Association between Gestational Weight Gain, Gestational Diabetes Risk, and Obstetric Outcomes: A Randomized Controlled Trial Post Hoc Analysis.
Excess gestational weight gain (GWG) is associated with the development of gestational diabetes mellitus (GDM). Lifestyle trials have not achieved much GWG limitation, and have largely failed to prevent GDM. We compared the effect of substantial GWG limitation on maternal GDM risk. Pregnant women with a body mass index (BMI) ≥29 kg/m² <20 weeks gestation without GDM (n = 436) were randomized, in a multicenter trial, to usual care (UC), healthy eating (HE), physical activity (PA), or HE and PA lifestyle interventions. GWG over the median was associated with higher homeostasis model assessment insulin resistance (HOMA-IR) and insulin secretion (Stumvoll phases 1 and 2), a higher fasting plasma glucose (FPG) at 24⁻28 weeks (4.66 ± 0.43 vs. 4.61 ± 0.40 mmol/L, p < 0.01), and a higher rate of caesarean section (38% vs. 27% p < 0.05). The GWG over the median at 35⁻37 weeks was associated with a higher rate of macrosomia (25% vs. 16%, p < 0.05). A post hoc comparison among women from the five sites with a GWG difference >3 kg showed no significance difference in glycaemia or insulin resistance between HE and PA, and UC. We conclude that preventing even substantial increases in GWG after the first trimester has little effect on maternal glycaemia. We recommend randomized controlled trials of effective lifestyle interventions, starting in or before the first trimester.


Reduction of neuromelanin-positive nigral volume in patients with MSA, PSP and CBD.
Diseases presenting extrapyramidal symptoms are accompanied by nigral cell loss. In the previous study, we demonstrated the reduction of the neuromelanin-positive volume of substantia nigra (SN) pars compacta (SNc) in patients with Parkinson's disease (PD) using 3-Tesla MRI. In the present study we investigated the neuromelanin-positive SNc volume in patients with the other parkinsonian disorders including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and compared the results with those with PD, spinocerebellar ataxia (SCA) and controls. Axial T1-weighted (T1W) images were obtained with a 3-Tesla MRI scanner. The border of the neuromelanin-positive region of the SNc was traced manually on these images with a pentablet pointing device and the SNc volume was calculated. The SNc volumes of 28 patients with MSA, 11 patients with PSP and 10 patients with CBD were compared with those of 80 patients with PD, 9 patients with SCA and 54 patients who had suffered mild acute ischemic stroke as controls. The mean volumes for the left and right SN were used for statistical analyses. The volumes of the neuromelanin-positive SNc region in patients with MSA, PSP and CBD, but not SCA were reduced to the same extent as PD patients compared with controls. Reduced volume of the neuromelanin-positive SNc region of patients with MSA, PSP and CBD was detected by neuromelanin MR imaging. Volumetric evaluation of neuromelanin MR imaging may provide a biomarker of nigral degeneration in patients with MSA, PSP and CBD as in patients with PD.


Vital Signs: Demographic and Substance Use Trends Among Heroin Users - United States, 2002-2013.
Heroin use and overdose deaths have increased significantly in the United States. Assessing trends in heroin use among demographic and particular substance-using groups can inform prevention efforts. FDA and CDC analyzed data from the National Survey on Drug Use and Health and National Vital Statistics System reported during 2002-2013. Trends in heroin use among demographic and substance using groups were compared for 2002-2004, 2005-2007, 2008-2010, and 2011-2013. A multivariable logistic regression model was used to identify characteristics associated with heroin abuse or dependence. Annual average rates of past-year heroin use increased from 1.6 per 1,000 persons aged ≥ 12 years in 2002-2004 to 2.6 per 1,000 in 2011-2013. Rates of heroin abuse or dependence were strongly positively correlated with rates of heroin-related overdose deaths over time. For the combined data years 2011-2013, the odds of past-year heroin abuse or dependence were highest among those with past-year cocaine or opioid pain reliever abuse or dependence. Heroin use has increased significantly across most demographic groups. The increase in heroin abuse or dependence parallels the increase in heroin-related overdose deaths. Heroin use is occurring in the context of broader poly-substance use. Further implementation of a comprehensive response that targets the wider range of demographic groups using heroin and addresses the key risk factors for heroin abuse and dependence is needed. Specific response needs include reducing inappropriate prescribing and use of opioids through early identification of persons demonstrating problematic use, stronger prescription drug monitoring programs, and other clinical measures; improving access to, and insurance coverage for, evidence-based substance abuse treatment, including medication-assisted treatment for opioid use disorders; and expanding overdose recognition and response training and access to naloxone to treat opioid pain reliever and heroin overdoses.


Targeting neuropilin-1 in human leukemia and lymphoma.
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (F(F)/(Y)XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence (D)(KLAKLAK)₂. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-(D)(KLAKLAK)₂ is a promising drug candidate in this setting.


Mindfulness-Based Stress Reduction, Fear Conditioning, and The Uncinate Fasciculus: A Pilot Study.
Mindfulness has been suggested to impact emotional learning, but research on these processes is scarce. The classical fear conditioning/extinction/extinction retention paradigm is a well-known method for assessing emotional learning. The present study tested the impact of mindfulness training on fear conditioning and extinction memory and further investigated whether changes in white matter fiber tracts might support such changes. The uncinate fasciculus (UNC) was of particular interest in the context of emotional learning. In this pilot study, 46 healthy participants were quasi-randomized to a Mindfulness-Based Stress Reduction (MBSR, N = 23) or waitlist control (N = 23) group and underwent a two-day fear conditioning, extinction learning, and extinction memory protocol before and after the course or control period. Skin conductance response (SCR) data served to measure the physiological response during conditioning and extinction memory phases. Diffusion tensor imaging (DTI) data were analyzed with probabilistic tractography and analyzed for changes of fractional anisotropy in the UNC. During conditioning, participants were able to maintain a differential response to conditioned vs. not conditioned stimuli following the MBSR course (i.e., higher sensitivity to the conditioned stimuli), while controls dropped the response. Extinction memory results were not interpretable due to baseline differences. MBSR participants showed a significant increase in fractional anisotropy in the UNC, while controls did not (group by time interaction missed significance). Pre-post changes in UNC were correlated with changes in the response to the conditioned stimuli. The findings suggest effects of mindfulness practice on the maintenance of sensitivity of emotional responses and suggest underlying neural plasticity. (ClinicalTrials.gov, Identifier NCT01320969, https://clinicaltrials.gov/ct2/show/NCT01320969).


Acquiring multiple signals along with the reaction time: improving recognition capability of a multidimensional colorimetric sensor array for sensitive protein detection.
The development of sensitive and cheap sensor arrays for identification of proteins plays an important role in many bioanalytical and clinical investigations. Here, we introduce a multidimensional colorimetric sensor array for the detection of multiple proteins based on acquiring multiple signals along with the reaction time to enhance the discrimination ability. In a single experiment, the unique fingerprint for each protein against the sensor array is generated from a response absorbance signal at three reaction time points (at 10 min, 15 min, and 20 min). Our colorimetric sensing system is able to identify ten proteins not only in aqueous solution at 10 nM but also in human urine at the 50 nM level with an accuracy of 100%. Moreover, the identification of HSA in urine at the nanomolar level within a linear range of 0.05-1.0 μM is achieved. Our sensing array system is sufficiently sensitive for the discrimination of pure HSA, binary mixtures of HSA and Lys at a total concentration of 50 nM in urine. This study indicates that the application of the real-time resolved response signals enables the enhancement of the discrimination ability for protein recognition.


Sleep problems in adolescence and overweight/obesity in young adults: is there a causal link?
This study aims to explore if there is a causal association between adolescence sleep problems and overweight/obesity (Ow/Ob) in young adults. Youth self-reports were used to explore if adolescence (mean age 13.90 years, SD ±0.32) sleep problems lead to general Ow/Ob, computed from body mass index (n = 1075), or abdominal Ow/Ob, computed from waist circumference and waist to height ratio (n = 1179), in young adults (mean age 20.65 years, SD±0.82). Directed acyclic graphs were used to identify potential confounders, modified Poisson regression with a robust error variance was used to model the associations, and inverse probability weights were used to account for loss to follow-up. At adolescence, 27.37% of the subjects reported having frequent sleep problems, and about a fifth of these subjects (22.65%) developed general Ow/Ob at young adulthood. Unadjusted regression analysis indicates a link between adolescent sleep problems and general Ow/Ob in young adults (incidence rate ratio [IRR]: 1.34, 95% confidence interval [CI]: 1.08-2.03), and this link was robust to adjustment for potential confounders (IRR: 1.47, 95% CI: 1.07-2.02). However, no such association was seen for adolescence sleep problems, and abdominal Ow/Ob computed from waist circumference (IRR: 1.30, 95% CI: 0.91-1.87) and waist to height ratio (IRR: 1.27, 95% CI: 0.86-1.88). Although there is evidence for a causal association between sleep problems and general Ow/Ob, the link between sleep problems and abdominal Ow/Ob needs more research to produce conclusive results. Nonetheless, behavioral interventions encouraging healthy sleep practice in young subjects are likely to influence future Ow/Ob outcome.


Low-power phonon lasing through position-modulated Kerr-type nonlinearity.
We demonstrate low-power amplification process in cavity optomechanics (COM). This operation is based on the nonlinear position-modulated self-Kerr interaction. Owing to this nonlinear term, the effective coupling highly scales with the photon number, resulting in a giant enhancement of the cooperativity. Even for small nonlinearity, the system reaches the amplification threshold for weak driving strength, leading to low-power phonon lasing. This amplifier can be phase-preserving and provides a practical advantage related to the power consumption issues. This work opens up new avenues to perform low-power and efficient amplifiers in optomechanics and related fields.


ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection.
Vertebrate DNA can be chemically modified by methylation of the 5 position of the cytosine base in the context of CpG dinucleotides. This modification creates a binding site for MBD (methyl-CpG-binding domain) proteins which target chromatin-modifying activities that are thought to contribute to transcriptional repression and maintain heterochromatic regions of the genome. In contrast with DNA methylation, which is found broadly across vertebrate genomes, non-methylated DNA is concentrated in regions known as CGIs (CpG islands). Recently, a family of proteins which encode a ZF-CxxC (zinc finger-CxxC) domain have been shown to specifically recognize non-methylated DNA and recruit chromatin-modifying activities to CGI elements. For example, CFP1 (CxxC finger protein 1), MLL (mixed lineage leukaemia protein), KDM (lysine demethylase) 2A and KDM2B regulate lysine methylation on histone tails, whereas TET (ten-eleven translocation) 1 and TET3 hydroxylate methylated cytosine bases. In the present review, we discuss the most recent advances in our understanding of how ZF-CxxC domain-containing proteins recognize non-methylated DNA and describe their role in chromatin modification at CGIs.


Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins.
A history of high-level physical activity and/or acute infection might constitute stress factors affecting the plasma oxidant-antioxidant status and levels of heat shock proteins (HSPs) in patients with chronic fatigue syndrome (CFS). This case-control study compared data from 43 CFS patients to results from a matched control group of 23 healthy sedentary subjects. Five patients had no relevant previous history (group I). Eighteen had practised high-level sport (group II), and severe acute infection had been diagnosed in nine patients (group III). A combination of sport practice and infection was noted in 11 patients (group IV). After examination at rest, all subjects performed a maximal cycling exercise test. Plasma levels of two markers of oxidative stress [thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA)] and both HSP27 and HSP70 were measured. At rest, compared with the control group, the TBARS level was higher in groups II, III and IV patients, and the RAA level was lower in groups III and IV. In addition, HSP70 levels were significantly lower in all CFS groups, compared with controls, but negative correlations were found between resting HSP27 and HSP70 levels and the history of physical activity. After exercise, the peak level of TBARS significantly increased in groups II, III and IV, and the variations in HSP27 and HSP70 were attenuated or suppressed, with the greatest effects in groups III and IV. The presence of stress factors in the history of CFS patients is associated with severe oxidative stress and the suppression of protective HSP27 and HSP70 responses to exercise.


Longitudinal Modeling Approaches to Assess the Association Between Changes in 2 Clinical Outcome Assessments.
Understanding how one clinical outcome assessment (COA) (eg, a patient-reported outcome [PRO]) relates to a second COA (eg, a clinician-reported outcome [ClinRO]) may provide insights into disease burden or treatment efficacy. We aimed to briefly review commonly used cross-sectional methods to evaluate the association between a PRO and a ClinRO and to demonstrate the advantages of longitudinal modeling approaches, particularly a joint mixed model for repeated measures (MMRM), to evaluate this association. We generated an example longitudinal data set that included a PRO measured on an 11-point numeric rating scale and a binary ClinRO. The association between change in PRO score and ClinRO response at each time point was examined using 2 cross-sectional analyses: point biserial correlation and logistic regression. We conducted longitudinal analyses of the association between the 2 COAs across time points using MMRM and joint MMRM approaches. Point-biserial correlation and logistic regression analyses correctly captured the "built in" associations between the 2 COAs that strengthened over time, but each association was applicable only for a single time point. The MMRM approach provided correlations over time but only for a single outcome variable. The joint MMRM approach modeled the relationship between both outcome variables simultaneously, allowing for evaluation of the correlations both within and between the variables over time. Each analysis demonstrated the relationship between PRO score changes and ClinRO response. Longitudinal analysis methods, particularly the joint MMRM, allow for a more thorough examination of the correlations among the 2 outcomes than cross-sectional analysis methods.


Distinct structural alterations in proliferating cell nuclear antigen block DNA mismatch repair.
During DNA replication, mismatches and small loops in the DNA resulting from insertions or deletions are repaired by the mismatch repair (MMR) machinery. Proliferating cell nuclear antigen (PCNA) plays an important role in both mismatch-recognition and resynthesis stages of MMR. Previously, two mutant forms of PCNA were identified that cause defects in MMR with little, if any, other defects. The C22Y mutant PCNA protein completely blocks MutSα-dependent MMR, and the C81R mutant PCNA protein partially blocks both MutSα-dependent and MutSβ-dependent MMR. In order to understand the structural and mechanistic basis by which these two amino acid substitutions in PCNA proteins block MMR, we solved the X-ray crystal structures of both mutant proteins and carried out further biochemical studies. We found that these amino acid substitutions lead to subtle, distinct structural changes in PCNA. The C22Y substitution alters the positions of the α-helices lining the central hole of the PCNA ring, whereas the C81R substitution creates a distortion in an extended loop near the PCNA subunit interface. We conclude that the structural integrity of the α-helices lining the central hole and this loop are both necessary to form productive complexes with MutSα and mismatch-containing DNA.


The Time Dependent Propensity Function for Acceleration of Spatial Stochastic Simulation of Reaction-Diffusion Systems.
The inhomogeneous stochastic simulation algorithm (ISSA) is a fundamental method for spatial stochastic simulation. However, when diffusion events occur more frequently than reaction events, simulating the diffusion events by ISSA is quite costly. To reduce this cost, we propose to use the time dependent propensity function in each step. In this way we can avoid simulating individual diffusion events, and use the time interval between two adjacent reaction events as the simulation stepsize. We demonstrate that the new algorithm can achieve orders of magnitude efficiency gains over widely-used exact algorithms, scales well with increasing grid resolution, and maintains a high level of accuracy.


Bayesian fusion algorithm for improved oscillometric blood pressure estimation.
A variety of oscillometric algorithms have been recently proposed in the literature for estimation of blood pressure (BP). However, these algorithms possess specific strengths and weaknesses that should be taken into account before selecting the most appropriate one. In this paper, we propose a fusion method to exploit the advantages of the oscillometric algorithms and circumvent their limitations. The proposed fusion method is based on the computation of the weighted arithmetic mean of the oscillometric algorithms estimates, and the weights are obtained using a Bayesian approach by minimizing the mean square error. The proposed approach is used to fuse four different oscillometric blood pressure estimation algorithms. The performance of the proposed method is evaluated on a pilot dataset of 150 oscillometric recordings from 10 subjects. It is found that the mean error and standard deviation of error are reduced relative to the individual estimation algorithms by up to 7 mmHg and 3 mmHg in estimation of systolic pressure, respectively, and by up to 2 mmHg and 3 mmHg in estimation of diastolic pressure, respectively.


Corynebacterium striatum Cardiac Device-Related Infective Endocarditis: The First Case Report in a Patient With a Cardiac Resynchronization Therapy Defibrillator Device and Review of the Literature.
Corynebacterium striatum (C. striatum) is a skin commensal agent, rarely described as a cause of infective endocarditis. We describe a case of a 48-year-old man, with multiple comorbidities with cardiac resynchronization therapy defibrillator (CRT-D) device implanted 1 year before. A cardiac device-related infective endocarditis (CDRIE) due to C. striatum, with vegetations in the tricuspid valve adjacent to the electrode lead and concomitant lumbar spondylodiscitis were diagnosed. The patient was treated initially with a 6-week course of vancomycin with sterile blood cultures and reduction of inflammatory parameters. Surgery was refused at this stage. Six weeks later, he was readmitted due to C. striatum bacteriemia recurrence, with vegetations adhering to the electrode wire, being treated with daptomycin 10mg/kg body weight, after presenting renal toxicity to vancomycin. CRT-D device was removed with implantation of epicardial cardiac resynchronization therapy pacemaker (CRT-P). To our knowledge, this might be the first description of C. striatum CDRIE in a patient with a CRT-D. In the five cases described in the literature of CDRIE by this agent, early removal of the pacemaker was performed with good results. In this case, the device was removed only after failure of medical treatment alone.


Depletion effects and loop formation in self-avoiding polymers.
Langevin dynamics is employed to study the looping kinetics of self-avoiding polymers both in ideal and crowded solutions. A rich kinetics results from the competition of two crowding-induced effects: the depletion attraction and the enhanced viscous friction. For short chains, the enhanced friction slows down looping, while for longer chains, the depletion attraction renders it more frequent and persistent. We discuss the possible relevance of the findings for chromatin looping in living cells.


Conditional transformation models for survivor function estimation.
In survival analysis, the estimation of patient-specific survivor functions that are conditional on a set of patient characteristics is of special interest. In general, knowledge of the conditional survival probabilities of a patient at all relevant time points allows better assessment of the patient's risk than summary statistics, such as median survival time. Nevertheless, standard methods for analysing survival data seldom estimate the survivor function directly. Therefore, we propose the application of conditional transformation models (CTMs) for the estimation of the conditional distribution function of survival times given a set of patient characteristics. We used the inverse probability of censoring weighting approach to account for right-censored observations. Our proposed modelling approach allows the prediction of patient-specific survivor functions. In addition, CTMs constitute a flexible model class that is able to deal with proportional as well as non-proportional hazards. The well-known Cox model is included in the class of CTMs as a special case. We investigated the performance of CTMs in survival data analysis in a simulation that included proportional and non-proportional hazard settings and different scenarios of explanatory variables. Furthermore, we re-analysed the survival times of patients suffering from chronic myelogenous leukaemia and studied the impact of the proportional hazards assumption on previously published results.


From bite to mind: TMD--a personal and literature review.
The purpose of this study was to present a personal view of the development of prevailing opinions about temporomandibular disorders (TMD) during the last half century from a mechanistic to a psychosomatic concept. It also presents some hypotheses concerning: (1) the role of stress in the etiology of human oral parafunctions and its relationship to oral stereotypies in domestic animals; and (2) the pathogenetic mechanisms of masticatory muscle pain. The basis for this article was a review of personal experiences derived from clinical and research work with TMD patients. Studies of both older and more recent literature on TMD and related disorders--especially in the fields of stress research, psychosocial medicine, occupational medicine, and etiology--were also used. A clear line is found in the development of the ideas on etiology, pathogenesis, and therapy of TMD, from the mechanistic attitude of Costen syndrome through the introduction of psychologic and psychophysical theories by the Columbia and Chicago schools to the now increasingly accepted biopsychosocial concept and the view of refractory TMD as a chronic pain condition. The formerly dominant bite-centered therapies--including intraoral appliances, the effects of which still are unexplained--appear to be increasingly banished to the domain of placebo Hence, to an ever-increasing extent occlusal treatments are replaced by physiotherapy and cognitive behavior therapy. The presented hypotheses may have implications for the understanding of the origin of oral parafunction and masticatory muscle pain.


Domain decomposition-based structural condensation of large protein structures for understanding their conformational dynamics.
Normal mode analysis (NMA) with coarse-grained model, such as elastic network model (ENM), has allowed the quantitative understanding of protein dynamics. As the protein size is increased, there emerges the expensive computational process to find the dynamically important low-frequency normal modes due to diagonalization of massive Hessian matrix. In this study, we have provided the domain decomposition-based structural condensation method that enables the efficient computations on low-frequency motions. Specifically, our coarse-graining method is established by coupling between model condensation (MC; Eom et al., J Comput Chem 2007, 28, 1400) and component mode synthesis (Kim et al., J Chem Theor Comput 2009, 5, 1931). A protein structure is first decomposed into substructural units, and then each substructural unit is coarse-grained by MC. Once the NMA is implemented to coarse-grained substructural units, normal modes and natural frequencies for each coarse-grained substructural unit are assembled by using geometric constraints to provide the normal modes and natural frequencies for whole protein structure. It is shown that our coarse-graining method enhances the computational efficiency for analysis of large protein complexes. It is clearly suggested that our coarse-graining method provides the B-factors of 100 large proteins, quantitatively comparable with those obtained from original NMA, with computational efficiency. Moreover, the collective behaviors and/or the correlated motions for model proteins are well delineated by our suggested coarse-grained models, quantitatively comparable with those computed from original NMA. It is implied that our coarse-grained method enables the computationally efficient studies on conformational dynamics of large protein complex.


Dose and chemical species-specific effects of selenium against arsenite toxicity in cultured hepatocytes of rainbow trout (Oncorhynchus mykiss).
The present study evaluated the mechanistic underpinnings of the interactive effects of selenium (Se), both inorganic (selenite) and organic (selenomethionine (SeMet)), against arsenite (As-III) cytotoxicity using rainbow trout (Oncorhynchus mykiss) hepatocytes in primary culture. Arsenite is known to induce cytotoxic effects by disrupting cellular redox homeostasis. In contrast, Se is essential for the maintenance of cellular anti-oxidative machinery, but when present above a threshold concentration, can also induce reactive oxygen species (ROS) generation and cause oxidative damage. In this study, hepatocytes were exposed to 100 μM arsenite independently or in combination with selenite or SeMet (5-40 μM) for 24 h. Exposure to arsenite alone reduced cell viability by inducing intracellular ROS generation, which also corresponded with a concomitant decrease in cellular thiol (GSH : GSSG) ratio and the activities of enzymatic antioxidants (GPx and SOD). Both selenite and SeMet were found to ameliorate the arsenite-induced loss of cell viability and thiol balance significantly, but only at low-intermediate exposure levels (5-20 μM), with selenite being more effective than SeMet. Further analyses of cellular antioxidative pathways, using specific pharmacological treatments, revealed that selenite and SeMet mediate their protective effects against arsenite toxicity via different mechanisms. Selenite ameliorates arsenite-induced oxidative stress primarily by augmenting enzymatic antioxidants (especially SOD), whereas SeMet elicits its protective response essentially by upregulating the non-enzymatic antioxidative pathway that involves GSH. Overall, our study demonstrated that the antagonistic interactions of arsenite and Se at the cellular level are influenced by the exposure dose as well as the chemical speciation of Se.


Tetraethylammonium ions: effect of presynaptic injection on synaptic transmission.
Tetraethylammonium ions were injected into the presynaptic axon of the squid giant synapse. Injection of these ions caused prolongation of the action potential with decreased out ward current. The prolonged spike was associated with increased release and prolonged activity of the transmitter substance. Although the amplitude of the postsynaptic potential increased with presynaptic depolarization, strong depolarization blocked transmitter re lease. In the injected presynaptic axon, transmitter release was blocked by 10(-6) gram of tetrodotoxin per milliliter. Transmitter release appears to be under control of presynaptic potential levels.


Hippocampal GABA(A) Receptor and Pain Sensitivity during Estrous Cycle in the Rat.
Estradiol and progesterone as well as hippocampal GABA(A) receptors are believed to play a role in the modulation of pain. The aim of present study was to investigate the effect of intrahippocampal injections of GABA(A) receptor agonist (muscimol) and GABA(A) receptor antagonist (picrotoxin) on pain sensitivity during estrous cycle. Pain sensitivity was evaluated in rats by formalin test during all stages of estrous cycle. Animals were divided into five groups including; 1- control (intact animal); 2- sham 1 receiving 0.75 µl artificial cerebrospinal fluids (ACSF); 3- sham 2 receiving 0.75 µl alcoholic ACSF; 4- experimental 1 receiving 250 or 500 µg/rat of muscimol in 0.75 µl vehicle, and 5- experimental 2 receiving 20 or 30 µg/rat picrotoxin in 0.75 µl vehicle. Data were analyzed by Kruskal-Wallis followed by Tucky's test for pairwise comparisons using a P value of ≤0.50 for statistical significance. Muscimol significantly (P<0.05) decreased pain sensitivity in all stages of estrous cycle, and the analgesic effect was higher during proestrus and estrus stages of estrous cycle than that during metestrus and diestrus stages. Picrotoxin significantly (P<0.05) increased pain sensitivity in all stages of estrous cycle, and such a hyperalgesic effect was lower during proestrus and estrus stages of estrous cycle than that during metestrus and diestrus stages. The findings of the present study indicate that the role of hippocampal GABA(A) receptor in the control of the pain sensitivity can be modulated by variation in gonadal steroids during different stages of the estrous cycle.


SU-E-I-70: Semi-Automatic, User-Driven Breast, Chest Wall and FGT Segmentations Based on Hough Transform, Morphology Tools and Histogram Technology.
Preliminary analysis shows that breast fibroglandular tissue (FGT) ratio and background parenchymal enhancement (BPE) of magnetic resonance (MR) imaging are predictive of future breast cancer risk. Adequate methods for automatic/semi-automatic breast and chest wall segmentation, and FGT histogram extraction and analysis were not available. This method is tested on the retrospective HIPAA-compliant study, which includes 1275 women who underwent breast MR imaging between December 2002 and February 2008. The method works in user-directed stages for each image slice: 1. A straight-line and ellipse Hough transform are applied to detect chest wall boundaries and separate out the chest region if it is present. 2. Edge detection and morphology tools are deployed to segment out the breast region. Human input is required to justify and adjust the segmentation result. 3. Typical breast MRI histograms have double peaks, of fat regions and FGT content inside the segmented breast. Human input is needed here to justify and select a proper segmentation threshold value for whole breast FGT segmentation. Interactive GUIs were developed in Matlab for all the human input sections. Various chest wall boundary lines are detected by Hough transform. Breast region is segmented out either automatically by the morphology tools or redefined by researchers if there is no proper boundaries available in the MR images. Breast region is analyzed by histogram technology to separate FGT from fat. We have developed a semi-automatic human-guided breast segmentation method for MRI based on Hough transform, morphology tools and histogram technology. This approach enables novel breast segmentation and analysis.


Interface design and human factors considerations for model-based tight glycemic control in critical care.
Tight glycemic control (TGC) has shown benefits but has been difficult to implement. Model-based methods and computerized protocols offer the opportunity to improve TGC quality and compliance. This research presents an interface design to maximize compliance, minimize real and perceived clinical effort, and minimize error based on simple human factors and end user input. The graphical user interface (GUI) design is presented by construction based on a series of simple, short design criteria based on fundamental human factors engineering and includes the use of user feedback and focus groups comprising nursing staff at Christchurch Hospital. The overall design maximizes ease of use and minimizes (unnecessary) interaction and use. It is coupled to a protocol that allows nurse staff to select measurement intervals and thus self-manage workload. The overall GUI design is presented and requires only one data entry point per intervention cycle. The design and main interface are heavily focused on the nurse end users who are the predominant users, while additional detailed and longitudinal data, which are of interest to doctors guiding overall patient care, are available via tabs. This dichotomy of needs and interests based on the end user's immediate focus and goals shows how interfaces must adapt to offer different information to multiple types of users. The interface is designed to minimize real and perceived clinical effort, and ongoing pilot trials have reported high levels of acceptance. The overall design principles, approach, and testing methods are based on fundamental human factors principles designed to reduce user effort and error and are readily generalizable.


Along-Tract Statistical Mapping of Microstructural Abnormalities in Bipolar Disorder: A Pilot Study.
Investigating brain circuitry involved in bipolar disorder (BD) is key to discovering brain biomarkers for genetic and interventional studies of the disorder. Even so, prior research has not provided a fine-scale spatial mapping of brain microstructural differences in BD. In this pilot diffusion MRI dataset, we used BUndle ANalytics (BUAN), a recently developed analytic approach for tractography, to extract, map, and visualize the profile of microstructural abnormalities on a 3D model of fiber tracts in people with BD (N=38) and healthy controls (N=49), and investigate along-tract white matter (WM) microstructural differences between these groups. Using the BUAN pipeline, BD was associated with lower mean Fractional Anisotropy (FA) in fronto-limbic and interhemispheric pathways and higher mean FA in posterior bundles relative to controls. BUAN combines tractography and anatomical information to capture distinct along-tract effects on WM microstructure that may aid in classifying diseases based on anatomical differences.


A force balance model of early spindle pole separation in Drosophila embryos.
The formation and function of the mitotic spindle depends upon force generation by multiple molecular motors and by the dynamics of microtubules, but how these force-generating mechanisms relate to one another is unclear. To address this issue we have modeled the separation of spindle poles as a function of time during the early stages of spindle morphogenesis in Drosophila embryos. We propose that the outward forces that drive the separation of the spindle poles depend upon forces exerted by cortical dynein and by microtubule polymerization, and that these forces are antagonized by a C-terminal kinesin, Ncd, which generates an inward force on the poles. We computed the sum of the forces generated by dynein, microtubule polymerization, and Ncd, as a function of the extent of spindle pole separation and solved an equation relating the rate of pole separation to the net force. As a result, we obtained graphs of the time course of spindle pole separation during interphase and prophase that display a reasonable fit to the experimental data for wild-type and motor-inhibited embryos. Among the novel contributions of the model are an explanation of pole separation after simultaneous loss of Ncd and dynein function, and the prediction of a large value for the effective centrosomal drag that is needed to fit the experimental data. The results demonstrate the utility of force balance models for explaining certain mitotic movements because they explain semiquantitatively how the force generators drive a rapid initial burst of pole separation when the net force is great, how pole separation slows down as the force decreases, and how a stable separation of the spindle poles characteristic of the prophase steady state is achieved when the force reaches zero.


Middle cerebral artery occlusion causing intracerebral hemorrhage: radiologic findings.
Middle cerebral artery (MCA) occlusion usually leads to cerebral infarction but rarely causes cerebral hemorrhage without infarction. We retrospectively investigated the unique radiographic manifestations in cases of cerebral hemorrhage without infarction. Computed tomography (CT) and angiographic images obtained in four patients (aged 26 to 70 years) with MCA occlusion associated with intracerebral hemorrhage were reviewed. Two patients also underwent magnetic resonance imaging (MRI), and one of these underwent magnetic resonance angiography as well; these images were also examined. Cranial CT revealed periventricular hemorrhage with ventricular penetration in one patient and with putaminal penetration in two. Solitary ventricular hemorrhage was found in the fourth patient. Angiography showed ipsilateral occlusion at the M1 portion of the MCA, accompanied by moyamoya-like vessels. No aneurysm or arteriovenous malformation was detected. MRI showed absence of the flow void in the affected MCA and an abnormal flow void in dilated collateral vessels in the basal ganglia. MCA occlusion can cause periventricular or ventricular hemorrhage, which appears to result from bleeding from fragile dilated collateral vessels and, thus, to have an etiology similar to that of adult moyamoya disease. MRI shows promise as a tool for evaluating the occlusion site.


Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation.
A number of cytoplasmic signaling molecules are thought to mediate mitogenic signaling from the activated Neu receptor tyrosine kinase through binding specific phosphotyrosine residues located within the intracellular portion of Neu/c-ErbB-2. An activated neu oncogene containing tyrosine-to-phenylalanine substitutions at each of the known autophosphorylation sites was generated and assessed for its specific transforming potential in Rat1 and NIH 3T3 fibroblasts. Mutation of these sites resulted in a dramatic impairment of the transforming potential of neu. To assess the role of these tyrosine phosphorylation sites in cellular transformation, the transforming potential of a series of mutants in which individual tyrosine residues were restored to this transformation-debilitated neu mutant was evaluated. Reversion of any one of four mutated sites to tyrosine residues restored wild-type transforming activity. While each of these transforming mutants displayed Ras-dependent signaling, the transforming activity of two of these mutants was correlated with their ability to bind either the GRB2 or SHC adapter molecules that couple receptor tyrosine kinases to the Ras signaling pathway. By contrast, restoration of a tyrosine residue located at position 1028 completely suppressed the basal transforming activity of this mutated neu molecule or other transforming neu molecules which possessed single tyrosine residues. These data argue that the transforming potential of activated neu is mediated both by positive and negative regulatory tyrosine phosphorylation sites.


Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb.
The adult brain subventricular zone (SVZ) produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) in a specialized niche. Galectin-3 (Gal-3) regulates proliferation and migration in cancer and is expressed by activated macrophages after brain injury. The function of Gal-3 in the normal brain is unknown, but we serendipitously found that it was expressed by ependymal cells and SVZ astrocytes in uninjured mice. Ependymal cilia establish chemotactic gradients and astrocytes form glial tubes, which combine to aid neuroblast migration. Whole-mount preparations and electron microscopy revealed that both ependymal cilia and SVZ astrocytes were disrupted in Gal3(-/-) mice. Interestingly, far fewer new BrdU(+) neurons were found in the OB of Gal3(-/-) mice, than in wild-type mice 2 weeks after labeling. However, SVZ proliferation and cell death, as well as OB differentiation rates were unaltered. This suggested that decreased migration in vivo was sufficient to decrease the number of new OB neurons. Two-photon time-lapse microscopy in forebrain slices confirmed decreased migration; cells were slower and more exploratory in Gal3(-/-) mice. Gal-3 blocking antibodies decreased migration and dissociated neuroblast cell-cell contacts, whereas recombinant Gal-3 increased migration from explants. Finally, we showed that expression of phosphorylated epidermal growth factor receptor (EGFR) was increased in Gal3(-/-) mice. These results suggest that Gal-3 is important in SVZ neuroblast migration, possibly through an EGFR-based mechanism, and reveals a role for this lectin in the uninjured brain.


Brief Report on Hand-Hygiene Monitoring Systems: A Pilot Study of a Computer-Assisted Image Analysis Technique.
Various methodologies have been utilized in hand- hygiene (HH) research to measure the quality and compliance rates of hand washing. Some notable examples are direct observation, self-report, image quantification of fluorescence, microbial sampling, automated systems, and electronically assisted devices. While direct observation is considered the gold standard of HH monitoring systems, its methodological limitations (e.g., high staffing demands, participant reactivity, and undersampling) have yet to be overcome. As a result, there is renewed interest in developing technologies or methods of assessment that are cost-effective, accurate, and not intrusive. This article provides a brief review of HH monitoring systems while presenting a less resource-intensive methodology utilizing image analysis of fluorescence to assess hand washing. Results indicate that the proposed HH protocol could be used to replace human visual analysis of fluorescence, as well as provide a less resource-intensive option to assess HH under controlled conditions. Future implications and the need for additional research, such as cross-validating the results in a real-world clinical setting, are discussed.


Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels.
Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective downregulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G₀/G₁ arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBPβ was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBPα, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1(v/v). Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD.


Assessing behind armor blunt trauma in accordance with the National Institute of Justice Standard for Personal Body Armor Protection using finite element modeling.
To assess the possibility of injury as a result of behind armor blunt trauma (BABT), a study was undertaken to determine the conditions necessary to produce the 44-mm clay deformation as set forth in the National Institute of Justice (NIJ) Standard 0101.04. These energy levels were then applied to a three-dimensional Human Torso Finite Element Model (HTFEM) with soft armor vest. An examination will be made of tissue stresses to determine the effects of the increased kinetic energy levels on the probability of injury. A clay finite element model (CFEM) was created with a material model that required nonlinear properties for clay. To determine these properties empirically, the results from the CFEM were matched with experimental drop tests. A soft armor vest was modeled over the clay to create a vest over clay block finite element model (VCFEM) and empirical methods were again used to obtain material properties for the vest from experimental ballistic testing. Once the properties for the vest and clay had been obtained, the kinetic energy required to produce a 44-mm deformation in the VCFEM was determined through ballistic testing. The resulting kinetic energy was then used in the HTFEM to evaluate the probability of BABT. The VCFEM, with determined clay and vest material properties, was exercised with the equivalent of a 9-mm (8-gm) projectile at various impact velocities. The 44-mm clay deformation was produced with a velocity of 785 m/s. This impact condition (9-mm projectile at 785 m/s) was used in ballistic exercises of the HTFEM, which was modeled with high-strain rate human tissue properties for the organs. The impact zones were over the sternum anterior to T6 and over the liver. The principal stresses in both soft and hard tissue at both locations exceeded the tissue tensile strength. This study indicates that although NIJ standard 0101.04 may be a good guide to soft armor failure, it may not be as good a guide in BABT, especially at large projectile kinetic energies. Further studies, both numerical and experimental, are needed to assist in predicting injury using the NIJ standard.


Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and necrosis.
Studies in various tissues, including the kidney, have demonstrated that toxins elicit apoptosis under certain conditions and necrosis under others. The nature of the response has important consequences for the injured tissue in that necrotic cells elicit inflammatory responses, whereas apoptotic cells do not. Thus, there has been considerable interest in defining the mode of cell death elicited by known cytotoxins. The present studies examined the response of renal epithelial cells to oxalate, a metabolite excreted by the kidney that produces oxidant stress and death of renal cells at pathophysiological concentrations. These studies employed LLC-PK1 cells, a renal epithelial cell line from pig kidney and NRK-52E (NRK) cells, a line from normal rat kidney, and compared the effects of oxalate with those of known apoptotic agents. Changes in cellular and nuclear morphology, in nuclear size, in ceramide production, and in DNA integrity were assessed. The ability of bcl-2, an anti-apoptotic gene product, to attenuate oxalate toxicity was also assessed. These studies indicated that oxalate-induced death of renal epithelial cells exhibits several features characteristic of apoptotic cell death, including increased production of ceramide, increased abundance of apoptotic bodies, and marked sensitivity to the level of expression of the anti-apoptotic gene bcl-2. Oxalate-induced cell death also exhibits several characteristics of necrotic cell death in that the majority of the cells exhibited cellular and nuclear swelling after oxalate treatment and showed little evidence of DNA cleavage by TUNEL assay. These results suggest that toxic concentrations of oxalate trigger both forms of cell death in renal epithelial cells.


What's the Cost? Measuring the Economic Impact of Pediatric Sepsis.
Sepsis, life-threatening organ dysfunction secondary to infection, hospitalizes nearly 75,000 children each year in the United States. Most children survive sepsis. However, there is increasing recognition of the longer-term consequences of pediatric sepsis hospitalization on both the child and their family, including medical, psychosocial, and financial impacts. Here, we describe family spillover effects (the impact of illness on caregivers) of pediatric sepsis, why measurement of family spillover effects is important, and the ways in which family spillover effects can be measured.


Osmoregulation in Rhodobacter sphaeroides.
Betaine (N,N,N-trimethylglycine) functioned most effectively as an osmoprotectant in osmotically stressed Rhodobacter sphaeroides cells during aerobic growth in the dark and during anaerobic growth in the light. The presence of the amino acids L-glutamate, L-alanine, or L-proline in the growth medium did not result in a significant increase in the growth rate at increased osmotic strengths. The addition of choline to the medium stimulated growth at increased osmolarities but only under aerobic conditions. Under these conditions choline was converted via an oxygen-dependent pathway to betaine, which was not further metabolized. The initial rates of choline uptake by cells grown in media with low and high osmolarities were measured over a wide range of concentrations (1.9 microM to 2.0 mM). Only one kinetically distinguishable choline transport system could be detected. Kt values of 2.4 and 3.0 microM and maximal rates of choline uptake (Vmax) of 5.4 and 4.2 nmol of choline/min.mg of protein were found in cells grown in the minimal medium without or with 0.3 M NaCl, respectively. Choline transport was not inhibited by a 25-fold excess of L-proline or betaine. Only one kinetically distinguishable betaine transport system was found in cells grown in the low-osmolarity minimal medium as well as in a high-osmolarity medium containing 0.3 M NaCl. In cells grown and assayed in the absence of NaCl, betaine transport occurred with a Kt of 15.1 microM and a Vmax of 3.2 nmol/min . mg of protein, whereas in cells that were grown and assayed in the presence of 0.3 M NaCl, the corresponding values were 18.2 microM and 9.2 nmol of betaine/min . mg of protein. This system was also able to transport L-proline, but with a lower affinity than that for betaine. The addition of choline of betaine to the growth medium did not result in the induction of additional transport systems.


A scoping review of interventions for adults with dysarthria following traumatic brain injury.
Primary objective: To review the current literature on interventions for dysarthria following traumatic brain injury (TBI) for their effectiveness and methodological quality, and identify future directions for research in developing guidelines for treating dysarthria in this population.Research design: Scoping review.Methods and procedures: Electronic databases were searched up until July 2018 to find intervention trials for treating dysarthria following TBI. Articles were assessed by three reviewers to meet the following criteria: (1) population (adults with dysarthria following TBI only) and (2) intervention studies. Of the 1481 articles initially identified, 17 were selected based on inclusion criteria. 16 articles were single case designs (SCD) and one was a cohort study. Methodological qualities of eligible articles were examined using the single-case experimental design (SCED) rating scale; the cohort study was qualitatively described.Main outcomes and results: The interventions described fell into six broad categories - behavioral, prosthetic, instrumental, pharmacological, augmentative and alternative communication (AAC), and mixed intervention. Behavioral interventions received the most focus in the literature. The articles rated using the SCED received an average score of 6.8, indicating moderate methodological quality.Conclusions: This field currently lacks high-quality research. Further research is required to determine the best clinical practice.


Electricity production coupled to ammonium in a microbial fuel cell.
The production of electricity from ammonium was examined using a rotating-cathode microbial fuel cell (MFC). The addition of ammonium chloride, ammonium sulfate, or ammonium phosphate (monobasic) resulted in electricity generation, while adding sodium chloride, nitrate, or nitrite did not cause any increase in current production. The peak current increased with increasing amount of ammonium addition up to 62.3 mM of ammonium chloride, suggesting that ammonium was involved in electricity generation either directly as the anodic fuel or indirectly as substrates for nitrifiers to produce organic compounds for heterotrophs. Adding nitrate or nitrite with ammonium increased current production compared to solely ammonium addition. Using 16S rRNA-linked molecular analyses, we found ammonium-oxidizing bacteria and denitrifying bacteria on both the anode and cathode electrodes, whereas no anammox bacteria were detected. The dominant ammonium-oxidizing bacteria were closely related to Nitrosomonas europaea. The present MFC achieved an ammonium removal efficiency of 49.2 +/- 5.9 or 69.7 +/- 3.6%, depending on hydraulic retention time, but exhibited a very low Coulombic efficiency.


On the reliability of a geometric morphometric approach to sex determination: a blind test of six criteria of the juvenile ilium.
Despite the attention of many studies, researchers still struggle to identify criteria with which to sex juvenile remains at levels of accuracy and reproducibility comparable with those documented for adults. This study uses a sample of 82 juvenile ilia from an identified Portuguese population (Lisbon collection) to test the cross-applicability of a new approach by Wilson et al. [23] that uses geometric morphometric methods to sex the subadult ilium. Further, we evaluate the wider applicability of these methods for forensic casework, extending the age range of the original study by examining an additional 19 juvenile ilia from the St. Brides and Spitalfields collections, housed in London. Levels of accuracy for the Portuguese sample (62.2-89.0%) indicate that the methods can be used to document dimorphism in another sample. Discriminant functions are sample-specific, indicated by not better than average classification using cross-validation. We propose a methodological update, whereby we recommend disuse of the auricular surface morphology criterion, based upon reduced success rates and inadequate accuracy of female identification. We show, in addition to population differences, differences in the ontogeny of dimorphism may lead to differing degrees of success for female identification using some criteria. The success rates are highest between the ages of 11.00 and 14.99 years (93.3% males, 80.0% females).


The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A.
TNF-alpha modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-alpha is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-alpha modulates EC cell cycle and angiogenesis. Using primary ECs, we show that ezrin, previously considered to act primarily as a cytoskeletal protein and in cytoplasmic signaling, is a TNF-alpha-induced transcriptional repressor. TNF-alpha exposure leads to Rho kinase-mediated phosphorylation of ezrin, which translocates to the nucleus and binds to cell cycle homology region repressor elements within the cyclin A promoter. Overexpression of dominant-negative ezrin blocks TNF-alpha-induced modulation of ezrin function and rescues cyclin A expression and EC proliferation. In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model. These observations suggest that TNF-alpha regulates angiogenesis via Rho kinase induction of a transcriptional repressor function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.


Comparing the health and social protection effects of measles vaccination strategies in Ethiopia: An extended cost-effectiveness analysis.
Vaccination coverage rates often mask wide variation in access, uptake, and cost of providing vaccination. Financial incentives have been effective at creating demand for social services in a variety of settings. Using methods of extended cost-effectiveness analysis, we compare the health and economic implications of three different vaccine delivery strategies for measles vaccination in Ethiopia: i) routine immunization, ii) routine immunization with financial incentives, and iii) mass campaigns, known as supplemental immunization activities (SIAs). We examine annual birth cohorts of almost 3,000,000 births over a ten year period, exploring variation in these outcomes based on economic status to understand how various options may improve equity. SIAs naturally achieve higher levels of vaccine coverage, but at higher costs. Routine immunization combined with financial incentives bolsters demand among more economically vulnerable households. The relative appeal of routine immunization with financial incentives and SIAs will depend on the policy environment, including short-term financial limitations, time horizons, and the types of outcomes that are desired. While the impact of financial incentives has been more thoroughly studied in other policy arenas, such as education, consideration of this approach alongside standard vaccination models such as SIAs is timely given the dialog around measles eradication.


Cross-correlation-based image acquisition technique for manually-scanned optical coherence tomography.
We present a novel image acquisition technique for Optical Coherence Tomography (OCT) that enables manual lateral scanning. The technique compensates for the variability in lateral scan velocity based on feedback obtained from correlation between consecutive A-scans. Results obtained from phantom samples and biological tissues demonstrate successful assembly of OCT images from manually-scanned datasets despite non-uniform scan velocity and abrupt stops encountered during data acquisition. This technique could enable the acquisition of images during manual OCT needle-guided biopsy or catheter-based imaging, and for assembly of large field-of-view images with hand-held probes during intraoperative in vivo OCT imaging.


Enoxaparin versus dabigatran or rivaroxaban for thromboprophylaxis after hip or knee arthroplasty: Results of separate pooled analyses of phase III multicenter randomized trials.
Dabigatran and rivaroxaban are novel oral anticoagulants approved for prevention of venous thromboembolism after hip or knee arthroplasty. However, information assessing clinically important efficacy and bleeding outcomes of these 2 new agents versus low-molecular-weight heparin (enoxaparin) is lacking. We separately pooled efficacy and safety data from 6 phase III randomized trials (18 405 participants) comparing equivalent durations of treatment with enoxaparin (40 mg once daily [od] or 30 mg twice daily) versus dabigatran (220 mg od) or versus rivaroxaban (10 mg od) after hip or knee arthroplasty. Odds ratios (OR) for individual outcomes were calculated for each trial and were pooled using the Mantel-Haenszel method. Compared with dabigatran, enoxaparin had a similar risk of symptomatic venous thromboembolism plus all-cause mortality (0.9% versus 1.1%; OR, 0.76; 95% confidence interval [CI], 0.44 to 1.31; I²=76%) and bleeding (5.0% versus 5.6%; OR, 0.90; 95% CI, 0.71 to 1.15; I²=0%). Compared with rivaroxaban, enoxaparin had a 2-fold higher risk of symptomatic venous thromboembolism plus all-cause mortality (1.2% versus 0.6%; OR, 2.04; 95% CI, 1.32 to 3.17; P<0.001; number needed to treat, 167; I²=0%) but demonstrated a significant lower risk of bleeding (2.5% versus 3.1%; OR, 0.79; 95% CI, 0.62 to 0.99; P=0.049; number needed to harm, 167; I²=0%). In patients undergoing hip or knee arthroplasty, enoxaparin and dabigatran showed similar rates of efficacy and bleeding. Enoxaparin was less effective than rivaroxaban but had a lower risk of bleeding. These results may have important implications for the choice of prophylactic agent in major joint arthroplasty.


Detection of hereditary bisalbuminemia in a Greek family by capillary zone electrophoresis.
It is presented herein a case of a family, four members of which suffer from hereditary bisalbuminemia. The abnormality was initially detected in a 29-year old male, by serum protein electrophoresis (SPE), during the investigation for possible multiple sclerosis. SPE also revealed the presence of a double albumin band in sera of the patient's sister, father and grandmother, almost confirming the inherited (genetic) form of bisalbuminemia. Possible causes related with the acquired form of bisalbuminemia were excluded for all examined individuals. SPE was performed by both automatic capillary zone electrophoresis and agaroze gel electrophoresis. All tested samples were immunofixated with special antisera, in order to exclude the presence of monoclonal fractions. Total albumin, total proteins and immunoglobulins varied in normal ranges. The relative mobility of the albumin variant was determined by a simple mixing experiment, which gave evidence of the fast-type form of inherited bisalbuminemia. This is the first report of hereditary bisalbuminemia in Greece.


Epidemiology of hospitalised osteochondritis dissecans in young people: incidence, geographical variation and trends over time in England from 2002 to 2010.
Osteochondritis dissecans (OCD) is an important cause of knee pain in physically active adolescents, but its aetiology remains controversial. Modern data on its epidemiology are lacking. The aim of this study was to analyse the hospitalised incidence, age and sex distribution, trends over time and geographical variation in OCD in the whole of England. Hospital episode statistics (HES) data were analysed for OCD over the period 2002/3 to 2010/11 for England. HES datasets were record-linked so that anyone with multiple admissions for OCD was counted once only. The annual incidence rate for hospitalised OCD was 1.58 (95% CI 1.51-1.64) cases per 100,000 population. The peak age at diagnosis was 15-19 years for both sexes, and boys were affected more commonly than girls in the ratio 2:1. The hospitalised incidence of OCD varied significantly across England by government office region, from 1.05 (0.91-1.20) in London to 1.89 (1.70-2.09) in the North West Region. These data on the epidemiological features and trends over time in OCD provide new information about its basic epidemiological distribution. Its annual hospitalised incidence is about 1.6 cases per 100,000 population under 25 years, but varies significantly across England. These results have implications for planning rheumatology and orthopaedic services for both children and adults.


Preoperative diagnosis of gallbladder torsion by magnetic resonance cholangiopancreatography.
The patient was a 78-year-old woman who was diagnosed as having gallbladder torsion preoperatively. This is the first reported case diagnosed by magnetic resonance cholangiopancreatography (MRCP). Signs and symptoms of this condition are often subtle. Radiologic evaluation by ultrasonography and computed tomography (CT) showed acute cholecystitis with stone. Drip-infusion cholangiography CT failed to outline the gallbladder, and distortion of the extrahepatic bile ducts and interruption of the cystic duct were observed. MRCP showed 1) a v-shaped distortion of the extrahepatic bile ducts due to traction by the cystic duct, 2) tapering and twisting interruption of the cystic duct, 3) a distended and enlarged gallbladder that was deviated to the midline of the abdomen, and 4) a difference in intensity between the gallbladder and the extrahepatic bile ducts and the cystic duct. A definitive diagnosis of gallbladder torsion (volvulus) was made by MRCP preoperatively. If treated surgically, gallbladder detorsion before cholecystectomy is a helpful technique to avoid bile duct injury. This condition should be suspected in elderly women with acute cholecystitis or acute abdominal pain of unknown origin, and MRCP may be very useful in making a definitive diagnosis.


Outbreaks of diarrhoeal illness on passenger cruise ships, 1975-85.
We reviewed data from the Vessel Sanitation Program (VSP), established by the US Public Health Service in 1975, to describe the epidemiology of shipboard diarrhoeal outbreaks, determine the risk of outbreak-related illness among cruise ship passengers, and evaluate changes in rates and patterns of shipboard diarrhoeal illness since the VSP was implemented. When the programme began, none of the cruise ships passed periodic VSP sanitation inspections; since 1978, more than 50% of ships have met the standard each year. On cruises lasting 3-15 days and having at least 100 passengers, diarrhoeal disease outbreaks investigated by the Centers for Disease Control decreased from 8.1 to 3.0 per 10 million passenger days between 1975-79 and 1980-85. The proportion of outbreaks due to bacterial pathogens (36%) did not change. Seafood cocktail was implicated in 8 of 13 documented food-borne outbreaks. The risk of diarrhoeal disease outbreaks on cruise ships appears to have decreased since implementation of the VSP but has not been eliminated.


Developing a laddered algorithm for the management of intractable epistaxis: a risk analysis.
For patients with epistaxis in whom initial interventions, such as anterior packing and cauterization, had failed, options including prolonged posterior packing, transnasal endoscopic sphenopalatine artery ligation (TESPAL), and embolization are available. However, it is unclear which interventions should be attempted and in which order. While cost-effectiveness analyses have suggested that TESPAL is the most responsible use of health care resources, physicians must also consider patient risk to maintain a patient-centered decision-making process. To quantify the risk associated with the management of intractable epistaxis. A risk analysis was performed using literature-reported probabilities of treatment failure and adverse event likelihoods in an emergency department and otolaryngology hospital admissions setting. The literature search included articles from 1980 to May 2014. The analysis was modeled for a 50-year-old man with no other medical comorbidities. Severities of complications were modeled based on Environmental Protection Agency recommendations, and health state utilities were monetized based on a willingness to pay $22 500 per quality-adjusted life-year. Six management strategies were developed using posterior packing, TESPAL, and embolization in various sequences (P, T, and E, respectively). Total risk associated with each algorithm quantified in US dollars. Algorithms involving posterior packing and TESPAL as first-line interventions were found to be similarly low risk. The lowest-risk approaches were P-T-E ($2437.99 [range, $1482.83-$6976.40]), T-P-E ($2840.65 [range, $1136.89-$8604.97]), and T-E-P ($2867.82 [range, $1141.05-$9833.96]). Embolization as a first-line treatment raised the total risk significantly owing to the risk of cerebrovascular events (E-T-P, $11 945.42 [range, $3911.43-$31 847.00]; and E-P-T, $11 945.71 [range, $3919.91-$31 767.66]). Laddered approaches using TESPAL and posterior packing appear to provide the lowest risk. Combining risk and cost-effectiveness perspectives, we recommend a laddered approach to intractable epistaxis with TESPAL first, followed by either embolization or posterior packing.


Localization of planarian β-CATENIN-1 reveals multiple roles during anterior-posterior regeneration and organogenesis.
The β-catenin-dependent Wnt pathway exerts multiple context-dependent roles in embryonic and adult tissues. In planarians, β-catenin-1 is thought to specify posterior identities through the generation of an anteroposterior gradient. However, the existence of such a gradient has not been directly demonstrated. Here, we use a specific polyclonal antibody to demonstrate that nuclear β-CATENIN-1 exists as an anteroposterior gradient from the pre-pharyngeal region to the tail of the planarian Schmidtea polychroa High levels in the posterior region steadily decrease towards the pre-pharyngeal region but then increase again in the head region. During regeneration, β-CATENIN-1 is nuclearized in both anterior and posterior blastemas, but the canonical WNT1 ligand only influences posterior nuclearization. Additionally, β-catenin-1 is required for proper anterior morphogenesis, consistent with the high levels of nuclear β-CATENIN-1 observed in this region. We further demonstrate that β-CATENIN-1 is abundant in developing and differentiated organs, and is particularly required for the specification of the germline. Altogether, our findings provide the first direct evidence of an anteroposterior nuclear β-CATENIN-1 gradient in adult planarians and uncover novel, context-dependent roles for β-catenin-1 during anterior regeneration and organogenesis.


Differentiating symptomatic Parkin mutations carriers from patients with idiopathic Parkinson's disease: contribution of automated segmentation neuroimaging method.
Parkin (PARK2) gene mutations are the predominant cause of autosomal recessive parkinsonism. Characteristic features include: early onset symptoms with slow clinical course, good response to low doses of levodopa, and frequently treatment-induced dyskinesia. Studies using a voxel-based morphometry approach showed a decrease in the gray matter volume of the basal ganglia in mutation carriers during the symptomatic stages. A bilateral, presumably compensatory increase of basal ganglia gray matter value was recently demonstrated in asymptomatic Parkin mutation carriers. Behavioral disorders including: anxiety, psychosis, panic attacks, depression, disturbed sexual, behavioral and obsessive-compulsive disorders have been reported in these patients. A total of 28 Parkinson's Disease (PD) patients consisting of 10 Young-Onset without Parkin mutations (YOPD), 9 Young-Onset with Parkin mutations (YOPD-p), 9 Late-Onset without Parkin mutations (LOPD) and 32 healthy control subjects were studied with an automated volumetric assessment method to quantify subcortical atrophy. Patients but not controls also underwent a neuropsychological and neuropsychiatric assessment. Results revealed a reduction of bilateral caudate nuclei volumes in YOPD-p patients compared to the YOPD patients while there were no statistically significant differences between other groups. YOPD-p patients showed similar results to other patient groups on neuropsychiatric and neuropsychological evaluation measures. YOPD-p and YOPD patients showed a different pattern of volume changes in basal ganglia. Despite its relatively benign clinical course, carrying the Parkin mutation seems to be associated with greater atrophy in subcortical structures. Failure of compensatory mechanisms, different mutation types and pathophysiologic processes may underlie this diverse pattern of subcortical brain changes.


Methemoglobinemia associated with massive acetaminophen ingestion: a case series.
Background: Acetaminophen is a common pharmaceutical ingestion reported to US poison centers. In overdose, toxic metabolites are known to cause hepato- and nephrotoxicity. While G6PD deficiency may be a risk factor for methemoglobin production in the setting of acetaminophen overdose, it is rarely reported in patients who do not have this condition.Methods: We present two cases of methemoglobinemia following massive acetaminophen ingestion with no known history of G6PD deficiency or other substances known to induce methemoglobinemia. The two cases had peak methemoglobin measurements of 32% and 12% respectively, and both were treated with methylene blue.Discussion: A number of mechanisms may be involved in production of methemoglobin in the setting of massive acetaminophen ingestion including NAPQI-induced oxidation, depletion of glutathione stores, and production of oxidant-metabolites including paraaminophenol. While it is unlikely that the majority of acetaminophen overdoses result in any clinically significant methemoglobinemia, massive acetaminophen overdose may be complicated by development of methemoglobinemia.Conclusion: Physicians should be aware of the possibility that massive acetaminophen ingestion may be complicated by methemoglobinemia in rare instances. Further studies should aim to characterize the metabolic pathways leading to possible methemoglobinemia in humans after large acetaminophen ingestions.


Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies.
The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.


Phylogenetic analysis of a swine influenza A(H3N2) virus isolated in Korea in 2012.
Influenza A virus (IAV) can infect avian and mammalian species, including humans. The genome nature of IAVs may contribute to viral adaptation in different animal hosts, resulting in gene reassortment and the reproduction of variants with optimal fitness. As seen again in the 2009 swine-origin influenza A H1N1 pandemic, pigs are known to be susceptible to swine, avian, and human IAVs and can serve as a 'mixing vessel' for the generation of novel IAV variants. To this end, the emergence of swine influenza viruses must be kept under close surveillance. Herein, we report the isolation and phylogenetic study of a swine IAV, A/swine/Korea/PL01/2012 (swPL01, H3N2 subtype). After screening nasopharyngeal samples from pigs in the Gyeongsangnam-do region of Korea from December 2011 to May 2012, we isolated the swPL01 virus and sequenced its all of 8 genome segments (polymerase basic 2, PB2; polymerase basic 1, PB1; polymerase acidic, PA; hemagglutinin, HA; nucleocapsid protein, NP; neuraminidase, NA; matrix protein, M; and nonstructural protein, NS). The phylogenetic study, analyzed with reference strains registered in the National Center for Biotechnology Information (NCBI) database, indicated that the swPL01 virus was similar to the North American triple-reassortant swine strains and that the HA gene of the swPL01 virus was categorized into swine H3 cluster IV. The swPL01 virus had the M gene of the triple-reassortant swine H3N2 viruses, whereas that of other contemporary strains in Korea was transferred from the 2009 pandemic H1N1 virus. These data suggest the possibility that various swine H3N2 viruses may co-circulate in Korea, which underlines the importance of a sustained surveillance system against swine IAVs.


Partial regeneration/proliferation of the beta-cells in the islets of Langerhans by Nigella sativa L. in streptozotocin-induced diabetic rats.
This experiment was carried out to investigate the effect of N. sativa L. on histopathology of pancreatic beta-cells, and blood insulin and glucose concentrations in streptozotocin-induced diabetic rats. Fifty male Wistar rats (200-250 g) were divided into two experimental groups (diabetics with no treatment and diabetics with N. sativa L. treatment), each containing twenty-five rats. Diabetes was induced in both groups by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg). The experimental animals in both groups became diabetic within 24 hours after the administration of STZ. The rats in N. sativa L.-treated group were given the daily intraperitoneal injection of 0.20 ml/kg of N. sativa L. volatile oil for 30 days starting the day after STZ injection. Control rats received only the same amount of normal saline solution. The rats in both groups received the last injection 24 hours before the sacrification and 5 randomly-selected rats in each group were sacrificed before, and the 1, 10, 20 and 30 days after the STZ injection to collect blood and pancreatic tissue samples. The N. sativa L. treatment caused a decrease in the elevated serum glucose, an increase in the lowered serum insulin concentrations and partial regeneration/ proliferation of pancreatic beta-cells in STZ-induced diabetic rats with the elapse of the experiment. It is concluded that the hypoglycaemic action of N. sativa L. could be partly due to amelioration in the beta-cells of pancreatic islets causing an increase in insulin secretion. More studies are needed to demonstrate the exact mechanism of action of N. sativa L. on ameliorated blood glucose concentration in STZ-induced diabetes.


Development of implant movement checker for determining dental implant stability.
Noninvasive and nondestructive mobility assessment of dental implants is very important and useful for dental implantation diagnostic-aids. The development of implant movement (IM) checker based on microcontroller is presented in this paper. Data acquisition system and bender-type piezoelectric probe were used to improve measurement quality to the original tooth mobility (TM) tester. The adoption of a microcontroller and the use of a dental drill-sized measuring probe were sufficient in the reproducibility and reliability of the IM checker. When the implant was subjected to a constant force and amplitude, the acceleration of the model was detected using the measuring probe. The data acquisition system controlled for obtaining the appropriate acceleration signals based on the preload detection during measurement. Dental implant models of Molteno and Rigolac were made at different stiffness and were used to verify the reliability and validity of measurements. The values of measurements obtained by the IM checker were reliable and precise. The maximum error for perpendicular measurements was less than 12% measured by a new operator and decreased to 2% by an experienced operator. The IM checker was applied to monitor the stability of dental implantation, which compared the relative IM score of the new 5[see text] implant with the adjacent old 6 [see text] implant that had been used functionally for 3 years.


Doubts, denial and divine intervention: understanding delayed attendance and poor retention rates at a HIV treatment programme in rural Tanzania.
Irregular or delayed attendance at HIV treatment clinics among HIV-positive individuals can have negative implications for clinical outcomes and may ultimately undermine the effectiveness of national treatment programmes. This study explores factors influencing attendance at HIV clinic appointments among patients in a rural ward in north-west Tanzania. Forty-two in-depth interviews (IDI) and four focus group discussions were conducted with HIV-infected persons who had been referred to a nearby antiretroviral therapy (ART) clinic, and IDI were undertaken with 11 healthcare workers involved in diagnosis, referral and care of HIV-positive patients. The Health Belief Model was applied to explore the role of health-related beliefs and the perceived barriers and benefits associated with regular clinic attendance. Perceived susceptibility to HIV-related illnesses emerged as an important factor influencing clinic attendance, and was often manifest through expressions of acceptance or denial of HIV status and knowledge of HIV disease progression. Denial of HIV status was often associated with using alternative healers, and could occur prior to, during, or after starting ART. Perceptions of illness severity also influenced HIV clinic attendance, and often evolved in relation to changes in physical symptoms. Barriers to clinic attendance frequently included health systems factors, while physical and social benefits encouraged regular clinic attendance. Self-confidence in being able to sustain clinic attendance was often determined by patients' expectations or experiences of family support. These findings suggest that multi-faceted interventions are required to promote regular HIV clinic attendance, including on-going education, counselling and support in both clinic and community settings. These interventions also need to recognise the evolving needs of patients that accompany changes in physical health, and should address local beliefs around HIV aetiology. Decentralisation of HIV services to rural communities should be considered as a priority to redress the balance between perceived barriers to, and benefits of accessing HIV treatment programmes.


Neuroprotection by human umbilical cord blood-derived progenitors in ischemic brain injuries.
Stem cells have an extremely high potential to treat many devastating diseases, including neuronal injuries. Albeit the need for human neuronal stem cells, their quantities are very limited by relying on early human embryos as the main source. Therefore, progenitors of other origins, such as human umbilical cord blood (CB) are being considered. In the last decade, various populations isolated from the CB were reported to differentiate in vitro towards a neural phenotype. The conditions to induce the cell differentiation are not conclusive and may include addition of chemicals, cytokines and growth factors, including the nerve growth factor (NGF). Some CB cells were found to express the TrkANGF receptor, suggesting an endogenous role for this growth factor also in the CB environment. The ability of CB and derived stem cell populations to protect against neurological deficits was shown, both in vitro and in vivo, in models of ischemic brain injuries. In rodent models of stroke, heatstroke, brain trauma and brain damage at birth, CB cells either by intravenous injection or intrastriatal transplantation, were found to reduce the infarct size and the neurological deficits caused by the injury. The restorative effects of CB were suggested to be mediated by mechanisms other than cell replacement. Some of the proposed mechanisms involve reduced inflammation, nerve fiber reorganization by trophic actions, increased cell survival and enhanced angiogenesis. Furthermore, treatment with CB was found to have a therapeutic window of days compared with the present 36 hour window for the treatment of stroke with clinically available tools such as recombinant tissue plasminogen activator. Considering the encouraging results with whole CB and derived cells transplantation in ischemic injury models and since CB is widely available and have been used clinically, they may be an excellent source of cells for treatment of human brain ischemic disorders.


Speckle photography with different pupils in a multiple-exposure scheme.
The use of different multiple-aperture pupils for recording each image in speckle photography is proposed. The introduction of suitable spatial frequency carriers, by internally modulating imaged speckles, allows one to selectively isolate or combine the spectral content of different images into spatially separated regions in the Fourier plane. Theoretical and experimental results extend the speckle photography technique to the depiction of several specklegrams of multiple uniform in-plane displacements. In this case, because different pupils are considered for recording, the cross-correlation functions for the amplitudes and intensities in the image plane are calculated on the basis of the statistical properties of the object. Also, the ensemble-average intensity in the Fourier plane is analytically derived, and fringe visibility is investigated.


Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke.
It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (Tc) of male, C57BL/6J mice (n = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4°C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (Tc,Max)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to Tc,Max, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at Tc,Max, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury.NEW & NOTEWORTHY This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity.


Primary cilia: the chemical antenna regulating human adipose-derived stem cell osteogenesis.
Adipose-derived stem cells (ASC) are multipotent stem cells that show great potential as a cell source for osteogenic tissue replacements and it is critical to understand the underlying mechanisms of lineage specification. Here we explore the role of primary cilia in human ASC (hASC) differentiation. This study focuses on the chemosensitivity of the primary cilium and the action of its associated proteins: polycystin-1 (PC1), polycystin-2 (PC2) and intraflagellar transport protein-88 (IFT88), in hASC osteogenesis. To elucidate cilia-mediated mechanisms of hASC differentiation, siRNA knockdown of PC1, PC2 and IFT88 was performed to disrupt cilia-associated protein function. Immunostaining of the primary cilium structure indicated phenotypic-dependent changes in cilia morphology. hASC cultured in osteogenic differentiation media yielded cilia of a more elongated conformation than those cultured in expansion media, indicating cilia-sensitivity to the chemical environment and a relationship between the cilium structure and phenotypic determination. Abrogation of PC1, PC2 and IFT88 effected changes in both hASC proliferation and differentiation activity, as measured through proliferative activity, expression of osteogenic gene markers, calcium accretion and endogenous alkaline phosphatase activity. Results indicated that IFT88 may be an early mediator of the hASC differentiation process with its knockdown increasing hASC proliferation and decreasing Runx2, alkaline phosphatase and BMP-2 mRNA expression. PC1 and PC2 knockdown affected later osteogenic gene and end-product expression. PC1 knockdown resulted in downregulation of alkaline phosphatase and osteocalcin gene expression, diminished calcium accretion and reduced alkaline phosphatase enzymatic activity. Taken together our results indicate that the structure of the primary cilium is intimately associated with the process of hASC osteogenic differentiation and that its associated proteins are critical players in this process. Elucidating the dynamic role of the primary cilium and its associated proteins will help advance the application of hASC in generating autologous tissue engineered therapies in critical defect bone injuries.


Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.
An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) β-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS). Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN β-1a dose groups, and according to total time receiving sc IFN β-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed. Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years. These findings suggest that higher cumulative exposure to sc IFN β-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.


Hemitransdomal versus Dome-Binding Suture.
The dome-binding suture (DBS) and hemitransdomal suture (HTS) are suture techniques used to narrow and define the nasal tip. The DBS can create a pinched, unnatural appearance, while the HTS puts the lateral crus in a more favorable orientation. This allows a natural contour between the nasal tip and alar lobule while maintaining alar margin support. Objective measurement of the rotational axis of the lateral crus between the DBS and the HTS has not been reported in the literature. To determine whether the DBS or HTS technique results in a more favorable rotational axis of the lateral crus as measured by the alar surface septal angle (ASSA). Open rhinoplasty with cephalic trim and placement of a DBS or HTS was performed in 6 cadaveric heads, for a total of 12 lower lateral cartilages at the VirtuOHSU Simulation and Surgical Training Center at Oregon Health and Science University (OHSU). ASSA measurements were taken at baseline and after placement of either a DBS or HTS. A total of 36 ASSA measurements were obtained. The median baseline ASSA prior to suture placement was 142 degrees (interquartile range [IQR]: 131.5-145 degrees), following DBS placement was 141 degrees (IQR: 33-150.5 degrees), and following HTS placement was 112 degrees (IQR: 108-117 degrees). There was no statistically significant difference of ASSA measurements between baseline and DBS placement (p = 0.24), but there was a statistically significant difference between baseline and HTS (p < 0.0001) and between DBS and HTS (p < 0.0001). The HTS technique creates a more favorable rotational axis of the lateral crus as compared with the DBS, as measured by the ASSA. This study provides objective data to support the use of the HTS for nasal tip contouring.