A Markov Random Field Groupwise Registration Framework for Face Recognition.
In this paper, we propose a new framework for tackling face recognition problem. The face recognition problem is formulated as groupwise deformable image registration and feature matching problem. The main contributions of the proposed method lie in the following aspects: (1) Each pixel in a facial image is represented by an anatomical signature obtained from its corresponding most salient scale local region determined by the survival exponential entropy (SEE) information theoretic measure. (2) Based on the anatomical signature calculated from each pixel, a novel Markov random field based groupwise registration framework is proposed to formulate the face recognition problem as a feature guided deformable image registration problem. The similarity between different facial images are measured on the nonlinear Riemannian manifold based on the deformable transformations. (3) The proposed method does not suffer from the generalizability problem which exists commonly in learning based algorithms. The proposed method has been extensively evaluated on four publicly available databases: FERET, CAS-PEAL-R1, FRGC ver 2.0, and the LFW. It is also compared with several state-of-the-art face recognition approaches, and experimental results demonstrate that the proposed method consistently achieves the highest recognition rates among all the methods under comparison.


European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate due to publication of more relevant papers. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30(th), 2009. All pertinent papers were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (level A recommendation). Normative reference values are available for bright-field immunohistochemistry (level A recommendation) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (level A recommendation). Newly established laboratories should undergo adequate training in a well established skin biopsy laboratory and provide their own stratified age and gender-matched normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (level B recommendation). A reduced IENF density is associated with the risk of developing neuropathic pain (level B recommendation), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (level C recommendation). However, further studies are warranted to confirm the potential usefulness of skin biopsy with measurement of IENF density as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35,000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice Point).


Optimization of 4D vessel-selective arterial spin labeling angiography using balanced steady-state free precession and vessel-encoding.
Vessel-selective dynamic angiograms provide a wealth of useful information about the anatomical and functional status of arteries, including information about collateral flow and blood supply to lesions. Conventional x-ray techniques are invasive and carry some risks to the patient, so non-invasive alternatives are desirable. Previously, non-contrast dynamic MRI angiograms based on arterial spin labeling (ASL) have been demonstrated using both spoiled gradient echo (SPGR) and balanced steady-state free precession (bSSFP) readout modules, but no direct comparison has been made, and bSSFP optimization over a long readout period has not been fully explored. In this study bSSFP and SPGR are theoretically and experimentally compared for dynamic ASL angiography. Unlike SPGR, bSSFP was found to have a very low ASL signal attenuation rate, even when a relatively large flip angle and short repetition time were used, leading to a threefold improvement in the measured signal-to-noise ratio (SNR) efficiency compared with SPGR. For vessel-selective applications, SNR efficiency can be further improved over single-artery labeling methods by using a vessel-encoded pseudo-continuous ASL (VEPCASL) approach. The combination of a VEPCASL preparation with a time-resolved bSSFP readout allowed the generation of four-dimensional (4D; time-resolved three-dimensional, 3D) vessel-selective cerebral angiograms in healthy volunteers with 59 ms temporal resolution. Good quality 4D angiograms were obtained in all subjects, providing comparable structural information to 3D time-of-flight images, as well as dynamic information and vessel selectivity, which was shown to be high. A rapid 1.5 min dynamic two-dimensional version of the sequence yielded similar image features and would be suitable for a busy clinical protocol. Preliminary experiments with bSSFP that included the extracranial vessels showed signal loss in regions of poor magnetic field homogeneity. However, for intracranial vessel-selective angiography, the proposed bSSFP VEPCASL sequence is highly SNR efficient and could provide useful information in a range of cerebrovascular diseases. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.


Random-hole optical fiber evanescent-wave gas sensing.
Research on development of optical gas sensors based on evanescent-wave absorption in random-hole optical fibers is described. A process to produce random-hole optical fibers was recently developed that uses a novel in situ bubble formation technique. Gas molecules that exhibit characteristic vibrational absorption lines in the near-IR region that correspond to the transmission window for silica optical fiber have been detected through the evanescent field of the guided mode in the pore region. The presence of the gas molecules in the holes of the fiber appears as a loss at wavelengths that are characteristic of the particular gas species present in the holes. An experimental setup was constructed with these holey fibers for detection of acetylene gas. The results clearly demonstrate the characteristic absorptions in the optical spectra that correspond to the narrow-line absorptions of the acetylene gas, and this represents what is to our knowledge the first report of random-hole fiber gas sensing in the literature.


Associations between reduced diffusing capacity and airflow obstruction in community-based subjects.
The purpose of this analysis was to determine if abnormal diffusing capacity of the lung for carbon monoxide (DLco) identified a group of subjects with significantly different characteristics than those with normal lung function or airflow obstruction alone. Participants were a random sample of adults aged 45-70 years. They completed a detailed respiratory questionnaire, spirometry, methacholine challenge and measurement of single breath DLco. Subjects were categorized into one of three groups: airflow obstruction only, reduced DLco only, or both airflow obstruction and reduced DLco. Individuals with airflow obstruction and reduced DLco in combination reported more symptoms than those with either condition alone. In subjects with a combination of both airflow obstruction and reduced DLco, a significantly higher proportion reported use of medication and laboratory tests. Current smoking was significantly associated with a reduced DLco alone and in combination with airflow obstruction, however, the association was stronger in those with DLco and airflow obstruction. Bronchial hyperreactivity (BHR) was found to be a risk factor while atopy was associated with a reduced risk of DLco and airflow obstruction. Reduced DLco plus airflow obstruction together identifies a group of individuals with significantly more symptoms and worse lung function. Current cigarette smoking, early life serious respiratory infection and BHR were strongly associated with reduced DLco in combination with airflow obstruction.


Deficits in discrimination after experimental frontal brain injury are mediated by motivation and can be improved by nicotinamide administration.
One of the largest challenges in experimental neurotrauma work is the development of models relevant to the human condition. This includes both creating similar pathophysiology as well as the generation of relevant behavioral deficits. Recent studies have shown that there is a large potential for the use of discrimination tasks in rats to detect injury-induced deficits. The literature on discrimination and TBI is still limited, however. The current study investigated motivational and motor factors that could potentially contribute to deficits in discrimination. In addition, the efficacy of a neuroprotective agent, nicotinamide, was assessed. Rats were trained on a discrimination task and motivation task, given a bilateral frontal controlled cortical impact TBI (+3.0 AP, 0.0 ML from bregma), and then reassessed. They were also assessed on motor ability and Morris water maze (MWM) performance. Experiment 1 showed that TBI resulted in large deficits in discrimination and motivation. No deficits were observed on gross motor measures; however, the vehicle group showed impairments in fine motor control. Both injured groups were impaired on the reference memory MWM, but only nicotinamide-treated rats were impaired on the working memory MWM. Nicotinamide administration improved performance on discrimination and motivation measures. Experiment 2 evaluated retraining on the discrimination task and suggested that motivation may be a large factor underlying discrimination deficits. Retrained rats improved considerably on the discrimination task. The tasks evaluated in this study demonstrate robust deficits and may improve the detection of pharmaceutical effects by being very sensitive to pervasive cognitive deficits that occur after frontal TBI.


Milk quality control: instant and quantitative milk fat determination with a BODIPY sensor-based fluorescence detector.
The first fluorescent sensor for milk fat was developed. It exhibited a magnificent, yet selective turn-on feature towards fat molecules in a complicated milk matrix by a disaggregation-induced emission mechanism. Further construction of a handy fluorescence milk fat detector provided a convenient rapid tool to measure the fat amount quantitatively. This discovery may help enhance the milk quality control process.


Evidence-based current surgical practice: calculous gallbladder disease.
Gallbladder disease is common and, if managed incorrectly, can lead to high rates of morbidity, mortality, and extraneous costs. The most common complications of gallstones include biliary colic, acute cholecystitis, common bile duct stones, and gallstone pancreatitis. Ultrasound is the initial imaging modality of choice. Additional diagnostic and therapeutic studies including computed tomography, magnetic resonance imaging, magnetic resonance cholangiopancreatography, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography are not routinely required but may play a role in specific situations. Biliary colic and acute cholecystitis are best treated with early laparoscopic cholecystectomy. Patients with common bile duct stones should be managed with cholecystectomy, either after or concurrent with endoscopic or surgical relief of obstruction and clearance of stones from the bile duct. Mild gallstone pancreatitis should be treated with cholecystectomy during the initial hospitalization to prevent recurrence. Emerging techniques for cholecystectomy include single-incision laparoscopic surgery and natural orifice transluminal endoscopic surgery. Early results in highly selected patients demonstrate the safety of these techniques. The management of complications of the gallbladder should be timely and evidence-based, and choice of procedures, particularly for common bile duct stones, is largely influenced by facility and surgeon factors.


Contribution of subregions of human frontal cortex to novelty processing.
Novelty processing was studied in patients with lesions centered in either OFC or lateral pFC (LPFC). An auditory novelty oddball ERP paradigm was applied with environmental sounds serving as task irrelevant novel stimuli. Lesions to the LPFC as well as the OFC resulted in a reduction of the frontal Novelty P3 response, supporting a key role of both frontal subdivisions in novelty processing. The posterior P3b to target sounds was unaffected in patients with frontal lobe lesions in either location, indicating intact posterior cortical target detection mechanisms. LPFC patients displayed an enhanced sustained negative slow wave (NSW) to novel sounds not observed in OFC patients, indicating prolonged resource allocation to task-irrelevant stimuli after LPFC damage. Both patient groups displayed an enhanced NSW to targets relative to controls. However, there was no difference in behavior between patients and controls suggesting that the enhanced NSW to targets may index an increased resource allocation to response requirements enabling comparable performance in the frontal lesioned patients. The current findings indicate that the LPFC and OFC have partly shared and partly differential contributions to the cognitive subcomponents of novelty processing.


Quantitative Photoacoustic Image Reconstruction using Fluence Dependent Chromophores.
In biomedical photoacoustic imaging the images are proportional to the absorbed optical energy density, and not the optical absorption, which makes it difficult to obtain a quantitatively accurate image showing the concentration of a particular absorbing chromophore from photoacoustic measurements alone. Here it is shown that the spatially varying concentration of a chromophore whose absorption becomes zero above a threshold light fluence can be estimated from photoacoustic images obtained at increasing illumination strengths. This technique provides an alternative to model-based multiwavelength approaches to quantitative photoacoustic imaging, and a new approach to photoacoustic molecular and functional imaging.


CBFS: high performance feature selection algorithm based on feature clearness.
The goal of feature selection is to select useful features and simultaneously exclude garbage features from a given dataset for classification purposes. This is expected to bring reduction of processing time and improvement of classification accuracy. In this study, we devised a new feature selection algorithm (CBFS) based on clearness of features. Feature clearness expresses separability among classes in a feature. Highly clear features contribute towards obtaining high classification accuracy. CScore is a measure to score clearness of each feature and is based on clustered samples to centroid of classes in a feature. We also suggest combining CBFS and other algorithms to improve classification accuracy. From the experiment we confirm that CBFS is more excellent than up-to-date feature selection algorithms including FeaLect. CBFS can be applied to microarray gene selection, text categorization, and image classification.


Coupled-resonator-induced reflection in photonic-crystal waveguide structures.
We study the resonant transmission of light in a coupled-resonator optical waveguide interacting with two nearly identical side cavities. We reveal and describe a novel effect of the coupled-resonator-induced reflection (CRIR) characterized by a very high and easily tunable quality factor of the reflection line, for the case of the inter-site coupling between the cavities and the waveguide. This effect differs sharply from the coupled-resonator-induced transparency (CRIT)--an all-optical analogue of the electromagnetically-induced transparency--which has recently been studied theoretically and experimentally for the structures based on micro-ring resonators and photonic crystal cavities. Both CRIR and CRIT effects have the same physical origin which can be attributed to the Fano-Feshbach resonances in the systems exhibiting more than one resonance. We discuss the applicability of the novel CRIR effect to the control of the slow-light propagation and low-threshold all-optical switching.


GMTR: two-dimensional geo-fit multitarget retrieval model for michelson interferometer for passive atmospheric sounding/environmental satellite observations.
We present a new retrieval model designed to analyze the observations of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS), which is on board the ENVironmental SATellite (ENVISAT). The new geo-fit multitarget retrieval model (GMTR) implements the geo-fit two-dimensional inversion for the simultaneous retrieval of several targets including a set of atmospheric constituents that are not considered by the ground processor of the MIPAS experiment. We describe the innovative solutions adopted in the inversion algorithm and the main functionalities of the corresponding computer code. The performance of GMTR is compared with that of the MIPAS ground processor in terms of accuracy of the retrieval products. Furthermore, we show the capability of GMTR to resolve the horizontal structures of the atmosphere. The new retrieval model is implemented in an optimized computer code that is distributed by the European Space Agency as "open source" in a package that includes a full set of auxiliary data for the retrieval of 28 atmospheric targets.


The Resilience of Life to Astrophysical Events.
Much attention has been given in the literature to the effects of astrophysical events on human and land-based life. However, little has been discussed on the resilience of life itself. Here we instead explore the statistics of events that completely sterilise an Earth-like planet with planet radii in the range 0.5-1.5R ⊕ and temperatures of ∼300 K, eradicating all forms of life. We consider the relative likelihood of complete global sterilisation events from three astrophysical sources - supernovae, gamma-ray bursts, large asteroid impacts, and passing-by stars. To assess such probabilities we consider what cataclysmic event could lead to the annihilation of not just human life, but also extremophiles, through the boiling of all water in Earth's oceans. Surprisingly we find that although human life is somewhat fragile to nearby events, the resilience of Ecdysozoa such as Milnesium tardigradum renders global sterilisation an unlikely event.


Vitamin C is an essential antioxidant that enhances survival of oxidatively stressed human vascular endothelial cells in the presence of a vast molar excess of glutathione.
Cellular glutathione levels may exceed vitamin C levels by 10-fold, generating the question about the real antioxidant role that low intracellular concentrations of vitamin C can play in the presence of a vast molar excess of glutathione. We characterized the metabolism of vitamin C and its relationship with glutathione in primary cultures of human endothelial cells oxidatively challenged by treatment with hydrogen peroxide or with activated cells undergoing the respiratory burst, and analyzed the manner in which vitamin C interacts with glutathione to increase the antioxidant capacity of cells. Our data indicate that: (i) endothelial cells express transporters for reduced and oxidized vitamin C and accumulate ascorbic acid with participation of glutathione-dependent dehydroascorbic acid reductases, (ii) although increased intracellular levels of vitamin C or glutathione caused augmented resistance to oxidative stress, 10-times more glutathione than vitamin C was required, (iii) full antioxidant protection required the simultaneous presence of intracellular and extracellular vitamin C at concentrations normally found in vivo, and (iv) intracellular vitamin C cooperated in enhancing glutathione recovery after oxidative challenge thus providing cells with enhanced survival potential, while extracellular vitamin C was recycled through a mechanism involving the simultaneous neutralization of oxidant species. Therefore, in endothelial cells under oxidative challenge, vitamin C functions as an essential cellular antioxidant even in the presence of a vast molar excess of glutathione.


The societal monetary value of a QALY associated with EQ-5D-3L health gains.
There is an extensive body of empirical research that focuses on the societal monetary value of a quality-adjusted life year (MVQALY). Many of these studies have found the estimates to be inversely associated with the size of the health gain, and thus not conforming to the linearity assumption imposed in the QALY model. In this study, we explore the extent to which the MVQALY varies when it is associated with different types and magnitudes of quality of life (QoL) improvements. To allow for a comprehensive assessment, we derive the MVQALY corresponding to the full spectrum of health gains defined by the EQ-5D-3L instrument. The analysis was based on a large and representative sample of the population in Spain. A discrete choice experiment and a time trade-off exercise were used to derive a value set for utilities, followed by a willingness to pay questionnaire. The data were jointly analysed using regression analyses and bootstrapping techniques. Our findings indicate that societal values for a QALY corresponding to different EQ-5D-3L health gains vary approximately between 10,000€ and 30,000€. MVQALY associated with larger improvements on QoL was found to be lower than that associated with moderate QoL gains. The potential sources of the observed non-constant MVQALY are discussed.


Prism adaptation does not alter object-based attention in healthy participants.
Hemispatial neglect ('neglect') is a disabling condition that can follow damage to the right side of the brain, in which patients show difficulty in responding to or orienting towards objects and events that occur on the left side of space. Symptoms of neglect can manifest in both space- and object-based frames of reference. Although patients can show a combination of these two forms of neglect, they are considered separable and have distinct neurological bases. In recent years considerable evidence has emerged to demonstrate that spatial symptoms of neglect can be reduced by an intervention called prism adaptation. Patients point towards objects viewed through prismatic lenses that shift the visual image to the right. Approximately five minutes of repeated pointing results in a leftward recalibration of pointing and improved performance on standard clinical tests for neglect. The understanding of prism adaptation has also been advanced through studies of healthy participants, in whom adaptation to leftward prismatic shifts results in temporary neglect-like performance. Here we examined the effect of prism adaptation on the performance of healthy participants who completed a computerised test of space- and object-based attention. Participants underwent adaptation to leftward- or rightward-shifting prisms, or performed neutral pointing according to a between-groups design. Significant pointing after-effects were found for both prism groups, indicating successful adaptation. In addition, the results of the computerised test revealed larger reaction-time costs associated with shifts of attention between two objects compared to shifts of attention within the same object, replicating previous work. However there were no differences in the performance of the three groups, indicating that prism adaptation did not influence space- or object-based attention for this task. When combined with existing literature, the results are consistent with the proposal that prism adaptation may only perturb cognitive functions for which normal baseline performance is already biased.


Stimulus selectivity and spatial coherence of gamma components of the local field potential.
The gamma frequencies of the local field potential (LFP) provide a physiological correlate for numerous perceptual and cognitive phenomena and have been proposed to play a role in cortical function. Understanding the spatial extent of gamma and its relationship to spiking activity is critical for interpreting this signal and elucidating its function, but previous studies have provided widely disparate views of these properties. We addressed these issues by simultaneously recording LFPs and spiking activity using microelectrode arrays implanted in the primary visual cortex of macaque monkeys. We find that the spatial extent of gamma and its relationship to local spiking activity is stimulus dependent. Small gratings, and those masked with noise, induce a broadband increase in spectral power. This signal is tuned similarly to spiking activity and has limited spatial coherence. Large gratings, however, induce a gamma rhythm characterized by a distinctive spectral "bump," which is coherent across widely separated sites. This signal is well tuned, but its stimulus preference is similar across millimeters of cortex. The preference of this global gamma rhythm is sensitive to adaptation, in a manner consistent with its magnifying a bias in the neuronal representation of visual stimuli. Gamma thus arises from two sources that reflect different spatial scales of neural ensemble activity. Our results show that there is not a single, fixed ensemble contributing to gamma and that the selectivity of gamma cannot be used to infer its spatial extent.


Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA.
Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers.


Sizing up the market for assisted living.
Assisted living has emerged as an important housing and long-term care option for older Americans. To date, development of this sector has occurred largely without government financing or regulation. In this study we used primary data that we collected on county-level assisted living supply to gain a fuller understanding of this sector nationally. Reflecting their reliance on private resources, assisted living facilities are located disproportionately in areas with higher educational attainment, income, and housing wealth. As this sector evolves, policymakers will have to contend with issues related to access to services, public financing, quality of care, and regulatory oversight.


Candidalysins Are a New Family of Cytolytic Fungal Peptide Toxins.
Candidalysin is the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is secreted by Candida albicans and is critical for driving infection and host immune responses in several model systems. However, Candida infections are also caused by non-C. albicans species. Here, we identify and characterize orthologs of C. albicans candidalysin in C. dubliniensis and C. tropicalis. The candidalysins have different amino acid sequences, are amphipathic, and adopt a predominantly α-helical secondary structure in solution. Comparative functional analysis demonstrates that each candidalysin causes epithelial damage and calcium influx and activates intracellular signaling pathways and cytokine secretion. Importantly, C. dubliniensis and C. tropicalis candidalysins have higher damaging and activation potential than C. albicans candidalysin and exhibit more rapid membrane binding and disruption, although both fungal species cause less damage to epithelial cells than C. albicans. This study identifies the first family of peptide cytolysins in human-pathogenic fungi. IMPORTANCE Pathogenic fungi kill an estimated 1.5 million people every year. Recently, we discovered that the fungal pathogen Candida albicans secretes a peptide toxin called candidalysin during mucosal infection. Candidalysin causes damage to host cells, a process that supports disease progression. However, fungal infections are also caused by Candida species other than C. albicans. In this work, we identify and characterize two additional candidalysin toxins present in the related fungal pathogens C. dubliniensis and C. tropicalis. While the three candidalysins have different amino acid sequences, all three toxins are α-helical and amphipathic. Notably, the candidalysins from C. dubliniensis and C. tropicalis are more potent at inducing cell damage, calcium influx, mitogen-activated protein kinase signaling, and cytokine responses than C. albicans candidalysin, with the C. dubliniensis candidalysin having the most rapid membrane binding kinetics. These observations identify the candidalysins as the first family of peptide toxins in human-pathogenic fungi.


Regeneration after stroke: Stem cell transplantation and trophic factors.
Stroke is a leading cause of death and disability worldwide. However, there is only one Food and Drug Administration-approved drug for the treatment of ischemic stroke, i.e., tissue plasminogen activator, and its therapeutic window is limited to within 4.5 h after stroke. Since clinical trials for neuroprotection have failed to demonstrate efficacy, multipotent and pluripotent stem cell transplantations are viable candidates for stroke treatment by providing trophic factor support and/or cell replacement following injury. The goal of this review is to highlight the promise of stem cell transplantation as vehicles for trophic factor delivery. The beneficial effects of different stem cell types as transplants as well as ways to upregulate trophic factors in stem cells are described in this review. Stem cell transplantation has consistently shown beneficial effects in the ischemic stroke model, in part due to the beneficial factors that stem cells release around the stroke injury area, resulting in smaller infarct volumes and regeneration and functional recovery. Upregulation of beneficial factors in stem cells and neural progenitors before transplantation has been shown to be even more effective in treating the stroke injury than stem cells without upregulated factors. However, for both stem cells and genetic engineering, there remain many unanswered questions and potential for improvement. These include modifiable parameters such as the different stem cell types and different factors, as well as the various readouts for investigation, such as various in vivo effects, such as immune system modulation and enhancement of endogenous neurogenesis and angiogenesis.


MANAGEMENT AND OUTCOMES OF GIANT PROLACTINOMA: A SERIES OF 71 PATIENTS.
Objective: To describe outcomes of patients with giant prolactinoma (≥4 cm) and identify predictors of therapeutic response. Methods: In this retrospective study, complete biochemical and structural response were defined as prolactin (PRL) ≤25 ng/mL and no visible tumor at follow-up, respectively. Results: Giant prolactinoma (median size, 4.8 cm [range, 4 to 9.8 cm]; median PRL, 5,927 ng/mL [range, 120 to 100,000 ng/mL]) was diagnosed in 71 patients. Treatments included: dopamine agonists (DAs) (n = 70, 99%), surgery (n = 30, 42%), radiation (n = 10, 14%), and somatostatin analogs (n = 2, 3%). Patients treated with DA monotherapy were older compared with those who received subsequent therapies (47 years vs. 28 years; P = .003) but had similar initial PRL and tumor size. Surgically managed patients were younger compared with the nonsurgical group (35 years vs. 46 years; P = .02) and had lower initial PRL (3,121 ng/mL vs. 6,920 ng/mL; P = .02), yet they had similar tumor response. Hypopituitarism was more common following surgery compared to medical management: adrenal insufficiency (69% vs. 27%; P<.001), hypothyroidism (67% vs. 38%; P = .02), growth hormone deficiency (24% vs. 6%; P = .04), and diabetes insipidus (17% vs. 3%; P = .04). Therapeutic response did not correlate with sex, age, initial PRL, tumor size, or first-line therapy mode. At median follow-up of 4.8 years, the median PRL was 18.3 ng/mL (range, 0.6 to 12,680 ng/mL), and final volume was 0.9 cm3 (range, 0 to 43.0 cm3). In those with available data, 36/65 (55%) patients achieved PRL normalization, and 16/61 (26%) had no visible tumor at follow-up. Conclusion: Most patients with giant prolactinoma have excellent response to DA. Sex, age, initial PRL, and tumor size do not predict therapeutic response. Abbreviations: BRC = bromocriptine; CAB = cabergoline; CSF = cerebrospinal fluid; DA = dopamine agonist; MRI = magnetic resonance imaging; PRL = prolactin.


Antibiotic activity in vitro against methicillin-resistant Staphylococcus epidermidis and therapy of an experimental infection.
Staphylococcus epidermidis is a major pathogen in early prosthetic valve endocarditis and cerebrospinal fluid shunt infections. Approximately 10 to 15% of hospital isolates are methicillin resistant. Ten clinically significant isolates of the latter were collected for antibiotic studies in vitro and in an experimental infection in animals. Time-kill studies of five strains showed gentamicin to be the single most effective antibiotic; however, dwarf colony variants emerged as survivors with two of these strains when challenged with gentamicin alone. The addition of a second antibiotic to gentamicin did not significantly improve the bactericidal rate but prevented the emergence of variant strains. A blood culture isolate of methicillin-resistant S. epidermidis combined with 5% hog gastric mucin was used to establish an experimental intraperitoneal infection in mice. Neither methicillin nor nafcillin treatment reduced mortality below that of untreated animals. Cephalothin treatment delayed early mortality but did not diminish overall mortality. Gentamicin was the most effective single antibiotic, and gentamicin in combination with vancomycin was the most effective regimen overall. The combination of rifampin plus vancomycin was as effective as gentamicin alone. The combinations of cephalothin or nafcillin with gentamicin and cephalothin with vancomycin demonstrated antagonism. The antagonism was not due to multiple injections or drug-drug inactivation.


Primary neuroendocrine tumour of the breast: a case report and review of the literature.
Primary neuroendocrine tumour of the breast is a rare entity that first appeared in the 2003 World Health Organisation (WHO) classification of breast tumours. The data currently available on its prognosis are contradictory, although it seems clear that histological varieties such as small cell neuroendocrine carcinoma have a worse prognosis, due to their low degree of differentiation. The treatment of choice is surgery, and the indications for chemotherapy or radiotherapy do not differ greatly from those used for other breast tumours. It is crucial to underline the difficulty of establishing treatment protocols due to the low incidence of this histological type.


Regional and temporal specialization in the nucleus: a transcriptionally-active nuclear domain rich in PTF, Oct1 and PIKA antigens associates with specific chromosomes early in the cell cycle.
PTF (PSE-binding transcription factor) activates transcription of snRNA and related genes. We investigated its distribution in HeLa nuclei by immunofluorescence, and found it spread throughout the nucleoplasm in small foci. In some cells, PTF is also concentrated in one, or very few, discrete regions (diameter approximately 1.3 micron) that appear during G1 phase and disappear in S phase. Oct1, a transcription factor that interacts with PTF, is also enriched in these domains; RNA polymerase II, TBP and Sp1 are also present. Each domain typically contains 2 or 3 transcription 'factories' where Br-UTP is incorporated into nascent transcripts. Accordingly, we have christened this region the Oct1/PTF/transcription (OPT) domain. It colocalizes with some, but not all, PIKA domains. It is distinct from other nuclear domains, including coiled bodies, gemini bodies, PML bodies and the perinucleolar compartment. A small region on chromosome 6 (band 6p21) containing only approximately 30 Mbp DNA, and chromosomes 6 and 7, associate with the domain significantly more than other chromosomes. The domains may act like nucleoli to bring particular genes on specific chromosomes together to a region where the appropriate transcription and processing factors are concentrated, thereby facilitating the expression of those genes.


Nascent-Seq reveals novel features of mouse circadian transcriptional regulation.
A substantial fraction of the metazoan transcriptome undergoes circadian oscillations in many cells and tissues. Based on the transcription feedback loops important for circadian timekeeping, it is commonly assumed that this mRNA cycling reflects widespread transcriptional regulation. To address this issue, we directly measured the circadian dynamics of mouse liver transcription using Nascent-Seq (genome-wide sequencing of nascent RNA). Although many genes are rhythmically transcribed, many rhythmic mRNAs manifest poor transcriptional rhythms, indicating a prominent contribution of post-transcriptional regulation to circadian mRNA expression. This analysis of rhythmic transcription also showed that the rhythmic DNA binding profile of the transcription factors CLOCK and BMAL1 does not determine the transcriptional phase of most target genes. This likely reflects gene-specific collaborations of CLK:BMAL1 with other transcription factors. These insights from Nascent-Seq indicate that it should have broad applicability to many other gene expression regulatory issues.DOI:http://dx.doi.org/10.7554/eLife.00011.001.


Comparisons of different regressions tools in measurement of antioxidant activity in green tea using near infrared spectroscopy.
To rapidly and efficiently measure antioxidant activity (AA) in green tea, near infrared (NIR) spectroscopy was employed with the help of a regression tool in this work. Three different linear and nonlinear regressions tools (i.e. partial least squares (PLS), back propagation artificial neural network (BP-ANN), and support vector machine regression (SVMR)), were systemically studied and compared in developing the model. The model was optimized by a leave-one-out cross-validation, and its performance was tested according to root mean square error of prediction (RMSEP) and correlation coefficient (R(p)) in the prediction set. Experimental results showed that the performance of SVMR model was superior to the others, and the optimum results of the SVMR model were achieved as follow: RMSEP=0.02161 and R(p)=0.9691 in the prediction set. The overall results sufficiently demonstrate that the spectroscopy coupled with the SVMR regression tool has the potential to measure AA in green tea.


Cyclin specificity: how many wheels do you need on a unicycle?
Cyclin-dependent kinase (CDK) activity is essential for eukaryotic cell cycle events. Multiple cyclins activate CDKs in all eukaryotes, but it is unclear whether multiple cyclins are really required for cell cycle progression. It has been argued that cyclins may predominantly act as simple enzymatic activators of CDKs; in opposition to this idea, it has been argued that cyclins might target the activated CDK to particular substrates or inhibitors. Such targeting might occur through a combination of factors, including temporal expression, protein associations, and subcellular localization.


Electrically tunable high Q-factor micro-ring resonator based on blue phase liquid crystal cladding.
This work demonstrates an electrically tunable silicon nitride (SiN) micro-ring resonator with polymer-stabilized blue phase liquid crystals (PSBPLCs) cladding. An external vertical electric field is applied to modulate the refractive index of the PSBPLCs by exploiting its fast-response Kerr effect-induced birefringence. The consequent change in the refractive index of the cladding can vary the effective refractive index of the micro-ring resonator and shift the resonant wavelength. Crystalline structures of PSBPLCs with a scale of the order of hundreds of nanometers ensure that the resonator has a very low optical loss. The measured tuning range is 0.45 nm for TM polarized light under an applied voltage of 150V and the corresponding response time is in the sub-millisecond range with a Q-factor of greater than 20,000.


Influence of Feeding Types during the First Months of Life on Calciuria Levels in Healthy Infants: A Secondary Analysis from a Randomized Clinical Trial.
Dietary factors can modify calciuria. We aim to investigate urinary calcium excretion in healthy infants according to their protein. Secondary data analysis from a randomized clinical trial where healthy term infants were randomized after birth to a higher (HP) or lower (LP) protein content formula that was consumed until age 1 year. A non-randomized group of breastfed (BF) infants was used for reference. Anthropometry, dietary intakes and calciuria (calcium/creatinine ratios) from spot urine samples were assessed at ages 3 and 6 months. At 6 months, the kidney volumes were assessed using ultrasonography, and the serum urea and creatinine levels were determined. BF infants showed the highest calciuria levels, followed by the HP and the LP groups (p < 0.001 for all comparisons). Either protein intakes or formula types modulated the calciuria in linear regression models adjusted for other influencing dietary factors. The usual cut-off values classified 37.8% (BF), 16.8% (HP) and 4.9% (LP) of the infants as hypercalciuric. Feeding types during the first months of life affect calciuria, with BF infants presenting the highest levels. We propose new cut-off values, based on feeding types, to prevent the overestimation in hypercalciuria diagnoses among BF infants.


Topical cyclosporine 0.05% for the prevention of dry eye disease progression.
To assess the prognosis of dry eye in patients treated with cyclosporine 0.05% or artificial tears by using the International Task Force (ITF) guidelines. This was a single-center, investigator-masked, prospective, randomized, longitudinal trial. Dry eye patients received twice-daily treatment with either cyclosporine 0.05% (Restasis; Allergan, Inc., Irvine, CA; n = 36) or artificial tears (Refresh Endura; Allergan, Inc., Irvine, CA; n = 22) for 12 months. Disease severity was determined at baseline and month 12 according to the consensus guidelines developed by the ITF. Dry eye signs and symptoms were evaluated at baseline and months 4, 8, and 12. Baseline sign and symptom scores and the proportion of patients with the disease severity level 2 or 3 were comparable in both groups (P > 0.05). At month 12, 34 of 36 cyclosporine patients (94%) and 15 of 22 artificial tear patients (68%) experienced improvements or no change in their disease severity (P = 0.007) while 2 of 36 cyclosporine patients (6%) and 7 of 22 artificial tears patients (32%) had disease progression (P < 0.01). Cyclosporine 0.05% improved Schirmer test scores, tear breakup time, and Ocular Surface Disease Index scores throughout the study, with significant (P < 0.01) differences compared with artificial tears being observed at months 8 and 12. Treatment with cyclosporine 0.05% may slow or prevent disease progression in patients with dry eye at severity levels 2 or 3.


Cognitive behaviour therapy for chronic fatigue syndrome in adults.
Chronic fatigue syndrome (CFS) is a common, debilitating and serious health problem. Cognitive behaviour therapy (CBT) may help to alleviate the symptoms of CFS. To examine the effectiveness and acceptability of CBT for CFS, alone and in combination with other interventions, compared with usual care and other interventions. CCDANCTR-Studies and CCDANCTR-References were searched on 28/3/2008. We conducted supplementary searches of other bibliographic databases. We searched reference lists of retrieved articles and contacted trial authors and experts in the field for information on ongoing/completed trials. Randomised controlled trials involving adults with a primary diagnosis of CFS, assigned to a CBT condition compared with usual care or another intervention, alone or in combination. Data on patients, interventions and outcomes were extracted by two review authors independently, and risk of bias was assessed for each study. The primary outcome was reduction in fatigue severity, based on a continuous measure of symptom reduction, using the standardised mean difference (SMD), or a dichotomous measure of clinical response, using odds ratios (OR), with 95% confidence intervals (CI). Fifteen studies (1043 CFS participants) were included in the review. When comparing CBT with usual care (six studies, 373 participants), the difference in fatigue mean scores at post-treatment was highly significant in favour of CBT (SMD -0.39, 95% CI -0.60 to -0.19), with 40% of CBT participants (four studies, 371 participants) showing clinical response in contrast with 26% in usual care (OR 0.47, 95% CI 0.29 to 0.76). Findings at follow-up were inconsistent. For CBT versus other psychological therapies, comprising relaxation, counselling and education/support (four studies, 313 participants), the difference in fatigue mean scores at post-treatment favoured CBT (SMD -0.43, 95% CI -0.65 to -0.20). Findings at follow-up were heterogeneous and inconsistent. Only two studies compared CBT against other interventions and one study compared CBT in combination with other interventions against usual care. CBT is effective in reducing the symptoms of fatigue at post-treatment compared with usual care, and may be more effective in reducing fatigue symptoms compared with other psychological therapies. The evidence base at follow-up is limited to a small group of studies with inconsistent findings. There is a lack of evidence on the comparative effectiveness of CBT alone or in combination with other treatments, and further studies are required to inform the development of effective treatment programmes for people with CFS.


Living With Ambiguity: A Metasynthesis of Qualitative Research on Mild Cognitive Impairment.
Mild Cognitive Impairment (MCI) is a diagnosis proposed to describe an intermediate state between normal cognitive aging and dementia. MCI has been criticised for its conceptual fuzziness, its ambiguous relationship to dementia, and the tension it creates between medical and sociological understandings of "normal aging". We examined the published qualitative literature on experiences of being diagnosed and living with MCI using metasynthesis as the methodological framework. Two overarching conceptual themes were developed. The first, MCI and myself-in-time, showed that a diagnosis of MCI could profoundly affect a person's understanding of their place in the world. This impact appears to be mediated by multiple factors including a person's social support networks, which daily activities are affected, and subjective interpretations of the meaning of MCI. The second theme, Living with Ambiguity, describes the difficulties people experienced in making sense of their diagnosis. Uncertainty arose, in part, from lack of clarity and consistency in the information received by people with MCI, including whether they are even told MCI is the diagnosis. We conclude by suggesting an ethical tension is always at play when a MCI diagnosis is made. Specifically, earlier support and services afforded by a diagnosis may come at the expense of a person's anxiety about the future, with continued uncertainty about how his or her concerns and needs can be addressed.


Universal Reference RNA as a standard for microarray experiments.
Obtaining reliable and reproducible two-color microarray gene expression data is critically important for understanding the biological significance of perturbations made on a cellular system. Microarray design, RNA preparation and labeling, hybridization conditions and data acquisition and analysis are variables difficult to simultaneously control. A useful tool for monitoring and controlling intra- and inter-experimental variation is Universal Reference RNA (URR), developed with the goal of providing hybridization signal at each microarray probe location (spot). Measuring signal at each spot as the ratio of experimental RNA to reference RNA targets, rather than relying on absolute signal intensity, decreases variability by normalizing signal output in any two-color hybridization experiment. Human, mouse and rat URR (UHRR, UMRR and URRR, respectively) were prepared from pools of RNA derived from individual cell lines representing different tissues. A variety of microarrays were used to determine percentage of spots hybridizing with URR and producing signal above a user defined threshold (microarray coverage). Microarray coverage was consistently greater than 80% for all arrays tested. We confirmed that individual cell lines contribute their own unique set of genes to URR, arguing for a pool of RNA from several cell lines as a better configuration for URR as opposed to a single cell line source for URR. Microarray coverage comparing two separately prepared batches each of UHRR, UMRR and URRR were highly correlated (Pearson's correlation coefficients of 0.97). Results of this study demonstrate that large quantities of pooled RNA from individual cell lines are reproducibly prepared and possess diverse gene representation. This type of reference provides a standard for reducing variation in microarray experiments and allows more reliable comparison of gene expression data within and between experiments and laboratories.


Challenges in the classification of fibrotic ILD.
According to current international guidelines the idiopathic interstitial pneumonias (IIPs) are grouped into three categories; major, rare, and unclassifiable. Idiopathic pulmonary fibrosis (IPF) is one of the major IIPs and has been recognised as a distinct clinical entity since 2001. This has led to significant advances in our understanding and treatment of the disease and to the identification of new therapeutic targets. While multidisciplinary team assessment yields a definite diagnosis in many cases of interstitial lung disease (ILD), 15-25% of patients remain unclassifiable. This can be due to inadequate clinical, pathological, or radiological data (e.g., where a biopsy is not performed) or because results of investigations show major discrepancies, overlapping features, or mixed patterns. Patients with unclassifiable disease tend to be of similar age to those with IPF and older than those with connective tissue disorders. Survival of patients with unclassifiable disease is intermediate between IPF and non-IPF ILD. There is no single recommended treatment for patients with unclassifiable disease. However, the ILD-GAP index has recently been validated in this group and can risk-stratify patients based on four easily measurable variables. "Disease behaviour classification" (DBC) is an alternative, pragmatic approach to managing patients with unclassifiable disease. The ILD-GAP index has been shown to provide strong prognostic information in these hard-to-treat patients. In the future, new diagnostic tools such as protein biomarkers may become available to help guide therapeutic decisions.


The impact of class III (morbid) obesity on heterotopic ossification outcomes.
Obesity is associated with a chronic low inflammatory process that may act as common soil for the pathogenesis of obesity-related comorbidities including heterotopic ossification (HO). The purpose of this study is to compare the incidence of HO between patients with body mass index (BMI) <40 versus ≥40 after operative treatment of displaced acetabular fractures followed by radiation therapy (RT) ± indomethacin. This is a single institution retrospective chart review of 419 patients. All patients with well-documented BMI underwent operative treatment followed by RT ± indomethacin. All patients received 700 cGy to the soft tissues around the proximal femur and acetabulum without bone shielding. All RT were given postoperatively within 72 hours. The patients were divided into 2 groups: Group (A) BMI < 40 and Group (B) BMI ≥40. HO was assessed with X-ray. BMI was used as a surrogate measure to test the risk of HO despite prophylaxis. The incidence of HO among all patients is 21% (89 of 419), while among those in group A (BMI <40), 68 of 374 patients developed HO (18%); in the morbidly obese group (BMI ≥40) 21of 45 patients developed HO (47%). The difference between the rates of HO in the 2 groups was 29%; the χ(2) test showed a significant difference between the 2 BMI groups (P < .001 at α = 0.05). There is a higher incidence of HO among the morbidly obese patients despite RT ± indomethacin. RT doses for HO prophylaxis in morbidly obese patients need to be reassessed; also, understanding the signaling pathways in target tissues in obese patients at which adipokines control metabolism may reveal novel therapies. Higher radiation doses ± indomethacin may need to be considered and optimally evaluated in the context of a prospective, randomized clinical trial.


Fluctuating asymmetry and preferences for sex-typical bodily characteristics.
Body size and shape seem to have been sexually selected in a variety of species, including humans, but little is known about what attractive bodies signal about underlying genotypic or phenotypic quality. A widely used indicator of phenotypic quality in evolutionary analyses is degree of symmetry (i.e., fluctuating asymmetry, FA) because it is a marker of developmental stability, which is defined as an organism's ability to develop toward an adaptive end-point despite perturbations during its ontogeny. Here we sought to establish whether attractive bodies signal low FA to observers, and, if so, which aspects of attractive bodies are most predictive of lower FA. We used a 3D optical body scanner to measure FA and to isolate size and shape characteristics in a sample of 77 individuals (40 males and 37 females). From the 3D body scan data, 360 degrees videos were created that separated body shape from other aspects of visual appearance (e.g., skin color and facial features). These videos then were presented to 87 evaluators for attractiveness ratings. We found strong negative correlations between FA and bodily attractiveness in both sexes. Further, sex-typical body size and shape characteristics were rated as attractive and correlated negatively with FA. Finally, geometric morphometric analysis of joint configurations revealed that sex-typical joint configurations were associated with both perceived attractiveness and lower FA for male but not for female bodies. In sum, body size and shape seem to show evidence of sexual selection and indicate important information about the phenotypic quality of individuals.


Eat Smart, Live Strong intervention increases fruit and vegetable consumption among low-income older adults.
This study evaluated the impact of a four-session interactive nutrition education program-Eat Smart, Live Strong (ESLS)-on the consumption of fruit and vegetables by low-income older adults. A pre-post quasi-experimental design study was conducted with a longitudinal sample of 614 low-income Supplemental Nutrition Assistance Program (SNAP) participants and those eligible for SNAP, aged 60 to 80 years, in 17 intervention and 16 comparison senior centers in Michigan. The study compared participants' self-reports of their consumption of fruit and vegetables using a modified version of the University of California Cooperative Extension Food Behavior Checklist. ESLS increased participants' average daily consumption of fruit by 0.2 cups (P < 0.05) and vegetables by 0.31 cups (P < 0.01). ESLS, a four-session, cognitive-behavioral nutrition education program is an effective curriculum for helping low-income older adults eat more fruit and vegetables.


Genetic admixture history of Eastern Indonesia as revealed by Y-chromosome and mitochondrial DNA analysis.
Eastern Indonesia possesses more linguistic diversity than any other region in Southeast Asia, with both Austronesian (AN) languages that are of East Asian origin, as well as non-Austronesian (NAN) languages of likely Melanesian origin. Here, we investigated the genetic history of human populations from seven eastern Indonesian islands, including AN and NAN speakers, as well as the relationship between languages and genes, by means of nonrecombining Y-chromosomal (NRY) and mitochondrial DNA (mtDNA) analysis. We found that the eastern Indonesian gene pool consists of East Asian as well as Melanesian components, as might be expected based on linguistic evidence, but also harbors putative indigenous eastern Indonesian signatures that perhaps reflect the initial occupation of the Wallacea by aboriginal hunter-gatherers already in Palaeolithic times. Furthermore, both NRY and mtDNA data showed a complete lack of correlation between linguistic and genetic relationships, most likely reflecting genetic admixture and/or language shift. In addition, we noted a small fraction of the NRY and mtDNA data shared between eastern Indonesians and Australian Aborigines likely reflecting an ancient link between Asia and Australia. Our data thus provide insights into the complex genetic ancestry history of eastern Indonesian islanders characterized by several admixture episodes and demonstrate a clear example of the lack of the often-assumed correlation between the genes and languages of human populations.


Maternal and Child Health of Internally Displaced Persons in Ukraine: A Qualitative Study.
Due to the conflict that started in spring 2014 in Eastern Ukraine, a total of 1.75 million internally displaced persons (IDPs) fled the area and have been registered in government-controlled areas of the country. This paper explores perceived health, barriers to access to healthcare, caring practices, food security, and overall financial situation of mothers and young children displaced by the conflict in Ukraine. This is a qualitative study, which collected data through semi-structured in-depth interviews with nine IDP mothers via Skype and Viber with a convenience sample of participants selected through snowball technique. Contrary to the expectations, the perceived physical health of mothers and their children was found not to be affected by conflict and displacement, while psychological distress was often reported. A weak healthcare system, Ukraine's proneness to informal payments, and heavy bureaucracy to register as an IDP were reported in our study. A precarious social safety net to IDP mothers in Ukraine, poor dietary diversity, and a generalized rupture of vaccine stocks, with halted or delayed vaccinations in children were identified. Increasing social allowances and their timely delivery to IDP mothers might be the most efficient policy measure to improve health and nutrition security. Reestablishment and sustainability of vaccine stocks in Ukraine is urgent to avoid the risks of a public health crisis. Offering psychological support for IDP mothers is recommended.


B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB.
B-lymphocyte development requires the basic helix-loop-helix proteins encoded by the E2A gene. In this study, the control mechanism of E2A was further explored by disruption of the E2A-related genes, E2-2 and HEB. In contrast to E2A, E2-2 and HEB are not essential for the establishment of the B-cell lineage. However, both E2-2 and HEB are required for the generation of the normal numbers of pro-B cells in mouse embryos. Breeding tests among mice carrying different mutations revealed that E2-2 and HEB interact with E2A in many developmental processes including generation of B cells. Specifically, mice transheterozygous for any two mutations of these three genes produced fewer pro-B cells than the singly heterozygous littermates. This study indicates that B-cell development is dependent not only on an essential function provided by the E2A gene but also on a combined dosage set by E2A, E2-2, and HEB.


The Brazilian Longitudinal Study of Aging (ELSI-Brazil): Objectives and Design.
Brazil is experiencing among the world's fastest demographic aging worldwide. This demographic transition is occurring in a context of few resources and great social inequalities. The Brazilian Longitudinal Study of Aging (ELSI-Brazil) is a nationally representative study of 9,412 people aged 50 years or older, residing in 70 municipalities across the 5 Brazilian regions. ELSI-Brazil allows investigations of the aging process, its health, psychosocial and economic determinants, and societal consequences. The baseline examination (2015-2016) included detailed household and individual interviews and physical measurements (blood pressure, anthropometry, grip strength, and timed walk and balance tests). Blood tests and sample storage were performed in a subsample of study participants. Subsequent waves are planned for every 3 years. The study adopts a conceptual framework common to other large-scale longitudinal studies of aging in the world, such as the Health and Retirement Study, allowing cross-national comparisons. The goal of ELSI-Brazil is not only to build an understanding of aging in a large, Western, middle-income country in a rapid demographic transition but also to provide scientific data to support and study policy changes that may affect older adults. We describe the methodology of the study and some descriptive results of the baseline survey.


The adhesion between fibre posts and composite resin cores: the evaluation of microtensile bond strength following various surface chemical treatments to posts.
To evaluate the influence of various surface treatments to fibre posts on the microtensile bond strength with different composite resins. A total of 110 fibre posts were randomly divided into five groups, according to the surface pre-treatment performed. Group 1: immersion in 24% H(2)O(2) for 10 min and silanization for 60 s; group 2: immersion in 10% H(2)O(2) for 20 min and silanization for 60 s; group 3: immersion in 4% hydrofluoric acid gel for 60 s and silanization for 60 s; group 4: silanization of the post surface for 60 s and application of the bonding agent G-Bond; group 5: silanization of the post surface for 60 s (control group). After treatment, two posts were randomly selected from each group to evaluate the morphological aspect of the post surface with scanning electron microscopy. The remaining posts in each group were divided into five subgroups of five posts each, which differed in the type of composite resin used for the core build-up. Post-core strength were calculated and the differences among experimental groups were analysed with two-way anova and the Tukey test (alpha = 0.05). The post-core strengths achieved in groups 1 and 2 were significantly higher (P < 0.05), than those of groups 3, 4 and 5. The post-core strength in the control group was significantly lower (P < 0.05) than all other groups. Hydrogen peroxide and hydrofluoric acid both modified the surface morphology of fibre posts and with silane, significantly enhanced the interfacial strength between them and core materials.


Emerging land use practices rapidly increase soil organic matter.
The loss of organic matter from agricultural lands constrains our ability to sustainably feed a growing population and mitigate the impacts of climate change. Addressing these challenges requires land use activities that accumulate soil carbon (C) while contributing to food production. In a region of extensive soil degradation in the southeastern United States, we evaluated soil C accumulation for 3 years across a 7-year chronosequence of three farms converted to management-intensive grazing. Here we show that these farms accumulated C at 8.0 Mg ha(-1) yr(-1), increasing cation exchange and water holding capacity by 95% and 34%, respectively. Thus, within a decade of management-intensive grazing practices soil C levels returned to those of native forest soils, and likely decreased fertilizer and irrigation demands. Emerging land uses, such as management-intensive grazing, may offer a rare win-win strategy combining profitable food production with rapid improvement of soil quality and short-term climate mitigation through soil C-accumulation.


Thyroiditis: an integrated approach.
Thyroiditis is a general term that encompasses several clinical disorders characterized by inflammation of the thyroid gland. The most common is Hashimoto thyroiditis; patients typically present with a nontender goiter, hypothyroidism, and an elevated thyroid peroxidase antibody level. Treatment with levothyroxine ameliorates the hypothyroidism and may reduce goiter size. Postpartum thyroiditis is transient or persistent thyroid dysfunction that occurs within one year of childbirth, miscarriage, or medical abortion. Release of preformed thyroid hormone into the bloodstream may result in hyperthyroidism. This may be followed by transient or permanent hypothyroidism as a result of depletion of thyroid hormone stores and destruction of thyroid hormone-producing cells. Patients should be monitored for changes in thyroid function. Beta blockers can treat symptoms in the initial hyperthyroid phase; in the subsequent hypothyroid phase, levothyroxine should be considered in women with a serum thyroid-stimulating hormone level greater than 10 mIU per L, or in women with a thyroid-stimulating hormone level of 4 to 10 mIU per L who are symptomatic or desire fertility. Subacute thyroiditis is a transient thyrotoxic state characterized by anterior neck pain, suppressed thyroid-stimulating hormone, and low radioactive iodine uptake on thyroid scanning. Many cases of subacute thyroiditis follow an upper respiratory viral illness, which is thought to trigger an inflammatory destruction of thyroid follicles. In most cases, the thyroid gland spontaneously resumes normal thyroid hormone production after several months. Treatment with high-dose acetylsalicylic acid or nonsteroidal anti-inflammatory drugs is directed toward relief of thyroid pain.


Who Differentiates by Skin Color? Status Attributions and Skin Pigmentation in Chile.
A growing body of research has shown that phenotypes and skin pigmentation play a fundamental role in stratification dynamics in Latin American countries. However, the relevance of skin color on status attribution for different status groups has been little studied in the region. This article seeks to broaden the research on phenotypic status cues using Chile as a context for analysis - a Latin American country with a narrow although continuous spectrum of skin tones, marked status differences, and a mostly white elite. We draw on status construction theory to hypothesize that skin pigmentation in Chile has become a status cue, although its heuristic relevance could differ across status groups. Using visual stimuli and a repeated measure design, we studied this relationship and tested whether the use of skin pigmentation as a status cue is conditional upon the status of those categorizing others. The results reveal that participants attribute, on average, lower status to others of darker skin. Besides, skin pigmentation has a conditional effect on the social status of participants: whereas skin pigmentation does not work as a status cue for lower status participants, it is an important status marker for the categorizations that middle and especially higher status participants perform. The phenotypic composition of reference groups of low- and high-status individuals and system justification are discussed as potential explanations for these results.


A non-homogeneous hidden-state model on first order differences for automatic detection of nucleosome positions.
The ability to map individual nucleosomes accurately across genomes enables the study of relationships between dynamic changes in nucleosome positioning/occupancy and gene regulation. However, the highly heterogeneous nature of nucleosome densities across genomes and short linker regions pose challenges in mapping nucleosome positions based on high-throughput microarray data of micrococcal nuclease (MNase) digested DNA. Previous works rely on additional detrending and careful visual examination to detect low-signal nucleosomes, which may exist in a subpopulation of cells. We propose a non-homogeneous hidden-state model based on first order differences of experimental data along genomic coordinates that bypasses the need for local detrending and can automatically detect nucleosome positions of various occupancy levels. Our proposed approach is applicable to both low and high resolution MNase-Chip and MNase-Seq (high throughput sequencing) data, and is able to map nucleosome-linker boundaries accurately. This automated algorithm is also computationally efficient and only requires a simple preprocessing step. We provide several examples illustrating the pitfalls of existing methods, the difficulties of detrending the observed hybridization signals and demonstrate the advantages of utilizing first order differences in detecting nucleosome occupancies via simulations and case studies involving MNase-Chip and MNase-Seq data of nucleosome occupancy in yeast S. cerevisiae.


The role of self-monitoring of blood glucose in the routine management of children with insulin-dependent diabetes mellitus.
We report a double-crossover study to assess the impact of self-monitoring of blood glucose (SMBG) on the glycemic control of children with insulin-dependent diabetes mellitus (IDDM) on a conventional therapeutic regimen. Sixteen children were assigned to one of two groups--group A, period 1 (wk 1-13): urine testing plus SMBG; period 2 (wk 14-26): urine testing only; group B, period 1: urine only; period 2: urine testing plus SMBG. Frequent telephone contact was maintained throughout to help optimize insulin dose adjustment. At the outset, the two groups were similar in age, diabetes duration, and glycosylated hemoglobin levels (10.5 +/- 0.6% and 9.5 +/- 0.3% in groups A and B, respectively). No significant differences could be detected between the two groups at any stage of the study. There was, however, a trend toward lower mean blood glucose (MBG) concentration in both groups toward the end of the SMBG period. No complications of SMBG were noted, but compliance was a major problem in three children. SMBG confirmed symptoms of hypoglycemia in all children, and detected asymptomatic hypoglycemia (BG less than or equal to 40 mg/dl) in 11. Sixty-nine percent preferred SMBG to urine testing. We conclude that SMBG is an acceptable part of routine diabetes care in children. It is associated with very few complications and helps to confirm symptomatic hypoglycemia and detect asymptomatic hypoglycemia. However, the addition of SMBG to routine diabetes care does not necessarily lead to improved metabolic control.


The meaning of dignity in nursing home care as seen by relatives.
As part of an ongoing Scandinavian project on the dignity of care for older people, this study is based on 'clinical caring science' as a scientific discipline. Clinical caring science examines how ground concepts, axioms and theories are expressed in different clinical contexts. Central notions are caring culture, dignity, at-home-ness, the little extra, non-caring cultures versus caring cultures and ethical context - and climate. This study investigates the individual variations of caring cultures in relation to dignity and how it is expressed in caring acts and ethical contexts. Three assumptions are formulated: (1) the caring culture of nursing homes influences whether dignified care is provided, (2) an ethos that is reflected on and appropriated by the caregiver mirrors itself in ethical caring acts and as artful caring in an ethical context and (3) caring culture is assumed to be a more ontological or universal concept than, for example, an ethical context or ethical person-to-person acts. The methodological approach is hermeneutic. The data consist of 28 interviews with relatives of older persons from Norway, Denmark and Sweden. The principles of voluntariness, confidentiality and anonymity were respected during the whole research process. Three patterns were revealed: dignity as at-home-ness, dignity as the little extra and non-dignifying ethical context. Caring communion, invitation, at-home-ness and 'the little extra' are expressions of ethical contexts and caring acts in a caring culture. A non-caring culture may not consider the dignity of its residents and may be represented by routinized care that values organizational efficiency and instrumentalism rather than an individual's dignity and self-worth. An ethos must be integrated in both the organization and in the individual caregiver in order to be expressed in caring acts and in an ethical context that supports these caring acts.


A Spontaneous Mutation in Taar1 Impacts Methamphetamine-Related Traits Exclusively in DBA/2 Mice from a Single Vendor.
Major gene effects on traits associated with substance use disorders are rare. Previous findings in methamphetamine drinking (MADR) lines of mice, bred for high or low voluntary MA intake, and in null mutants demonstrate a major impact of the trace amine-associated receptor 1 (Taar1) gene on a triad of MA-related traits: MA consumption, MA-induced conditioned taste aversion and MA-induced hypothermia. While inbred strains are fundamentally genetically stable, rare spontaneous mutations can become fixed and result in new or aberrant phenotypes. A single nucleotide polymorphism in Taar1 that encodes a missense proline to threonine mutation in the second transmembrane domain (Taar1m1J ) has been identified in the DBA/2J strain. MA is an agonist at this receptor, but the receptor produced by Taar1m1J does not respond to MA or endogenous ligands. In the present study, we used progeny of the C57BL/6J × DBA/2J F2 cross, the MADR lines, C57BL/6J × DBA/2J recombinant inbred strains, and DBA/2 mice sourced from four vendors to further examine Taar1-MA phenotype relations and to define the chronology of the fixation of the Taar1m1J mutation. Mice homozygous for Taar1m1J were found at high frequency early in selection for high MA intake in multiple replicates of the high MADR line, whereas Taar1m1J homozygotes were absent in the low MADR line. The homozygous Taar1m1J genotype is causally linked to increased MA intake, reduced MA-induced conditioned taste aversion, and reduced MA-induced hypothermia across models. Genotype-phenotype correlations range from 0.68 to 0.96. This Taar1 polymorphism exists in DBA/2J mice sourced directly from The Jackson Laboratory, but not DBA/2 mice sourced from Charles River (DBA/2NCrl), Envigo (formerly Harlan Sprague Dawley; DBA/2NHsd) or Taconic (DBA/2NTac). By genotyping archived samples from The Jackson Laboratory, we have determined that this mutation arose in 2001-2003. Our data strengthen the conclusion that the mutant Taar1m1J allele, which codes for a non-functional receptor protein, increases risk for multiple MA-related traits, including MA intake, in homozygous Taar1m1J individuals.


Recent advances in the treatment of lower-risk non-del(5q) myelodysplastic syndromes (MDS).
Patients with lower-risk myelodysplastic syndromes (MDS) are affected primarily by symptoms of chronic anemia and fatigue rather than progression to acute myeloid leukemia. Severe thrombocytopenia, although less common in lower-risk MDS, is associated with increased risk of bleeding. For anemic patients, the principal aim of treatment is to improve anemia and decrease red blood cell transfusions. For transfusion-dependent patients with lower-risk MDS without chromosome 5q deletion [non-del(5q) MDS], there are limited effective treatments. Erythropoiesis-stimulating agents (ESAs) are generally first-line therapy, yielding frequent responses with a median duration of 18-24 months. Immunosuppressive therapy or allogeneic stem cell transplantation are restricted to select patients. New strategies for ESA-refractory or relapsed patients include lenalidomide, alone or in combination with ESAs; oral azacitidine; and new molecules such as the activin receptor type II ligand traps luspatercept and sotatercept. In thrombocytopenic patients, thrombopoietin receptor agonists are under evaluation. While trials to evaluate these treatment strategies are underway, efforts are needed to optimize therapies through better patient selection and response prediction as well as integrating molecular and genetic data into clinical practice. We provide an overview of current treatment approaches for lower-risk non-del(5q) MDS and explore promising directions for future research.


Inferring epidemiologic dynamics from viral evolution: 2014-2015 Eurasian/North American highly pathogenic avian influenza viruses exceed transmission threshold, R0 = 1, in wild birds and poultry in North America.
Highly pathogenic avian influenza virus (HPAIV) is a multihost pathogen with lineages that pose health risks for domestic birds, wild birds, and humans. One mechanism of intercontinental HPAIV spread is through wild bird reservoirs, and wild birds were the likely sources of a Eurasian (EA) lineage HPAIV into North America in 2014. The introduction resulted in several reassortment events with North American (NA) lineage low-pathogenic avian influenza viruses and the reassortant EA/NA H5N2 went on to cause one of the largest HPAIV poultry outbreaks in North America. We evaluated three hypotheses about novel HPAIV introduced into wild and domestic bird hosts: (i) transmission of novel HPAIVs in wild birds was restricted by mechanisms associated with highly pathogenic phenotypes; (ii) the HPAIV poultry outbreak was not self-sustaining and required viral input from wild birds; and (iii) reassortment of the EA H5N8 generated reassortant EA/NA AIVs with a fitness advantage over fully Eurasian lineages in North American wild birds. We used a time-rooted phylodynamic model that explicitly incorporated viral population dynamics with evolutionary dynamics to estimate the basic reproductive number (R0) and viral migration among host types in domestic and wild birds, as well as between the EA H5N8 and EA/NA H5N2 in wild birds. We did not find evidence to support hypothesis (i) or (ii) as our estimates of the transmission parameters suggested that the HPAIV outbreak met or exceeded the threshold for persistence in wild birds (R0 > 1) and poultry (R0 ≈ 1) with minimal estimated transmission among host types. There was also no evidence to support hypothesis (iii) because R0 values were similar among EA H5N8 and EA/NA H5N2 in wild birds. Our results suggest that this novel HPAIV and reassortments did not encounter any transmission barriers sufficient to prevent persistence when introduced to wild or domestic birds.


A hydrogel-based in vitro assay for the fast prediction of antibiotic accumulation in Gram-negative bacteria.
The pipeline of antibiotics has been for decades on an alarmingly low level. Considering the steadily emerging antibiotic resistance, novel tools are needed for early and easy identification of effective anti-infective compounds. In Gram-negative bacteria, the uptake of anti-infectives is especially limited. We here present a surprisingly simple in vitro model of the Gram-negative bacterial envelope, based on 20% (w/v) potato starch gel, printed on polycarbonate 96-well filter membranes. Rapid permeability measurements across this polysaccharide hydrogel allowed to correctly predict either high or low accumulation for all 16 tested anti-infectives in living Escherichia coli. Freeze-fracture TEM supports that the macromolecular network structure of the starch hydrogel may represent a useful surrogate of the Gram-negative bacterial envelope. A random forest analysis of in vitro data revealed molecular mass, minimum projection area, and rigidity as the most critical physicochemical parameters for hydrogel permeability, in agreement with reported structural features needed for uptake into Gram-negative bacteria. Correlating our dataset of 27 antibiotics from different structural classes to reported MIC values of nine clinically relevant pathogens allowed to distinguish active from nonactive compounds based on their low in vitro permeability specifically for Gram-negatives. The model may help to identify poorly permeable antimicrobial candidates before testing them on living bacteria.


Population-based cohort study of variation in the use of emergency cholecystectomy for benign gallbladder diseases.
The aims of this prospective population-based cohort study were to identify the patient and hospital characteristics associated with emergency cholecystectomy, and the influences of these in determining variations between hospitals. Data were collected for consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing the performance of emergency cholecystectomy were analysed by means of multilevel, multivariable logistic regression modelling using a two-level hierarchical structure with patients (level 1) nested within hospitals (level 2). Data were collected on 4744 cholecystectomies from 165 hospitals. Increasing age, lower ASA fitness grade, biliary colic, the need for further imaging (magnetic retrograde cholangiopancreatography), endoscopic interventions (endoscopic retrograde cholangiopancreatography) and admission to a non-biliary centre significantly reduced the likelihood of an emergency cholecystectomy being performed. The multilevel model was used to calculate the probability of receiving an emergency cholecystectomy for a woman aged 40 years or over with an ASA grade of I or II and a BMI of at least 25·0 kg/m2 , who presented with acute cholecystitis with an ultrasound scan showing a thick-walled gallbladder and a normal common bile duct. The mean predicted probability of receiving an emergency cholecystectomy was 0·52 (95 per cent c.i. 0·45 to 0·57). The predicted probabilities ranged from 0·02 to 0·95 across the 165 hospitals, demonstrating significant variation between hospitals. Patients with similar characteristics presenting to different hospitals with acute gallbladder pathology do not receive comparable care.


Single-Nucleotide RNA Maps for the Two Major Nosocomial Pathogens Enterococcus faecalis and Enterococcus faecium.
Enterococcus faecalis and faecium are two major representative clinical strains of the Enterococcus genus and are sadly notorious to be part of the top agents responsible for nosocomial infections. Despite their critical implication in worldwide public healthcare, essential and available resources such as deep transcriptome annotations remain poor, which also limits our understanding of post-transcriptional control small regulatory RNA (sRNA) functions in these bacteria. Here, using the dRNA-seq technique in combination with ANNOgesic analysis, we successfully mapped and annotated transcription start sites (TSS) of both E. faecalis V583 and E. faecium AUS0004 at single nucleotide resolution. Analyzing bacteria in late exponential phase, we capture ~40% (E. faecalis) and 43% (E. faecium) of the annotated protein-coding genes, determine 5' and 3' UTR (untranslated region) length, and detect instances of leaderless mRNAs. The transcriptome maps revealed sRNA candidates in both bacteria, some found in previous studies and new ones. Expression of candidate sRNAs is being confirmed under biologically relevant environmental conditions. This comprehensive global TSS mapping atlas provides a valuable resource for RNA biology and gene expression analysis in the Enterococci. It can be accessed online at www.helmholtz-hiri.de/en/datasets/enterococcus through an instance of the genomic viewer JBrowse.


Infant feeding counselling in Uganda in a changing environment with focus on the general population and HIV-positive mothers - a mixed method approach.
Health workers' counselling practices are essential to improve infant feeding practices. This paper will assess how infant feeding counselling was done and experienced by counsellors and mothers in Eastern Uganda in the context of previous guidelines. This has implications for implementation of the new infant feeding guidelines from 2009. This paper combines qualitative and quantitative data from Mbale District in Eastern Uganda. Data was collected from 2003 to 2005 in a mixed methods approach. This includes: key-informant interviews among eighteen health workers in the public hospital, health clinics and non-governmental organisations working with people living with HIV, fifteen focus group discussions in the general population and among clients from an HIV clinic, two cross-sectional surveys including 727 mothers from the general population and 235 HIV-positive mothers. The counselling sessions were often improvised. Health workers frequently had pragmatic approaches to infant feeding as many clients struggled with poverty, stigma and non-disclosure of HIV. The feasibility of the infant feeding recommendations was perceived as challenging among health workers, both for HIV-positive mothers and in the general population. Group counselling with large groups was common in the public health service. Some extra infant feeding teaching capacities were mobilised for care-takers of undernourished children. A tendency to simplify messages giving one-sided information was seen. Different health workers presented contradicting simplified perspectives in some cases. Outdated training was a common concern with many health workers not being given courses or seminars on infant feeding since professional graduation. Other problems were minimal staffing, lack of resources, and programs being started and subsequently stopped abruptly. Many of the HIV-counsellors in the non-governmental organisations got extended training in counselling which seemed to be beneficial. Health workers were faced with challenges related to workload, resources, scientific updating, and also a need to adjust to frequent changes in programs, recommendations and guidelines. The clients were faced with difficult choices, poverty, lack of education and stigma. Feasibility of the recommendations was a major concern. Systematic approaches to update health workers should be a priority.


TSC2 Deficiency Unmasks a Novel Necrosis Pathway That Is Suppressed by the RIP1/RIP3/MLKL Signaling Cascade.
Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The current study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using l-buthionine-sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage, and necrotic cell death in TSC-deficient cells in a highly synergistic and cell context-specific manner. Furthermore, blocking RIP1/RIP3/MLKL-dependent signaling using chemical inhibitors necrostatin-1 (Nec-1) and necrosulfonamide (NSA) synergizes with BSO and auranofin in killing TSC-deficient cells. Expression analysis demonstrated that RIP1, RIP3, and MLKL protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction in a glutaminolysis-dependent and autophagy-independent manner. Finally, supplementation with the mitochondrial metabolite α-ketoglutarate, whose synthesis is regulated by RIP1/RIP3/MLKL, rescues cells from the sensitizing effect of Nec-1 and NSA. Together, this study identifies a previously unrecognized novel regulated necrotic death pathway that involves mitochondrial homeostasis, is suppressed by the RIP1/RIP3/MLKL signaling in TSC-deficient cells, and could be a promising therapeutic target for TSC-associated tumors. Cancer Res; 76(24); 7130-9. ©2016 AACR.


POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.
The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases.


Is there value in using physician billing claims along with other administrative health care data to document the burden of adolescent injury? An exploratory investigation with comparison to self-reports in Ontario, Canada.
Administrative health care databases may be particularly useful for injury surveillance, given that they are population-based, readily available, and relatively complete. Surveillance based on administrative data, though, is often restricted to injuries that result in hospitalization. Adding physician billing data to administrative data-based surveillance efforts may improve comprehensiveness, but the feasibility of such an approach has rarely been examined. It is also not clear how injury surveillance information obtained using administrative health care databases compares with that obtained using self-report surveys. This study explored the value of using physician billing data along with hospitalization data for the surveillance of adolescent injuries in Ontario, Canada. We aimed i) to document the burden of adolescent injury using administrative health care data, focusing on the relative contribution of physician billing information; and ii) to explore data quality issues by directly comparing adolescent injuries identified in administrative and self-report data. The sample included adolescents aged 12 to 19 years who participated in the 1996-1997 cross-sectional Ontario Health Survey, and whose survey responses were linked to administrative health care datasets (N = 2067). Descriptive analysis was used to document the burden of injuries as a proportion of all physician care by gender and location of care, and to examine the distribution of both administratively-defined and self-reported activity-limiting injuries according to demographic characteristics. Administratively-defined and self-reported injuries were also directly compared at the individual level. Approximately 10% of physician care for the sample was identified as injury-related. While 18.8% of adolescents had self-reported injury in the previous year, 25.0% had documented administratively-defined injury. The distribution of injuries according to demographic characteristics was similar across data sources, but congruence was low at the individual level. Possible reasons for discrepancies between the data sources included recall errors in the survey data and errors in the physician billing data algorithm. If further validated, physician billing data could be used along with hospital inpatient data to make an important and unique contribution to adolescent injury surveillance. The limitations inherent in different datasets highlight the need to continue rely on multiple information sources for complete injury surveillance information.


Septic Arthritis Masquerading as a Flare of Rheumatoid Arthritis: A Not So Straightforward Diagnosis.
A typical presentation of septic arthritis (SA) includes pain, swelling, and erythema in the affected joint. Often, patients complain of inability to bear weight on the affected limb. However, some patients may present with subtle symptoms of pain and no fever or obvious swelling of the affected limb thus making the initial suspicion of SA low. Especially, patients with rheumatoid arthritis (RA) may present with polyarticular joint pain and initial synovial fluid analysis from an infected joint not consistent with overt septic arthritis. In such situations, the diagnosis of septic arthritis could be missed on delayed. In this case report, we present a 79-year-old female with a history of RA who presents with polyarticular pain, most notably in her right knee. SA was not initially suspected because of her history of RA and her current presentation with polyarticular pain. The initial synovial analysis did not suggest SA as well. However, cultures of synovial fluid from her right knee confirmed SA. Thus, we have highlighted that physicians should have a high suspicion for SA when addressing joint pain in RA patients.


A synthesis of occupational behavior and sensory integration concepts in theory and practice, part 2: clinical applications.
This is the second of two papers addressing the occupational behavior and sensory integration approaches to occupational therapy for children. In the previous paper, basic concepts from these two approaches were discussed as presenting different, yet complementary, perspectives. The use of play was identified as central to occupational therapy practice from either perspective. Concepts from both approaches were integrated into a general systems model of play development in infancy and early childhood. This paper discusses play and sensory integration as interdependent developmental phenomena that are a function of interactions between the environment (input) and the child's internal processing (throughput). When input-throughput interactions do not permit the growth of competence, dysfunction occurs. Consideration of possible input and throughput deficits are suggested for assessment of individual children, and treatment guidelines are drawn from both the sensory integration and occupational behavior literature.