[The use of the electrophoresis of water-insoluble preparations of fencarol and parmidine from dimexide solutions].
Hepatic mitochondrial respiration was recorded by polarography in various metabolic states using relevant substrates and inhibitors in rat male experiments in vivo and in vitro. The above measurements were made following electrophoresis of parmidine and phencarol in 50% dimexide solution. Parmidine from dimexide solution proved indifferent to mitochondrial energy apparatus, while phencarol could inhibit NADH-dehydrogenase link of the respiratory chain and arrest dimexide inhibition of succinate oxidase system. The findings provided a basis for therapeutic procedures which were tested in 105 patients. The immediate response of coronary and neurodermatitis patients appeared satisfactory.


A dose-rate effect in single-particle electron microscopy.
A low beam intensity, low electron dose imaging method has been developed for single-particle electron cryo-microscopy (cryo-EM). Experiments indicate that the new technique can reduce beam-induced specimen movement and secondary radiolytic effects, such as "bubbling". The improvement in image quality, especially for multiple-exposure data collection, will help single-particle cryo-EM to reach higher resolution.


Cisplatin-induced testicular dysfunction and its amelioration by Launaea taraxacifolia leaf extract.
This study investigates the ameliorative potential of Launea taraxacifolia (LT) aqueous leaf extract on cisplatin-induced testicular dysfunction in Wistar rats. Thirty rats were randomly divided into six groups (A-F) of 5 rats each: Group A which served as control received water; Group B was intraperitoneally (ip) injected 10 mg kg(-1) body wt cisplatin on day 21; Groups C and D were given 100 and 400 mg of LT via oral administration, respectively, for 21 days while Groups E and F received similar treatment as Groups C and D, respectively, and then exposed to ip administration of 10 mg kg(-1) body weight cisplatin on the 21st day. Exclusively, Cisplatin-exposed Group B rats showed reduced sperm characteristics and increased sperm morphological abnormalities; distorted histological architecture of seminiferous tubules; significantly increased lipid peroxidation (LPO) and decreased activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH)levels in the testes. These parameters in LT alone treated Groups C and D were not markedly different compared with the control group. The rats with the combined treatment in Groups E and F showed significantly improved sperm parameters, testicular histo-architecture and antioxidant enzymatic activities. Conclusively, aqueous extract of L. taraxacifolia has protective potential against cisplatin damage.


Cranial asymmetry in Eocene archaeocete whales and the evolution of directional hearing in water.
Eocene archaeocete whales gave rise to all modern toothed and baleen whales (Odontoceti and Mysticeti) during or near the Eocene-Oligocene transition. Odontocetes have asymmetrical skulls, with asymmetry linked to high-frequency sound production and echolocation. Mysticetes are generally assumed to have symmetrical skulls and lack high-frequency hearing. Here we show that protocetid and basilosaurid archaeocete skulls are distinctly and directionally asymmetrical. Archaeocete asymmetry involves curvature and axial torsion of the cranium, but no telescoping. Cranial asymmetry evolved in Eocene archaeocetes as part of a complex of traits linked to directional hearing (such as pan-bone thinning of the lower jaws, mandibular fat pads, and isolation of the ear region), probably enabling them to hear the higher sonic frequencies of sound-producing fish on which they preyed. Ultrasonic echolocation evolved in Oligocene odontocetes, enabling them to find silent prey. Asymmetry and much of the sonic-frequency range of directional hearing were lost in Oligocene mysticetes during the shift to low-frequency hearing and bulk-straining predation.


STAMPS: development and verification of swallowing kinematic analysis software.
Swallowing impairment is a common complication in various geriatric and neurodegenerative diseases. Swallowing kinematic analysis is essential to quantitatively evaluate the swallowing motion of the oropharyngeal structures. This study aims to develop a novel swallowing kinematic analysis software, called spatio-temporal analyzer for motion and physiologic study (STAMPS), and verify its validity and reliability. STAMPS was developed in MATLAB, which is one of the most popular platforms for biomedical analysis. This software was constructed to acquire, process, and analyze the data of swallowing motion. The target of swallowing structures includes bony structures (hyoid bone, mandible, maxilla, and cervical vertebral bodies), cartilages (epiglottis and arytenoid), soft tissues (larynx and upper esophageal sphincter), and food bolus. Numerous functions are available for the spatiotemporal parameters of the swallowing structures. Testing for validity and reliability was performed in 10 dysphagia patients with diverse etiologies and using the instrumental swallowing model which was designed to mimic the motion of the hyoid bone and the epiglottis. The intra- and inter-rater reliability tests showed excellent agreement for displacement and moderate to excellent agreement for velocity. The Pearson correlation coefficients between the measured and instrumental reference values were nearly 1.00 (P < 0.001) for displacement and velocity. The Bland-Altman plots showed good agreement between the measurements and the reference values. STAMPS provides precise and reliable kinematic measurements and multiple practical functionalities for spatiotemporal analysis. The software is expected to be useful for researchers who are interested in the swallowing motion analysis.


Observation and measurement of hand hygiene and patient identification improve compliance with patient safety practices.
Measurement, a crucial step in any quality improvement activity, is difficult in two important patient safety processes: hand hygiene and patient identification. This study describes a program at the UCLA Medical Center, called Measure to Achieve Patient Safety (MAPS), which uses undergraduate student volunteers to carry out observations in the hospital. This program has been an important part of UCLA's efforts for quality improvement in patient safety efforts. Since 2004, approximately 20 students per year plus two student leaders have been selected to participate in the MAPS program. They were trained in techniques of measuring and observation and in professional behavior. They participated in weekly and monthly meetings with program leadership, received continuing education from the UCLA patient safety staff, and were trained in observational measurement. The students' observational results have been systematically reported to clinicians and departmental and hospital leadership. Handwashing increased from 50% to 93%, and nurses' checking of two identifiers at the time of medication administration increased from 50% to 95%. Compliance with proper patient identification at the time of nurse-to-transporter handoffs of patients for procedures increased to >90%. This unique program has made a significant contribution to UCLA's quality, safety, and service programs. MAPS has been widely accepted by the clinical staff and has also been valuable to the student volunteers. Such an approach is easily adaptable to other academic medical centers.


[The role of biologic agents in the therapy of ankylosing spondylitis].
Ankylosing spondylitis is a chronic, inflammatory rheumatic disease which etiology and pathogenesis are not yet fully understood. The inflammation involves the spine and also the peripheral joints might be affected in some cases resulting in a progressive ankylosis, restricted mobility, significant disability, loss of productivity and decreased quality of life. Gene technology based new drugs of the past decade, the biologic agents, offer an alternative opportunity for the treatment of ankylosing spondylitis in comparison with the previous drugs with doubtful efficiency. In Hungary infliximab and etanercept has been registered for ankylosing spondylitis. The aim of this study was to evaluate the efficacy of infliximab and etanercept by the available randomised controlled trials. A systematic search of the literature was performed from 01. 01. 2000 to 08. 31. 2005. and the relevant publications were analysed following the concepts of evidence based medicine. 7 double blind, randomised, placebo controlled trials were identified, three for infliximab (n = 389) and four for etanercept (n = 431). Although the inclusion criteria, the duration of the trials and the primary endpoints were different, the results confirm that both drugs significantly decrease symptoms and disease activity, and this effect is sustained during the therapy, nevertheless half of the patients did not achieve the standardised criteria of 50% decrease in disease activity. Both agents are well tolerated by patients. The outcomes of long-term therapy are reassuring by open extension studies of three years. Guidelines for biologic therapy has been developed in Hungary determining the target patient group, the conditions of the therapy and also an arthritis centre network has been established. Though individual admission is feasible, biologic drugs are not under reimbursement in Hungary. High drug costs makes the implementation of this new therapeutic opportunity difficult in the daily medical practice.


The prevalence of secondary dentinal lesions in cheek teeth from horses with clinical signs of pulpitis compared to controls.
With the advent of detailed oral examination in horses using dental mirrors and rigid endoscopy, secondary dentinal lesions are observed more frequently. More information regarding the association of secondary dentinal defects with apical dental disease would improve the sensitivity of oral examination as a diagnostic aid for pulpitis. To assess prevalence and severity of secondary dentinal defects observed on examination of occlusal surfaces of cheek teeth (CT) from horses showing clinical signs of pulpitis compared to asymptomatic controls. Records from all cases of equine CT exodontia at the University of Bristol over a 4 year period were examined. Case selection criteria included the presence of clinical signs of pulpitis, an intact extracted tooth and availability of a complete history and follow up. Cases where coronal fracture or periodontal pocketing featured were excluded. CT from cadavers with no history of dental disease served as normal controls. Triadan positions and eruption ages of control teeth were matched with those of teeth extracted from cases. CT from selected cases and control teeth were examined occlusally. Secondary dentinal defects were identified and graded. Prevalence of occlusal lesions in CT with pulpitis and controls was compared. From the records of 120 horses where exodontia was performed, 40 cases matched selection criteria. Twenty-three mandibular and 21 maxillary CT were extracted from cases. The controls consisted of 60 mandibular and 60 maxillary CT from 7 cadaver skulls. Secondary dentinal defects were significantly over-represented in CT extracted from cases of pulpitis (P < 0.001). Of diseased mandibular CT, 56.5% had defects compared to none of the controls. Of diseased maxillary CT, 57% had defects compared with 1.6% of controls. Multiple defective secondary dentinal areas and severe lesions were more prevalent in diseased mandibular CT compared with diseased maxillary CT. CONCLUSIONS AND PRACTICAL SIGNIFICANCE: Careful examination of occlusal secondary dentine is an essential component in investigation of suspected pulpitis in equine CT.


Correlation Between Gut Microbiome Composition and Acute Pain Perception in Young Healthy Male Subjects.
Recently, there has been growing interest in the gut-brain axis because it is emerging as a player influencing the health status of the host human. It is a known fact that the gut microbiome (GM) through the gut-brain axis has been implicated in numerous diseases. We previously reported that stool condition was associated with pain perception. Stool consistency and constipation are known to be associated with GM composition. Thus, we imagine that GM composition could influence pain perception. The aim of this study was to investigate the correlations between GM composition and pain perception and psychological states in young healthy male subjects. A total of 42 healthy young male volunteers completed the present study. The volunteers' pain perceptions were assessed by pressure pain threshold, current perception threshold, temporal summation of pain, and conditioned pain modulation, and a questionnaire on psychological state was obtained. During the current perception threshold examination, we used 5, 250, and 2,000 Hz to stimulate C, Aδ, and Aβ fibers. In addition, GM composition was evaluated by using 16S rRNA analysis. Pressure pain threshold showed a significant and negative correlation with Bacteroidetes phylum, in contrast to a significant and positive correlation with Firmicutes phylum. Current perception threshold of Aδ and Firmicutes phylum showed a significant correlation. There was a negative correlation between anxiety state and Bifidobacterium genus. In contrast, there was no significant correlation between psychological states and pain perceptions. The present study showed that acute pain perception was associated with GM composition in young healthy males.


Flexible Assertive Community Treatment in Rural and Remote Areas: A Qualitative Study of the Challenges and Adaptations of the Model.
Flexible assertive community treatment (FACT) is an innovative model for providing long-term treatment to people with severe mental illness. The model was developed in the Netherlands but is now used in other countries, including Norway, which has a geography different from the Netherlands, with many rural and remote areas. Implementation of innovations is context dependent. The FACT model's potential in rural and remote areas has not been studied. Therefore, we aimed to gain knowledge regarding the challenges and modifications of the model in rural and remote contexts and discuss how they can affect the model's potential in such areas. This knowledge can improve the understanding of how FACT or similar services can be adapted to function most optimally in such conditions. We sought to address the following questions: Which elements of the FACT model do team leaders of the rural FACT teams find particularly challenging due to the context, and what modifications have the teams made to the model? Digital interviews were conducted with five team leaders from five rural FACT teams in different parts of Norway. They were selected using purposive sampling to include team leaders from some of the most rural teams in Norway. The interviews were analyzed using thematic text analysis. The following three themes described elements of the FACT model that were experienced particularly challenging in the rural and remote context: multidisciplinary shared caseload approach, intensive outreach and crisis management. The following eight themes described the modifications that the teams had made to the model: intermunicipal collaboration, context-adaptive planning, delegation of tasks to municipal services, part-time employment, different geographical locations of staff, use of digital tools, fewer FACT board meetings, and reduced caseload. Rural and remote contexts challenge the FACT model's potential. However, modifications can be made, some of which can be considered innovative modifications that can increase the model's potential in such areas, while others might move the teams further away from the model.


Visual quality assessment after network transmission incorporating NS2 and Evalvid.
On the basis of Evalvid tool integrated in NS2 (Network Simulator version 2), the paper gets new set of tools, myEvalvid, to establish the simulation and evaluation platform for multimedia transmission. Then the paper investigates the effects of various influence factors when multimedia information is transmitted in the network and the relationships among these factors. Based on the analysis, the paper gets different evaluation models, respectively. In this paper, we study the impact on performance of several basic source and network parameters of video streams, namely, GOP (Group of Pictures) pattern, compression quantitative parameters, packet length, and packet error rate. Simulation results show that different parameters lead to different distortion levels which are calculated according to the reconstruction images at the receiver and the original images. The experimental results show that the video transmission and quality evaluation model we designed can evaluate multimedia transmission performance over complex environment very well.


Is there an association between the use of anabolic-androgenic steroids and criminality?
The aim of this study was to improve our understanding of the proposed association between anabolic-androgenic steroids (AAS) and criminality. The study was based on interviews and criminality data involving 32 users of AAS who had sought treatment for AAS-related problems at a psychiatric addiction clinic in Sweden. A score derived from the number of crimes, their level of severity and the relevant time periods was computed to allow comparisons between subgroups sorted according to type and timing of drug use. The criminal activity level increased for 69% of the individuals after having started to use drugs. This was particularly obvious in the group who had started its involvement with drugs by using AAS. Crimes of violence and weapon offences showed a great increase in incidence after drug use had been initiated. The study also showed a significant decrease in criminality after treatment, particularly among individuals who had started their drug use with AAS. The results suggest that there is an association between the use of AAS and criminality, especially with regard to crimes of violence and weapon offences, and that this criminality may be enhanced when AAS are combined with other drugs of abuse.


A Photo Elicitation Study on Chronically Ill Adolescents' Identity Constructions During Transition.
Adolescence is an important phase of life with increasing independence and identity development, and a vulnerable period of life for chronically ill adolescents with a high occurrence of insufficient treatment adherence. We conducted four photo elicitation focus group interviews with 14 adolescents (12-20 years) with juvenile idiopathic arthritis to investigate identity constructions during transition. Using a discourse analysis approach, six identity types were identified distributed on normal and marginal identities, which were lived either at home (home arena) or outside home with peers (out arena). Most participants positioned themselves as normal in the out arena and as ill in the home arena. Few participants positioned themselves as ill in an out arena, and they described how peers perceived this as a marginal and skewed behavior. This study contributes to a better understanding of why it can be extremely difficult to live with a chronic illness during adolescence.


Functional and biochemical properties of chronically stimulated human skeletal muscle.
The present study was undertaken to investigate in a randomized controlled trial the effects of chronic (10 weeks, 4 h per day, 7 days per week) low-frequency (15 Hz) stimulation (CLFS) of the knee extensor and hamstring muscles of both legs in healthy volunteers via surface electrodes. A control group (n=10) underwent the same treatment (sham stimulation) as the CLFS-treated group (n=10), except that stimulation intensity was kept at a level which did not evoke contractions. Biopsy samples were taken before the onset and after cessation of stimulation from the right vastus lateralis muscle of all subjects. The biopsy samples were analyzed for changes in myosin heavy chain (MHC) isoforms and activities of citrate synthase (CS) and glyceraldehyde phosphate dehydrogenase (GAPDH) as markers of aerobic-oxidative and anaerobic pathways of energy metabolism, respectively. In addition, functional properties, i.e., oxygen consumption (VO(2)) and work capacity, were assessed. Sham stimulation did not affect the functional properties and had no detectable effect on MHC isoform and enzyme activity patterns. Conversely, CLFS induced changes in the MHC isoform pattern in the fast-to-slow direction with an approximately 20% decrease in the relative concentration of MHCIId/x (from 28% to 22%) and an approximately 10% increase in the relative concentration of MHCI (from 30% to 34%). In addition, CLFS led to a approximately 9% increase in the activity of CS concomitant with an approximatley 7% decrease in the activity of GAPDH. This increase in aerobic-oxidative capacity was accompanied by improved work capacity and VO(2) at the anaerobic threshold by 26% and 20%, respectively.


Improving the mixed model for repeated measures to robustly increase precision in randomized trials.
In randomized trials, repeated measures of the outcome are routinely collected. The mixed model for repeated measures (MMRM) leverages the information from these repeated outcome measures, and is often used for the primary analysis to estimate the average treatment effect at the primary endpoint. MMRM, however, can suffer from bias and precision loss when it models intermediate outcomes incorrectly, and hence fails to use the post-randomization information harmlessly. This paper proposes an extension of the commonly used MMRM, called IMMRM, that improves the robustness and optimizes the precision gain from covariate adjustment, stratified randomization, and adjustment for intermediate outcome measures. Under regularity conditions and missing completely at random, we prove that the IMMRM estimator for the average treatment effect is robust to arbitrary model misspecification and is asymptotically equal or more precise than the analysis of covariance (ANCOVA) estimator and the MMRM estimator. Under missing at random, IMMRM is less likely to be misspecified than MMRM, and we demonstrate via simulation studies that IMMRM continues to have less bias and smaller variance. Our results are further supported by a re-analysis of a randomized trial for the treatment of diabetes.


Factors Associated with Increased Analgesic Use in German Women with Endometriosis during the COVID-19 Pandemic.
(1) Background: Endometriosis is a frequent chronic pain condition in women of fertile age. Pain management with analgesics is frequently used by women with endometriosis. During the COVID-19 pandemic, access to health services was temporarily restricted in various countries for persons without serious conditions, resulting in increased physical and mental health issues. The present study was conducted in order to assess the risk factors predicting increased analgesic intake by women with endometriosis during the COVID-19 pandemic. (2) Methods: The increased intake of over-the-counter (OTC) and prescription-only (PO) analgesics was assessed with an anonymous online questionnaire, along with demographic, pandemic-specific, disease-specific, and mental health characteristics. Anxiety and depression were assessed with the Generalized Anxiety Disorder Scale (GAD-2) and the Patient Health Questionnaire for Depression (PHQ-2), respectively. Pain-induced disability was assessed with the pain-induced disability index (PDI). (3) Results: A high educational level (OR 2.719; 95% CI 1.137-6.501; p = 0.025) and being at higher risk for depressive disorders, as measured by PHQ-2 ≥ 3 (OR 2.398; 95% CI 1.055-5.450; p = 0.037), were independent risk factors for an increased intake of OTC analgesics. Current global pain-induced disability (OR 1.030; 95% CI 1.007-1.054; p = 0.010) was identified as a risk factor for an increased intake of PO pain medication. The degree of reduction in social support and in social networks were independent predictors of an increased intake of PO analgesics in a univariate logistic regression analysis, but lost significance when adjusted for additional possible influencing factors. (4) Conclusions: In this population, an increased intake of OTC analgesics was related to a higher educational level and having a depressive disorder, while a higher pain-induced disability was an independent risk factor for an increased intake of PO analgesics. Pandemic-specific factors did not significantly and independently influence an increased intake of analgesics in women with endometriosis during the first wave of the COVID-19 pandemic in Germany. Healthcare providers should be aware of the possible factors related to increased analgesic use in women with endometriosis in order to identify persons at risk for the misuse of pain medication and to prevent potential adverse effects.


The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing.
A functional mooring sequence, known to be required for apolipoprotein B (apoB) mRNA editing, exists in the mRNA encoding the neurofibromatosis type I (NF1) tumor suppressor. Editing of NF1 mRNA modifies cytidine in an arginine codon (CGA) at nucleotide 2914 to a uridine (UGA), creating an in frame translation stop codon. NF1 editing occurs in normal tissue but was several-fold higher in tumors. In vitro editing and transfection assays demonstrated that apoB and NF1 RNA editing will take place in both neural tumor and hepatoma cells. Unlike apoB, NF1 editing did not demonstrate dependence on rate-limiting quantities of APOBEC-1 (the apoB editing catalytic subunit) suggesting that different trans-acting factors may be involved in the two editing processes.


Genetic Association of MMP10, MMP14, and MMP16 with Dental Caries.
Matrix metalloproteinases (MMPs), which degrade extracellular proteins as part of a variety of physiological processes, and their inhibitors have been implicated in the dental caries process. Here we investigated 28 genetic variants spanning the MMP10, MMP14, and MMP16 genes to detect association with dental caries experience in 13 age- and race-stratified (n = 3,587) samples from 6 parent studies. Analyses were performed separately for each sample, and results were combined across samples by meta-analysis. Two SNPs (rs2046315 and rs10429371) upstream of MMP16 were significantly associated with caries in an individual sample of white adults and via meta-analysis across 8 adult samples after gene-wise adjustment for multiple comparisons. Noteworthy is SNP rs2046315 (p = 8.14 × 10-8) association with caries in white adults. This SNP was originally nominated in a genome-wide-association study (GWAS) of dental caries in a sample of white adults and yielded associations in a subsequent GWAS of surface level caries in white adults as well. Therefore, in our study, we were able to recapture the association between rs2046315 and dental caries in white adults. Although we did not strengthen evidence that MMPs 10, 14, and 16 influence caries risk, MMP16 is still a likely candidate gene to pursue.


Comparison of drug survival and clinical outcome in patients with ankylosing spondylitis treated with etanercept or adalimumab.
To compare rates of drug survival and clinical response during 2 years of follow-up in ankylosing spondylitis (AS) patients treated with etanercept or adalimumab in routine care. Biological-naïve consecutive AS patients treated with etanercept (n = 163) or adalimumab (n = 82) were followed. Treatment discontinuation was due to inefficacy, adverse events, loss to follow-up, planning a pregnancy, or uveitis. Disease activity was assessed by the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP). Moderate disease activity was defined as an ASDAS-CRP < 2.1. Twenty-seven patients (32.9%) treated with adalimumab and 30 (18.4%) with etanercept discontinued treatment. Cox regression analysis demonstrated a significant difference in survival rate between discontinuation of the drug in adalimumab patients compared with etanercept patients [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.3-4.5, p = 0.005; corrected for confounding factors: HR 2.5, 95% CI 1.3-4.5, p = 0.006]. There was no significant difference at 2 years of follow-up between the adalimumab- and the etanercept-treated patients in mean ± sd ASDAS-CRP (1.9 ± 1.1 and 2.0 ± 0.9, respectively, p = 0.624), and 23 out of 34 (67.6%) compared to 71 out of 117 (60.7%) reached ASDAS-CRP moderate disease activity (odds ratio 0.738, 95% CI 0.329-1.657, p = 0.530). No significant difference was found between AS patients treated with etanercept and those treated with adalimumab in mean ASDAS-CRP and reaching ASDAS-CRP minimal disease activity at 2 year follow-up. Drug survival rate was higher in etanercept- compared to adalimumab-treated patients. However, this should be interpreted cautiously as the risk of allocation bias cannot be excluded.


Regulation and extracellular glucosyltransferase production and the relationship between extracellular and cell-associated activities in Streptococcus mutans.
The regulation of extracellular glucosyltransferase production in Streptococcus mutans GS-5 has been studied using a chemically defined medium. Most of the glucosyltransferase activity produced by cells grown in the chemically defined medium was extracellular, in contrast with the distribution between cell-associated and extracellular glucosyltransferase activity when cells were grown in complex medium. The production of extracellular glucosyltransferase activity coincided with the logarithmic growth phase, and further accumulation ceased when glucose was exhausted from the medium. Accumulation of extracellular glucosyltransferase activity was inhibited immediately by chloramphenicol and rifamycin, added either at the beginning of growth or during mid-logarithmic growth. Low concentrations of chloramphenicol inhibited both cellular protein synthesis and the accumulation of extracellular glucosyltransferase activity to the same extent, indicating a close coupling between glucosyltransferase synthesis and secretion. Experiments using cell lysates showed that no intracellular accumulation of glucosyltransferase activity occurred in the presence of the inhibitors and that the intracellular activity is very low relative to the cell-surface activity. The utilization of cells depleted of cell-associated glucosyltransferase activity indicated that most of the cell-associated glucosyltransferase activity does not act as a precursor for the extracellular enzyme. Sugar analogue inhibitors of glycoprotein synthesis did not have any specific effects on the synthesis or secretion of extracellular glucosyltransferase activity.


Ten new paediatric emergency medicine commandments.
We suggest the top ten tips that any clinician working in a pediatric emergency department should always keep in mind. A literature review was conducted using, as a starting point, the previously published Ten Commandments for Emergency Medicine, Pediatric Emergency Medicine, and Perinatal Medicine. A standard curriculum for pediatric emergency physicians is lacking. These ten commandments should be considered as advice for physicians who practice this profession every day and not as unbreakable rules established from above.


Inactivation of Escherichia coli O157:H7 in moisture-enhanced nonintact beef by pan-broiling or roasting with various cooking appliances set at different temperatures.
This study evaluated inactivation of Escherichia coli O157:H7 in moisture-enhanced restructured nonintact beef cooked to 65 °C using different cooking appliances set at different temperatures. Batches (2 kg) of coarse-ground beef (approximately 5% fat) were mixed with an 8-strain composite (100 mL) of rifampicin-resistant E. coli O157:H7 (6.4 ± 0.1 log CFU/g) and a solution (100 mL) of sodium chloride plus sodium tripolyphosphate to yield concentrations (wt/wt) of 0.5% and 0.25%, respectively, in the final product. Beef portions of 2.54 cm thickness (15 cm dia) were prepared and were vacuum-packaged and frozen (-20 °C, 42 h). Partially thawed (-2.5 ± 1.0 °C) portions were pan-broiled (Presto electric skillet and Sanyo grill) or roasted (Oster toaster oven and Magic Chef kitchen oven) to 65 °C. The appliances were set at, and preheated before cooking to 149 or 204 °C (electric skillet), 149 or 218 °C (grill), 149 or 232 °C (toaster oven), and 149, 204, or 260 °C (kitchen oven). Temperatures of appliances and beef samples were monitored with thermocouples, and meat samples were analyzed for surviving microbial populations. In general, the higher the appliance temperature setting, the shorter the time needed to reach 65 °C, and the higher the edge and surface temperatures of the meat samples. Temperatures of 204 to 260 °C, regardless of appliance, resulted in greater (P < 0.05) pathogen reductions (3.3 to 5.5 log CFU/g) than those obtained at 149 °C (1.5 to 2.4 log CFU/g). The highest (P < 0.05) reduction (5.5 log CFU/g) was obtained in samples cooked in the kitchen oven set at 260 °C. The results should be useful to the food service industry for selection of effective nonintact beef cooking protocols, and for use in risk assessments for nonintact meat products. Practical Application: Results of this study should be useful for developing cooking recommendations to enhance the safety of nonintact beef products, and for use in risk assessments of such products.


Ego-relevance in team production.
We study how individuals' effort contribution to a team production task varies depending on whether the task is ego relevant or not. We conduct an experiment to test the effect of ego-relevance when the team production depends on the team's top- or bottom-performer. Ego-relevance is manipulated by calling the Raven IQ Test an "IQ Task" or a "Pattern Task." We find that the effort contributed to the task is affected by ego-relevance and the impact of the team production function on effort contribution is mediated by the teammate's expected effort contribution. Ego-relevance increases the responsiveness to the teammate's expected effort contributions. Similarly, more responsive behavior is noticeable when the team production depends on the bottom-performer. However, we do not observe interaction-effects between ego-relevance and the team production function that affect effort contributions.


Fluorescent dye nano-assemblies by thiol attachment directed to the tips of gold nanorods for effective emission enhancement.
The conjugation of dye-labelled DNA oligonucleotides with gold nanorods has been widely explored for the development of multifunctional fluorescent nanoprobes. Here, we show that the functionalization route is crucial to achieve enhanced emission in dye nano-assemblies based on gold nanorods. By using a tip-selective approach for thiol attachment of dye molecules onto gold nanorods, it was possible to effectively increase the emission by more than 10-fold relatively to that of a free dye. On the other hand, a non-selective approach revealed that indiscriminate surface functionalization has a detrimental effect on the enhancement. Simulations of discrete dipole approximation gave further insight into the surface distribution of plasmon-enhanced emission by confirming that tip regions afford an effective enhancement, while side regions exhibit a negligible effect or even emission quenching. The contrast between dye nano-assemblies obtained from tip- and non-selective functionalization was further characterized by single-particle fluorescence emission. These studies showed that tip-functionalized gold nanorods with an average of only 30 dye molecules have a comparable to or even stronger emission than non-selectively functionalized particles with approximately 10 times more dye molecules. The results herein reported could significantly improve the performance of dye nano-assemblies for imaging or sensing applications.


A review on chitosan/metal oxide nanocomposites for applications in environmental remediation.
A cleaner and safer environment is one of the most important requirements in the future. It has become increasingly urgent and important to fabricate novel environmentally-friendly materials to remove various hazardous pollutants. Compared with traditional materials, chitosan is a more environmentally friendly material due to its abundance, biocompatibility, biodegradability, film-forming ability and hydrophilicity. As an abundant of -NH2 and -OH groups on chitosan molecular chain could chelate with all kinds of metal ions efficiently, chitosan-based materials hold great potential as a versatile supporting matrix for metal oxide nanomaterials (MONMs) (TiO2, ZnO, SnO2, Fe3O4, etc.). Recently, many chitosan/metal oxide nanomaterials (CS/MONMs) have been reported as adsorbents, photocatalysts, heterogeneous Fenton-like agents, and sensors for potential and practical applications in environmental remediation and monitoring. This review analyzed and summarized the recent advances in CS/MONMs composites, which will provide plentiful and meaningful information on the preparation and application of CS/MONMs composites for wastewater treatment and help researchers to better understand the potential of CS/MONMs composites for environmental remediation and monitoring. In addition, the challenges of CS/MONM have been proposed.


Anesthesia for nonobstetric surgery in the pregnant patient.
Each year over 75,000 pregnant women in the United States undergo nonobstetric surgery. The operations include those directly related to pregnancy, such as cerclage, those indirectly related to pregnancy, such as ovarian cystectomy, and those unrelated to gestation, such as appendectomy. When a pregnant woman presents for surgery, it is a stressful event for everyone involved. Issues about the surgical problem itself often seem secondary to maternal (and physician) concerns about the effect of surgery and anesthesia on the developing fetus, or the potential to trigger preterm labor. This article reviews the physiologic and anatomic changes that affect anesthetic care during pregnancy. The author also reviews the effects of anesthetic drugs and perioperative events on the fetus and on the pregnancy outcome. The relatively small number of published series are reviewed as well as the controversial recommendations regarding fetal and maternal monitoring during surgery.


ACR Appropriateness Criteria® Renal Failure.
Renal failure can be divided into acute kidney injury and chronic kidney disease. Both are common and result in increased patient morbidity and mortality. The etiology is multifactorial and differentiation of acute kidney injury from chronic kidney disease includes clinical evaluation, laboratory tests, and imaging. The main role of imaging is to detect treatable causes of renal failure such as ureteral obstruction or renovascular disease and to evaluate renal size and morphology. Ultrasound is the modality of choice for initial imaging, with duplex Doppler reserved for suspected renal artery stenosis or thrombosis. CT and MRI may be appropriate, particularly for urinary tract obstruction. However, the use of iodinated and gadolinium-based contrast should be evaluated critically depending on specific patient factors and cost-benefit ratio. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations.
Dystroglycan is a transmembrane glycoprotein whose interactions with the extracellular matrix (ECM) are necessary for normal muscle and brain development, and disruptions of its function lead to dystroglycanopathies, a group of congenital muscular dystrophies showing extreme genetic and clinical heterogeneity. Specific glycans bound to the extracellular portion of dystroglycan, α-dystroglycan, mediate ECM interactions and most known dystroglycanopathy genes encode glycosyltransferases involved in glycan synthesis. POMK, which was found mutated in two dystroglycanopathy cases, is instead involved in a glycan phosphorylation reaction critical for ECM binding, but little is known about the clinical presentation of POMK mutations or of the function of this protein in the muscle. Here, we describe two families carrying different truncating alleles, both removing the kinase domain in POMK, with different clinical manifestations ranging from Walker-Warburg syndrome, the most severe form of dystroglycanopathy, to limb-girdle muscular dystrophy with cognitive defects. We explored POMK expression in fetal and adult human muscle and identified widespread expression primarily during fetal development in myocytes and interstitial cells suggesting a role for this protein during early muscle differentiation. Analysis of loss of function in the zebrafish embryo and larva showed that pomk function is necessary for normal muscle development, leading to locomotor dysfuction in the embryo and signs of muscular dystrophy in the larva. In summary, we defined diverse clinical presentations following POMK mutations and showed that this gene is necessary for early muscle development.


An archaebacterial ATPase, homologous to ATPases in the eukaryotic 26 S proteasome, activates protein breakdown by 20 S proteasomes.
In eukaryotes, the 20 S proteasome is the proteolytic core of the 26 S proteasome, which degrades ubiquitinated proteins in an ATP-dependent process. Archaebacteria lack ubiquitin and 26 S proteasomes but do contain 20 S proteasomes. Many archaebacteria, such as Methanococcus jannaschii, also contain a gene (S4) that is highly homologous to the six ATPases in the 19 S (PA700) component of the eukaryotic 26 S proteasome. To test if this putative ATPase may regulate proteasome function, we expressed it in Escherichia coli and purified the 50-kDa product as a 650-kDa complex with ATPase activity. When mixed with the well characterized 20 S proteasomes from Thermoplasma acidophilum and ATP, this complex stimulated degradation of several unfolded proteins 8-25-fold. It also stimulated proteolysis by 20 S proteasomes from another archaebacterium and mammals. This effect required ATP hydrolysis since ADP and the nonhydrolyzable analog, 5'-adenylyl beta, gamma-imidophosphate, were ineffective. CTP and to a lesser extent GTP and UTP were also hydrolyzed and also stimulated proteolysis. We therefore named this complex PAN for proteasome-activating nucleotidase. However, PAN did not promote the degradation of small peptides, which, unlike proteins, should readily diffuse into the proteasome. This ATPase complex appears to have been the evolutionary precursor of the eukaryotic 19 S complex, before the coupling of proteasome function to ubiquitination.


GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.
Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism. This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient. Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist.


Human Skin Aging and the Anti-Aging Properties of Retinol.
The skin is the most-extensive and -abundant tissue in the human body. Like many organs, as we age, human skin experiences gradual atrophy in both the epidermis and dermis. This can be primarily attributed to the diminishing population of epidermal stem cells and the reduction in collagen, which is the primary structural protein in the human body. The alterations occurring in the epidermis and dermis due to the aging process result in disruptions to the structure and functionality of the skin. This creates a microenvironment conducive to age-related skin conditions such as a compromised skin barrier, slowed wound healing, and the onset of skin cancer. This review emphasizes the recent molecular discoveries related to skin aging and evaluates preventive approaches, such as the use of topical retinoids. Topical retinoids have demonstrated promise in enhancing skin texture, diminishing fine lines, and augmenting the thickness of both the epidermal and dermal layers.


Pseudomonas aeruginosa SoxR does not conform to the archetypal paradigm for SoxR-dependent regulation of the bacterial oxidative stress adaptive response.
SoxR is a transcriptional regulator that controls an oxidative stress response in Escherichia coli. The regulator is primarily activated by superoxide anion-dependent oxidation. Activated SoxR turns on transcription of a single gene, soxS, which encodes a transcriptional regulator that activates a regulon that includes dozens of oxidative stress response genes. SoxR homologues have been identified in many bacterial species, including the opportunistic pathogen Pseudomonas aeruginosa. However, the expected SoxR partner, SoxS, has not been found in P. aeruginosa. Thus, the primary gene target(s) of P. aeruginosa SoxR is unknown and the involvement of this regulator in the oxidative stress response of the bacterium remains unclear. We utilized transcriptome profiling to identify the P. aeruginosa SoxR regulon and constructed and characterized an unmarked P. aeruginosa DeltasoxR mutant. We provide evidence indicating that P. aeruginosa SoxR activates a six-gene regulon in response to O(2)(.-)-induced stress. The regulon includes three transcriptional units: (i) the recently identified mexGHI-ompD four-gene operon, which encodes a multidrug efflux pump system involved in quorum-sensing signal homeostasis; (ii) gene PA3718, encoding a probable efflux pump; and (iii) gene PA2274, encoding a probable monooxygenase. We also demonstrate that P. aeruginosa SoxR is not a key regulatory player in the oxidative stress response. Finally, we show that P. aeruginosa SoxR is required for virulence in a mouse model of intrapulmonary infection. These results demonstrate that the E. coli-based SoxRS paradigm does not hold in P. aeruginosa and foster new hypotheses for the possible physiological role of P. aeruginosa SoxR.


Have contemporary hip resurfacing designs reached maturity? A review.
The increasing prevalence of hip replacements in young patients is expected to fuel the demand for hip resurfacing arthroplasty. Patient selection, surgical technique, and implant design can influence the clinical outcomes for these patients. In this review, we discuss whether contemporary hip resurfacing designs have reached maturity and suggest design considerations for future-generation implants. These design-related factors include the amount and extent of cement fixation, adoption of cementless femoral fixation, optimization of implant position, minimization of stress-shielding, improvement in modularity or sizing and geometry options, metallurgy, development of alternative bearing options, and examination of in vivo cup deformation. In addition, this review is based on an understanding of the causes of failure of revision hip resurfacing arthroplasty, which is essential to help guide research, implant design, and clinical decision-making.


Biochemical characterization and immunocytochemical localization of EM66, a novel peptide derived from secretogranin II, in the rat pituitary and adrenal glands.
Characterization of secretogranin II (SgII) mRNA in various vertebrates has revealed selective conservation of the amino acid sequences of two regions of the protein, i.e., the bioactive peptide secretoneurin and a flanking novel peptide that we named EM66. To help elucidate the possible role of EM66, we examined the occurrence as well as the cellular and subcellular distribution of EM66 in rat pituitary and adrenal glands by using a polyclonal antibody raised against the recombinant human EM66 peptide. High-performance liquid chromatography (HPLC) analysis of rat pituitary and adrenal extracts combined with a radioimmunoassay resolved EM66-immunoreactive material exhibiting the same retention time as recombinant EM66. In the rat pituitary, double-labeling immunohistochemical (IHC) studies showed that EM66 immunoreactivity (IR) was present in gonadotrophs, lactotrophs, thyrotrophs, and melanotrophs, whereas corticotrophs were devoid of labeling. EM66-IR was also observed in nerve endings in the neural lobe. Immunocytochemical staining at the electron microscopic level revealed that EM66-IR is sequestered in the secretory granules within gonadotrophs and lactotrophs. In the adrenal medulla, double IHC labeling showed that EM66-IR occurs exclusively in epinephrine-synthesizing cells. At the ultrastructural level, EM66-IR was seen in chromaffin vesicles of adrenomedullary cells. These results demonstrate that post-translational processing of SgII generates a novel peptide that exhibits a cell-specific distribution in the rat pituitary and adrenal glands where it is stored in secretory granules, supporting the notion that EM66 may play a role in the endocrine system.


Role of Imaging in the Evaluation of Male Infertility.
Infertility is defined herein as the inability to achieve pregnancy after frequently engaging in unprotected sexual intercourse for 1 year. Among infertile couples, the cause of infertility involves the male partner in approximately 50% of cases. Male infertility is usually caused by conditions affecting sperm production, sperm function, or both, or blockages that prevent the delivery of sperm. Chronic health problems, injuries, lifestyle choices, anatomic problems, hormonal imbalances, and genetic defects can have a role in male infertility. The diagnostic workup of male infertility should include a thorough medical and reproductive history, physical examination, and semen analysis, followed by imaging. The main role of imaging is identification of the causes of infertility, such as congenital anomalies and disorders that obstruct sperm transport and may be correctable. Scrotal ultrasonography is the most common initially performed noninvasive examination used to image the male reproductive system, including the testes and extratesticular structures such as the epididymis. Magnetic resonance (MR) imaging is another noninvasive imaging modality used in the pelvis to evaluate possible obstructive lesions involving the ductal system. MR imaging of the brain is extremely useful for evaluating relevant neurologic abnormalities, such as pituitary gland disorders, that are suspected on the basis of hormone analysis results. Invasive techniques are usually reserved for therapeutic interventions in patients with known abnormalities. In this article, the causes and imaging findings of obstructive and nonobstructive azoospermia are discussed. In addition to detecting treatable conditions that are related to male infertility, identifying the life-threatening entities associated with infertility and the genetic conditions that could be transmitted to offspring-especially in patients who undergo assisted reproduction-is critical. ©RSNA, 2017.


Biomechanical Characteristics of Hand Coordination in Grasping Activities of Daily Living.
Hand coordination can allow humans to have dexterous control with many degrees of freedom to perform various tasks in daily living. An important contributing factor to this important ability is the complex biomechanical architecture of the human hand. However, drawing a clear functional link between biomechanical architecture and hand coordination is challenging. It is not understood which biomechanical characteristics are responsible for hand coordination and what specific effect each biomechanical characteristic has. To explore this link, we first inspected the characteristics of hand coordination during daily tasks through a statistical analysis of the kinematic data, which were collected from thirty right-handed subjects during a multitude of grasping tasks. Then, the functional link between biomechanical architecture and hand coordination was drawn by establishing the clear corresponding causality between the tendinous connective characteristics of the human hand and the coordinated characteristics during daily grasping activities. The explicit functional link indicates that the biomechanical characteristic of tendinous connective architecture between muscles and articulations is the proper design by the Creator to perform a multitude of daily tasks in a comfortable way. The clear link between the structure and the function of the human hand also suggests that the design of a multifunctional robotic hand should be able to better imitate such basic architecture.


[Hepatitis C--a health problem also in Norway].
Hepatitis C is a large global health problem; approximately 20 - 30 000 are infected in Norway. Hepatitis C-infection is often chronic and can progress into chronic liver disease, liver cirrhosis and hepatocellular carcinoma. The most important transmission route is through percutaneous exposure to infected blood. The aim of this article is to describe the clinical course, microbiological diagnostic approaches, therapy, prophylaxis and public health aspects of Hepatitis C infection. The paper is based on results from annual health examinations (conducted since 2001) of persons who abuse drugs intravenously in Oslo, from diagnostic work in a national reference laboratory for Hepatitis C and studies of literature (retrieved from Pubmed). The prevalence of Hepatitis C varies by country and subgroup of patients. In Norway the prevalence is 0.13 % among new blood donors, 0.7 % among pregnant women, 0.55 % in the general adult population and approximately 70 % among persons who abuse drugs intravenously. Treatment with pegylated interferon and ribavirin induces sustained virological response in 80 % of patients with genotypes 2 and 3 and in 30 - 40 % of those with genotype 1.


Different enzyme activities of sialyltransferases in gynecological cancer cell lines.
Due to rarity of a relationship between sialyltransferase enzyme activities and gynecological cancers, we arranged the study to evaluate sialyltransferase enzyme activity in the various kinds of gynecological cancer cell lines. Ten cell lines from various kinds of gynecological cancers and two cell lines from normal tissue were enrolled in this study. The activities of each subtype of sialyltransferases were detected using Gal beta1,3GalNAc-acetyl-lactosamine)-Obz1 (acceptor for ST2,3Gal I), Gal beta1,3GlcNAc beta1,3Gal beta1,4GlcNAc (acceptor for ST2,3Gal III), Gal beta1,4GlcNAc (acceptor for ST2,3Gal IV), asialo-bovine submaxillary mucin (acceptor for ST2,6GalNAc I), asialo-fetuin (acceptor for STalpha2,6GalNAc II), and fetuin (acceptor for ST2,6GalNAc III), respectively. The amounts of sialic acids were measured using fluorescein-conjugated Sambucus nigra agglutinin (SNA) specific for alpha2,6-sialic acids and fluorescein-conjugated Maackia Amurensis agglutinin (MAA) specific for alpha2,3-sialic acids. The activities of two sialyltransferase subtypes, ST3Gal I & ST6GalNAc II, were significantly higher in nearly all cell lines. More specifically, cervical cancer cell line-ME 180, ovarian cancer cell line-ES-2, and choriocarcinoma cell line-BeWo showed high levels of ST3Gal I enzyme activity; all gynecological cancer cell lines except endometrial cancer cell line-RL95-2 had high levels of ST6GalNAc II enzyme activity when compared with a normal control cell line--fibroblast cell line (CCD-966Sk). Cell lines tested in this study have diverse levels of surface alpha2,6-sialic acid sugar chains (enhanced SNA binding) when compared with alpha2,3-sialic acid sugar chains (enhanced MAA binding) but we found that some cell lines such as Ca Ski (cervical cancer cell line), CC7T (cervical cancer cell line), PA-I (ovarian cancer cell line), and BeWo showed significantly altered cell surface alpha2,6-sialic acid sugar chains. Increasing enzyme activity of ST3Gal I and ST6GalNAc II might be important in various kinds of gynecological cancers. More specifically, enhanced activity of sialyltransferases involving alpha2,6-sialic acid sugar chains might be more important in cancer development. Future studies will investigate whether the enzyme activity of these sialyltransferases can be helpful for clinical practice.


[Influence of local anesthesia and energy level on the clinical outcome of extracorporeal shock wave-treatment of chronic plantar fasciitis].
The efficacy of low energy extracorporeal shock wave treatment (ESWT) for chronic plantar fasciitis is discussed controversially. It is unclear whether the simultaneous application of local anesthesia (LA) interferes with clinical outcome. 60 patients with a chronic plantar fasciitis were enrolled in a triple-arm (20 patients per group), prospective randomized and observer-blinded pilot trial. The patients were randomly assigned to receive either active ESWT without LA (;3 x 1 500 shocks, total energy flux density [EFD] per shock 0.09 mJ/mm(2) [Group A]), ESWT with LA (3 x 1 500 shocks, EFD 0.18 mJ/mm(2) per shock [Group B]) or ESWT with LA (3 x 1 500 shocks, EFD 0.09 mJ/mm(2) [Group C]). Main outcome measures were: pain during first stepps in the morning (measured on a 0-10 point visual analogue scale) and number of patients with > 50 % reduction of pain and no further therapy needed, measured at 6 weeks after the last ESWT. Group A improved in the VAS from 6.4 (SD: 1.7) to 2.2 (SD: 2.6) points, group B from 6.7 (SD: 1.5) to 4.1 (SD: 2.4) points, group C from 6.2 (SD: 1.6) to 3.8 (SD: 2.5) points. A reduction of pain of at least 50 % was achieved in 60 % of group A, in 36 % of group B and in 30 % of group C. Group A without LA showed a significantly higher improvement in the VAS and subjective evaluation than groups B (p = 0.007) and C (p = 0.016). At 6 weeks success rates after low-energy ESWT with local anesthesia were significantly lower than after identical low-energy ESWT without local anesthesia. Higher energy levels could not balance the disadvantage of this effect. LA significantly influenced the clinical results after low energy ESWT in a negative way. Blinding patients by LA in ESWT studies must therefore be considered a systematic error in study design.


Dissipation layers in Rayleigh-Bénard convection: a unifying view.
Boundary layers play an important role in controlling convective heat transfer. Their nature varies considerably between different application areas characterized by different boundary conditions, which hampers a uniform treatment. Here, we argue that, independent of boundary conditions, systematic dissipation measurements in Rayleigh-Bénard convection capture the relevant near-wall structures. By means of direct numerical simulations with varying Prandtl numbers, we demonstrate that such dissipation layers share central characteristics with classical boundary layers, but, in contrast to the latter, can be extended naturally to arbitrary boundary conditions. We validate our approach by explaining differences in scaling behavior observed for no-slip and stress-free boundaries, thus paving the way to an extension of scaling theories developed for laboratory convection to a broad class of natural systems.


Systematic analysis of breast cancer morphology uncovers stromal features associated with survival.
The morphological interpretation of histologic sections forms the basis of diagnosis and prognostication for cancer. In the diagnosis of carcinomas, pathologists perform a semiquantitative analysis of a small set of morphological features to determine the cancer's histologic grade. Physicians use histologic grade to inform their assessment of a carcinoma's aggressiveness and a patient's prognosis. Nevertheless, the determination of grade in breast cancer examines only a small set of morphological features of breast cancer epithelial cells, which has been largely unchanged since the 1920s. A comprehensive analysis of automatically quantitated morphological features could identify characteristics of prognostic relevance and provide an accurate and reproducible means for assessing prognosis from microscopic image data. We developed the C-Path (Computational Pathologist) system to measure a rich quantitative feature set from the breast cancer epithelium and stroma (6642 features), including both standard morphometric descriptors of image objects and higher-level contextual, relational, and global image features. These measurements were used to construct a prognostic model. We applied the C-Path system to microscopic images from two independent cohorts of breast cancer patients [from the Netherlands Cancer Institute (NKI) cohort, n = 248, and the Vancouver General Hospital (VGH) cohort, n = 328]. The prognostic model score generated by our system was strongly associated with overall survival in both the NKI and the VGH cohorts (both log-rank P ≤ 0.001). This association was independent of clinical, pathological, and molecular factors. Three stromal features were significantly associated with survival, and this association was stronger than the association of survival with epithelial characteristics in the model. These findings implicate stromal morphologic structure as a previously unrecognized prognostic determinant for breast cancer.


Pharmacology of moxonidine, an I1-imidazoline receptor agonist.
Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of moxonidine into the RVLM of anesthetized SHRs. Selective I1-receptor antagonists introduced into this area abolish the action of systemic moxonidine. Receptor binding studies have shown high and selective affinity of moxonidine for I1-receptors vs. alpha(2)-adrenergic receptors. In vivo studies using a variety of selective I1 or alpha(2)-adrenergic agonists and antagonists have confirmed the primary role of I1-receptors in blood pressure regulation by moxonidine. In addition to lowering blood pressure, moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effect attributed to central alpha 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential.


AN APPROACH TO BILIARY TRACT OPERATIONS.
By changing the position of the patient and of the operating team and by using a right-angle incision, superb exposure of the right upper quadrant abdominal contents can be had with little or no retraction by human effort.


Review of the literature supporting a scientific basis for the chiropractic subluxation complex.
A review of the literature reveals strong evidence for both the mechanical model of disease production (structural) and the neurobiological model (functional). Outdated models which attempt to describe a scientific basis for chiropractic theory are inadequate and indeed harmful to the progress and acceptance of chiropractic. Pragmatic or empirical arguments that "Chiropractic works and that's what counts" have served a useful purpose, but now must be augmented by extant research findings. The "paradigm shift" is on. Research investigators around the world are focusing on the multiple components of the chiropractic subluxation complex (CSC), a definitive, provable clinical entity. No longer can "informed" critics support the accusation that "chiropractic practice is based upon irrational, untenable premises." Only a few more pieces of the puzzle need to be fitted into place to produce the "big picture," i.e., the vertebral column is one of the most neglected vital organs in the human body--the sine qua non of the neurobiomechanical system--which influences every structure and function. Historically, its role in maintaining health has been almost totally ignored and for nearly a century chiropractors have battled against the consequences of this neglect. The scientific community is about to see that chiropractic is leading the way in discovering the "new world" in health care. Past, present and future research is discussed.


[Bilateral cerebellar infarction caused by intracranial dissection of the vertebral artery after long periods of "Shiatsu"].
For five years, a 56-year-old woman had undergone "Shiatsu" (a technique that uses fingers and the palm of the hand to apply pressure to particular sections of the body's surface to correct neck stiffness and body imbalances in order to maintain and promote health). She suddenly developed neck pain, dizziness, dysphagia, and speech and gait disturbances during treatment. A neurological examination detected bradylalia and truncal and mild bilateral limb ataxia of the cerebellar type. Diffusion-weighted brain MRI showed multiple hyperintense signal lesions at the bilateral cerebellar hemisphere in the posterior inferior cerebellar artery territory. Three-dimensional computed tomographic angiography (3D-CTA) revealed irregular stenosis of the intracranial right vertebral artery (string sign). Dissection of the intracranial portion of the vertebral artery owing to trauma is rare. Physicians need to be aware of patients who have acute dissecting infarction after long periods of repeated trivial pressure such as "Shiatsu". 3D-CTA is a very useful diagnostic procedure for arterial dissection.


Development of a Preclinical Laser Speckle Contrast Imaging Instrument for Assessing Systemic and Retinal Vascular Function in Small Rodents.
To develop and test a non-contact, contrast-free, retinal laser speckle contrast imaging (LSCI) instrument for use in small rodents to assess vascular anatomy, quantify hemodynamics, and measure physiological changes in response to retinal vascular dysfunction over a wide field of view (FOV). A custom LSCI instrument capable of wide-field and non-contact imaging in small rodents was constructed. The effect of camera gain, laser power, and exposure duration on speckle contrast variance was standardized before the repeatability of LSCI measurements was determined in vivo. Finally, the ability of LSCI to detect alterations in local and systemic vascular function was evaluated using a laser-induced branch retinal vein occlusion and isoflurane anesthesia model, respectively. The LSCI system generates contrast-free maps of retinal blood flow with a 50° FOV at >376 frames per second (fps) and under a short exposure duration (>50 µs) with high reliability (intraclass correlation R = 0.946). LSCI was utilized to characterize retinal vascular anatomy affected by laser injury and longitudinally measure alterations in perfusion and blood flow profile. Under varied doses of isoflurane, LSCI could assess cardiac and systemic vascular function, including heart rate, peripheral resistance, contractility, and pulse propagation. We present a LSCI system for detecting anatomical and physiological changes in retinal and systemic vascular health and function in small rodents. Detecting and quantifying early anatomical and physiological changes in vascular function in animal models of retinal, systemic, and neurodegenerative diseases could strengthen our understanding of disease progression and enable the identification of new prognostic and diagnostic biomarkers for disease management and for assessing treatment efficacies.


Haptic Adaptive Feedback to Promote Motor Learning With a Robotic Ankle Exoskeleton Integrated With a Video Game.
Background: Robotic devices have been used to rehabilitate walking function after stroke. Although results suggest that post-stroke patients benefit from this non-conventional therapy, there is no agreement on the optimal robot-assisted approaches to promote neurorecovery. Here we present a new robotic therapy protocol using a grounded exoskeleton perturbing the ankle joint based on tacit learning control. Method: Ten healthy individuals and a post-stroke patient participated in the study and were enrolled in a pilot intervention protocol that involved performance of ankle movements following different trajectories via video game visual feedback. The system autonomously modulated task difficulty according to the performance to increase the challenge. We hypothesized that motor learning throughout training sessions would lead to increased corticospinal excitability of dorsi-plantarflexor muscles. Transcranial Magnetic Stimulation was used to assess the effects on corticospinal excitability. Results: Improvements have been observed on task performance and motor outcomes in both healthy individuals and post-stroke patient case study. Tibialis Anterior corticospinal excitability increased significantly after the training; however no significant changes were observed on Soleus corticospinal excitability. Clinical scales showed functional improvements in the stroke patient. Discussion and Significance: Our findings both in neurophysiological and performance assessment suggest improved motor learning. Some limitations of the study include treatment duration and intensity, as well as the non-significant changes in corticospinal excitability obtained for Soleus. Nonetheless, results suggest that this robotic training framework is a potentially interesting approach that can be explored for gait rehabilitation in post-stroke patients.


Physiological effects induced by antiorthostatic hypokinesia.
The main purpose of the present investigation was to reproduce some physiological reactions in the sensory system which are similar to those observed during the first day of the adaptation to weightlessness. This was achieved by a 5-day bed rest experiment during which the test subjects were kept in the antiorthostatic position at angles of 0 degrees, -4 degrees, -8 degrees, -12 degrees. Our investigations allowed simulation of the acute stage of adaptation to weightlessness and assessment of gravity-induced blood redistribution in the development of the above physiological reactions.


A Genome-Scale Insight into the Effect of Shear Stress During the Fed-Batch Production of Clavulanic Acid by Streptomyces Clavuligerus.
Streptomyces clavuligerus is a filamentous Gram-positive bacterial producer of the β-lactamase inhibitor clavulanic acid. Antibiotics biosynthesis in the Streptomyces genus is usually triggered by nutritional and environmental perturbations. In this work, a new genome scale metabolic network of Streptomyces clavuligerus was reconstructed and used to study the experimentally observed effect of oxygen and phosphate concentrations on clavulanic acid biosynthesis under high and low shear stress. A flux balance analysis based on experimental evidence revealed that clavulanic acid biosynthetic reaction fluxes are favored in conditions of phosphate limitation, and this is correlated with enhanced activity of central and amino acid metabolism, as well as with enhanced oxygen uptake. In silico and experimental results show a possible slowing down of tricarboxylic acid (TCA) due to reduced oxygen availability in low shear stress conditions. In contrast, high shear stress conditions are connected with high intracellular oxygen availability favoring TCA activity, precursors availability and clavulanic acid (CA) production.


Efficiency of ultrasound and ultrasound-guided fine needle aspiration cytology in preoperative assessment of axillary lymph node metastases in breast cancer.
We performed this study to detect preoperative axillary metastases with ultrasound (US)-guided fine needle aspiration biopsy (FNAB), to eliminate the need for time-consuming and costly sentinel lymph node (SLN) scintigraphy and biopsy steps in the treatment of breast cancer patients, and in that of with suspicious US findings, and to evaluate the accuracy of preoperative US-guided FNAB for patients with suspicious lymph node metastases on US. Patients with a suspicious breast lump or histopathologically proven breast cancer underwent breast-axillary US. Increase in lymph node size, cortical thickening, non-hilar cortical flow, and hilar changes were evaluated with gray scale-color Doppler US. FNAB was performed if US results were suspicious for malignancy. Thirty-eight axillary lymph nodes (ALN) underwent FNAB. ALN dissection, SLN scintigraphy, and biopsy steps were bypassed in 23 axillas with positive ALN FNAB (60.5%). The sensitivity of ALN FNAB was 88.46%; specificity and positive predictive value were 100%; and negative predictive value was 66.6% (inadequate cytology included; 76.7%, 100%, 100%, 53.3%, respectively). Asymmetrical cortical thickening, non-hilar cortical flow, and increase in hypoechogenity were only detected in metastatic nodes. Cortical thickening, and lymph node and breast mass size was higher in the metastatic group. By performing FNAB on suspicious lymph nodes, the routine, high-cost SLN scintigraphy and intraoperative gamma probe steps may be skipped, and axilla dissection can be performed directly. This leads to the elimination of the need for SLN investigation in more than half of the patients. The assessment of ALN metastases with preoperative US-guided FNAB is a cost-effective method with high specificity, that eliminates the need for costly and time-consuming SLN scintigraphy and biopsy steps, and helps in preoperative staging.


Science vs conspiracy: collective narratives in the age of misinformation.
The large availability of user provided contents on online social media facilitates people aggregation around shared beliefs, interests, worldviews and narratives. In spite of the enthusiastic rhetoric about the so called collective intelligence unsubstantiated rumors and conspiracy theories-e.g., chemtrails, reptilians or the Illuminati-are pervasive in online social networks (OSN). In this work we study, on a sample of 1.2 million of individuals, how information related to very distinct narratives-i.e. main stream scientific and conspiracy news-are consumed and shape communities on Facebook. Our results show that polarized communities emerge around distinct types of contents and usual consumers of conspiracy news result to be more focused and self-contained on their specific contents. To test potential biases induced by the continued exposure to unsubstantiated rumors on users' content selection, we conclude our analysis measuring how users respond to 4,709 troll information-i.e. parodistic and sarcastic imitation of conspiracy theories. We find that 77.92% of likes and 80.86% of comments are from users usually interacting with conspiracy stories.


Upregulation in Inflammation and Collagen Expression in Perirenal but Not in Mesenteric Adipose Tissue from Diabetic Munich Wistar Frömter Rats.
Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected patients. We determined the effect of diabetes induction on (i) kidney and CV damage and (ii) on the expression of proinflammatory and profibrotic factors in both the PRAT and the mesenteric adipose tissue (MAT) of Munich Wistar Frömter (MWF) rats. The 16-week-old male MWF rats (n = 10 rats/group) were fed standard chow (MWF-C) or a high-fat/high-sucrose diet for 6 weeks together with low-dose streptozotocin (15 mg/kg i.p.) at the start of dietary exposure (MWF-D). Phenotyping was performed at the end of treatment through determining water intake, urine excretion, and oral glucose tolerance; use of the homeostatic model assessment-insulin resistance index (HOMA-IR) evidenced the development of overt diabetes manifestation in MWF-D rats. The kidney damage markers Kim-1 and Ngal were significantly higher in MWF-D rats, as were the amounts of PRAT and MAT. A diabetes-induced upregulation in IL-1, IL-6, Tnf-α, and Tgf-β was observed in both the PRAT and the MAT. Col1A1 was increased in the PRAT but not in the MAT of MWF-D, whereas IL-10 was lower and higher in the PRAT and the MAT, respectively. Urinary albumin excretion and blood pressure were not further increased by diabetes induction, while heart weight was higher in the MWF-D. In conclusion, our results show a proinflammatory and profibrotic in vivo environment in PRAT induced by diabetes which might be associated with kidney damage progression in the MWF strain.


Characterization of the core and accessory genomes of Pseudomonas aeruginosa using bioinformatic tools Spine and AGEnt.
Pseudomonas aeruginosa is an important opportunistic pathogen responsible for many infections in hospitalized and immunocompromised patients. Previous reports estimated that approximately 10% of its 6.6 Mbp genome varies from strain to strain and is therefore referred to as "accessory genome". Elements within the accessory genome of P. aeruginosa have been associated with differences in virulence and antibiotic resistance. As whole genome sequencing of bacterial strains becomes more widespread and cost-effective, methods to quickly and reliably identify accessory genomic elements in newly sequenced P. aeruginosa genomes will be needed. We developed a bioinformatic method for identifying the accessory genome of P. aeruginosa. First, the core genome was determined based on sequence conserved among the completed genomes of twelve reference strains using Spine, a software program developed for this purpose. The core genome was 5.84 Mbp in size and contained 5,316 coding sequences. We then developed an in silico genome subtraction program named AGEnt to filter out core genomic sequences from P. aeruginosa whole genomes to identify accessory genomic sequences of these reference strains. This analysis determined that the accessory genome of P. aeruginosa ranged from 6.9-18.0% of the total genome, was enriched for genes associated with mobile elements, and was comprised of a majority of genes with unknown or unclear function. Using these genomes, we showed that AGEnt performed well compared to other publically available programs designed to detect accessory genomic elements. We then demonstrated the utility of the AGEnt program by applying it to the draft genomes of two previously unsequenced P. aeruginosa strains, PA99 and PA103. The P. aeruginosa genome is rich in accessory genetic material. The AGEnt program accurately identified the accessory genomes of newly sequenced P. aeruginosa strains, even when draft genomes were used. As P. aeruginosa genomes become available at an increasingly rapid pace, this program will be useful in cataloging the expanding accessory genome of this bacterium and in discerning correlations between phenotype and accessory genome makeup. The combination of Spine and AGEnt should be useful in defining the accessory genomes of other bacterial species as well.


The pancreatic beta-cell recognition of insulin secretagogues. Effects of calcium and sodium on glucose metabolism and insulin release.
The transport and oxidation of glucose, the content of fructose 1,6-diphosphate, and the release of insulin were studied in microdissected pancreatic islets of ob/ob mice incubated in Krebs-Ringer bicarbonate medium. Under control conditions glucose oxidation and insulin release showed a similar dependence on glucose concentration with the steepest slope in the range 5-12mm. The omission of Ca(2+), or the substitution of choline ions for Na(+), or the addition of diazoxide had little if any effect on glucose transport. However, Ca(2+) or Na(+) deficiency as well as diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) or ouabain partially inhibited glucose oxidation. These alterations of medium composition also increased the islet content of fructose 1,6-diphosphate, as did the addition of adrenaline. Phentolamine [2-N-(3-hydroxyphenyl)-p-toluidinomethyl-2-imidazoline] counteracted the effects of adrenaline and Ca(2+) deficiency on islet fructose 1,6-diphosphate. After equilibration in Na(+)-deficient medium, the islets exhibited an increase in basal insulin release whereas the secretory response to glucose was inhibited. The inhibitory effects of Na(+) deficiency on the secretory responses to different concentrations of glucose correlated with those on (14)CO(2) production. When islets were incubated with 17mm-glucose, the sudden replacement of Na(+) by choline ions resulted in a marked but transient stimulation of insulin release that was not accompanied by a demonstrable increase of glucose oxidation. Galactose and 3-O-methylglucose had no effect on glucose oxidation or on insulin release. The results are consistent with a metabolic model of the beta-cell recognition of glucose as insulin secretagogue and with the assumption that Ca(2+) or Na(+) deficiency, or the addition of adrenaline or diazoxide, inhibit insulin release at some step distal to stimulus recognition. In addition the results suggest that these conditions create a partial metabolic block of glycolysis in the beta-cells. Hence the interrelationship between the processes of stimulus recognition and insulin discharge may involve a positive feedback of secretion on glucose metabolism.


Chroogomphus rutilus Regulates Bone Metabolism to Prevent Periodontal Bone Loss during Orthodontic Tooth Movement in Osteoporotic Rats.
Osteoporosis (OP) leads to the acceleration of tooth movement and aggravation of periodontal bone loss during orthodontic treatment. Chroogomphus rutilus (CR) is abundant in nutrients and demonstrates remarkable antioxidant and anti-inflammatory properties. In the present study, the components of CR, including 35.00% total sugar, 0.69% reducing sugar, 14.40% crude protein, 7.30% total ash, 6.10% crude fat, 0.51% total flavonoids, 1.94% total triterpenoids, 0.32% total sterol, 1.30% total saponins, 1.69% total alkaloids, and 1.02% total phenol, were first systematically examined, followed by an investigation into its regulatory effects on bone metabolism in order to mitigate bone loss during orthodontic tooth movement in osteoporotic rats. The results of the imaging tests revealed that CR treatment reduced periodontal bone loss and normalized tooth movement in the OP. In conjunction with analyses of intestinal flora and metabolomics, CR enhances the prevalence of anti-inflammatory genera while reducing the production of inflammatory metabolites. Meanwhile, CR reduced the levels of periodontal inflammatory factors, including TNF-α, IL-1β, and IL-6, by activating Wnt/β-catenin signaling, and promoted periodontal bone formation. These findings imply that CR is a potent supplementary therapy for controlling periodontal bone remodeling in patients with OP undergoing orthodontic treatment.


Evaluation of a small trauma team for major resuscitation.
There has been a great improvement in the early management of trauma patients, encapsulated by ATLS. Initial in-hospital management of significant trauma is undertaken by a trauma team, the number and content of which varies. No study has demonstrated that large trauma teams per se improve patient survival, compared to smaller teams working in the same tertiary referral centre environment. This is a retrospective study of pedestrian road traffic accident patients, who were major resuscitation cases admitted over a 6-month period to this hospital, which is a Level I Trauma Centre. Most major trauma resuscitations are undertaken by a small trauma team, led by one doctor. The performance of the small trauma team was evaluated by applying TRISS methodology and comparing our patient group with MTOS (US). There were 77 patients. The majority (52 per cent) had polytrauma, 80 per cent required intubation, the median ISS was 27 and the median RTS was 5.03. Ten per cent required resuscitative procedures and 75 per cent required urgent surgery. Using TRISS methodology the Z statistic was +0.54 and the Unit's M statistic was 0.492. There were more unexpected survivors than deaths. Seventy-one per cent were initially treated by one doctor. Only two patients had three or more doctors at the initial resuscitation. The use of small trauma teams within this Level I Trauma Centre does not appear to give results that are any worse than those of units that routinely use larger teams. This could be evaluated in other centres and may have implications for training, manpower and costing.


Introducing Machine Learning Concepts with WEKA.
This chapter presents an introduction to data mining with machine learning. It gives an overview of various types of machine learning, along with some examples. It explains how to download, install, and run the WEKA data mining toolkit on a simple data set, then proceeds to explain how one might approach a bioinformatics problem. Finally, it includes a brief summary of machine learning algorithms for other types of data mining problems, and provides suggestions about where to find additional information.


Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects and Challenges.
Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin (DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame mRNA and induce the production of internally-deleted dystrophin as seen in the less severe Becker muscular dystrophy. Currently, multiple exon skipping has gained special interest as a new therapeutic modality for this approach. Previous retrospective database studies represented a potential therapeutic application of multiple exon skipping. Since then, public DMD databases have become more useful with an increase in patient registration and advances in molecular diagnosis. Here, we provide an update on DMD genotype-phenotype associations using a global DMD database and further provide the rationale for multiple exon skipping development, particularly for exons 45⁻55 skipping and an emerging therapeutic concept, exons 3⁻9 skipping. Importantly, this review highlights the potential of multiple exon skipping for enabling the production of functionally-corrected dystrophin and for treating symptomatic patients not only with out-of-frame deletions but also those with in-frame deletions. We will also discuss prospects and challenges in multiple exon skipping therapy, referring to recent progress in antisense chemistry and design, as well as disease models.


Pathophysiology of ischemic cell death: I. Time of onset of irreversible damage; importance of the different components of the ischemic insult.
Rabbit retina was used as an example of organized central nervous tissue in in vitro experiments designed to characterize the onset of cell death from ischemia. Retinas were subjected to progressively longer periods of different types of ischemic insult and then given an opportunity to recover before being tested for irreversible damage, using failure to reinstitute protein synthesis as the principal criterion. Anoxia was more damaging than substrate deprivation, but they were synergistic in combination. Restricting the volume of extracellular fluid during the combined deprivation, to simulate complete circulatory arrest in vivo, caused irreversible damage to occur even sooner. The cells were able to recover from 20 min of the complete ischemia, but it took them more than 2 h to do so. After 30 min, there was extensive irreversible damage. Loss of viability was usually associated with failure to reinstitute energy metabolism, as assessed by 2-deoxyglucose uptake. Under some circumstances loss of viability may have been the consequence of the failed energy metabolism. Increasing medium Mg++, prior to ischemia, to levels that greatly reduce energy requirements caused a significant improvement in the recovery of 2-deoxyglucose uptake.


Dynamin and Rab5a-dependent trafficking and signaling of the neurokinin 1 receptor.
Understanding the molecular mechanisms of agonist-induced trafficking of G-protein-coupled receptors is important because of the essential role of trafficking in signal transduction. We examined the role of the GTPases dynamin 1 and Rab5a in substance P (SP)-induced trafficking and signaling of the neurokinin 1 receptor (NK1R), an important mediator of pain, depression, and inflammation, by studying transfected cells and enteric neurons that naturally express the NK1R. In unstimulated cells, the NK1R colocalized with dynamin at the plasma membrane, and Rab5a was detected in endosomes. SP induced translocation of the receptor into endosomes containing Rab5a immediately beneath the plasma membrane and then in a perinuclear location. Expression of the dominant negative mutants dynamin 1 K44E and Rab5aS34N inhibited endocytosis of SP by 45 and 32%, respectively. Dynamin K44E caused membrane retention of the NK1R, whereas Rab5aS34N also impeded the translocation of the receptor from superficially located to perinuclear endosomes. Both dynamin K44E and Rab5aS34N strongly inhibited resensitization of SP-induced Ca(2+) mobilization by 60 and 85%, respectively, but had no effect on NK1R desensitization. Dynamin K44E but not Rab5aS34N markedly reduced SP-induced phosphorylation of extracellular signal regulated kinases 1 and 2. Thus, dynamin mediates the formation of endosomes containing the NK1R, and Rab5a mediates both endosomal formation and their translocation from a superficial to a perinuclear location. Dynamin and Rab5a-dependent trafficking is essential for NK1R resensitization but is not necessary for desensitization of signaling. Dynamin-dependent but not Rab5a-dependent trafficking is required for coupling of the NK1R to the mitogen-activated protein kinase cascade. These processes may regulate the nociceptive, depressive, and proinflammatory effects of SP.


No evidence of important difference in summary treatment effects between COVID-19 preprints and peer-reviewed publications: a meta-epidemiological study.
Preprints became a major source of research communication during the COVID-19 pandemic. We aimed to evaluate whether summary treatment effect estimates differ between preprint and peer-reviewed journal trials. A meta-epidemiological study. Data were derived from the COVID-NMA living systematic review (covid-nma.com) up to July 20, 2022. We identified all meta-analyses evaluating pharmacological treatments vs. standard of care or placebo for patients with COVID-19 that included at least one preprint and one peer-reviewed journal article. Difference in effect estimates between preprint and peer-reviewed journal trials were estimated by the ratio of odds ratio (ROR); ROR <1 indicated larger effects in preprint trials. Thirty-seven meta-analyses including 114 trials (44 preprints and 70 peer-reviewed publications) were selected. The median number of randomized controlled trials (RCTs) per meta-analysis was 2 (interquartile range [IQR], 2-4; maximum, 11), median sample size of RCTs was 199 (IQR, 99-478). Overall, there was no statistically significant difference in summary effect estimates between preprint and peer-reviewed journal trials (ROR, 0.88; 95% CI, 0.71-1.09; I2 = 17.8%; τ2 = 0.06). We did not find an important difference between summary treatment effects of preprints and summary treatment effects of peer-reviewed publications. Systematic reviewers and guideline developers should assess preprint inclusion individually, accounting for risk of bias and completeness of reporting.


Relationship between serum concentrations of organochlorine pesticides and metabolic syndrome among non-diabetic adults.
This study was performed to investigate if organochlorine pesticides (OCPs) were associated with metabolic syndrome and insulin resistance among non-diabetes. Among subjects who participated in a community-based health survey, 50 non-diabetic subjects with metabolic syndrome and 50 normal controls were selected. Insulin resistance was measured by the homeostasis model assessment (HOMA-IR). Eight OCPs were selected. After adjusting for confounders except for body mass index (BMI), beta-hexachlorocyclohexane (beta-HCH) and heptachlor epoxide were positively associated with metabolic syndrome. Odds ratios across tertiles of beta-HCH and heptachlor epoxide were 1.0, 3.2 and 4.4, and 1.0, 4.0 and 6.0, respectively (p for trend = 0.01 and <0.01). After additional adjustment for body mass index (BMI), heptachlor epoxide still showed an increasing trend with adjusted odds ratios of 1.0, 4.1, and 4.6 (p for trend = 0.10). When the five components of metabolic syndrome (with the definition of high fasting glucose (> or =100 mg/dL)) were separately analyzed, all components were positively, but not significantly, associated with heptachlor epoxide. As the serum concentration of heptachlor epoxide increased, HOMA-IR increased significantly in subjects with metabolic syndrome even after adjusting for BMI (p value <0.05 and <0.01). Despite the small sample size, this study suggests that the background exposure to some OCPs may be associated with metabolic syndrome.


Importance of early appropriate intervention including antibiotics and wound care for device-related infection in patients with left ventricular assist device.
A left ventricular assist device (LVAD) is essential for treating patients with advanced heart failure. However, LVAD-related infection is a significant cause of mortality and morbidity, with bloodstream infection (BSI) especially associated with high mortality. We investigated the incidence of infectious complications in patients who received an LVAD and evaluated the effects of early and appropriate intervention for LVAD-related infection. We retrospectively reviewed 27 consecutive patients who underwent continuous-flow LVAD (CF-LVAD; n = 16) or pulsatile-flow LVAD (PF-LVAD; n = 11) implantation at the National Cerebral and Cardiovascular Center between April 2011 and March 2013. Incidences of LVAD-related infections, such as drive-line infection in patients with CF-LVAD, cannula infection in patients with PF-LVAD, and BSI in patients with both types, were examined (follow-up period, 342 ± 229 days). The mandatory antibiotic prophylaxis protocol at our institution includes teicoplanin (400 mg) 2 days before LVAD implantation and doripenem (1000 mg) within 1 hour of skin incision. In addition, the driveline exit sites undergo sterile cleansing with diluted hydrogen peroxide and placement of an antimicrobial occlusive dressing for wound care, with dressing changes performed 2-3 times per day. More than 90% of all patients suffered from a drive-line infection within 12 months after LVAD implantation. However, BSI developed in only 12.5% of CF-LVAD and 10% of PF-LVAD patients within 12 months (log-rank test; P = .875). LVAD-related infections, such as drive-line and cannula infections, were common, whereas the incidence of BSI was low in our LVAD-implanted patients. Our results highlight the importance of early and appropriate intervention including antibiotics and wound care for device-related infections for reducing the incidence of potentially fatal BSI.