A real-time spike classification method based on dynamic time warping for extracellular enteric neural recording with large waveform variability.
Computationally efficient spike recognition methods are required for real-time analysis of extracellular neural recordings. The enteric nervous system (ENS) is important to human health but less well-understood with few appropriate spike recognition algorithms due to large waveform variability. Here we present a method based on dynamic time warping (DTW) with high tolerance to variability in time and magnitude. Adaptive temporal gridding for "fastDTW" in similarity calculation significantly reduces the computational cost. The automated threshold selection allows for real-time classification for extracellular recordings. Our method is first evaluated on synthesized data at different noise levels, improving both classification accuracy and computational complexity over the conventional cross-correlation based template-matching method (CCTM) and PCA+k-means clustering without time warping. Our method is then applied to analyze the mouse enteric neural recording with mechanical and chemical stimuli. Successful classification of biphasic and monophasic spikes is achieved even when the spike variability is larger than millisecond in width and millivolt in magnitude. In comparison with conventional template matching and clustering methods, the fastDTW method is computationally efficient with high tolerance to waveform variability. We have developed an adaptive fastDTW algorithm for real-time spike classification of ENS recording with large waveform variability against colony motility, ambient changes and cellular heterogeneity.


Glial responses during epileptogenesis in Mus musculus point to potential therapeutic targets.
The Mesio-Temporal Lobe Epilepsy syndrome is the most common form of intractable epilepsy. It is characterized by recurrence of focal seizures and is often associated with hippocampal sclerosis and drug resistance. We aimed to characterize the molecular changes occurring during the initial stages of epileptogenesis in search of new therapeutic targets for Mesio-Temporal Lobe Epilepsy. We used a mouse model obtained by intra-hippocampal microinjection of kainate and performed hippocampal whole genome expression analysis at 6h, 12h and 24h post-injection, followed by multilevel bioinformatics analysis. We report significant changes in immune and inflammatory responses, neuronal network reorganization processes and glial functions, predominantly initiated during status epilepticus at 12h and persistent after the end of status epilepticus at 24h post-kainate. Upstream regulator analysis highlighted Cyba, Cybb and Vim as central regulators of multiple overexpressed genes implicated in glial responses at 24h. In silico microRNA analysis indicated that miR-9, miR-19b, miR-129, and miR-223 may regulate the expression of glial-associated genes at 24h. Our data support the hypothesis that glial-mediated inflammatory response holds a key role during epileptogenesis, and that microglial cells may participate in the initial process of epileptogenesis through increased ROS production via the NOX complex.


Gene therapy in disorders of lipoprotein metabolism.
Current pharmacologic interventions in lipid metabolism are insufficient in a subset of patients at increased risk of cardiovascular disease. In particular, several monogenetic disorders of lipid metabolism with diverse clinical complications are beyond treatment to date. Somatic gene transfer is a potential approach to treat these disorders. This review describes the efforts made thus far to develop gene therapy for 3 major classes of dyslipidemia: Increased levels of low-density lipoprotein cholesterol, reduced levels of high-density lipoprotein cholesterol and increased plasma triglyceride levels. For many of the genetic causes underlying these conditions, proof-of-principle studies have been performed and in combination with improved vectors some of these strategies may be feasible for clinical use in the future.


Accumulation of adrenocorticotropin secretory granules in the midbody of telophase AtT20 cells: evidence that secretory granules move anterogradely along microtubules.
During the cell cycle the distribution of the ACTH-containing secretory granules in AtT20 cells, as revealed by immunofluorescence labeling and electron microscopy of thin sections, undergoes a cycle of changes. In interphase cells the granules are concentrated in the Golgi region, where they form, and also at the tips of projections from the cells, where they accumulate. These projections contain many microtubules extending to their tips. During metaphase and anaphase the granules are randomly distributed in the cytoplasm of the rounded-up mitotic cells. On entry into telophase there is a rapid and striking redistribution of the granules, which accumulate in large numbers in the midbody as it develops during cytokinesis. This accumulation of secretory granules in the midbody is dependent upon the presence of microtubules. The changing pattern of distribution of the secretory granules during the cell cycle fulfills the predictions of a model envisaging first that secretory granules associate with and move along interphase microtubules in a net anterograde direction away from the centrioles, and secondly that they do not associate with microtubules of the mitotic spindle during metaphase and anaphase.


Simultaneous Quantitation of Methamphetamine, Ketamine, Opiates and their Metabolites in Urine by SPE and LC-MS-MS.
Heroin, methamphetamine and ketamine have been the most commonly abused drugs in Taiwan. The presence of these drugs and their metabolites in postmortem specimens has been routinely monitored in our laboratory mostly by gas chromatographic-mass spectrometric methods. This study aimed to evaluate a more effective approach to simultaneously quantify these analytes (i.e., amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), morphine, codeine, 6-acetylmorphine, 6-acetylcodeine, ketamine and norketamine) in postmortem urine and blood specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Samples (1 mL) were extracted via solid-phase extraction, evaporated and reconstituted in the mobile phase for injection into the LC-MS-MS system. Respective deuterated analogs of these analytes were used as internal standards. Chromatographic separation was achieved by an Agilent Zorbax SB-Aq analytical column at 50°C. Mass spectrometric analysis was performed by electrospray ionization in positive-ion dynamic multiple reaction monitoring mode with optimized collision energy for respective precursor ion selected for each analyte, and the monitoring of two transition ions. Performance characteristics were assessed using drug-free samples that were fortified with 50-1,000 ng/mL of the 10 analytes. Analytical parameters evaluated and resulting data are as follows: (i) average extraction recoveries (n= 3) were better than 80%, except for MDMA (71%) and morphine (74%); (ii) inter-day and intra-day precision ranges (%CV) were 1.59-8.80% and 0.57-3.89%, respectively; (iii) calibration linearity (r2), detection limit and quantitation limit for all analytes were >0.999, 1 and 5 ng/mL, respectively; (iv) matrix effects (ion suppression) were observed for three analytes, but were satisfactorily compensated for by the deuterated internal standards adopted in the analytical protocol. This method was successfully applied to the analysis of specimens collected from unknown death cases from various district prosecutors' offices in Taiwan, and was also found helpful to understanding whether the detected opiates were derived from heroin or legal morphine/codeine-containing medications.


Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation.
Daily life stressors are a major environmental factor contributing to precipitation and exacerbation of mental illness. Animal models using repeated homotypic stress induce anxious and depressive phenotypes and are used to study the pathophysiology of affective disorders. Here we discuss data demonstrating that repeated homotypic stress produces temporally and anatomically distinct changes in endocannabinoid signaling components within stress-responsive brain regions. We also present evidence describing the neural and behavioral correlates of these adaptations in endocannabinoid signaling. These data support a role for endocannabinoid signaling in the central nervous system response to chronic, homotypic stress, and specifically in the process of stress-response habituation. The clinical implications of these findings for the pathophysiology and treatment of affective disorders are discussed.


Variational Hierarchical Mixtures for Probabilistic Learning of Inverse Dynamics.
Well-calibrated probabilistic regression models are a crucial learning component in robotics applications as datasets grow rapidly and tasks become more complex. Unfortunately, classical regression models are usually either probabilistic kernel machines with a flexible structure that does not scale gracefully with data or deterministic and vastly scalable automata, albeit with a restrictive parametric form and poor regularization. In this paper, we consider a probabilistic hierarchical modeling paradigm that combines the benefits of both worlds to deliver computationally efficient representations with inherent complexity regularization. The presented approaches are probabilistic interpretations of local regression techniques that approximate nonlinear functions through a set of local linear or polynomial units. Importantly, we rely on principles from Bayesian nonparametrics to formulate flexible models that adapt their complexity to the data and can potentially encompass an infinite number of components. We derive two efficient variational inference techniques to learn these representations and highlight the advantages of hierarchical infinite local regression models, such as dealing with non-smooth functions, mitigating catastrophic forgetting, and enabling parameter sharing and fast predictions. Finally, we validate this approach on large inverse dynamics datasets and test the learned models in real-world control scenarios.


Health-related quality of life following pediatric critical illness.
The aims of this focused review of the literature on children surviving critical illness were to (1) determine whether health-related quality of life (HRQL) represents a clinically meaningful outcome measure for children surviving critical illness and (2) evaluate the HRQL measures implemented in pediatric critical care studies to date. This was a focused review of the literature from 1980 to 2015 based on a search of EMBASE/PubMed, MEDLINE and PsycInfo assessing trends and determinants of HRQL outcomes in children surviving critical illness. We also evaluated the psychometric properties of the HRQL instruments used in the studies identified by examining each measure's reported reliability, validity and sensitivity to clinical change. The literature search identified 253 pediatric articles for potential inclusion in the review, among which data from 78 studies were ultimately selected for inclusion. Of the 22 measures utilized in the studies reviewed, only four demonstrated excellent psychometric properties for use in pediatric critical care trials. Trends in HRQL identified in the studies reviewed suggest significant ongoing morbidity for children surviving critical illness. Key determinants of poor HRQL outcomes include reason for PICU admission (sepsis, meningoencephalitis, trauma), antecedents (chronic comorbid conditions), treatments received (prolonged cardiopulmonary resuscitation, long-stay patients, invasive technology), psychological outcomes (post-traumatic stress disorder, parent anxiety/depression) and social and environmental characteristics (low socioeconomic status, parental education and functioning). Validated pediatric HRQL instruments are now available. Significant impact on HRQL has been demonstrated in acute and acute on chronic critical illness. Future pediatric critical care interventional trials should include both mortality as well as long-term HRQL measurements to truly ascertain the full impact of critical illness in children.


Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer-Advances and Challenges.
There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.


β-Carotene during the suckling period is absorbed intact and induces retinoic acid dependent responses similar to preformed vitamin A in intestine and liver, but not adipose tissue of young rats.
We studied β-carotene (BC) absorption and metabolism and compared BC and retinyl palmitate (RE) for their impact on white adipose tissue (WAT) development in suckling rats. Rat pups received daily orally from days 1-20 of life either the vehicle or vitamin A (approx. ×3 that ingested daily from maternal milk) in the form of BC or RE. Intact BC was found in serum and liver of BC-supplemented rats. Both BC and RE supplementation increased retinoic acid mediated transcriptional responses in intestine (on Isx and Bco1) and the liver (on Cyp26a1 and Cpt1a). In contrast, responses in WAT were dependent on the vitamin A source: WAT of BC-supplemented rats, like WAT of control rats, was enriched in larger adipocytes with increased adipogenic markers (peroxisome proliferator-activated receptor γ and downstream genes) and reduced markers of proliferative status (proliferating cell nuclear antigen) compared to WAT of RE-supplemented rats. BC is partly absorbed intact by suckling rats, which resembles the situation in humans and suggests that suckling rats may be an appropriate animal model to study BC uptake, metabolism and biological activity, particularly in infants. Vitamin A supplementation with BC or RE in early life differentially affects WAT and may thus entail different outcomes regarding adiposity programming.


Arsenic toxicity in the human nerve cell line SK-N-SH in the presence of chromium and copper.
As, Cr, and Cu represent one potential combination of multiple metals/metalloids exposures since these three elements are simultaneously leached from chromated copper arsenate (CCA)-treated wood, a common product used for building construction, at levels that can be potentially harmful. This study investigated the neurotoxicity of As associated with CCA-treated wood when accompanied by Cr and Cu. The toxicity was evaluated on the basis of a cytotoxicity model using human neuroblastoma cell line SK-N-SH. The cells were cultured with CCA-treated wood leachates or with solutions containing arsenate [As(V)], divalent copper [Cu(II)], trivalent chromium [Cr(III)] alone or in different combinations of the three elements. The toxicity was evaluated using variations in cell replication compared to controls after 96 h exposure. Among the three elements present in wood leachates, As played the primary role in the observed toxic effects, which were exerted through multiple pathways, including the generation of oxidative stress. DOM affected the absorption of metals/metalloids into the test cells, which however did not obviously appear to impact toxicity. As toxicity was enhanced by Cu(II) and inhibited by Cr(III) at concentrations below U.S. EPA's allowable maximum contaminant levels in drinking waters. Thus assessing As toxicity in real environments is not sufficient if based solely on the result from As.


The effects of a reduced-sodium, high-potassium salt substitute on food taste and acceptability in rural northern China.
A potassium chloride-containing salt substitute lowers blood pressure levels, but its overall acceptability has been of concern due to its potential adverse effects on food taste. In a large-scale, blinded randomised trial evaluating the comparative effects of a salt substitute (65 % sodium chloride, 25 % potassium chloride and 10 % magnesium sulphate) and a normal salt (100 % sodium chloride) on blood pressure, we collected data on the saltiness, flavour and overall acceptability of food. We performed this at baseline, 1, 6 and 12 months post-randomisation using 100 mm visual analogue scales for assessments of both home-cooked foods and a standard salty soup. The mean age of the 608 participants from rural northern China was 60 years and 56 % of them were females. In the primary analyses, the changes in the saltiness, flavour and overall acceptability of both home-cooked foods and a standard salty soup were not different between the randomised groups (all P>0.08). In the secondary analyses, weighting each of the data points according to the lengths of the respective follow-up intervals, the flavour of both home-cooked foods (mean difference = - 1.8 mm, P = 0.045) and a standard salty soup (mean difference = - 1.9 mm, P = 0.03) was slightly weaker in the salt substitute group. We conclude that salt substitution is both an effective and an acceptable means of blood pressure control. Possible small differences in flavour did not importantly deter the use of the salt substitute in this study group, although the acceptability of the salt substitute by a more general population group would need to be confirmed.


Photobleaching GFP reveals protein dynamics inside live cells.
Cell biologists have used photobleaching to investigate the lateral mobility of fluorophores on the cell surface since the 1970s. Fusions of green fluorescent protein (GFP) to specific proteins extend photobleaching techniques to the investigation of protein dynamics within the cell, leading to renewed interest in photobleaching experiments. This article revisits general photobleaching concepts, reviews what can be learned from them and discusses applications illustrating the potential of photobleaching GFP fusion proteins inside living cells.


Accelerating the spread of laboratory quality improvement efforts in Botswana.
In 2002, the Ministry of Health (MoH) of Botswana began its journey toward laboratory accreditation in an effort to enhance the quality of laboratory services. After a difficult start, the MoH recognised the need for a more practical and sustainable method for change that could be implemented nationally; they therefore adopted the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme. This study describes the process and lessons learned in implementing SLMTA and the role of supplemental training and mentoring so as to achieve Botswana's national laboratory quality improvement goal. Eight laboratories were enrolled into the SLMTA programme in 2010, which included a series of workshops and improvement projects conducted over nine months. Four of these laboratories received supplementary training and focused mentorship from the Botswana Bureau of Standards (BOBS). Laboratory performance was measured at baseline and exit using the World Health Organization Regional Office for Africa's Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) checklist. One laboratory did not receive an exit audit and was thus excluded from the analysis. An 18 percentage-point improvement was observed when comparing the median baseline score (53%) to the median exit score (71%) for the seven laboratories. Laboratories that received additional training and mentorship from BOBS improved 21 percentage points, whilst non-BOBS-mentored laboratories improved eight percentage points. Hospital management buy-in and strong laboratory staff camaraderie were found to be essential for the positive changes observed. SLMTA facilitated improvements in laboratory quality management systems, yielding immediate and measurable results. This study suggests that pairing the SLMTA programme with additional training and mentorship activities may lead to further increases in laboratory performance; and that SLMTA is a practical approach to extending quality improvement to MOH laboratories.


Metabolomics reveals an involvement of pantothenate for male production responding to the short-day stimulus in the water flea, Daphnia pulex.
Under favorable conditions, the micro-crustacean Daphnia pulex produces female offspring by parthenogenesis, whereas under unfavorable conditions, they produce male offspring to induce sexual reproduction (environmental sex determination: ESD). We recently established a suitable system for ESD studies using D. pulex WTN6 strain, in which the sex of the offspring can be regulated by alterations in day-length; long-day and short-day conditions can induce female and male offspring, respectively. Taking advantage of this system, we have already demonstrated that methyl farnesoate (MF) synthesis is necessary for male offspring production, and identified ionotropic glutamate receptors as an upstream regulator of MF signaling. Despite these findings, the molecular mechanisms associated with MF signaling have not yet been well elucidated. In this study, we analyzed the whole metabolic profiles of mother daphnids reared under long-day (female-producing) and short-day (male-producing) conditions, and discovered that pantothenate (vitamin B5), a known precursor to coenzyme A, was significantly accumulated in response to the short-day condition. To confirm the innate role of pantothenate in D. pulex, this metabolite was administered to mother daphnids resulting in a significantly increased proportion of male offspring producing mothers. This study provides novel insights of the metabolic mechanisms of the ESD system in D. pulex.


A Case of Reversed Ophthalmic Artery Flow without Occlusion of the Internal Carotid Artery.
Background: We report a case of reversed ophthalmic artery (OA) flow showing neither occlusion of the internal carotid artery (ICA) nor ophthalmic symptoms.Case: An 82-year-old man had transient blindness in both eyes. After left carotid endarterectomy, ophthalmic symptoms improved in the right and left eyes. Afterwards, he had a relapse in the left eye.Results: There was no unusual impression in the ophthalmic examinations, but color Doppler imaging showed reduced flow in the left OA, reversal of flow direction in the right OA. The central retinal artery (CRA) and short posterior ciliary arteries (SPCA) were not detected in the left eye but were detected in the right eye. Digital subtraction angiography demonstrated that the right OA was not contrasted with the right ICA, despite there being no stenosis or occlusion of the right ICA.Conclusions: We suggest that carotid surgery may affect the ocular circulation of the opposite side, and reversed OA flow as a collateral pathway from the external carotid artery may occur in the absence of carotid artery stenosis. Good circulation of the CRA and SPCA may preclude manifestation of ophthalmic symptoms even if the OA flow is reversed.


The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland.
Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and sex-matched controls. Serum levels of folate, homocysteine and vitamin B(12) were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B(12) did not differ significantly between groups. A MTHFR C677T genotype is associated with increased risk of depressive episodes in this homogenous patient population.


Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life.
Daycare attendance and siblings are associated with viral-induced wheezing in children. Preexisting immunologic factors may influence the expression of viral infections in infancy, and in turn, recurrent infections may influence the development of immune responses. A total of 285 children were enrolled in the Childhood Origins of Asthma Project at birth and followed for at least 1 year. Cord blood and 1-year mononuclear cells were stimulated with phytohemagglutinin, and cytokine-response profiles were measured by enzyme-linked immunosorbent assay. Nasal lavage was performed for moderate to severe respiratory illnesses. Daycare attendance and/or siblings significantly increased the likelihood of contracting respiratory syncytial virus (1.5-1.6-fold increase) and rhinovirus (1.8-2.1-fold increase), and increased the risk of rhinovirus-induced wheezing (14-18% vs. 2%, p = 0.011). Cord blood IFN-gamma responses were inversely related to the frequency of viral respiratory infections (r(s) = -0.11, p = 0.05), and more significant for subjects with high exposure to other children (r(s) = -0.27, p = 0.028). The interval change in infantile IFN-gamma responses correlated positively with the frequency of viral infections in infancy (r(s) = 0.12, p = 0.047). These data suggest that neonatal IFN-gamma responses may influence antiviral activity, or may represent a marker of antiviral immunity maturation. Conversely, the frequency of viral infections in infancy can influence IFN-gamma responses.


Economic analysis of home vs hospital-based parenteral nutrition in Ontario, Canada.
Advances in technology and infrastructure have facilitated transfer of complex services from acute care hospitals to the home. This increases the burden on community resources but may provide net savings to the health care system. We undertook a retrospective cohort study of patients transferred from hospital to home while receiving home parenteral nutrition (PN) to assess their costs of care. A detailed review of medical records was undertaken for all patients managed by the Hamilton Health Sciences Home PN Program between 1996 and 2001 whose PN was initiated in hospital. Mean per diem direct medical costs were estimated from the perspective of the provincial Ministry of Health for 3 periods: the last 2 weeks before discharge and the first month after discharge. Costs were compared among time intervals and among patients subgroups defined by age and underlying disease. Twenty-nine eligible subjects were identified. Common indications for PN included malignancy (n = 12), inflammatory bowel disease (n = 6), and intestinal ischemia (n = 4). Mean per diem costs in the last week of hospitalization were higher than those in the first month after discharge (dollars 567 vs dollars 405, p < .0001). Acute care resources accounted for <10% of the overall costs on home PN. The estimated monthly savings per patient maintained on home PN were dollars 4860 (95% confidence interval dollars 2700-dollars 7000). Savings were even greater among patients with underlying malignancy and advanced age. Home PN is cost saving when compared with hospital-based PN. Neither age nor underlying malignancy should pose a barrier to receipt of home PN.


Inclusion of blended lipid solutions as functional ingredients to alter the fatty acid profile of beef patties.
Beef patties formulated to contain beef fat, plant oil, and a rosemary extract to increase unsaturated fatty acid content and maintain desirable sensory attributes were compared to control beef patties formulated without plant oils. Treatment patties were formulated to a fat content of 10% or 20% by combining beef trimmings (6% fat) with 4% or 14% addition of a lipid blend. Blends contained 57% beef tallow, 0.3% rosemary extract, and 43% of high oleic safflower oil (SO), olive oil (OO), or corn oil (CO). Lipid oxidation, as measured by TBA values, of treatment patties were similar to control patties after 0 and 3 d of refrigerated (2 °C) storage and up to 56 d of frozen (-10 °C) storage. Cooked lipid blend patties having a fat content of 10% or 20% were similar to or higher than control patties for juiciness and were no different for other sensory attributes evaluated. At fat levels of 10% or 20%, oleic acid (18: 1) in cooked SO patties (46.1% and 50.3%, respectively) and OO patties (43.8% and 48.1%, respectively) was higher than the control (37.3% and 37.6%, respectively). Unsaturated to saturated fatty acid ratios at the 10% or 20% fat levels were higher in SO (1.37 and 1.60, respectively) and CO (1.40 and 1.48, respectively) patties than the control (0.97 and 0.94, respectively). Beef patties manufactured with varying lipid blends increased unsaturated fatty acid content and were similar in physical characteristics and sensory attributes of all beef patties formulated without lipid blends. The development of healthier beef products that will be more appealing to consumers has long been an industry goal. The authors believe that lipid blends such as the one used in this study could be used to create such products, not only in the form of beef patties, but any number of processed meat products. Because the materials and equipment used to create the lipid blends in this study are widely available, their incorporation into meat products would represent a small capital investment. This is an important factor in bringing a reasonably priced, healthier product to consumers.


Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury.
Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.


Flexural wave propagation velocity and bone mineral density in females with and without tibial bone stress injuries.
Case-control nonexperimental design. To compare flexural wave propagation velocity (FWPV) and tibial bone mineral density (BMD) in women with and without tibial bone stress injuries (BSIs). Physical therapists, particularly in military and sports medicine settings, routinely diagnose and manage stress fractures or bone stress injuries. Improved methods of preparticipation quantification of tibial strength may provide markers of BSI risk and thus potentially reduce morbidity. Bone mineral density, FWPV, bone geometry, and historical variables were collected from 14 subjects diagnosed with tibial BSIs and 14 age-matched controls; all 28 were undergoing military training. No difference was found between groups in FWPV and tibial BMD when analyzed with t tests (post hoc power = 0.89 and 0.81, respectively). Furthermore, no difference was found in tibial length, tibial width, femoral neck BMD, and lumbar spine BMD among the groups. There were no differences between the 2 groups in smoking history, birth control pill use, and onset of menarche. Finally, sensitivity and positive likelihood ratios for FWPV (0.14 and 0.63), tibial BMD (0.0 and 0.0), and lumbar BMD (0.18 and 2.0) were low, while specificity was high (0.77, 0.93, and 0.91, respectively). Current bone analysis devices and methods may not be sensitive enough to detect differences in tibial material and structure; local stresses on bone may be more important in the development of BSIs than the overall structural stiffness.


Clinical Performance of Emergency Surgical Officers in Southern Ethiopia.
Serious shortage of gynecologists and surgeons for several decades leading to a three-year masters level training was initiated in 2009. However, systematic analysis was not done to assess the graduates' performance. The purpose of this study was to assess improvement in access to emergency surgical and obstetrical care services. Both quantitative and qualitative methods were employed to assess the competence of emergency surgical officers (ESOs) in their decision making and surgical skills in eight hospitals between 2012 and 2014. Anesthesia time, post-operative hospital stay and change in hemoglobin level were, among others, used as proxy indicators of their surgical skills. A total of 4075 obstetric and surgical operations was performed in the study hospitals. Of which, 93% were done on emergency base. Of the total emergency procedures, 3570(94%) were done by ESOs. Nearly two-thirds (63%) of all the emergency operations were cesarean sections, which were done by ESOs. Out of 239 uterine ruptures, hysterectomy was done for 58%. The proportion of cesarean and instrumental deliveries over the total deliveries were 13% and 0.7%, respectively. Explorative laparotomies and appendectomies were the majority of the non-obstetric emergency operations. Interviewed staff in the respective hospitals stated that ESOs' clinical decision making, surgical skill and commitment to discharge their responsibilities were in the best possible. The study showed that deployment of ESOs made the emergency surgery services accessible to the majority, and their clinical decision making and surgical skills were remarkable.


The future of rheumatoid arthritis and hand surgery - combining evolutionary pharmacology and surgical technique.
Rheumatoid arthritis is a systemic autoimmune disease of uncertain aetiology, which is characterized primarily by synovial inflammation with secondary skeletal destructions.Rheumatoid Arthritis is diagnosed by the presence of four of the seven diagnostic criteria, defined by The American College of Rheumatology.Approximately half a million adults in the United Kingdom suffer from rheumatoid arthritis with an age prevalence between the second and fourth decades of life; annually approximately 20,000 new cases are diagnosed.The management of Rheumatoid Arthritis is complex; in the initial phase of the disease it primarily depends on pharmacological management. With disease progression, surgical input to correct deformity comes to play an increasingly important role. The treatment of this condition is also intimately coupled with input from both the occupational therapists and physiotherapy.


Identification of a Novel Deactivating Small-Molecule Compound for Fibrogenic Hepatic Stellate Cells.
Liver fibrosis progresses to decompensated liver cirrhosis, for which medical needs remain unmet. We recently developed IC-2, a small-molecule compound that suppresses Wnt/β-catenin signaling, and found that IC-2 also suppresses liver fibrosis. In this study, we performed three-step screening of newly synthesized IC-2 derivatives to identify other small-molecule compounds that suppress liver fibrosis. The screening system consisted of three steps: a cell viability assay, a transcription factor 4 (TCF4) reporter assay, and induction of α-smooth muscle actin (α-SMA) and collagen 1α1 (Col1A1) expression in response to each compound. Screening using human LX-2 hepatic stellate cells (HSCs) was performed to target HSCs, which are the driver cells of liver fibrosis. In the first step, since 9b and 9b-CONH2 at 100 μM did not have any effects on cell viability, they were omitted in the next screening. Additionally, the conditions that led to > 40% inhibition of the controls were also excluded in subsequent screening. The second step was performed under 31 conditions for 19 small-molecule compounds. Sixteen small-molecule compounds caused significant reduction of TCF4 activity relative to that of 0.1% DMSO. Of the 16 compounds, the 10 showing the greatest suppression of TCF4 activity were selected for the third step. Expressions of mRNA for α-SMA and Col1A1 were significantly reduced by seven and three small-molecule compounds, respectively. The greatest reductions in the α-SMA and Col1A1 mRNA expressions were observed in the cells treated with IC-2-F. Protein expressions of α-SMA and Col1A1 caused by IC-2-F were also comparable to those caused by IC-2. IC-2-F was identified as a novel deactivating small-molecule compound for HSCs in vitro. These data suggest that IC-2-F is a promising medicine for liver fibrosis.


An outbreak of lupinosis in sheep.
Lupinosis is a mycotoxicosis caused by the ingestion of toxins produced by the fungus phomopsis leptostromiformis which grows on lupin plants. An outbreak of natural lupinosis in lambs occurred in Caceres, Spain. Clinical signs were inappetence, depression, constipation, weakness and different degrees of jaundice. Blood samples were analysed every 7 d for 5 w for hematocrit, total protein, glucose, total bilirubin, and GOT, GPT and alkaline phosphatase activities. The last 4 parameters were increased and returned to normal values after 2-3 w. The liver was swollen and a bright yellow color; microscopically fatty metamorphosis, necrotic areas and infiltration of polymorphonuclears were observed. This is the first time that lupinosis is described in Spain.


Cerebral blood flow studies in man using recirculation corrected height/area (H/A) computations for intravenous injection of 133Xenon.
Our height/area (recirculation-corrected) non-invasive cerebral blood flow method compares well with k1 values and k average as determined from k1, k2, p1 and p2 by Obrist computations. The height/area method provides regional flow measurements with less variability than k1 due to low regional head counts, head motion and end-tidal gas sample variations. Derivation of the mathematical model is for a single flow compartment and suited for tomographic measurements such as PET. Collimated detector data using our computation provides a good approximation of flow even for multiple compartments. Our approach permits a lower counting rate by either a smaller isotope dose or better detector collimation than multicompartment curve fitting methods.


Computational systems biology in cancer brain metastasis.
Brain metastases occur in 20-40% of patients with advanced malignancies. A better understanding of the mechanism of this disease will help us to identify novel therapeutic strategies. In this review, we will discuss the systems biology approaches used in this area, including bioinformatics and mathematical modeling. Bioinformatics has been used for identifying the molecular mechanisms driving brain metastasis and mathematical modeling methods for analyzing dynamics of a system and predicting optimal therapeutic strategies. We will illustrate the strategies, procedures, and computational techniques used for studying systems biology in cancer brain metastases. We will give examples on how to use a systems biology approach to analyze a complex disease. Some of the approaches used to identify relevant networks, pathways, and possibly biomarkers in metastasis will be reviewed into details. Finally, certain challenges and possible future directions in this area will also be discussed.


Liver stiffness and perfusion changes for hepatic sinusoidal obstruction syndrome in rabbit model.
Hepatic sinusoidal obstruction syndrome (SOS) is caused by damage to hepatic sinusoidal endothelial cells that results in fibrous obliteration of intrahepatic venules and necrosis of hepatocytes. Currently the diagnosis is primarily based on nonspecific clinical features and invasive liver biopsy. Therefore, noninvasive imaging methods are required for the early diagnosis and severity assessment of hepatic SOS. To determine the effectiveness of supersonic shear wave imaging (SSI) and dual energy computed tomography (DECT) for diagnosing hepatic SOS using a rabbit model. Among nine New Zealand white rabbits (3-4 kg, male), three in control group ingested normal saline for 20 d and six in the SOS group ingested 6-thioguanine (5 mg/kg/d) for 20 d. Liver stiffness was measured using SSI on days 0, 3, 10, and 20. On the same days, liver perfusion was evaluated from virtual monochromatic images of 55 keV and iodine map using DECT. Morphologic changes in the liver were assessed using CT. Final pathology scores were compared between the two groups. Liver stiffness and perfusion parameters were compared according to the groups, days, and pathology scores. Final pathology scores were significantly higher in the SOS than the control group (median 22 vs 2, P = 0.024). No gross morphologic changes were seen in livers. Liver stiffness, Hounsfield Unit values, and iodine concentrations were higher in the SOS compared to the control group on days 10 and 20 (all, P ≤ 0.007). Compared to day 0, liver stiffness and perfusion parameters were higher on day 20 in the SOS group (all, P ≤ 0.001). Correlation coefficients for liver stiffness (r = 0.635), Hounsfield Unit values (r = 0.587), and iodine concentration (r = 0.611) with final pathology scores were positive without significance (all, P > 0.05). Liver stiffness and perfusion parameters were significantly increased in the livers of a rabbit SOS model. SSI and DECT might aid in early diagnosis of hepatic SOS.


ECG alterations suggestive of hyperkalemia in normokalemic versus hyperkalemic patients.
In periarrest situations and during resuscitation it is essential to rule out reversible causes. Hyperkalemia is one of the most common, reversible causes of periarrest situations. Typical electrocardiogram (ECG) alterations may indicate hyperkalemia. The aim of our study was to compare the prevalence of ECG alterations suggestive of hyperkalemia in normokalemic and hyperkalemic patients. 170 patients with normal potassium (K+) levels and 135 patients with moderate (serum K+ = 6.0-7.0 mmol/l) or severe (K+ > 7.0 mmol/l) hyperkalemia, admitted to the Department of Emergency Medicine at the Somogy County Kaposi Mór General Hospital, were selected for this retrospective, cross-sectional study. ECG obtained upon admission were analyzed by two emergency physicians, independently, blinded to the objectives of the study. Statistical analysis was performed using SPSS22 software. χ2 test and Fischer exact tests were applied. 24% of normokalemic patients and 46% of patients with elevated potassium levels had some kind of ECG alteration suggestive of hyperkalemia. Wide QRS (31.6%), peaked T-waves (18.4%), Ist degree AV-block (18.4%) and bradycardia (18.4%) were the most common and significantly more frequent ECG alterations suggestive of hyperkalemia in severely hyperkalemic patients compared with normokalemic patients (8.2, 4.7, 7.1 and 6.5%, respectively). There was no significant difference between the frequency of ECG alterations suggestive of hyperkalemia in normokalemic and moderately hyperkalemic patients. Upon examining ECG alterations not typically associated with hyperkalemia, we found that prolonged QTc was the only ECG alteration which was significantly more prevalent in both patients with moderate (17.5%) and severe hyperkalemia (21.1%) compared to patients with normokalemia (5.3%). A minority of patients with normal potassium levels may also exhibit ECG alterations considered to be suggestive of hyperkalemia, while more than half of the patients with hyperkalemia do not have ECG alterations suggesting hyperkalemia. These results imply that treatment of hyperkalemia in the prehospital setting should be initiated with caution. Multiple ECG alterations, however, should draw attention to potentially life threatening conditions.


Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo.
Perforin is a key effector protein in the vertebrate immune system and is secreted by cytotoxic T lymphocytes and natural killer cells to help eliminate virus-infected and transformed target cells. The ability to modulate perforin activity in vivo could be extremely useful, especially in the context of bone marrow stem cell transplantation where early rejection of immunologically mismatched grafts is driven by the recipient's natural killer cells, which overwhelmingly use perforin to kill their targets. Bone marrow stem cell transplantation is a potentially curative treatment for both malignant and nonmalignant disorders, but when the body recognizes the graft as foreign, it is rejected by this process, often with fatal consequences. Here we report optimization of a previously identified series of benzenesulfonamide-based perforin inhibitors for their physicochemical and pharmacokinetic properties, resulting in the identification of 16, the first reported small molecule able to prevent rejection of transplanted bone marrow stem cells in vivo by blocking perforin function.


Flexibility in a changing arctic food web: Can rough-legged buzzards cope with changing small rodent communities?
Indirect effects of climate change are often mediated by trophic interactions and consequences for individual species depend on how they are tied into the local food web. Here we show how the response of demographic rates of an arctic bird of prey to fluctuations in small rodent abundance changed when small rodent community composition and dynamics changed, possibly under the effect of climate warming. We observed the breeding biology of rough-legged buzzards (Buteo lagopus) at the Erkuta Tundra Monitoring Site in southern Yamal, low arctic Russia, for 19 years (1999-2017). At the same time, data on small rodent abundance were collected and information on buzzard diet was obtained from pellet dissection. The small rodent community experienced a shift from high-amplitude cycles to dampened fluctuations paralleled with a change in species composition toward less lemmings and more voles. Buzzards clearly preferred lemmings as prey. Breeding density of buzzards was positively related to small rodent abundance, but the shift in small rodent community lead to lower numbers relative to small rodent abundance. At the same time, after the change in small rodent community, the average number of fledglings was higher relative to small rodent abundance than earlier. These results suggest that the buzzard population adapted to a certain degree to the changes in the major resource, although at the same time density declined. The documented flexibility in the short-term response of demographic rates to changes in structure and dynamics of key food web components make it difficult to predict how complex food webs will be transformed in a warmer Arctic. The degree of plasticity of functional responses is indeed likely to vary between species and between regions, depending also on the local food web context.


Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma.
Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.


Patients' informed consent to medical services in Georgia.
Informed consent requires that a patient understands the purpose, benefits and potential risks of a medical or surgical intervention and then agrees to it. It is important not only ethically and legally but for the effectiveness of care. Studies show that, in some cases, patients have no real information on the medical service to be provided so their informed consent is just a formality. This study aims to determine problems arising from a patient's informed consent. As part of a cross-sectional study, surgical patients were interviewed using a semi-structured questionnaire. 34% of patients (n = 68) did not know what the surgical intervention was; 57% (n = 114) received sufficient information on their diagnosis and methods of treatment; however, 26% (n = 52) agreed with it only partially; 62% (n = 124) of patients knew they needed surgery; 66% (n = 132) were adequately informed on risks and benefits of alternative ways of treatment; 58% (n = 116) were informed of potential risks during surgery. The study demonstrated patients need to be better informed about different treatment options, consequences of treatment refusal. Doctors have to provide information to patients in a manner understandable to them. Medical personnel need to be educated as to what constitutes informed consent and the importance of adhering to such requirements.


Evaluation of the performance of French physician-staffed emergency medical service in the triage of major trauma patients.
Proper prehospital triage of trauma patients is a cornerstone for the process of care of trauma patients. In France, emergency physicians perform this process according to a national triage algorithm called Vittel Triage Criteria (VTC), introduced in 2002 to help the triage decision-making process. The aim of this two-center study was to evaluate the performance of the triage process based on the VTC to identify major trauma patients in the Paris area. This was a retrospective analysis of two cohorts. The first cohort consisted of all patients admitted between January 2011 and September 2012 in two trauma referral centers in the region of Paris (Ile de France) and allowed estimation of overtriage. Undertriage was assessed in a second cohort made up of all prehospital trauma interventions from one emergency medicine sector during the same period. Adequate triage was defined by a direct admission of patients with an Injury Severity Score (ISS) greater than 15 into one of the regional trauma centers, and undertriage was defined as an initial nonadmission to a trauma center. Overtriage was defined by an admission of patients with an ISS of 15 or lower to a trauma center. The performance of the VTC was evaluated according to a strict to-the-letter application of the VTC and termed as theoretical triage. Logistic regression was performed to identify VTC criteria able to predict major trauma. Among 998 admitted patients of the first cohort, 173 patients (17%) were excluded because they were not directly admitted in the first 24 hours. In the first cohort (n = 825), adequate triage was 58% and overtriage was 42%. In the second cohort (n = 190), adequate triage was 40%, overtriage was 60%, and undertriage was less than 1%. Theoretical triage generated a nonsignificantly lower overtriage and a higher undertriage compared with observed triage. The most powerful predictors of major trauma were paralysis (odds ratio [OR,] 0.09; 95% confidence interval [CI], 0.03-0.22), flail chest (OR, 0.1; 95% CI, 0.01-0.03), and Glasgow Coma Scale (GCS) score of less than 13 (OR, 0.28; 95% CI, 0.17-0.45), whereas global assessments of speed and mechanism alone were poor predictors (positive likelihood ratio, 0.92-1.4). In the Paris area, the French physician-based prehospital triage system for patients with suspicion of major trauma showed a high rate of overtriage and a low rate of undertriage. Criteria of global assessment of speed and mechanism alone were poor predictors of major trauma.


Subjective well-being, religiosity and anxiety: a cross-sectional study applied to a sample of Brazilian medical students.
To assess associations between subjective well-being (SWB), religiosity, anxiety and other factors in a sample of Brazilian medical students from a public university in northeastern Brazil. The present study followed a cross-sectional, observational, analytical approach. Data were collected by administering a self-applicable questionnaire composed of questions focused on sociodemographic data and based on the Satisfaction With Life Scale (SWL), Positive Affect and Negative Affect Scale (PANAS), Penn State Worry Questionnaire (PSWQ), and the Duke Religiosity Index (DUREL). The sample comprised 417 medical school students (73.54% of all the enrolled students). The medical students assessed presented a medium level of satisfaction with life, low mean positive emotion levels and high anxiety/uneasiness levels. Surprisingly, lower anxiety and intrinsic religiosity (IR) scores were associated with higher scores in the two SWB parameters (positive emotions and satisfaction with life). Furthermore, the factors leisure activities, good sleep quality, financial support, age, and gender were associated with the highest SWB scores (with emotional and cognitive components, or with only one of these two components). Data in the current study corroborated the negative association between SWB and anxiety; however, in opposition to the literature, they also evidenced a negative association between SWB and IR. In addition, the present research signaled the need for creating preventive intervention programs to increase SWB through positive psychological techniques and/or to decrease anxiety by applying, for instance, cognitive-behavioral therapy paradigms and/or mindfulness techniques to medical students.


Outcomes research in podiatric medicine.
Outcomes research has become a high priority for the podiatric medical profession, according to the results of a recent survey of members of the American Podiatric Medical Association (APMA). The methods of population-based studies using claims data, health-related quality-of-life measures, decision and cost-effectiveness analysis, and quality improvement are discussed and their contributions to the podiatric medical profession highlighted. The integration of this methodology into the podiatric medical literature has been sparse. Future work needs to address the training of future researchers in these methods, the establishment of collaborative arrangements, and the development of uniform clinical and health-related quality-of-life measures.


Digoxin for atrial fibrillation and atrial flutter: A systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.
During recent years, systematic reviews of observational studies have compared digoxin to no digoxin in patients with atrial fibrillation or atrial flutter, and the results of these reviews suggested that digoxin seems to increase the risk of all-cause mortality regardless of concomitant heart failure. Our objective was to assess the benefits and harms of digoxin for atrial fibrillation and atrial flutter based on randomized clinical trials. We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, BIOSIS for eligible trials comparing digoxin versus placebo, no intervention, or other medical interventions in patients with atrial fibrillation or atrial flutter in October 2016. Our primary outcomes were all-cause mortality, serious adverse events, and quality of life. Our secondary outcomes were heart failure, stroke, heart rate control, and conversion to sinus rhythm. We performed both random-effects and fixed-effect meta-analyses and chose the more conservative result as our primary result. We used Trial Sequential Analysis (TSA) to control for random errors. We used GRADE to assess the quality of the body of evidence. 28 trials (n = 2223 participants) were included. All were at high risk of bias and reported only short-term follow-up. When digoxin was compared with all control interventions in one analysis, we found no evidence of a difference on all-cause mortality (risk ratio (RR), 0.82; TSA-adjusted confidence interval (CI), 0.02 to 31.2; I2 = 0%); serious adverse events (RR, 1.65; TSA-adjusted CI, 0.24 to 11.5; I2 = 0%); quality of life; heart failure (RR, 1.05; TSA-adjusted CI, 0.00 to 1141.8; I2 = 51%); and stroke (RR, 2.27; TSA-adjusted CI, 0.00 to 7887.3; I2 = 17%). Our analyses on acute heart rate control (within 6 hours of treatment onset) showed firm evidence of digoxin being superior compared with placebo (mean difference (MD), -12.0 beats per minute (bpm); TSA-adjusted CI, -17.2 to -6.76; I2 = 0%) and inferior compared with beta blockers (MD, 20.7 bpm; TSA-adjusted CI, 14.2 to 27.2; I2 = 0%). Meta-analyses on acute heart rate control showed that digoxin was inferior compared with both calcium antagonists (MD, 21.0 bpm; TSA-adjusted CI, -30.3 to 72.3) and with amiodarone (MD, 14.7 bpm; TSA-adjusted CI, -0.58 to 30.0; I2 = 42%), but in both comparisons TSAs showed that we lacked information. Meta-analysis on acute conversion to sinus rhythm showed that digoxin compared with amiodarone reduced the probability of converting atrial fibrillation to sinus rhythm, but TSA showed that we lacked information (RR, 0.54; TSA-adjusted CI, 0.13 to 2.21; I2 = 0%). The clinical effects of digoxin on all-cause mortality, serious adverse events, quality of life, heart failure, and stroke are unclear based on current evidence. Digoxin seems to be superior compared with placebo in reducing the heart rate, but inferior compared with beta blockers. The long-term effect of digoxin is unclear, as no trials reported long-term follow-up. More trials at low risk of bias and low risk of random errors assessing the clinical effects of digoxin are needed. PROSPERO CRD42016052935.


Multiparametric positron emission tomography/magnetic resonance imaging in nasopharyngeal carcinoma: Correlations between magnetic resonance imaging functional parameters and 18F-fluorodeoxyglucose positron emission tomography imaging biomarkers and their predictive value for treatment failure.
The clinical significance of positron emission tomography/magnetic resonance imaging (PET/MRI) functional parameters in nasopharyngealcarcinoma (NPC) remains unclear. The purpose of this prospective study was two-fold: (1) to investigate the associations between simultaneously acquired PET/MRI perfusion, diffusion, and glucose metabolism parameters in patients with NPC and (2) to analyze their predictive value with respect to treatment failure. We enrolled 85 patients with primary NPC who simultaneously underwent18F-fluorodeoxyglucose PET/CT and PET/MRI before definitive treatment. The following variables were determined: (1) functional parameters from the MRI component, including perfusion values (Ktrans ,kep ,ve , and initial area under the enhancement curve) and apparent diffusion coefficient (ADC) values, and (2) PET parameters, including metabolic tumor volume (MTV). The reciprocal interrelationships between these parameters and their correlations with treatment failure were examined. We observed significant negative associations between Ktrans and ADC (r = -0.215, P = 0.049) as well as between ve and ADC (r = -0.22, P = 0.04). Correlations between PET and MRI functional parameters were not statistically significant. Treatment failures were observed in 21.2% of patients without distant metastases. Multivariate analysis identified ve as a significant independent predictor for treatment failure (P = 0.022), whereas MTV showed a borderline significance (P = 0.095). Patients in whom both ve and MTV values were increased had a significantly higher rate of treatment failure (62.5%) than those with either one (21.9%) or no (7.7%) increased parameter (P = 0.004). Correlation analyses revealed complex interrelationships among PET and MRI indices measured in patients with NPC. These parameters may have a complementary role in predicting treatment failure in this clinical setting.


Ruminal lactic acidosis: relationship of forestomach motility to nondissociated volatile fatty acids levels.
Ruminal lactic acidosis was produced in 9 overnight fasted rumen-fistulated sheep by placing ground wheat (40 g/kg of body weight) into the rumen. Ruminal stasis occurred within 8 hours of grain engorgement in 6 sheep (early stasis group) and between 10 and 12 hours in the remaining 3 sheep (late stasis group). The initial impairment to forestomach motility was a decrease in the mean frequency of reticulo-ruminal contractions which occurred within 4 hours of the intraruminal placement of wheat in the early stasis group and within 6 hours in the late stasis group. Since blood pH, carbon dioxide pressure, and serum bicarbonate were all normal, systemic acidosis was not a contributing factor to this decrease in contraction frequency. The concentrations of total nondissociated volatile fatty acids (VFA; acetic, propionic, and butyric acid) in ruminal fluid, however, were significantly increased, being 13.60 mM/L (mean, pH 4.92) in the early stasis group and 15.77 mM/L (pH 4.80) in the late stasis group. Free DL-lactic acid in ruminal fluids was 6.37 +/- 6.1 mM/L (mean +/- SD) in the early stasis group and 9.72 +/- 4.2 mM/L in the late stasis group. A reduction in contraction amplitude was observed within 6 hours of grain engorgement in the early stasis group and within 8 hours in the late stasis group. At these times, the concentrations of nondissociated VFA were 10.19 mM/L (pH 4.46) in the early stasis group and 10.52 mM/L (pH 4.62) in the late stasis group. The ruminal values of free DL-lactic acid were 13.93 mM/L in the early stasis group and 16.14 mM/L in the late stasis group.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of a national quality improvement collaborative on prehospital care for acute myocardial infarction and stroke in England.
Previous studies have shown wide variations in prehospital ambulance care for acute myocardial infarction (AMI) and stroke. We aimed to evaluate the effectiveness of implementing a Quality Improvement Collaborative (QIC) for improving ambulance care for AMI and stroke. We used an interrupted time series design to investigate the effect of a national QIC on change in delivery of care bundles for AMI (aspirin, glyceryl trinitrate [GTN], pain assessment and analgesia) and stroke (face-arm-speech test, blood pressure and blood glucose recording) in all English ambulance services between January 2010 and February 2012. Key strategies for change included local quality improvement (QI) teams in each ambulance service supported by a national coordinating expert group that conducted workshops educating staff in QI methods to improve AMI and stroke care. Expertise and ideas were shared between QI teams who met together at three national workshops, between QI leads through monthly teleconferences, and between the expert group and participants. Feedback was provided to services using annotated control charts. We analyzed change over time using logistic regression with three predictor variables: time, gender, and age. There were statistically significant improvements in care bundles in nine (of 12) participating trusts for AMI (OR 1.04, 95% CI 1.04, 1.04), nine for stroke (OR 1.06, 95% CI 1.05, 1.07), 11 for either AMI or stroke, and seven for both conditions. Overall care bundle performance for AMI increased in England from 43 to 79% and for stroke from 83 to 96%. Successful services all introduced provider prompts and individualized or team feedback. Other determinants of success included engagement with front-line clinicians, feedback using annotated control charts, expert support, and shared learning between participants and organizations. This first national prehospital QIC led to significant improvements in ambulance care for AMI and stroke in England. The use of care bundles as measures, clinical engagement, application of quality improvement methods, provider prompts, individualized feedback and opportunities for learning and interaction within and across organizations helped the collaborative to achieve its aims.


Molecular analysis of metastasis in a polyomavirus middle T mouse model: the role of osteopontin.
In order to study metastatic disease, we employed the use of two related polyomavirus middle T transgenic mouse tumor transplant models of mammary carcinoma (termed Met and Db) that display significant differences in metastatic potential. Through suppression subtractive hybridization coupled to the microarray, we found osteopontin (OPN) to be a highly expressed gene in the tumors of the metastatic mouse model, and a lowly expressed gene in the tumors of the lowly metastatic mouse model. We further analyzed the role of OPN in this model by examining sense and antisense constructs using in vitro and in vivo methods. With in vivo metastasis assays, the antisense Met cells showed no metastatic tumor formation to the lungs of recipient mice, while wild-type Met cells, with higher levels of OPN, showed significant amounts of metastasis. The Db cells showed a significantly reduced metastasis rate in the in vivo metastasis assay as compared with the Met cells. Db cells with enforced overexpression of OPN showed elevated levels of OPN but did not demonstrate an increase in the rate of metastasis compared with the wild-type Db cells. We conclude that OPN is an essential regulator of the metastatic phenotype seen in polyomavirus middle T-induced mammary tumors. Yet OPN expression alone is not sufficient to cause metastasis. These data suggest a link between metastasis and phosphatidylinositol-3-kinase-mediated transcriptional upregulation of OPN, but additional phosphatidylinositol-3-kinase-regulated genes may be essential in precipitating the metastasis phenotype in the polyomavirus middle T model.


Scaling of Algorithmic Bias in Pulse Oximetry with Signal-to-Noise Ratio.
Recent work has noted a skin-color bias in existing pulse oximetry systems in their estimation of arterial oxygen saturation. Frequently, the algorithm used by these systems estimate a "ratio-of-ratios", called the "R-value", on their way to estimating the oxygen saturation. In this work, we focus on an "SNR-related" bias that is due to noise in measurements. We derive expressions for the SNR-related bias in R-value estimation, and observe how it scales with the signal-to-noise ratio (SNR). We show that the bias can arise at two steps of R-value estimation: in estimating the max and min of a pulsatile signal, and, additionally in taking ratios to estimate the R-value. We assess the bias resulting from the combination of the two steps, but also separate out contributions of each step. By doing so, we deduce that the bias induced in max and min estimation is likely to dominate. Because the SNR tends to get worse with higher melanin concentration, our result provides a sense of scaling of this bias with melanin concentration.


Factors affecting food chain transfer of mercury in the vicinity of the Nyanza Site, Sudbury River, Massachusetts.
The influence of the Nyanza Chemical Waste Dump Superfund Site on the Sudbury River, Massachusetts, was assessed by analysis of sediment, fish prey organisms, and predator fish from four locations in the river system. Whitehall Reservoir is an impoundment upstream of the site, and Reservoir #2 is an impoundment downstream of the site. Cedar Street is a flowing reach upstream of the site, and Sherman Bridge is a flowing reach downstream of the site. Collections of material for analysis were made three times, in May, July, and October. Sediment was analyzed for acid-volatile sulfide (AVS), simultaneously-extracted (SEM) metals (As, Cd, Cr, Hg, Pb, Sb, Zn), and total recoverable Hg. The dominant predatory fish species collected at all sites, largemouth bass (Micropterus salmoides), was analyzed for the same suite of metals as sediment. Analysis of stomach contents of bass identified small fish (yellow perch Perca flavescens, bluegill Lepomis macrochirus, and pumpkinseed Lepomis gibbosus), crayfish, and dragonfly larvae as the dominant prey organisms. Samples of the prey were collected from the same locations and at the same times as predator fish, and were analyzed for total and methyl mercury. Results of AVS and SEM analyses indicated that sediments were not toxic to aquatic invertebrates at any site. The SEM concentrations of As, Cd, and Cr were significantly higher at Reservoir #2 than at the reference sites, and SEM As and Cd were significantly higher at Sherman Bridge than at Cedar St. Sediment total Hg was elevated only at Reservoir #2. Hg was higher at site-influenced locations in all fish species except brown bullhead (Ameiurus nebulosus). Cd was higher in bluegill, black crappie (Pomoxis nigromaculatus), and brown bullhead, and Cr was higher in largemouth bass fillet samples but not in whole-body samples. There were no seasonal differences in sediment or prey organism metals, but some metals in some fish species did vary over time in an inconsistent manner. Predator fish Hg concentration was significantly linearly related to weighted prey organism methyl Hg concentration. Largemouth bass Hg was significantly lower at Reservoir #2 in our study than in previous investigations in 1989 and 1990. High concentrations of inorganic Hg remain in river sediment as a result of operation of the Nyanza site, and fish Hg concentrations in river reaches downstream of the site are elevated compared to upstream reference sites. However, the differences are relatively small and Hg concentrations in largemouth bass from the site-influenced locations are no higher than those from some other, nearby uncontaminated sites. We hypothesize that this results from burial of contaminated sediment with cleaner material, which reduces bioavailability of contaminants and possibly reduces methylation of mercury.


Impact of aortic annulus size on valve hemodynamics and clinical outcomes after transcatheter and surgical aortic valve replacement: insights from the PARTNER Trial.
The objective was to evaluate the effects of aortic annulus size on valve hemodynamics and clinical outcomes in those patients included in the Placement of Aortic Transcatheter Valves (PARTNER) randomized controlled trial cohort A and the nonrandomized continued access cohort. Patients included the randomized controlled trial (n=574) and nonrandomized continued access (n=1358) cohorts were divided in tertiles according to aortic annulus diameter (small aortic annulus tertile, medium aortic annulus tertile, and large aortic annulus tertile [LAA], respectively) as measured by transthoracic echocardiography. Severe prosthesis-patient mismatch was defined as an effective aortic orifice area of <0.65 cm(2)/m(2). In the randomized controlled trial cohort, patients in the small aortic annulus tertile who underwent transcatheter aortic valve replacement had a lower incidence of severe prosthesis-patient mismatch (19.7% versus 37.5%; P=0.03) and only a trend toward a higher incidence of moderate-to-severe paravalvular leaks compared with surgical aortic valve replacement (5.7% versus 0%; P=0.06). In the LAA tertile, there were no differences in the rate of prosthesis-patient mismatch between groups, and a significant increase in moderate-to-severe paravalvular leaks was associated with transcatheter aortic valve replacement (9% versus 0%; P=0.01). There were no differences in mortality between transcatheter aortic valve replacement and surgical aortic valve replacement. In the nonrandomized continued access cohort, there were no differences in prosthesis-patient mismatch between the small aortic annulus and LAA tertiles, but a higher rate of moderate-to-severe paravalvular leaks was observed in the LAA tertile (5.9% versus 11.5%; P=0.009). Patients in the LAA tertile had a higher mortality rate at 1-year follow-up (P=0.02), and differences persisted in multivariable analysis (P=0.048 for LAA versus medium aortic annulus tertile, P=0.035 for LAA versus small aortic annulus tertile). Aortic annulus size had a major impact on valve hemodynamics and clinical outcomes after transcatheter aortic valve replacement and surgical aortic valve replacement. This study highlights the importance of considering aortic annulus size in the evaluation of high-risk patients who are candidates for aortic valve replacement. http://www.clinicaltrials.gov. Unique identifier: NCT00530894.


MicroRNA-449 in cell fate determination.
The microRNAs 449a, b, and c (miR-449) are potent inducers of cell death, cell cycle arrest, and/or cell differentiation. They belong to the same family as the p53-responsive microRNAs miR-34. Instead of p53, however, the cell cycle regulatory transcription factor E2F1 induces miR-449. All members of this microRNA family are capable of mediating cell cycle arrest and apoptosis and might thereby contribute to tumor suppression. Underlying mechanisms include the downregulation of histone acetyl transferases and consecutive activation of p53, but also the targeting of cyclin dependent kinases and their association partners. Thus, miR-34 and miR-449 provide an asymmetric feedback loop to balance E2F and p53 activities. More recently, it was discovered that miR-449 displays strong tissue specificity, with high levels in lung and testes. Two model systems (Xenopus embryos and cultured human cells) revealed that miR-449 is essential for the development of ciliated epithelia, and this appears to depend on miR-449-mediated modulation of the Notch signaling pathway. Here we summarize our current knowledge on cell fate determination by miR-449, and we propose future directions to explore the function of miR-449 in cell regulation and organismal development. MiR-449 helps to ensure proper cell function but also to avoid cancer, marking a close link between cell differentiation and tumor suppression.


Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts.
Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1β-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1β-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1β-/- mice. Moreover, Pgc-1β-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1β-/- mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1β-/- systems in widespread cardiac regions.


Stain removal efficacy: an in vitro evaluation using quantitative image analysis.
This study developed a computer image analysis technique as a quantitative means to measure changes in dental stain after brushing with various dentifrices. Enamel specimens with naturally occurring mature stain were cut from bovine incisors. The specimens were subjected to in vitro toothbrushing with one of the four tested groups, consisting of two dentifrices that make claims of stain removal (Aquafresh Whitening and Rembrandt Sensitive), a regular dentifrice, (Aquafresh Triple Protection), and water. Digital images of stain specimens were recorded under standardized lighting conditions and analyzed with an image analysis software. The area-intensity stain determinant, which accounted for the reflected intensity and the corresponding areas of stain, was computed. Stain removal efficacy was calculated based on the difference in area-intensity stain determinant before and after brushing. Brushing with any of the tested dentifrices removed more stain than did brushing with water alone. The finding that brushing with a regular dentifrice resulted in higher stain removal efficacy than brushing with water seems to indicate a role for abrasivity. Aquafresh Whitening had a higher stain removal efficacy than did Rembrandt for the removal of mature calcified stain used in this study. However, there were certain stains that none of the dentifrices removed. Computer image analysis provides an objective and quantitative measurement to distinguish in vitro stain removal efficacy of dentifrices.


[Isolation and some properties of the very high density Lpm-lipoprotein from mink serum].
A procedure for isolation of a very high density Lpm-lipoprotein (Lpm) consisting of 7-15% polyethyleneglycol precipitation and subsequent gel-filtration on a bio-gel A-5m column was developed. An immunoelectrophoretically pure Lpm with molecular weight of about 800 000 was obtained. The procedure used does not change the allo- and heteroantigenic properties of Lpm.


[Effect of temperature on homoeotic mutation expression in Drosophila. I. Homoeotic transformation in Proboscipedia mutants].
It is generally adopted that the homoeotic gene proboscipedia causes the transformation of the distal parts of proboscis into corresponding tarsal or antennal (aristal) segments. It is shown that actually the homoeotic effect of the mutation proboscipedia consists in the transformation of the oral lobes of proboscis into a whole prothoracic leg. Sometimes the distal parts of the homoeotic leg (segments of tarsus, claws) can coexist with or be substituted for by the aristal filaments. The transformation of oral lobes of proboscic into the leg is most conspicuous at 29 degrees C, while at 16 degrees C the substitution of tarsal structures by aristal ones is observed more frequently. The homology between the corresponding elements of the proboscis, legs and antenna (as revealed by the pattern of homoeosis) is discussed.


[Policies and practices towards equity: a broad approach].
This paper presents a preliminary overview of policies and practices in health focusing equity. It begins with a brief description of the actions developed by the Collective Health Nursing Department of the School of Nursing of the University of Sao Paulo, Brazil, to support the struggle for social equity. It also presents the different perspectives of the concept that can be identified in health literature, each of them shaping distinct policies and practices.


Site-specific thrombin receptor antibodies inhibit Ca2+ signaling and increased endothelial permeability.
Thrombin receptor is activated by thrombin-mediated cleavage of the receptor's NH2 terminus between Arg-41 and Ser-42, generating a new NH2 terminus that functions as a "tethered ligand" by binding to sites on the receptor. We prepared antibodies (Abs) directed against specific receptor domains to study the tethered ligand-receptor interactions required for signaling the increase in endothelial permeability to albumin. We used polyclonal Abs directed against the peptide sequences corresponding to the extracellular NH2 terminus [residues 70-99 (AbDD) and 1-160 (AbEE)] and extracellular loops 1 and 2 [residues 161-178 (AbL1) and 244-265 (AbL2)] of the seven-transmembrane thrombin receptor. Receptor activation was determined by measuring changes in cytosolic Ca2+ concentration ([Ca2+]i) in human dermal microvascular endothelial cells (HMEC) loaded with Ca(2+)-sensitive fura 2-acetoxymethyl ester dye. The transendothelial 125I-labeled albumin clearance rate (a measure of endothelial permeability) was determined across the confluent HMEC monolayers. AbEE (300 micrograms/ml), directed against the entire extracellular NH2-terminal extension, inhibited the thrombin-induced increases in [Ca2+]i and the endothelial 125I-albumin clearance rate (> 90% reduction in both responses). AbDD (300 micrograms/ml), directed against a sequence within the NH2-terminal extension, inhibited 70% of the thrombin-induced increase in [Ca2+]i and 60% of the increased 125I-albumin clearance rate. AbL2 (300 micrograms/ml) inhibited these responses by 70 and 80%, respectively. However, AbL1 (300 micrograms/ml) had no effect on either response. We conclude that NH2-terminal extension and loop 2 are critical sites for thrombin receptor activation in endothelial cells and thus lead to increased [Ca2+]i and transendothelial permeability to albumin.


Imaging the Beta-cell mass: why and how.
Diabetes is a disorder characterized by beta-cell loss or exhaustion and insulin deficiency. At present, knowledge is lacking on the underlying causes and for the therapeutic recovery of the beta-cell mass. A better understanding of diabetes pathogenesis could be obtained through exact monitoring of the fate of beta-cells under disease and therapy conditions. This could pave the way for a new era of intervention by islet replacement and regeneration regimens. Monitoring the beta-cell mass requires a reliable method for noninvasive in vivo imaging. Such a method is not available at present due to the lack of a beta-cell-specific contrast agent. The only existing method to monitor islet cells in vivo consists of labeling islet transplants with iron nanoparticles prior to transplantation and visualization of the transplanted islets by magnetic resonance imaging (MRI). Therefore, accurate assessment of the native beta-cell mass is still limited to autopsy studies. Endeavors to find a biological structure specific for beta-cells led to the discovery of potential candidates that have been tested for noninvasive imaging. Among them are the ligand to the vesicular monoamine transporter type 2 (VMAT-2), which is called dihydrotetrabenazine (DTBZ), antibodies to zinc transporter (ZnT-8) and the monoclonal antibody IC2. While DTBZ and antibodies to ZnT-8 showed binding activities to more than beta-cells, the anti-IC2 monoclonal antibody showed binding properties exclusively to insulin-producing beta-cells. This effect was demonstrated in many previous investigations, and has been further substantiated more recently. Thus, at present, IC2 seems to be the only useful marker for noninvasive functional imaging of native beta-cells. Experiments with a radioisotope-chelated IC2 structure on pancreas ex vivo showed that the tracer specifically bound to the beta-cell surface and could be detected by nuclear imaging. In the near future, these promising findings may offer a new way to monitor the beta-cell mass in vivo under disease and therapy conditions so that we can learn more about diabetes pathogenesis and options for disease prevention.


Going into the groin: Injection into the femoral vein among people who inject drugs in three urban areas of England.
There have been increasing concerns about injection into the femoral vein - groin injecting - among people who inject drugs in a number of countries, though most studies have been small. The extent, reasons and harms associated with groin injecting are examined. Participants were recruited using respondent driven sampling (2006-2009). Weighted data was examined using bivariate analyses and logistic regression. The mean age was 32 years; 25% were women (N=855). During the preceding 28 days, 94% had injected heroin and 13% shared needles/syringes. Overall, 53% reported ever groin injecting, with 9.8% first doing so at the same age as starting to inject. Common reasons given for groin injecting included: "Can't get a vein elsewhere" (68%); "It is discreet" (18%); and "It is quicker" (14%). During the preceding 28 days, 41% had groin injected, for 77% this was the only body area used (for these "It is discreet" was more frequently given as a reason). In the multivariable analysis, groin injection was associated with: swabbing injection sites; saving filters for reuse; and receiving opiate substitution therapy. It was less common among those injecting into two body areas, and when other people (rather than services) were the main source of needles. Groin injection was more common among those with hepatitis C and reporting ever having deep vein thrombosis or septicaemia. Groin injection was common, often due to poor vascular access, but for some it was out of choice. Interventions are required to reduce injecting risk and this practice.


Predicting Motor Sequence Learning in People With Parkinson Disease.
Skill acquisition (ie, performance changes during practice) occurs in a nonlinear fashion. Despite this, motor learning is typically measured by comparing discrete timepoints. Thus, typical measures of motor learning do not detect skill acquisition characteristics that may be clinically meaningful. Reliable prediction of motor skill learning in people with Parkinson disease (PD) would allow therapists to more effectively individualize practice doses to fit specific patients' needs. The purposes of this study were to (a) characterize postural skill acquisition in people with PD, and identify factors (such as acquisition rate and practice dose to plateau) that predict learning, and (b) investigate whether levodopa medication (L-dopa) status during practice impacted learning. Twenty-seven adults with PD practiced a postural motor task over 3 days, followed by 2 retention tests. Participants were randomized to practice either ON or OFF L-dopa. Data for repeating and random sequences were each analyzed using nonlinear curve-fitting and mixed-effects regressions. Learning was defined as pretest minus retention test performance. Participants with less physical impairment demonstrated less learning on the repeating and random sequence tasks compared with participants with more impairment. Participants who improved faster during practice demonstrated less learning on the repeating sequence task compared with participants who improved more slowly. Reaching plateau during practice was not related to learning. L-dopa did not impair learning. Participants' skill acquisition characteristics were related to learning a postural motor task. Patient-specific factors, such as the rate of skill acquisition, level of physical function, and medication status, may influence how postural motor practice is delivered during balance rehabilitation.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A250).


Molecular subtypes and scoring tools related to Foxo signaling pathway for assessing hepatocellular carcinoma prognosis and treatment responsiveness.
Background: Transcription factors in Foxo signaling pathway influence hepatocellular carcinoma metastasis through epithelial mesenchymal transition-related pathways. Prognostic factors in the Foxo signaling pathway are feasible for HCC prognosis and therapeutic management. Methods: Based on the differentially expressed genes and Foxo signaling pathway genes in HCC, the ConsensusClusterPlus package was conducted to identify Foxo signaling pathway-related molecular subtypes in HCC. Based on the DEGs in the FMSs, the optimal prognostic factors in HCC were screened by cox and least absolute shrinkage and selection operator (LASSO) cox analysis to form the Foxo prognosis score (FPS). The prognostic predictive effectiveness of FPS was assessed by Kaplan Meier (K-M) analysis and Receiver Operating Characteristic (ROC) analysis. Additionally, tumor microenvironment (TME) score, tumor mutation burden (TMB) and treatment sensitivity differences in FMSs and FPS groups were also evaluated. Results: There were low, medium and high Foxo signaling pathway activity molecular subtypes in HCC named FMS 1, FMS 2 and FMS 3, respectively. FMS 1 with lowest Foxo signaling pathway activity presented an excellent survival advantage, while FMS 3 with highest Foxo signaling pathway activity exhibited an inhibitory TME status. According to FPS grouping, low FPS exhibited favorable survival, low TMB and anti-tumor activity. Patients in the low FPS group were mostly in the early stage of cancer. Moreover, we found that patients with high and low FPS exhibited different sensitivity to chemotherapy, and patients with low FPS were more sensitive to immunotherapy. Conclusion: We revealed a novel molecular subtype and prognostic tool based on Foxo signaling pathway signature, which could potentially provide a direction for accurate and effective assessment of potential personalized treatment options and prognostic management for HCC patients.


Feature analysis and centromere segmentation of human chromosome images using an iterative fuzzy algorithm.
Classification of homologous chromosomes is essential to advanced studies of cancer genetics. Centromere intensities are believed to be an important differentiating feature between homologs. Therefore, segmentation of centromeres is a major step toward the realization of homolog classification. This paper describes an iterative fuzzy algorithm which successfully segments centromeres from images of human chromosomes prepared using fluorescence in-situ hybridization technique. The algorithm is based on assigning a fuzzy membership value to each pixel in the centromere image. An iterative algorithm then updates and minimizes a defined error function. Chromosome 22, a highly heteromorphic chromosome, is used to verify the centromere segmentation method. Homologs of this chromosome are classified based on their segmented centromere intensities as well as their morphological differences. The classification results of these two methods agree completely and are used to validate our developed algorithm.


The protein subunit of telomerase displays patterns of dynamic evolution and conservation across different metazoan taxa.
Most animals employ telomerase, which consists of a catalytic subunit known as the telomerase reverse transcriptase (TERT) and an RNA template, to maintain telomere ends. Given the importance of TERT and telomere biology in core metazoan life history traits, like ageing and the control of somatic cell proliferation, we hypothesised that TERT would have patterns of sequence and regulatory evolution reflecting the diverse life histories across the Animal Kingdom. We performed a complete investigation of the evolutionary history of TERT across animals. We show that although TERT is almost ubiquitous across Metazoa, it has undergone substantial sequence evolution within canonical motifs. Beyond the known canonical motifs, we also identify and compare regions that are highly variable between lineages, but show conservation within phyla. Recent data have highlighted the importance of alternative splice forms of TERT in non-canonical functions and although animals may share some conserved introns, we find that the selection of exons for alternative splicing appears to be highly variable, and regulation by alternative splicing appears to be a very dynamic feature of TERT evolution. We show that even within a closely related group of triclad flatworms, where alternative splicing of TERT was previously correlated with reproductive strategy, we observe highly diverse splicing patterns. Our work establishes that the evolutionary history and structural evolution of TERT involves previously unappreciated levels of change and the emergence of lineage specific motifs. The sequence conservation we describe within phyla suggests that these new motifs likely serve essential biological functions of TERT, which along with changes in splicing, underpin diverse functions of TERT important for animal life histories.


Pathophysiology of infections after internal fixation of fractures.
Infection complicating internal fixation of fractures is a serious complication that is difficult to treat. Whenever metallic devices are implanted in vivo, successful biointegration requires that host cells colonize the highly reactive implant surface. Bacteria such as staphylococci can also become adherent to metallic or polymeric implants and will compete with host cells for colonization of the implant surface. Once adherent, these bacteria form a biofilm and undergo phenotypic changes that make them resistant to the normal host immune response as well as to antibiotics. Furthermore, metallic implants themselves cause specific deficits in the function of the local immune system that may render the host response to infection inadequate. Any associated soft-tissue injury causes even greater impairment of local immune function. Despite the potentially detrimental impact of internal fixation, fracture stability is of paramount importance in achieving fracture union and in preventing infection. It has been demonstrated in animal models that contaminated fractures without internal fixation develop clinical infection more commonly than similar fractures treated with internal fixation at the time of colonization. Because of the potential for infection whenever internal fixation is utilized, appropriate prophylactic antibiotic coverage for staphylococci and Gram-negative organisms should be provided. Open wounds and severely damaged soft tissues require aggressive management so that a viable soft-tissue envelope is maintained around the implant. Host factors such as smoking and malnourishment should be corrected. Early diagnosis and aggressive treatment of implant-related infection with antibiotics, debridement, and maintenance of stable internal fixation are essential to successful treatment.