multiple re-excisions for margin clearance helps optimize cosmetic results in patients undergoing breast conservation surgery. Intra-operative touch preparation cytology (IOTPC) may decrease the need for multiple re-excisions and thereby improve cosmesis. The literature suggests that IOTPC can be useful in evaluation of margins. Klimberg et al. evaluated the touch preparation technique prospectively in 428 patients undergoing breast biopsy for undiagnosed breast masses. Margin evaluation was correct in 100% of the lesions and was used to re-excise the margins when touch prep results were positive. They reported a diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 100% for the touch prep technique. To the best of our knowledge, there has been no published data on the role of IOTPC for evaluation of margins in re-excision cases. This report describes our experience with IOTPC for margin assessment for re-excision partial mastectomy at Beth Israel Medical Center (BIMC). The purpose of this study is to determine whether IOTPC is reliable for evaluating margins in patients undergoing re-excision for involved or close margins. A prospective study of 30 patients, who have undergone re-excision partial mastectomy for involved or close margins after breast conservation surgery with the use of IOTPC for margin assessment at BIMC was performed. The re-excision lumpectomy specimens were oriented by the surgeon intra-operatively and were submitted fresh to pathology for cytologic assessment. The touch prep method consisted of touching the corresponding margin onto the glass slide. The principle of this technique is that if cancer cells are present they will stick to the slide, while fat cells will not. A slide was prepared for each re-excision specimen. Air-dried samples were stained immediately using the Diff-Quik method and examined under the microscope by a cytopathologist. Thirty patients underwent re-excision lumpectomy for involved or close margins with touch preparation cytology for assessment of 68 margins. Twenty-six patients had invasive ductal carcinoma and/or ductal carcinoma in situ, three patients had invasive lobular carcinoma and the remaining one patient had a combination of invasive lobular and ductal carcinoma. There was a correlation between touch prep cytology and final pathology in 56/68 margins, which accounts for 82.4% of the cases. Intra-operative touch preparation cytology for assessment of margins in patients undergoing re-excision lumpectomy for involved or close margins has a sensitivity of 75%, specificity of 82.8%, positive predictive value of 21.4%, and negative predictive value of 98.2%. This high negative predictive value and a single false negative margin are quite significant. Therefore, based on our experience, IOTPC can be a useful tool for intra-operative assessment of margins for patients undergoing re-excision partial mastectomy.


Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia.
White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.


Identifying socio-demographic and socioeconomic determinants of health inequalities in a diverse London community: the South East London Community Health (SELCoH) study.
Responses to public health need require information on the distribution of mental and physical ill health by demographic and socioeconomic factors at the local community level. The South East London Community Health (SELCoH) study is a community psychiatric and physical morbidity survey. Trained interviewers conducted face-to-face computer assisted interviews with 1698 adults aged 16 years and over, from 1076 randomly selected private households in two south London boroughs. We compared the prevalence of common mental disorders, hazardous alcohol use, long standing illness and general physical health by demographic and socioeconomic indicators. Unadjusted and models adjusted for demographic and socioeconomic indicators are presented for all logistic regression models. Of those in the sample, 24.2% reported common mental disorder and 44.9% reported having a long standing illness, with 15.7% reporting hazardous alcohol consumption and 19.2% rating their health as fair or poor. The pattern of indicators identifying health inequalities for common mental disorder, poor general health and having a long term illness is similar; individuals who are socioeconomically disadvantaged have poorer health and physical health worsens as age increases for all groups. The prevalence of poor health outcomes by ethnic group suggests that there are important differences between groups, particularly for common mental disorder and poor general health. Higher socioeconomic status was protective for common mental disorder, fair or poor health and long standing illness, but those with higher socioeconomic status reported higher levels of hazardous alcohol use. The proportion of participants who met the criteria for common mental disorder with co-occurring functional limitations was similar or greater to those with poor physical health. Health service providers and policy makers should prioritise high risk, socially defined groups in combating inequalities in individual and co-occurring poor mental and physical problems. In population terms, poor mental health has a similar or greater burden on functional impairment than long term conditions and perceived health.


Parasite evolution in response to sex-based host heterogeneity in resistance and tolerance.
Heterogenity between sexes in terms of both the level and the type of immune response to infection is documented in many species, but its role on parasite evolution is only beginning to be explored. We adopt an evolutionary epidemiology approach to study how the ability of a host to respond to infection through active immunity (resistance) or through minimizing deleterious effects of a given parasite load (tolerance) affects the evolution of parasite virulence. Consistently with earlier models, we find that increases in host resistance and tolerance both favour more virulent parasite strains. However, we show that qualitatively different results can be obtained if dimorphism between the sexes occurs through resistance or through tolerance depending on the contact pattern between the sexes. Finally, we find that variations in host sex ratio can amplify the consequences of heterogeneity for parasite evolution. These results are analysed in the light of several examples from the literature to illustrate the prevalence of sexually dimorphic immune responses and the potential for further study of the role of sexual dimorphism on parasite evolution. Such studies are likely to be highly relevant for improving treatment of chronic infections and control of infectious diseases, and understanding the role of sex in immune function.


Comparative evaluation of megadose methylprednisolone with dexamethasone for treatment of primary typical optic neuritis.
To compare the efficacy of intravenous methylprednisolone and intravenous dexamethasone on visual recovery and evaluate their side-effects for the treatment of optic neuritis. Prospective, randomized case-controlled study including 21 patients of acute optic neuritis presenting within eight days of onset and with visual acuity less then 20/60 in the affected eye who were randomly divided into two groups. Group I received intravenous dexamethasone 200 mg once daily for three days and Group II received intravenous methylprednisolone 250 mg/six-hourly for three days followed by oral prednisolone for 11 days. Parameters tested were pupillary reactions, visual acuity, fundus findings, color vision, contrast sensitivity, Goldmann visual fields and biochemical investigations for all patients at presentation and follow-up. Both groups were age and sex-matched. LOGMAR visual acuity at presentation was 1.10 +/- 0.52 in Group I and 1.52 +/- 0.43 in Group II. On day 90 of steroid therapy, visual acuity improved to 0.28 +/- 0.33 in Group I and 0.36 +/- 0.41 in Group II ( P =0.59). At three months there was no statistically significant difference in the color vision, contrast sensitivity, stereoacuity, Goldman fields and the amplitude and latency of visually evoked response between the two groups. The concentration of vitamin C, glucose, sodium, potassium, urea and creatinine were within the reported normal limits. Intravenous dexamethasone is an effective treatment for optic neuritis. However, larger studies are required to establish it as a safe, inexpensive and effective modality for the treatment of optic neuritis.


The eIF2α kinases: their structures and functions.
Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2α on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell's armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2α is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2α kinases in their kinase domains, underlying their common role in phosphorylating eIF2α, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2α kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2α kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed.


The role of positive and negative emotions in life satisfaction judgment across nations.
This study examined how the frequency of positive and negative emotions is related to life satisfaction across nations. Participants were 8,557 people from 46 countries who reported on their life satisfaction and frequency of positive and negative emotions. Multilevel analyses showed that across nations, the experience of positive emotions was more strongly related to life satisfaction than the absence of negative emotions. Yet, the cultural dimensions of individualism and survival/self-expression moderated these relationships. Negative emotional experiences were more negatively related to life satisfaction in individualistic than in collectivistic nations, and positive emotional experiences had a larger positive relationship with life satisfaction in nations that stress self-expression than in nations that value survival. These findings show how emotional aspects of the good life vary with national culture and how this depends on the values that characterize one's society. Although to some degree, positive and negative emotions might be universally viewed as desirable and undesirable, respectively, there appear to be clear cultural differences in how relevant such emotional experiences are to quality of life.


Potential genoprotective role for UDP-glucuronosyltransferases in chemical carcinogenesis: initiation of micronuclei by benzo(a)pyrene and benzo(e)pyrene in UDP-glucuronosyltransferase-deficient cultured rat skin fibroblasts.
UDP-glucuronosyltransferases (UGTs) are cytoprotective and may also be genoprotective. Since over 10% of the population have hereditary deficiencies in UGTs, this family of enzymes could constitute an important determinant of susceptibility to chemical carcinogenesis, teratogenesis, and neurodegeneration. Fibroblasts contain Phase I and II drug-metabolizing enzymes, including UGTs, and undergo mitosis, rendering them susceptible to xenobiotic genotoxicity associated with micronucleus formation, which is thought to reflect carcinogenic initiation. Accordingly, skin fibroblasts may provide an accessible model for elucidating genoprotective mechanisms in both animals and humans and for characterizing the potential role of UGTs as determinants of individual toxicological susceptibility. To test this hypothesis, the carcinogen/teratogen benzo(a)pyrene [B(a)P], or its noncarcinogenic B(e)P isomer, was incubated with cultured skin fibroblasts obtained from male RHA-J/J rats. These rats have a hereditary homozygous deficiency in bilirubin UGT and demonstrate reduced xenobiotic glucuronidation, enhanced cytochrome P-450-catalyzed bioactivation, covalent binding, and toxicity of acetaminophen and B(a)P. Control fibroblasts were cultured from UGT-normal congenic homozygous male RHA-(+/+) rats and male Wistar rats. The cells were incubated with 10 microM B(a)P or B(e)P either for assessment of micronucleus formation or for quantifying the bioactivation and covalent binding of B(a)P and the glucuronidation of its hydroxylated metabolites. Compared to control fibroblasts incubated only with buffer, micronucleus formation was not enhanced by either DMSO vehicle or B(e)P. In contrast, B(a)P significantly enhanced micronucleus formation in all cells, and UGT-deficient cells (RHA-J/J) had a > 2-fold higher B(a)P-initiated micronucleus formation compared to UGT-normal cells (RHA-(+/+)) (P < 0.05). Glucuronidation of total B(a)P metabolites was 10% lower in RHA-J/J UGT-deficient fibroblasts, and the covalent binding of B(a)P to protein, reflective of an electrophilic reactive intermediate and DNA-alkylating agent, was up to 3-fold higher in RHA-J/J UGT-deficient fibroblasts or fibroblast homogenates compared to UGT-normal controls (P < 0.05). In fibroblast homogenates, addition of the UGT cosubstrate UDP-glucuronic acid reduced B(a)P covalent binding, corroborating the cytoprotective importance of UGTs. There was a highly significant correlation between decreasing glucuronidation of B(a)P metabolites and increasing bioactivation and covalent binding of B(a)P (r = -0.889; P = 0.018) in fibroblasts from RHA-J/J and RHA-(+/+) rat strains, indicating an important genoprotective role for UGT. These results provide the first evidence that hereditary UGT deficiencies may enhance susceptibility to chemical carcinogenesis and suggest that skin fibroblasts may provide a useful and highly sensitive model for human risk assessment.


Teeth outside the mouth: The evolution and development of shark denticles.
Vertebrate skin appendages are incredibly diverse. This diversity, which includes structures such as scales, feathers, and hair, likely evolved from a shared anatomical placode, suggesting broad conservation of the early development of these organs. Some of the earliest known skin appendages are dentine and enamel-rich tooth-like structures, collectively known as odontodes. These appendages evolved over 450 million years ago. Elasmobranchs (sharks, skates, and rays) have retained these ancient skin appendages in the form of both dermal denticles (scales) and oral teeth. Despite our knowledge of denticle function in adult sharks, our understanding of their development and morphogenesis is less advanced. Even though denticles in sharks appear structurally similar to oral teeth, there has been limited data directly comparing the molecular development of these distinct elements. Here, we chart the development of denticles in the embryonic small-spotted catshark (Scyliorhinus canicula) and characterize the expression of conserved genes known to mediate dental development. We find that shark denticle development shares a vast gene expression signature with developing teeth. However, denticles have restricted regenerative potential, as they lack a sox2+ stem cell niche associated with the maintenance of a dental lamina, an essential requirement for continuous tooth replacement. We compare developing denticles to other skin appendages, including both sensory skin appendages and avian feathers. This reveals that denticles are not only tooth-like in structure, but that they also share an ancient developmental gene set that is likely common to all epidermal appendages.


PlantMetabolomics.org: a web portal for plant metabolomics experiments.
PlantMetabolomics.org (PM) is a web portal and database for exploring, visualizing, and downloading plant metabolomics data. Widespread public access to well-annotated metabolomics datasets is essential for establishing metabolomics as a functional genomics tool. PM integrates metabolomics data generated from different analytical platforms from multiple laboratories along with the key visualization tools such as ratio and error plots. Visualization tools can quickly show how one condition compares to another and which analytical platforms show the largest changes. The database tries to capture a complete annotation of the experiment metadata along with the metabolite abundance databased on the evolving Metabolomics Standards Initiative. PM can be used as a platform for deriving hypotheses by enabling metabolomic comparisons between genetically unique Arabidopsis (Arabidopsis thaliana) populations subjected to different environmental conditions. Each metabolite is linked to relevant experimental data and information from various annotation databases. The portal also provides detailed protocols and tutorials on conducting plant metabolomics experiments to promote metabolomics in the community. PM currently houses Arabidopsis metabolomics data generated by a consortium of laboratories utilizing metabolomics to help elucidate the functions of uncharacterized genes. PM is publicly available at http://www.plantmetabolomics.org.


Malaria control in the municipality of San Esteban, Honduras.
To assess the burden of malaria in San Esteban, Department of Olancho, Honduras, and provide recommendations for control. Malaria causes appreciable morbidity in San Esteban. In 2006, health workers reported an increase in malaria cases and requested recommendations for control. In 2005, 385 cases (Plasmodium vivax, 316; P. falciparum, 69) were detected from 4 007 blood smears in the San Esteban laboratory (slide positivity rate = 9.6%). During May-July 2006, we assessed the burden of malaria and made recommendations. We reviewed epidemiologic data from slide-confirmed malaria cases in 2005 and 2006 and conducted a knowledge, attitudes, and practices survey in households to assess malaria diagnostic, treatment, and prevention practices. During May-July 2006, 143 laboratory-confirmed malaria cases were detected (P. vivax, 134; P. falciparum, 9) in San Esteban, compared with 104 (P. vivax, 79; P. falciparum, 25) in May-July 2005. From January 2005 to July 2006, 538 cases were detected in San Esteban, with increased frequency in May-October and the highest incidence in children 0-14 years old. We administered 112 surveys in 19 communities. Seventy percent of respondents reported a history of malaria in a household member, with the highest frequency reported in mothers (45%) and children under 14 years old (37%). Most households did not have mosquito protection such as bed nets, screens, or indoor residual insecticide. Malaria is ongoing in San Esteban, with increased incidence in children. We recommend increased availability and promotion of insecticide-treated bed nets, improved timing and coverage of indoor residual spraying, and improved community malaria practices through education sessions.


Multiple Signal Pathways Involved in Crocetin-Induced Apoptosis in KYSE-150 Cells.
Crocetin is a carotenoid extracted from the traditional Chinese medical herb saffron. Previous studies have demonstrated that crocetin possesses anticancer properties that are effective against various cancers. As an extension of our earlier study, the present study explored the underlying mechanisms in crocetin's anticancer effect on KYSE-150 cells. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), Mitogen-activated protein kinases (MAPK), and p53/p21 signal pathways play an important role in carcinogenesis, progression, and metastasis of carcinoma cells. Thus, we investigated crocetin's effects on the PI3K/AKT, MAPK, and p53/p21 pathways in esophageal squamous carcinoma cell line KYSE-150 cells. KYSE-150 cells were treated with various concentrations of crocetin. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide assay, Annexin V/PI stain as well as Rh123 stain were used to evaluate the cell viability, apoptosis, and MMP. Western blot was used to detect the expression of PI3K, AKT, ERK1/2, p38, c-Jun NH-terminal kinase (JNK), P53, P21, Bcl-2, Bax, and cleaved caspase-3, which were associated with cell proliferation and apoptosis. Our results showed that crocetin significantly inhibited the proliferation of KYSE-150 cells in a dose- and time-dependent manner. Crocetin also markedly induced cell apoptosis. Furthermore, we have found that crocetin not only inhibited the activation of PI3K/AKT, extracellular signal-regulated kinase-1/2 (ERK1/2), and p38 but also upregulated the p53/p21 level. These regulations ultimately triggered the mitochondrial-mediated apoptosis pathway with an eventual disruption of MMP, increased levels of Bax and cleaved caspase-3, and decreased levels of Bcl-2. These findings suggested that crocetin interfered with multiple signal pathways in KYSE-150 cells. Therefore, this study suggested that crocetin could potentially be used as a therapeutic candidate for the treatment of esophageal cancer.


Physician nutrition education.
Nutrition education for physicians in the United States is limited in scope, quality, and duration due to a variety of factors. As new data and quality improvement initiatives highlight the importance of nutrition and a generation of nutrition experts retire, there is a need for new physician educators and leaders in clinical nutrition. Traditional nutrition fellowships and increased didactic lecture time in school and postgraduate training are not feasible strategies to develop the next generation of physician nutrition specialists in the current environment. One strategy is the development of short immersion courses for advanced trainees and junior attendings. The most promising courses include a combination of close mentorship and adult learning techniques such as lectures, clinical experiences, literature review, curricular development, research and writing, multidisciplinary interactions, and extensive group discussion. These courses also allow the opportunity for advanced discourse, development of long-term collaborative relationships, and continued longitudinal career development for alumni after the course ends. Despite these curricular developments, ultimately the field of nutrition will not mature until the American Board of Medical Specialties recognizes nutrition medicine with specialty board certification.


Accuracy of physician-estimated probability of brain injury in children with minor head trauma.
To evaluate the accuracy of physician estimates of the probability of intracranial injury in children with minor head trauma. This is a subanalysis of a large prospective multicentre cohort study performed from July 2001 to November 2005. During data collection for the derivation of a clinical prediction rule for children with minor head trauma, physicians indicated their estimate of the probability of brain injury visible on computed tomography (P-Injury) and the probability of injury requiring intervention (P-Intervention) by choosing one of the following options: 0%, 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, and 100%. We compared observed frequencies to expected frequencies of injury using Pearson's χ2-test in analyses stratified by the level of each type of predicted probability and by year of age. In 3771 eligible subjects, the mean predicted risk was 4.6% (P-Injury) and 1.4% (P-Intervention). The observed frequency of injury was 4.1% (any injury) and 0.6% (intervention). For all levels of P-Injury from 1% to 40%, the observed frequency of injury was consistent with the expected frequency. The observed frequencies for the 50%, 75%, and 90% levels were lower than expected (p<0.05). For estimates of P-Intervention, the observed frequency was consistently higher than the expected frequency. Physicians underestimated risk for infants (mean P-Intervention 6.2%, actual risk 12.3%, p<0.001). Physician estimates of probability of any brain injury in children were collectively accurate for children with low and moderate degrees of predicted risk. Risk was underestimated in infants.


Deep transverse friction massage for treating tendinitis.
Deep transverse friction massage (DTFM) is one of several physiotherapy interventions suggested for the management of tendinitis pain. To assess the efficacy of DTFM for treating tendinitis. We searched the MEDLINE, EMBASE, HealthSTAR, Sports Discus, CINAHL, the Cochrane Controlled Trials Register, PEDro, the specialized registry of the Cochrane musculoskeletal group and the Cochrane field of Physical and Related Therapies up to the end of June 2002. The reference list of the trials and key experts in the area were also consulted for additional studies. All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing therapeutic ultrasound with control or another active intervention in patients with all types of tendinitis, such as iliotibial band friction syndrome and extensor carpi radialis tendinitis (i.e. tennis elbow or lateral epicondylitis or lateralis epicondylitis humeri), were selected. Two reviewers determined the studies to be included based upon the inclusion and exclusion criteria (LB, VR). Data were independently abstracted by two reviewers (VR, LB), and checked by a third reviewer (BS) using a pre-developed form of the Cochrane Musculoskeletal Group. The two reviewers, using a validated checklist, assessed the methodological quality of the RCTs and CCTs independently. The pooled analysis was performed using weighted mean differences (WMDs) for continuous outcomes. One RCT included patients with ITBFS. DTFM combined with rest, stretching exercises, cryotherapy and therapeutic ultrasound was compared to the control group (rest, stretching exercises, cryotherapy and therapeutic ultrasound only). This trial showed no statistical difference in the three types of pain relief measured after four consecutive sessions of DTFM combined with other physiotherapy modalities for runners. There was a clinically important relative percentage difference in pain while running of 22%. A RCT on ECRT showed no statistical difference in pain relief, grip strength and the three types of functional status measured after 9 consecutive sessions within 5 weeks of DTFM compared with other physiotherapy modalities. DTFM combined with other physiotherapy modalities did not show consistent benefit over the control of pain, or improvement of grip strength and functional status for patients with ITBFS or for patients with ECRT. These conclusions are limited by the small sample size of the included RCTs. No conclusions can be drawn concerning the use or non use of DTFM for the treatment of ITBFS. Future trials, utilizing specific ITBFS methods and adequate sample sizes are needed, before conclusions can be drawn regarding the specific effect of DTFM on tendinitis.


Time course of insulin resistance associated with feeding dogs a high-fat diet.
The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.


Identification of a lineage of multipotent hematopoietic progenitors.
All multipotent hematopoietic progenitors in C57BL-Thy-1.1 bone marrow are divided among three subpopulations of Thy-1.1(lo) Sca-1+ Lin(-/lo) c-kit+ cells: long-term reconstituting Mac-1- CD4- c-kit+ cells and transiently reconstituting Mac-1(lo) CD4- or Mac-1(lo) CD4(lo) cells. This study shows that the same populations, with similar functional activities, exist in mice whose hematopoietic systems were reconstituted by hematopoietic stem cells after lethal irradiation. We demonstrate that these populations form a lineage of multipotent progenitors from long-term self-renewing stem cells to the most mature multipotent progenitor population. In reconstituted mice, Mac-1- CD4- c-kit+ cells gave rise to Mac-1(lo) CD4- cells, which gave rise to Mac-1(lo) CD4(lo) cells. Mac-1- CD4- c-kit+ cells had long-term self-renewal potential, with each cell being capable of giving rise to more than 10(4) functionally similar Mac-1- CD4- c-kit+ cells. At least half of Mac-1(lo) CD4- cells had transient self-renewal potential, detected in the spleen 7 days after reconstitution. Mac-1(lo) CD4(lo) cells did not have detectable self-renewal potential. The identification of a lineage of multipotent progenitors provides an important tool for identifying genes that regulate self-renewal and lineage commitment.