Attenuated total reflection angular spectra of a system of alternating plasma-dielectric layers.
The attenuated total reflection (ATR) angular spectra of a five-film system have been observed. Successive layers of Ag-LiF-Ag-LiF-Ag are evaporated onto the base of a glass prism. Surface plasma wave resonances corresponding to coupled oscillations at the plasma-dielectric interfaces were found for p-polarization. Guided light modes coupled between the two dielectric layers were observed in both p- and s-polarized spectra. If guided mode reflectance resonances occur at less than the critical angle they have associated with them resonance transmissions. In general the ATR resonances of the five-film system occur as doublets, which form a splitting of the resonances of a single dielectric slab bounded by Ag layers. The resonant oscillations are demonstrated by detailed calculations of the Poynting vector field and electric field oscillations, which also help in understanding the source of discrepancies between experimental and calculated ATR spectra. These discrepancies are thought to be due largely to the surface roughness of evaporated LiF films. The roughness is modeled as thin cermet layers at the LiF-Ag interfaces, and the optical constants of the cermets are calculated by the Maxwell Garnett theory. When the ATR spectra are then computed with the pseudolayers inserted, much improved agreement with experiment can be obtained.


Analysis of ubiquitin signaling and chain topology cross-talk.
Protein ubiquitination is a powerful post-translational modification implicated in many cellular processes. Although ubiquitination is associated with protein degradation, depending on the topology of polyubiquitin chains, protein ubiquitination is connected to non-degradative events in DNA damage response, cell cycle control, immune response, trafficking, intracellular localization, and vesicle fusion events. It has been shown that a ubiquitin chain can contain two or more topologies at the same time. These branched chains add another level of complexity to ubiquitin signaling, increasing its versatility and specificity. Mass spectrometry-based proteomics has been playing an important role in the identification of all types of ubiquitin chains and linkages. This review aims to provide an overview of ubiquitin chain topology and associated signaling pathways and discusses the MS-based proteomic methodologies used to determine such topologies. SIGNIFICANCE: Ubiquitination plays important roles in many cellular processes. Proteins can be monoubiquitinated or polyubiquitinated forming non-branched or branched chains in a high number of possible combinations, each associated with different cellular processes. The detection and the topology of ubiquitin chains is thus of extreme importance in order to explain such processes. Advances in mass spectrometry based proteomics allowed for the discovery and topology mapping of many ubiquitin chains. This review revisits the state of the art in ubiquitin chain identification by mass spectrometry and gives an insight on the implication of such chains in many cellular processes.


The effectiveness of lifestyle interventions to reduce cardiovascular risk in patients with severe mental disorders: meta-analysis of intervention studies.
Patients with severe mental illness have higher prevalences of cardiovascular risk factors (CRF). The objective is to determine whether interventions to modify lifestyles in these patients reduce anthropometric and analytical parameters related to CRF in comparison to routine clinical practice. Systematic review of controlled clinical trials with lifestyle intervention in Medline, Cochrane Library, Embase, PsycINFO and CINALH. Change in body mass index, waist circumference, cholesterol, triglycerides and blood sugar. Meta-analyses were performed using random effects models to estimate the weighted mean difference. Heterogeneity was determined using i(2) statistical and subgroups analyses. 26 studies were selected. Lifestyle interventions decrease anthropometric and analytical parameters at 3 months follow up. At 6 and 12 months, the differences between the intervention and control groups were maintained, although with less precision. More studies with larger samples and long-term follow-up are needed.


Dynamic recruitment of axin by Dishevelled protein assemblies.
Dishevelled (Dvl) proteins are cytoplasmic components of the Wnt signalling pathway, which controls numerous cell fate decisions during animal development. During Wnt signalling, Dvl binds to the intracellular domain of the frizzled transmembrane receptors, and also to axin to block its activity, which results in the activation of beta-catenin and, consequently, in a transcriptional switch. We have previously reported that the DIX domain of mammalian Dvl2 allows it to form dynamic protein assemblies. Here, we show that these Dvl2 assemblies recruit axin, and also casein kinase Iepsilon. Using photobleaching experiments of GFP-tagged Dvl2 and axin to study the dynamics of their interaction, we found that the recruitment of axin-GFP by Dvl2 assemblies is accompanied by a striking acceleration of the dynamic properties of axin-GFP. We also show that the interaction between Dvl2 and axin remains highly dynamic even after Wnt-induced relocation to the plasma membrane. We discuss how the recruitment of casein kinase Iepsilon by Dvl2 assemblies might impact on the recruitment of axin to the plasma membrane during Wnt signalling.


Intussusception, rotavirus, and oral vaccines: summary of a workshop.
Rotavirus gastroenteritis continues to cause substantial morbidity and mortality worldwide, despite widespread breastfeeding and use of oral rehydration therapy. This burden of disease indicates that an effective, safe rotavirus vaccine is needed, and in 1998 the first rhesus-human reassortant rotavirus tetravalent vaccine, Rotashield, was licensed in the United States. However, the recommendations for its use were withdrawn in 1999 because of the recognition of an uncommon but serious adverse event, intussusception. A workshop in September 2001 was held to review the subsequent developments and research regarding this association, the proceedings of which are summarized here. Although the pathogenesis of this association remains unknown, epidemiologic evidence supports a causal relationship, with a population attributable risk of approximately 1 per 10 000 (range of 1 in 5000 to 1 in 12 000) vaccine recipients. Whether this association will exist with other candidate rotavirus vaccine strains and whether the attributable risk for intussusception would be similar in other populations administered this vaccine are unclear. Because perceptions of vaccine safety derive from the relative disease burdens of the illness prevented and adverse events induced, the acceptance of rare adverse events may vary substantially in different settings. Nevertheless, a continuing consensus on the need for a safe and effective vaccine to prevent rotavirus gastroenteritis, especially for use in developing countries, exists.


Hepatic and extrahepatic metabolism of salbutamol in anesthetized rabbits.
Orally administered salbutamol undergoes an extensive first-pass effect. This study investigated the roles of the intestine (INT), liver (HEP), and lung (LUN) in salbutamol extraction. Salbutamol was administered to five groups of anesthetized rabbits by the following routes: intraduodenal (ID) (800 micrograms/kg), intraportal (IP), (60 micrograms/kg), intrajugular (IV) (60 micrograms/kg), endotracheal (ET) (60 micrograms/kg), and intraarterial (IA) (60 micrograms/kg). Multiple blood samples were drawn and the areas under salbutamol plasma concentrations-time curves (AUCs) were calculated. Since IA salbutamol administration generated 100% bioavailability (F), AUCIA was used as a reference for comparison. Salbutamol F values for the ID, IP, IV, and ET routes were 0.013, 0.15, 0.53, and 0.53, respectively. The ratio of the AUC of salbutamol administered before the organ (ID, IP, IV, or ET) to the AUC estimated when given after the organ (IP, IV, and IA) allowed assessment of the extraction ratio (E) of INT, HEP, and LUN, respectively. EINT was 0.92, EHEP was 0.71, and ELUN was 0.47. The mean ratio of the AUC of the metabolite (AUCM) over the AUC of the parent compound was 704 +/- 77 for the ID, compared with 83 +/- 12 for the IP, 11 +/- 1 for the IV, 1.7 +/- 0.3 for the ET routes, and 4 +/- 1 for the IA routes. On the other hand, when the AUCM was normalized by the dose, this ratio was INT = HEP > LUN, suggesting that the ability of INT to conjugate salbutamol is not very important.(ABSTRACT TRUNCATED AT 250 WORDS)


FIMO: scanning for occurrences of a given motif.
A motif is a short DNA or protein sequence that contributes to the biological function of the sequence in which it resides. Over the past several decades, many computational methods have been described for identifying, characterizing and searching with sequence motifs. Critical to nearly any motif-based sequence analysis pipeline is the ability to scan a sequence database for occurrences of a given motif described by a position-specific frequency matrix. We describe Find Individual Motif Occurrences (FIMO), a software tool for scanning DNA or protein sequences with motifs described as position-specific scoring matrices. The program computes a log-likelihood ratio score for each position in a given sequence database, uses established dynamic programming methods to convert this score to a P-value and then applies false discovery rate analysis to estimate a q-value for each position in the given sequence. FIMO provides output in a variety of formats, including HTML, XML and several Santa Cruz Genome Browser formats. The program is efficient, allowing for the scanning of DNA sequences at a rate of 3.5 Mb/s on a single CPU. FIMO is part of the MEME Suite software toolkit. A web server and source code are available at http://meme.sdsc.edu.


Enhancing patient freedom in rehabilitation robotics using gaze-based intention detection.
Several design strategies for rehabilitation robotics have aimed to improve patients' experiences using motivating and engaging virtual environments. This paper presents a new design strategy: enhancing patient freedom with a complex virtual environment that intelligently detects patients' intentions and supports the intended actions. A 'virtual kitchen' scenario has been developed in which many possible actions can be performed at any time, allowing patients to experiment and giving them more freedom. Remote eye tracking is used to detect the intended action and trigger appropriate support by a rehabilitation robot. This approach requires no additional equipment attached to the patient and has a calibration time of less than a minute. The system was tested on healthy subjects using the ARMin III arm rehabilitation robot. It was found to be technically feasible and usable by healthy subjects. However, the intention detection algorithm should be improved using better sensor fusion, and clinical tests with patients are needed to evaluate the system's usability and potential therapeutic benefits.


Impact of lympho-vascular space invasion on tumor characteristics and survival outcome of women with low-grade serous ovarian carcinoma.
To examine association of lympho-vascular space invasion (LVSI) with clinico-pathological factors and to evaluate survival of women with low-grade serous ovarian carcinoma containing areas of LVSI. This is a multicenter retrospective study examining consecutive cases of surgically treated stage I-IV low-grade serous ovarian carcinoma (n = 178). Archived histopathology slides for the ovarian tumors were reviewed, and LVSI was scored as present or absent. LVSI status was correlated to clinico-pathological findings and survival outcome. LVSI was seen in 79 cases (44.4%, 95% confidence interval [CI] 37.1-51.7). LVSI was associated with increased risk of omental metastasis (87.0% vs 64.9%, odds ratio [OR] 3.62, P = 0.001), high pelvic lymph node ratio (median 12.9% vs 0%, P = 0.012), and malignant ascites (49.3% vs 32.6%, OR 2.01, P = 0.035). On multivariable analysis, controlling for age, stage, and cytoreductive status, presence of LVSI in the ovarian tumor remained an independent predictor for decreased progression-free survival (5-year rates 21.0% vs 35.7%, adjusted-hazard ratio 1.57, 95%CI 1.06-2.34, P = 0.026). LVSI was significantly associated with increased risk of recurrence in lymph nodes (OR 2.62, 95%CI 1.08-6.35, P = 0.047). LVSI in the ovarian tumor is associated with adverse clinico-pathological characteristics and decreased progression-free survival in women with low-grade serous ovarian carcinoma.


Ascending enteric reflex contraction: roles of acetylcholine and tachykinins in relation to distension and propagation of excitation.
The ascending reflex contraction of intestinal circular muscle involves both cholinergic and tachykininergic transmission, which are thought to be activated by different degrees of distension. Substance P, however, is colocalized with acetylcholine in myenteric neurons, and the present study examined the role of these transmitter substances in relation to low- and high-degree distension and with regard to ascending propagation of excitation. Reflex contractions in segments of the guinea pig isolated small intestine were evoked by inflation of an intraluminal balloon and recorded orally to the site of distension. Atropine (12.5 nM), hexamethonium (3 microM) and the neurokinin (NK)2-selective tachykinin antagonist MEN 10,376 (10 microM) inhibited contractions induced by low-degree distension to a larger extent than contractions induced by high-degree distension, whereas the receptor-nonselective tachykinin antagonist spantide (30 microM) did not differentiate in this way. Atropine, hexamethonium and spantide also depressed the propagation of excitation, i.e., the response recorded 2 cm away from the distension site was inhibited to a larger degree than the response recorded 1 cm away from the distension site. In contrast, MEN 10,376 did not interfere with the ascending propagation of excitation, and the NK1-selective tachykinin antagonist GR 82,334 (10 microM) was without effect on the ascending reflex contraction. These observations show that tachykinins and acetylcholine comediate ascending reflex contractions triggered by both low- and high-degree distension. When seen in context with the known projection of myenteric neurons, the findings relating to the ascending propagation of excitation indicate that NK2 receptors participate in neuromuscular transmission only, whereas neuroneuronal transmission involves both nicotinic and muscarinic acetylcholine receptors.


Residual effects of lovastatin and simvastatin on urinary mevalonate excretions in patients with familial hypercholesterolemia.
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors are widely used to decrease plasma cholesterol levels in patients with heterozygous familial hypercholesterolemia (FH) who are at increased risk of premature coronary artery disease. Tissue-culture and animal studies have indicated that administration of HMG CoA reductase inhibitors (eg, lovastatin, simvastatin, etc) induces a compensatory increase in the activity of HMG CoA reductase, both by increasing its synthesis and decreasing catabolism. To determine in human subjects whether cessation of therapy with this class of drugs leads to induction of HMG CoA reductase activity and above-normal rates of cholesterol biosynthesis, we measured urinary concentrations of mevalonic acid (an indicator of cholesterol biosynthesis) after the cessation of therapy with lovastatin and simvastatin (80 mg/day) in patients with heterozygous FH. Plasma concentrations of LDL increased promptly on discontinuation of reductase inhibitor therapy but did not increase above pretreatment levels at any point after drug discontinuation. Similarly, the 24-hour urinary excretion of mevalonic acid was reduced during treatment with lovastatin or simvastatin and increased promptly on discontinuation of drug but did not increase to levels exceeding those found at baseline when the patients were receiving dietary therapy only. We conclude that cessation of treatment with HMG CoA reductase inhibitors in patients with FH does not result in a rebound increase in cholesterol biosynthesis and that no rebound overshoot occurs in plasma concentrations of low-density-lipoprotein cholesterol.


Balanced and Bias-Corrected Computation of Conformational Entropy Differences for Molecular Trajectories.
The mutual information (MI) expansion is applied to two molecular systems to probe algorithms that serve to estimate conformational entropy differences more precisely. The individual terms of the MI expansion are evaluated with a histogram method. Internal coordinates are used to avoid spurious correlations, which would require higher order terms in the MI expansion. Two approaches are applied that compensate for systematic errors that occur with a histogram method: (1) Simulation data are balanced by using the same number of coordinate sets (frames) for both conformer domains considered for the entropy difference computation. Balancing puts fluctuations of the histogram bin contents on the same level for both conformer domains, allowing efficient error cancellation. (2) Bias correction compensates for systematic deviations due to a finite number of frames per bin. Applying both corrections improves the precision of entropy differences drastically. Estimates of entropy differences are compared to thermodynamic benchmarks of a simple polymer model and trialanine, where excellent agreement was found. For trialanine, the average error for the estimated conformational entropy difference is only 0.3 J/(mol K), which is 100 times smaller than without applying the two corrections. Guidelines are provided for efficiently estimating conformational entropies. The program ENTROPICAL, used for the computations, is made available, which can be used for molecular dynamics or Monte Carlo simulation data on macromolecules like oligopeptides, polymers, proteins, and ligands.


Rosai-Dorfman disease of vertebra: Case report and literature review.
Rosai-Dorfman disease is a rare benign histiocytic disorder that arises predominantly in lymph nodes with fever and malaise, but can affect various organs, with or without lymphadenopathy. Solitary extranodal skeletal lesions are extremely rare. Herein, we describe a case of isolated disease of thoracic spine, with vertebral body fracture. A 14-year-old girl presented with cervical back pain for about one month as the only symptom. There was no lymphadenopathy. Results of laboratory tests were within reference ranges. The radiological examinations revealed collapse, osteolytic lesion and compressive fracture, which reduced vertical diameter of C4 vertebral body. The patient made a complete recovery after a limited C4 laminectomy, spondylodesis C3/C5 vertebra and biopsy of the lesion. Histologically, nonspecific cellular milieu and atypical histiocytic proliferation with emperipolesis, with CD68 and S100 positivity, confirmed a diagnosis of Rosai-Dorfman disease. Isolated extranodal skeletal Rosai-Dorfman disease should be considered among the differential diagnoses of similar changes, such as Langerhans cell histiocytosis, Erdheim-Cheister disease, eosinophilic granuloma, osteomyelitis, metastasis and lymphoma.


Fathers' engagement in pregnancy and childbirth: evidence from a national survey.
Early involvement of fathers with their children has increased in recent times and this is associated with improved cognitive and socio-emotional development of children. Research in the area of father's engagement with pregnancy and childbirth has mainly focused on white middle-class men and has been mostly qualitative in design. Thus, the aim of this study was to understand who was engaged during pregnancy and childbirth, in what way, and how paternal engagement may influence a woman's uptake of services, her perceptions of care, and maternal outcomes. This study involved secondary analysis of data on 4616 women collected in a 2010 national maternity survey of England asking about their experiences of maternity care, health and well-being up to three months after childbirth, and their partners' engagement in pregnancy, labour and postnatally. Data were analysed using descriptive statistics, chi-square, binary logistic regression and generalised linear modelling. Over 80% of fathers were 'pleased or 'overjoyed' in response to their partner's pregnancy, over half were present for the pregnancy test, for one or more antenatal checks, and almost all were present for ultrasound examinations and for labour. Three-quarters of fathers took paternity leave and, during the postnatal period, most fathers helped with infant care. Paternal engagement was highest in partners of primiparous white women, those living in less deprived areas, and in those whose pregnancy was planned. Greater paternal engagement was positively associated with first contact with health professionals before 12 weeks gestation, having a dating scan, number of antenatal checks, offer and attendance at antenatal classes, and breastfeeding. Paternity leave was also strongly associated with maternal well-being at three months postpartum. This study demonstrates the considerable sociodemographic variation in partner support and engagement. It is important that health professionals recognise that women in some sociodemographic groups may be less supported by their partner and more reliant on staff and that this may have implications for how women access care.


Regeneration of axons and synaptic connections by touch sensory neurons in the leech central nervous system.
In studies of axonal regeneration, it has been difficult to determine (a) whether growth along the normal pathway is important for restoration of connections with previous targets and (b) whether the new synapses resemble the old in strength and location. To address these problems at the level of individual nerve cells, we have studied touch (T) sensory neurons in the leech after their axons have been severed and we have confirmed that their axons regenerate electrical connections with some of their usual synaptic targets in the central nervous system. Injections of horseradish peroxidase and Lucifer Yellow dye into separate T cells in unoperated animals showed that T cell axons typically run close to one another within single ganglia or from ganglion to ganglion. Knowledge of one T cell's arborizations thus revealed the groundplan of others in the same ganglia and the sites of apparent contact with its synaptic targets. For regenerating axons, those sprouts that encountered the normal pathway (as marked by homologous axons) grew preferentially along it. Despite the striking coincidence of old and new pathways, regenerated branching patterns within the ganglionic neuropils were usually incomplete and sometimes had atypical branches. Synaptic connections with normal targets (other T cells as well as S and C cells) were abnormally weak physiologically. The numbers of apparent contacts seen with the light microscope were also lower than normal. In addition, the strength of the synaptic potentials, normalized to the number of contacts (calculated as microvolts per contact), was generally smaller in the regenerated connections than in the controls, and smallest at earliest times, during the first 6 weeks following injury. It thus appears to be characteristic of T cell regeneration that axon regrowth is aided by the recognition of specific pathways and that successful regeneration, as assayed anatomically and physiologically, occurs frequently but usually incompletely.


Functional features of nociceptive-induced suppression of alpha band electroencephalographic oscillations.
Nociceptive stimuli can induce a transient suppression of electroencephalographic oscillations in the alpha frequency band (ie, alpha event-related desynchronization, α-ERD). Here we investigated whether α-ERD could be functionally distinguished in 2 temporally and spatially segregated subcomponents as suggested by previous studies. In addition, we tested whether the degree of dependence of nociceptive-induced α-ERD magnitude on the prestimulus α-power would have been larger than the degree of dependence on the poststimulus α-power. Our findings confirmed the dissociation between a sensory-related α-ERD maximally distributed over contralateral central electrodes, and a task-related α-ERD (possibly affected by motor-related activity), maximally distributed at posterior parietal and occipital electrodes. The cortical sources of these activities were estimated to be located at the level of sensorimotor and bilateral occipital cortices, respectively. Importantly, the time course of the α-ERD revealed that functional segregation emerged only at late latencies (400 to 750 ms) whereas topographic similarity was observed at earlier latencies (250 to 350 ms). Furthermore, the nociceptive-induced α-ERD magnitude was significantly more dependent on prestimulus than poststimulus α-power. Altogether these findings provide direct evidence that the nociceptive-induced α-ERD reflects the summation of sensory-related and task-related cortical processes, and that prestimulus fluctuations can remarkably influence the non-phase-locked nociceptive α-ERD. Present results extend the functional understanding of α-oscillation suppression during pain perception and demonstrate the influence of prestimulus variability on this cortical phenomenon. This work has the potential to guide pain clinicians in a more accurate interpretation on physiological and psychological modulations of α-oscillations.


The neural correlates of linguistic distinctions: unaccusative and unergative verbs.
Unaccusative verbs like fall are special in that their sole argument is syntactically generated at the object position of the verb rather than at the subject position. Unaccusative verbs are derived by a lexical operation that reduces the agent from transitive verbs. Their insertion into a sentence often involves a syntactic movement from the object to the subject position. To explore the neurological reality of the distinction between different verb types and to identify the cortical activations associated with the lexical and syntactic operations, we compared unaccusative verbs with verbs that do not undergo such operations--unergatives (verbs with one argument, an agent) and transitives (verbs with two arguments). The observed pattern of activation revealed that the brain distinguishes between unaccusative and unergative verbs, lending neurological support for the linguistic distinction. A conjunction analysis between the comparisons between unaccusatives and the other verb types revealed activations in the left inferior frontal gyrus and the left posterior middle temporal gyrus. These, together with previous neuroimaging results, suggest that the inferior frontal gyrus may be involved with the execution of the syntactic operation, whereas the middle temporal gyrus may be responsible for the lexical operation that derives unaccusative verbs.


DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas.
DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron. We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets. Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC. Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236-46. ©2016 AACR.


In vitro susceptibility of Borrelia burgdorferi isolates to three antibiotics commonly used for treating equine Lyme disease.
Lyme disease in humans is predominantly treated with tetracycline, macrolides or beta lactam antibiotics that have low minimum inhibitory concentrations (MIC) against Borrelia burgdorferi. Horses with Lyme disease may require long-term treatment making frequent intravenous or intramuscular treatment difficult and when administered orally those drugs may have either a high incidence of side effects or have poor bioavailability. The aim of the present study was to determine the in vitro susceptibility of three B. burgdorferi isolates to three antibiotics of different classes that are commonly used in practice for treating Borrelia infections in horses. Broth microdilution assays were used to determine minimum inhibitory concentration of three antibiotics (ceftiofur sodium, minocycline and metronidazole), for three Borrelia burgdorferi isolates. Barbour-Stoner-Kelly (BSK K + R) medium with a final inoculum of 106 Borrelia cells/mL and incubation periods of 72 h were used in the determination of MICs. Observed MICs indicated that all isolates had similar susceptibility to each drug but susceptibility to the tested antimicrobial agents varied; ceftiofur sodium (MIC = 0.08 μg/ml), minocycline hydrochloride (MIC = 0.8 μg/ml) and metronidazole (MIC = 50 μg/ml). The MIC against B. burgorferi varied among the three antibiotics with ceftiofur having the lowest MIC and metronidazole the highest MIC. The MIC values observed for ceftiofur in the study fall within the range of reported serum and tissue concentrations for the drug metabolite following ceftiofur sodium administration as crystalline-free acid. Minocycline and metronidazole treatments, as currently used in equine practice, could fall short of attaining MIC concentrations for B. burgdorferi.


General practitioners' approach to hypertension in urban Pakistan: disturbing trends in practice.
Control of blood pressure (BP) remains suboptimal worldwide. The objective of this study was to determine whether (primary) general practitioners' (GPs) approach to high BP is in accordance with international guidelines. We conducted a cross-sectional survey of 1000 randomly selected GPs from urban areas in Pakistan during 2002. A rigorously developed questionnaire on (1) type of practice and (2) detection, (3) evaluation, (4) treatment, and (5) source of information about high BP was administered by trained medical personnel. A total of 1051 GPs were approached, and 1000 (95%) consented to enroll; 766 were male and 655 had been in practice > or =10 years. The average number of patients (SD) seen per day was 48.2 (42.7). Overall, 30.6% (29.0% to 32.3%) and 79.7% (78.3% to 81.0%) of GPs used incorrect BP cutoffs to diagnose hypertension in patients <60 and > or =60 years, respectively. Appropriate therapy for hypertension in the elderly was initiated by only 34.7% (33.0% to 36.3%) of GPs. The use of sedatives either alone (23.8%) or in combination with antihypertensive agents as first-line medication for lowering BP was reported by 45.0% (43.2% to 46.7%). Thiazide diuretics were rarely prescribed (4.2%). Sublingual antihypertensive agents were prescribed by 68.7% (67.1% to 70.3%) of GPs for treating very high levels of BP. The practices of recent graduates from medical school were not better than those of older graduates. GPs in Pakistan underdiagnose and undertreat high BP, especially in the elderly. Our findings underscore the need for urgent revision of teaching curricula in medical schools with regard to the risks, complications, and management of hypertension, as well as the initiation of widespread and intensive continuing medical education for all physicians involved in the management of patients with hypertension. Particular efforts are needed to encourage the use of low-cost thiazide diuretics as antihypertensive agents in developing countries.


The plastid-localized pfkB-type carbohydrate kinases FRUCTOKINASE-LIKE 1 and 2 are essential for growth and development of Arabidopsis thaliana.
Transcription of plastid-encoded genes requires two different DNA-dependent RNA polymerases, a nuclear-encoded polymerase (NEP) and plastid-encoded polymerase (PEP). Recent studies identified two related pfkB-type carbohydrate kinases, named FRUCTOKINASE-LIKE PROTEIN (FLN1 and FLN2), as components of the thylakoid bound PEP complex in both Arabidopsis thaliana and Sinapis alba (mustard). Additional work demonstrated that RNAi-mediated reduction in FLN expression specifically diminished transcription of PEP-dependent genes. Here, we report the characterization of Arabidopsis FLN knockout alleles to examine the contribution of each gene in plant growth, chloroplast development, and in mediating PEP-dependent transcription. We show that fln plants have severe phenotypes with fln1 resulting in an albino phenotype that is seedling lethal without a source of exogenous carbon. In contrast, fln2 plants display chlorosis prior to leaf expansion, but exhibit slow greening, remain autotrophic, can grow to maturity, and set viable seed. fln1 fln2 double mutant analysis reveals haplo-insufficiency, and fln1 fln2 plants have a similar, but more severe phenotype than either single mutant. Normal plastid development in both light and dark requires the FLNs, but surprisingly skotomorphogenesis is unaffected in fln seedlings. Seedlings genetically fln1-1 with dexamethasone-inducible FLN1-HA expression at germination are phenotypically indistinguishable from wild-type. Induction of FLN-HA after 24 hours of germination cannot rescue the mutant phenotype, indicating that the effects of loss of FLN are not always reversible. Examination of chloroplast gene expression in fln1-1 and fln2-1 by qRT-PCR reveals that transcripts of PEP-dependent genes were specifically reduced compared to NEP-dependent genes in both single mutants. Our results demonstrate that each FLN protein contributes to wild type growth, and acting additively are absolutely essential for plant growth and development.


A novel subset of adult gamma delta thymocytes that secretes a distinct pattern of cytokines and expresses a very restricted T cell receptor repertoire.
We have characterized the function, phenotype, ontogenic development, and T cell receptor (TCR) repertoire of a subpopulation of gamma delta thymocytes, initially defined by expressing low levels of Thy-1, that represents around 5% and 30% of total gamma delta thymocytes in adult C57BL/6 and DBA/2 mice, respectively. Activation of FACS-sorted Thy-1dull gamma delta thymocytes from DBA/2 mice with anti-gamma delta monoclonal antibodies in the presence of interleukin-2 (IL-2) results in the secretion of high levels of several cytokines, including interferon-gamma (IFN-gamma), IL-4, IL-10, and IL-3. In contrast, only IFN-gamma was detected in parallel cultures of Thy-1bright gamma delta thymocytes. Virtually all Thy-1dull gamma delta thymocytes express high levels of CD44 and low levels of the heat-stable antigen and CD62 ligand, while around half of them express the NK1.1 marker. Thy-1dull gamma delta thymocytes are barely detectable in newborn animals, and their representation increases considerably during the first 2 weeks of postnatal life. The majority of Thy-1dull gamma delta thymocytes from DBA/2 mice express TCR encoded by the V gamma 1 gene and a novel V delta 6 gene named V delta 6.4. Sequence analysis of these functionally rearranged gamma and delta genes revealed highly restricted V delta-D delta-J delta junctions, and somewhat more diverse V gamma-J gamma junctions. We conclude that Thy-1dull gamma delta thymocytes exhibit properties that are equivalent to those of natural killer TCR alpha beta T cells. Both cell populations produce the same distinct pattern of cytokines upon activation, share a number of phenotypic markers originally defined for activated or memory T cells, display similar postnatal kinetics of appearance in the thymus and express a very restricted TCR repertoire.


Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS-2/8 Chondrosarcoma Cells.
Chondrosarcoma is the second most common primary bone sarcoma. Treatment of chondrosarcoma is limited to surgery due to radiation and chemotherapy resistance of this cancer. An ideal treatment for chondrosarcoma would be a well-tolerated, minimally invasive local or systemic treatment modality to halt or slow tumor growth prior to resection of local, unresectable local, or metastatic disease. Palovarotene, an agonist of nuclear retinoic acid receptor γ (RARγ) has shown therapeutic action for treatment of heterotopic ossification and osteochondroma without serious adverse effects in animal models. We hypothesized that selective agonists of RARγ would have an inhibitory effect on chondrosarcoma. All human chondrosarcoma specimens expressed RARγ as determined by immunohistochemical staining. The ΗCS-2/8 chondrosarcoma cell line, established from low-grade human chondrosarcoma, was used to examine the actions of RARγ agonists. In ΗCS2/8 pellet cultures, RARγ agonist treatment reduced the mass size and significantly decreased total glycosaminoglycan, protein amounts, and gene expression levels of cartilage matrix molecules when compared with control groups. Systemic treatment with RARγ agonists significantly inhibited the growth of ΗCS-2/8 cell transplants in vivo. Furthermore, local injection of RARγ agonist-loaded poly-lactic acid nanoparticles induced regression of the mass size of the transplants. Histologic analysis demonstrated that RARγ agonist treatment inhibited cell proliferation activity and stimulated encapsulation of the tumor. These findings indicate that RARγ agonists, including palovarotene, may have an anti-tumor effect on low-grade chondrosarcomas. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1045-1051, 2020.


WT1 influences apoptosis through transcriptional regulation of Bcl-2 family members.
WT1 is a zinc finger transcriptional regulatory protein that has been implicated in both normal development and in the generation of a variety of malignancies. Alternative splicing of the WT1 mRNA results in the expression of four major protein isoforms. There is increasing evidence that one of the functions of WT1 is the regulation of apoptosis, but there are conflicting reports about whether WT1 is pro- or anti-apoptotic. Careful review of the literature suggests that these apparent contradictions probably reflect cell lineage and isoform-specific differences in WT1 function. Expression of WT1 prevents programmed cell death in some cell types but promotes it in others, and different WT1 isoforms exert distinct effects as well. Investigation into the mechanisms by which WT1 regulates apoptosis has revealed that several bcl-2 family members are either direct or indirect WT1 target genes, including bcl-2 itself, the pro-apoptotic family members Bak and Bax, and the anti-apoptotic family member Bfl-1/A1. The specific bcl-2 family members regulated by WT1 expression vary by cell type and by isoform. Thus, a complete understanding of the role of WT1 in apoptosis will have to account for lineage- and isoform-specific effects of WT1 at both the cellular and molecular levels.


Phytogenic biosynthesis and emission of methyl acetate.
Acetylation of plant metabolites fundamentally changes their volatility, solubility and activity as semiochemicals. Here we present a new technique termed dynamic (13) C-pulse chasing to track the fate of C1-3 carbon atoms of pyruvate into the biosynthesis and emission of methyl acetate (MA) and CO2 . (13) C-labelling of MA and CO2 branch emissions respond within minutes to changes in (13) C-positionally labelled pyruvate solutions fed through the transpiration stream. Strong (13) C-labelling of MA emissions occurred only under pyruvate-2-(13) C and pyruvate-2,3-(13) C feeding, but not pyruvate-1-(13) C feeding. In contrast, strong (13) CO2 emissions were only observed under pyruvate-1-(13) C feeding. These results demonstrate that MA (and other volatile and non-volatile metabolites) derive from the C2,3 atoms of pyruvate while the C1 atom undergoes decarboxylation. The latter is a non-mitochondrial source of CO2 in the light generally not considered in studies of CO2 sources and sinks. Within a tropical rainforest mesocosm, we also observed atmospheric concentrations of MA up to 0.6 ppbv that tracked light and temperature conditions. Moreover, signals partially attributed to MA were observed in ambient air within and above a tropical rainforest in the Amazon. Our study highlights the potential importance of acetyl coenzyme A (CoA) biosynthesis as a source of acetate esters and CO2 to the atmosphere.


Mucosal microbiome in patients with recurrent aphthous stomatitis.
Recurrent aphthous stomatitis (RAS) is the most common disease affecting oral mucosae. Etiology is unknown, but several factors have been implicated, all of which influence the composition of microbiota residing on oral mucosae, which in turn modulates immunity and thereby affects disease progression. Although no individual pathogens have been conclusively shown to be causative agents of RAS, imbalanced composition of the oral microbiota may play a key role. In this study, we sought to determine composition profiles of bacterial microbiota in the oral mucosa associated with RAS. Using high-throughput 16S rRNA gene sequencing, we characterized the most abundant bacterial populations residing on healthy and ulcerated mucosae in patients with RAS (recruited using highly stringent criteria) and no associated medical conditions; we also compared these to the bacterial microbiota of healthy controls (HCs). Phylum-level diversity comparisons revealed decreased Firmicutes and increased Proteobacteria in ulcerated sites, as compared with healthy sites in RAS patients, and no differences between RAS patients with healthy sites and HCs. Genus-level analysis demonstrated higher abundance of total Bacteroidales in RAS patients with healthy sites over HCs. Porphyromonadaceae comprising species associated with periodontal disease and Veillonellaceae predominated in ulcerated sites over HCs, while no quantitative differences of these families were observed between healthy sites in RAS patients and HCs. Streptococcaceae comprising species associated with oral health predominated in HCs over ulcerated sites but not in HCs over healthy sites in RAS patients. This study demonstrates that mucosal microbiome changes in patients with idiopathic RAS--namely, increased Bacteroidales species in mucosae of RAS patients not affected by active ulceration. While these changes suggest a microbial role in initiation of RAS, this study does not provide data on causality. Within this limitation, the study contributes to the understanding of the potential role of mucosal microbiome changes in oral mucosal disease.


Sport, sex and age increase risk of illness at the Rio 2016 Summer Paralympic Games: a prospective cohort study of 51 198 athlete days.
To describe the epidemiology of illness at the Rio 2016 Summer Paralympic Games. A total of 3657 athletes from 78 countries, representing 83.5% of all athletes at the Games, were monitored on the web-based injury and illness surveillance system (WEB-IISS) over 51 198 athlete days during the Rio 2016 Summer Paralympic Games. Illness data were obtained daily from teams with their own medical support through the WEB-IISS electronic data capturing systems. The total number of illnesses was 511, with an illness incidence rate (IR) of 10.0 per 1000 athlete days (12.4%). The highest IRs were reported for wheelchair fencing (14.9), para swimming (12.6) and wheelchair basketball (12.5) (p<0.05). Female athletes and older athletes (35-75 years) were also at higher risk of illness (both p<0.01). Illnesses in the respiratory, skin and subcutaneous and digestive systems were the most common (IRs of 3.3, 1.8 and 1.3, respectively). (1) The rate of illness was lower than that reported for the London 2012 Summer Paralympic Games; (2) the sports with the highest risk were wheelchair fencing, para swimming and wheelchair basketball; (3) female and older athletes (35-75 years) were at increased risk of illness; and (4) the respiratory system, skin and subcutaneous system and digestive system were most affected by illness. These results allow for comparison at future Games.


Characterisation of a resolution enhancing image inversion interferometer.
Image inversion interferometers have the potential to significantly enhance the lateral resolution and light efficiency of scanning fluorescence microscopes. Self-interference of a point source's coherent point spread function with its inverted copy leads to a reduction in the integrated signal for off-axis sources compared to sources on the inversion axis. This can be used to enhance the resolution in a confocal laser scanning microscope. We present a simple image inversion interferometer relying solely on reflections off planar surfaces. Measurements of the detection point spread function for several types of light sources confirm the predicted performance and suggest its usability for scanning confocal fluorescence microscopy.


Is Radial Deviation of Wrist Related With Median Nerve Swelling in Patients With Rheumatoid Arthritis? A Radiographic, Ultrasonographic, and Electroneuromyographic Study.
This study aims to investigate whether or not radial deviation developing after wrist involvement of rheumatoid arthritis (RA) is a cause of median nerve swelling. The study included 51 RA patients (12 males, 39 females; mean age 50.9±8.9 years; range, 18 to 65 years) without carpal tunnel syndrome (CTS) detected by electroneuromyography. Duruöz hand index, visual analog scale, and painDETECT questionnaire were performed in clinical assessment. Radiographic measurements including radial inclination (RI) angle were performed. Using ultrasonography, the median nerve cross-sectional areas (CSAs) were measured from the four levels of the distal one third of the forearm, radioulnar joint, pisiform bone, and hook of hamate, while the ulnar nerve CSAs were measured from the pisiform bone. The study was completed with 102 hands of 51 patients. A negative correlation was found between the RI and the median CSAs measured from the radioulnar joint (R=-0.49; p=0.00), the pisiform bone (R= -0.45; p=0.00), and hook of hamate (R= -0.60, p=0.00). When the hands were divided into three groups according to the ranges of RI specified in the literature, the median nerve CSA was found to be significantly higher in the group with low RI at these levels (p<0.001). In patients with RA without CTS, the increase in the median nerve CSAs may be associated with radiographic measures such as radial deviation.


The Change in Fingertip Contact Area as a Novel Proprioceptive Cue.
Humans, many animals, and certain robotic hands have deformable fingertip pads [1, 2]. Deformable pads have the advantage of conforming to the objects that are being touched, ensuring a stable grasp for a large range of forces and shapes. Pad deformations change with finger displacements during touch. Pushing a finger against an external surface typically provokes an increase of the gross contact area [3], potentially providing a relative motion cue, a situation comparable to looming in vision [4]. The rate of increase of the area of contact also depends on the compliance of the object [5]. Because objects normally do not suddenly change compliance, participants may interpret an artificially induced variation in compliance, which coincides with a change in the gross contact area, as a change in finger displacement, and consequently they may misestimate their finger's position relative to the touched object. To test this, we asked participants to compare the perceived displacements of their finger while contacting an object varying pseudo-randomly in compliance from trial to trial. Results indicate a bias in the perception of finger displacement induced by the change in compliance, hence in contact area, indicating that participants interpreted the altered cutaneous input as a cue to proprioception. This situation highlights the capacity of the brain to take advantage of knowledge of the mechanical properties of the body and of the external environment.


High frequency of phylogenetically diverse reductive dehalogenase-homologous genes in deep subseafloor sedimentary metagenomes.
Marine subsurface sediments on the Pacific margin harbor diverse microbial communities even at depths of several hundreds meters below the seafloor (mbsf) or more. Previous PCR-based molecular analysis showed the presence of diverse reductive dehalogenase gene (rdhA) homologs in marine subsurface sediment, suggesting that anaerobic respiration of organohalides is one of the possible energy-yielding pathways in the organic-rich sedimentary habitat. However, primer-independent molecular characterization of rdhA has remained to be demonstrated. Here, we studied the diversity and frequency of rdhA homologs by metagenomic analysis of five different depth horizons (0.8, 5.1, 18.6, 48.5, and 107.0 mbsf) at Site C9001 off the Shimokita Peninsula of Japan. From all metagenomic pools, remarkably diverse rdhA-homologous sequences, some of which are affiliated with novel clusters, were observed with high frequency. As a comparison, we also examined frequency of dissimilatory sulfite reductase genes (dsrAB), key functional genes for microbial sulfate reduction. The dsrAB were also widely observed in the metagenomic pools whereas the frequency of dsrAB genes was generally smaller than that of rdhA-homologous genes. The phylogenetic composition of rdhA-homologous genes was similar among the five depth horizons. Our metagenomic data revealed that subseafloor rdhA homologs are more diverse than previously identified from PCR-based molecular studies. Spatial distribution of similar rdhA homologs across wide depositional ages indicates that the heterotrophic metabolic processes mediated by the genes can be ecologically important, functioning in the organic-rich subseafloor sedimentary biosphere.


Taming a wandering attention: short-form mindfulness training in student cohorts.
Mindfulness training (MT) is a form of mental training in which individuals engage in exercises to cultivate an attentive, present centered, and non-reactive mental mode. The present study examines the putative benefits of MT in University students for whom mind wandering can interfere with learning and academic success. We tested the hypothesis that short-form MT (7 h over 7 weeks) contextualized for the challenges and concerns of University students may reduce mind wandering and improve working memory. Performance on the sustained attention to response task (SART) and two working memory tasks (operation span, delayed-recognition with distracters) was indexed in participants assigned to a waitlist control group or the MT course. Results demonstrated MT-related benefits in SART performance. Relative to the control group, MT participants had higher task accuracy and self-reported being more "on-task" after the 7-week training period. MT did not significantly benefit the operation span task or accuracy on the delayed-recognition task. Together these results suggest that while short-form MT did not bolster working memory task performance, it may help curb mind wandering and should, therefore, be further investigated for its use in academic contexts.


Expanding the roles for 2-oxoglutarate-dependent oxygenases in plant metabolism.
Covering: up to 2018 2-Oxoglutarate-dependent oxygenases (2ODOs) comprise a large enzyme superfamily in plant genomes, second in size only to the cytochromes P450 monooxygenase (CYP) superfamily. 2ODOs participate in both primary and specialized plant pathways, and their occurrence across all life kingdoms points to an ancient origin. Phylogenetic evidence supports substantial expansion and diversification of 2ODOs following the split from the common ancestor of land plants. More conserved roles for these enzymes include oxidation within hormone metabolism, such as the recently described capacity of Dioxygenase for Auxin Oxidation (DAO) for governing auxin homeostasis. Conserved structural features among 2ODOs has provided a basis for continued investigation into their mechanisms, and recent structural work is expected to illuminate intriguing reactions such as that of 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO). Phylogenetic radiation among this superfamily combined with neo- and subfunctionalization has enabled recruitment to highly specialized pathways, including those yielding medicines, flavours, dyes, poisons, and compounds important for plant-environment interactions. Catalytic versatility of 2ODOs in plants and across broader taxa continues to inspire biochemists tasked with the discovery of new enzymes. This highlight article summarizes recent reports up to 2018 of 2ODOs within plant metabolism. Furthermore, the respective contributions of 2ODOs and other oxidases to natural product biosynthesis are discussed as a framework for continued discovery.


A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation.
Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg·h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.


Robotic approach to the reduction of dental anxiety in children.
We introduced a humanoid robot for the use of techno-psychological distraction techniques in children aged 4-10 to reduce their anxiety and improve their behaviour during dental treatment. Two hundred children (98 boys, 102 girls; mean age: 6.5 ± 1.66 years) appointed for first time for dental caries were included and randomly divided into two groups [N = 100 for each group; RG: Robot Group (accompanied by the robot), CG: Control Group (without robot accompaniment)]. Half of the children were treated under local anaesthesia (infiltration anaesthesia) (n = 50 within each group) and half of the children were treated without any local anaesthesia (n = 50 within each group) within each group. The success rate of the new robotic distraction technique was evaluated by using Parental Corah Dental Anxiety Scale, Facial Image Scale (FIS), physiological pulse rate and Frankl Behaviour Rating Scale (FBRS). Pulse rates, which measured during treatment and after treatment, were statistically higher in CG than in RG (p < .05). After dental treatment, the FIS score was significantly higher in CG than RG (p < .05). 88.3% of the children in RG stated that they wanted the robot to be with them at the next treatment session. Robotic technology can successfully help in coping with dental anxiety and stress, and helps children to behave better in dental office.


Clinical and radiologic correlations of central pontine myelinolysis syndrome.
To characterize clinical and radiologic features of patients with central pontine myelinolysis (CPM) and identify variables that predict outcome. We retrospectively studied patients diagnosed as having CPM identified by a search of Mayo Clinic medical records from January 1, 1999, through December 31, 2010. Diagnosis was made by clinical and radiologic features. Favorable outcome was defined by a modified Rankin Scale score of 2 or lower. Volume of signal abnormality on brain magnetic resonance imaging (MRI) was quantified by a neuroradiologist blinded to outcomes. Wilcoxon rank sum tests were used to assess association between volume of signal abnormality and outcomes at discharge and last follow-up. Of 24 patients, 14 (58%) had only CPM, and 10 (42%) had extrapontine involvement. Hyponatremia was documented in 18 patients (75%), with median sodium nadir of 114 mmol/L. Eighteen patients (75%) had alcoholism, and malnutrition was documented in 12 (50%). Presenting symptoms included encephalopathy (n=18 [75%]), ataxia (n=11 [46%]), dysarthria (n=7 [29%]), eye movement abnormalities (n=6 [25%]), and seizures (n=5 [21%]). Favorable outcome was seen in 15 patients (63%) at last follow-up. Findings on initial brain MRI were normal in 5 patients, but all MRI scans were abnormal with serial imaging. The volume of radiologic signal abnormality was not associated with outcome at discharge or last follow-up (P=.67 and P=.37, respectively). Clinical outcome in patients with CPM is not predicted by the volume of radiologic T2 signal abnormality on MRI or the severity of hyponatremia. Serial brain imaging is of value because a substantial proportion of patients have normal findings on initial MRI.


Acoustically modulated biomechanical stimulation for human cartilage tissue engineering.
Bioacoustofluidics can be used to trap and levitate cells within a fluid channel, thereby facilitating scaffold-free tissue engineering in a 3D environment. In the present study, we have designed and characterised an acoustofluidic bioreactor platform, which applies acoustic forces to mechanically stimulate aggregates of human articular chondrocytes in long-term levitated culture. By varying the acoustic parameters (amplitude, frequency sweep, and sweep repetition rate), cells were stimulated by oscillatory fluid shear stresses, which were dynamically modulated at different sweep repetition rates (1-50 Hz). Furthermore, in combination with appropriate biochemical cues, the acoustic stimulation was tuned to engineer human cartilage constructs with structural and mechanical properties comparable to those of native human cartilage, as assessed by immunohistology and nano-indentation, respectively. The findings of this study demonstrate the capability of acoustofluidics to provide a tuneable biomechanical force for the culture and development of hyaline-like human cartilage constructs in vitro.


A Cost-Consequence Analysis of Preemptive SLCO1B1 Testing for Statin Myopathy Risk Compared to Usual Care.
There is a well-validated association between SLCO1B1 (rs4149056) and statin-associated muscle symptoms (SAMS). Preemptive SLCO1B1 pharmacogenetic (PGx) testing may diminish the incidence of SAMS by identifying individuals with increased genetic risk before statin initiation. Despite its potential clinical application, the cost implications of SLCO1B1 testing are largely unknown. We conducted a cost-consequence analysis of preemptive SLCO1B1 testing (PGx+) versus usual care (PGx-) among Veteran patients enrolled in the Integrating Pharmacogenetics in Clinical Care (I-PICC) Study. The assessment was conducted using a health system perspective and 12-month time horizon. Incremental costs of SLCO1B1 testing and downstream medical care were estimated using data from the U.S. Department of Veterans Affairs' Managerial Cost Accounting System. A decision analytic model was also developed to model 1-month cost and SAMS-related outcomes in a hypothetical cohort of 10,000 Veteran patients, where all patients were initiated on simvastatin. Over 12 months, 13.5% of PGx+ (26/193) and 11.2% of PGx- (24/215) participants in the I-PICC Study were prescribed Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline-concordant statins (Δ2.9%, 95% CI -4.0% to 10.0%). Differences in mean per-patient costs for lipid therapy prescriptions, including statins, for PGx+ compared to PGx- participants were not statistically significant (Δ USD 9.53, 95% CI -0.86 to 22.80 USD). Differences in per-patient costs attributable to the intervention, including PGx testing, lipid-lowering prescriptions, SAMS, laboratory and imaging expenses, and primary care and cardiology services, were also non-significant (Δ- USD 1004, 95% CI -2684 to 1009 USD). In the hypothetical cohort, SLCO1B1-informed statin therapy averted 109 myalgias and 3 myopathies at 1-month follow up. Fewer statin discontinuations (78 vs. 109) were also observed, but the SLCO1B1 testing strategy was 96 USD more costly per patient compared to no testing (124 vs. 28 USD). The implementation of SLCO1B1 testing resulted in small, non-significant increases in the proportion of patients receiving CPIC-concordant statin prescriptions within a real-world primary care context, diminished the incidence of SAMS, and reduced statin discontinuations in a hypothetical cohort of 10,000 patients. Despite these effects, SLCO1B1 testing administered as a standalone test did not result in lower per-patient health care costs at 1 month or over 1 year of treatment. The inclusion of SLCO1B1, among other well-validated pharmacogenes, into preemptive panel-based testing strategies may provide a better balance of clinical benefit and cost.


Environmental determinants of enhanced sensitivity to the behavioral effects of naltrexone.
Dose-effect curves for naltrexone were determined in three squirrel monkeys studied sequentially under four different schedule conditions: a schedule of shock postponement; a fixed-interval schedule of shock presentation; a fixed-ratio schedule of food presentation; and a fixed-ratio schedule of stimulus-shock termination. In general, responding under the shock-postponement or the fixed-interval schedules was decreased minimally by doses of naltrexone up to 30 mg/kg, and these effects were not altered appreciably after daily injections of naltrexone under the fixed-interval schedule. Under the fixed-ratio schedule of food presentation naltrexone (0.3 to 10 mg/kg) produced dose-related decreases in responding, and after repeated daily injections of naltrexone the dose-effect curve was shifted more than 3-fold to the left. Under the fixed-ratio schedule of stimulus-shock termination, however, this supersensitivity to naltrexone was not apparent: responding was decreased appreciably only after 17.6 mg/kg of naltrexone. When the fixed-ratio schedule of food presentation was reinstated, the supersensitivity to naltrexone observed previously under this schedule was not evident initially, but reappeared quickly in two of the monkeys. The greater rate-decreasing effects of naltrexone under the fixed-ratio schedules compared to the other schedules may reflect a dependency related to the control rate of responding. Supersensitivity to naltrexone occurred only under the fixed-ratio schedule of food presentation and could be reversed temporarily by intervening exposure to the schedule of stimulus-shock termination. These results extend earlier findings that the behavioral effects of drugs can be dependent upon both past and present environmental influences.


Visualizing the human connectome.
Innovations in data visualization punctuate the landmark advances in human connectome research since its beginnings. From tensor glyphs for diffusion-weighted imaging, to advanced rendering of anatomical tracts, to more recent graph-based representations of functional connectivity data, many of the ways we have come to understand the human connectome are through the intuitive insight these visualizations enable. Nonetheless, several unresolved problems persist. For example, probabilistic tractography lacks the visual appeal of its deterministic equivalent, multimodal representations require extreme levels of data reduction, and rendering the full connectome within an anatomical space makes the contents cluttered and unreadable. In part, these challenges require compromises between several tensions that determine connectome visualization practice, such as prioritizing anatomic or connectomic information, aesthetic appeal or information content, and thoroughness or readability. To illustrate the ongoing negotiation between these priorities, we provide an overview of various visualization methods that have evolved for anatomical and functional connectivity data. We then describe interactive visualization tools currently available for use in research, and we conclude with concerns and developments in the presentation of connectivity results.


Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis.
IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results.


The diets of early hominins.
Diet changes are considered key events in human evolution. Most studies of early hominin diets focused on tooth size, shape, and craniomandibular morphology, as well as stone tools and butchered animal bones. However, in recent years, dental microwear and stable isotope analyses have hinted at unexpected diversity and complexity in early hominin diets. Some traditional ideas have held; others, such as an increasing reliance on hard-object feeding and a dichotomy between Australopithecus and Paranthropus, have been challenged. The first known evidence of C(4) plant (tropical grasses and sedges) and hard-object (e.g., seeds and nuts) consumption dates to millions of years after the appearance of the earliest probable hominins, and there are no consistent trends in diet change among these species through time.


Molecular typing of multiple-antibiotic-resistant Salmonella enterica serovar Typhi from Vietnam: application to acute and relapse cases of typhoid fever.
The rate of multiple-antibiotic resistance is increasing among Salmonella enterica serovar Typhi strains in Southeast Asia. Pulsed-field gel electrophoresis (PFGE) and other typing methods were used to analyze drug-resistant and -susceptible organisms isolated from patients with typhoid fever in several districts in southern Vietnam. Multiple PFGE and phage typing patterns were detected, although individual patients were infected with strains of a single type. The PFGE patterns were stable when the S. enterica serovar Typhi strains were passaged many times in vitro on laboratory medium. Paired S. enterica serovar Typhi isolates recovered from the blood and bone marrow of individual patients exhibited similar PFGE patterns. Typing of S. enterica serovar Typhi isolates from patients with relapses of typhoid indicated that the majority of relapses were caused by the same S. enterica serovar Typhi strain that was isolated during the initial infection. However, some individuals were infected with distinct and presumably newly acquired S. enterica serovar Typhi isolates.


Value of immunohistochemistry in distinguishing peritoneal mesothelioma from serous carcinoma of the ovary and peritoneum: a review and update.
At present, a large number of immunohistochemical markers that can be used in the differential diagnosis between epithelioid peritoneal mesotheliomas and serous carcinomas are available. However, great differences of opinion exist regarding the individual value of some of these markers. This article provides a critical review of all of the information that is currently available on those markers that have the greatest potential for assisting in distinguishing between peritoneal mesotheliomas and serous carcinomas. The conclusion of this review indicates that the positive serous carcinoma markers, by and large, have a higher degree of sensitivity and specificity in assisting in discriminating between these malignancies than the positive mesothelioma markers. From a practical point of view, a combination of MOC-31 (or Ber-EP4), estrogen receptors, and calretinin immunostaining should allow a clear distinction to be made between epithelioid peritoneal mesotheliomas and serous carcinomas in most cases.


Evaluation of Bacillus Strains for Plant Growth Promotion and Predictability of Efficacy by In Vitro Physiological Traits.
Bacilli are commonly used as plant growth-promoting agents but can be limited in effectiveness to certain crop and soil environments. The objectives of this study were to (1) identify Bacillus strains that can be consistent in promoting the growth of corn, wheat, and soybean and (2) determine whether physiological traits expressed in vitro can be predictive of growth promotion efficacy/consistency and be used for selecting effective strains. Twelve Bacillus strains isolated from wheat rhizospheres were evaluated in greenhouse pot tests with nonsterile soil for their effects on the growth of corn, soybean, and wheat. The strains also were assessed in vitro for multiple physiological traits. All 12 strains increased corn growth significantly compared to the controls. The four most efficacious strains on corn-Bacillus megaterium R181, B. safensis R173, B. simplex R180, and Paenibacillus graminis R200-also increased the growth of soybean and wheat. No set of traits was a predictor of growth promotion efficacy. The number of traits expressed by a strain also was not an indicator of efficacy as strain R200 that was positive for only one trait showed high growth promotion efficacy. Effective strains can be identified through pot tests on multiple crop plants, but in vitro physiological assays are unreliable for strain selection.


Cognitive Functions and Depression in Patients with Irritable Bowel Syndrome.
Background. Irritable bowel syndrome (IBS) is associated with depression and depression with impaired cognitive functions. The primary aim was to study associations between depression and cognitive functions in patients with IBS. Methods. IBS (according to the Rome III criteria), cognitive functions (evaluated with a set of neuropsychological tests), and depression (measured with Beck Depression Inventory II and Montgomery-Åsberg Depression Scale) were analysed in patients with idiopathic depression and in patients with unspecified neurological symptoms. Results. 18 and 48 patients with a mean age of 47 and 45 years were included in the "Depression" and "Neurological" group, respectively. In the "Depression" group, the degree of depression was significantly higher in patients with IBS than in those without. Depression was associated with impaired cognitive function in 6 out of 17 neuropsychological tests indicating reduced set shifting, verbal fluency, attention, and psychomotor speed. IBS was statistically significantly associated with depression but not with any of the tests for cognitive functions. Conclusions. IBS was associated with depression but not with impaired cognitive functions. Since the idiopathic depression was associated with cognitive deficits, the findings could indicate that the depression in patients with IBS differs from an idiopathic depression.


Phylogenomic analyses reveal an exceptionally high number of evolutionary shifts in a florally diverse clade of African legumes.
Detarioideae is well known for its high diversity of floral traits, including flower symmetry, number of organs, and petal size and morphology. This diversity has been characterized and studied at higher taxonomic levels, but limited analyses have been performed among closely related genera with contrasting floral traits due to the lack of fully resolved phylogenetic relationships. Here, we used four representative transcriptomes to develop an exome capture (target enrichment) bait for the entire subfamily and applied it to the Anthonotha clade using a complete data set (61 specimens) representing all extant floral diversity. Our phylogenetic analyses recovered congruent topologies using ML and Bayesian methods. Anthonotha was recovered as monophyletic contrary to the remaining three genera (Englerodendron, Isomacrolobium and Pseudomacrolobium), which form a monophyletic group sister to Anthonotha. We inferred a total of 35 transitions for the seven floral traits (pertaining to flower symmetry, petals, stamens and staminodes) that we analyzed, suggesting that at least 30% of the species in this group display transitions from the ancestral condition reconstructed for the Anthonotha clade. The main transitions were towards a reduction in the number of organs (petals, stamens and staminodes). Despite the high number of transitions, our analyses indicate that the seven characters are evolving independently in these lineages. Petal morphology is the most labile floral trait with a total of seven independent transitions in number and seven independent transitions to modification in petal types. The diverse petal morphology along the dorsoventral axis of symmetry within the flower is not associated with differences at the micromorphology of petal surface, suggesting that in this group all petals within the flower might possess the same petal identity at the molecular level. Our results provide a solid evolutionary framework for further detailed analyses of the molecular basis of petal identity.


Ultrasound-guided radiofrequency thermal ablation of liver tumors: percutaneous, laparoscopic, and open surgical approaches.
Only 10% to 20% of patients with primary and colorectal metastatic liver tumors are candidates for curative surgical resection. Even after curative treatment, tumors recur commonly in the liver. As a less invasive therapy, radiofrequency thermal ablation (RFA) of primary, metastatic, and recurrent liver tumors was performed under percutaneous, laparoscopic, or open intraoperative ultrasound guidance. The safety and local control efficacy of RFA were investigated. RFA was performed mostly in patients with unresectable hepatomas or metastatic liver tumors. Patients with large tumors, major vessel or bile duct invasion, limited extrahepatic metastases, or liver dysfunction were not excluded. An RFA system with a 15-gauge electrode-cannula with four-pronged retractable needles was used. All patients were followed for more than 8 months to assess morbidity and mortality, and to determine tumor recurrence. Sixty RFA operations were performed in 46 patients: 11 patients underwent repeat RFA once or twice. A total of 204 tumors were treated: 70 hepatomas and 134 metastatic tumors. Tumor size ranged from 5 mm to 180 mm (mean 36 mm). RFA was performed in 29 operations for 81 tumors percutaneously, in seven operations for 14 tumors laparoscopically, and in 24 operations for 109 tumors by open surgery. Combined colorectal resection was carried out in five operations and combined hepatic resection was carried out in three operations. There was one death (1.7%) from liver failure, and there were three major complications (5%): one case of bile leakage and two biliary strictures due to thermal injury. There were no intra-abdominal infectious or bleeding complications. The length of hospital stay ranged from 0 to 2, 1 to 3, and 4 to 7 days for percutaneous, laparoscopic, and open surgical RFA, respectively. During a mean follow-up period of 20.5 months, local tumor recurrence at the RFA site was diagnosed in 18 (8.8%) of 204 tumors. The risk factors for local recurrence included large tumor size and major vessel invasion: recurrence rates for tumors less than 4 cm, 4 to 10 cm, and greater than 10 cm, and for those with vessel invasion were 3.3%, 14.7%, 50%, and 47.8%, respectively. Ten of 18 tumors recurring locally were retreated by RFA, and eight of them showed no further recurrence. Ultrasound-guided RFA is a relatively safe, well-tolerated, and versatile treatment option that offers excellent local control of primary and metastatic liver tumors. The appropriate use of percutaneous, laparoscopic, and open surgical RFA is beneficial in the management of patients with liver tumors in a variety of situations.


[Study on treatment of "cytokine storm" by anti-2019-nCoV prescriptions based on arachidonic acid metabolic pathway].
Since the outbreak of 2019-nCoV, the epidemic has developed rapidly and the situation is grim. LANCET figured out that the 2019-nCoV is closely related to "cytokine storm". "Cytokine storm" is an excessive immune response of the body to external stimuli such as viruses and bacteria. As the virus attacking the body, it stimulates the secretion of a large number of inflammatory factors: interleukin(IL), interferon(IFN), C-X-C motif chemokine(CXCL) and so on, which lead to cytokine cascade reaction. With the exudation of inflammatory factors, cytokines increase abnormally in tissues and organs, interfering with the immune system, causing excessive immune response of the body, resulting in diffuse damage of lung cells, pulmonary fibrosis, and multiple organ damage, even death. Arachidonic acid(AA) metabolic pathway is principally used to synthesize inflammatory cytokines, such as monocyte chemotactic protein 1(MCP-1), tumor necrosis factor(TNF), IL, IFN, etc., which is closely related to the occurrence, development and regression of inflammation. Therefore, the inhibition of AA metabolism pathway is benefit for inhibiting the release of inflammatory factors in the body and alleviating the "cytokine storm". Based on the pharmacophore models of the targets on AA metabolic pathway, the traditional Chinese medicine database 2009(TCMD 2009) was screened. The potential herbs were ranked by the number of hit molecules, which were scored by pharmacophore fit value. In the end, we obtained the potential active prescriptions on "cytokine storm" according to the potential herbs in the "National novel coronavirus pneumonia diagnosis and treatment plan(trial version sixth)". The results showed that the hit components with the inhibitory effect on AA were magnolignan Ⅰ, lonicerin and physcion-8-O-β-D-glucopy-ranoside, which mostly extracted from Magnoliae Officinalis Cortex, Zingiberis Rhizoma Recens, Lonicerae Japonicae Flos, Rhei Radix et Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Scutellariae Radix, Gardeniae Fructus, Ginseng Radix et Rhizoma, Arctii Fructus, Dryopteridis Crassirhizomatis Rhizoma, Paeoniaeradix Rubra, Dioscoreae Rhizoma. Finally the anti-2019-nCoV prescriptions were analyzed to obtain the potential active prescriptions on AA metabolic pathway, Huoxiang Zhengqi Capsules, Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Qingfei Paidu Decoction, Xuebijing Injection, Reduning Injection and Tanreqing Injection were found that may prevent 2019-nCoV via regulate cytokines. This study intends to provide reference for clinical use of traditional Chinese medicine to resist new coronavirus.


Monitoring daily intraocular pressure fluctuations with self-tonometry in healthy subjects.
To evaluate the accuracy of the intraocular pressure (IOP) measured by healthy subjects with icare® Home and to observe the IOP fluctuation and pattern of IOP fluctuation in healthy subjects over three consecutive days. Sixty healthy subjects were recruited to the study. IOP was measured by the subjects themselves and by study staff using icare® Home tonometers on visits 1 and 2, as well as by study staff using Goldmann applanation tonometry (GAT). Furthermore, the subjects measured their IOP at home for three consecutive days. Twenty-three per cent of the study eyes were excluded in the statistical analysis due to dropout or non-compliance to the schedule. Approximately 70% of the icare® Home measurements were within 3 mmHg of the GAT measurements. Ten to 16% of the study eyes had IOP peaks outside office hours. Sixty-three per cent of the study eyes had different IOP patterns on consecutive days. Rebound self-tonometry appears to be accurate and could be used to monitor short- and long-term IOP variations. The difference between IOP patterns on consecutive days raises questions as to the certainty of a single IOP measurement as a measure of treatment effect.


Neutrophil functions and clinical performance after total fasting in patients with rheumatoid arthritis.
The effects of fasting for 7 days were investigated in 13 patients with rheumatoid arthritis (RA) in comparison with a control regimen in a cross-over trial. The effects of fasting on clinical performance and blood neutrophil functions were studied. During fasting, with a mean weight loss of 5.1 kg, clinical inflammation in the joints and the erythrocyte sedimentation rate (ESR) decreased. During the control period the joints either remained unchanged or deteriorated, and no change was observed in the body weight or the ESR. The locomotion of neutrophils under agarose, induced by a reference serum, decreased during the fasting period (p less than 0.001), but no change in their locomotion was induced by an Escherichia coli bacterial factor. During the control period, however, the locomotion induced by either stimulant was significantly decreased. Generation of migration-stimulating factors from the patients' plasma declined 3 days after the end of fasting (p less than 0.001). The adherence of the neutrophils to nylon fibres was unchanged during both periods. The bactericidal capacity improved during fasting, both in comparison with the initial value (p less than 0.005) and with the values from the control period (p less than 0.001). An association was found between improvement in inflammatory activity of the joints and enhancement of neutrophil bactericidal capacity. Fasting appears to improve the clinical status of patients with RA. This could partly be due to the observed changes in the functions of the neutrophils, since the latter contribute to the inflammatory joint reactions.


Principal component analysis reveals differential attentional modulation of the vocal response to pitch perturbation.
The auditory-vocal system modifies voice fundamental frequency (F0) with auditory feedback. The responses to F0 changes in auditory feedback are known to depend on the task. The hypothesis explored in this study is that the task dependency is the result of multiple components of the F0 responses differently modulated with different tasks. Attention to audition was manipulated by task condition by the instruction to ignore or to count the number of the F0 shifts heard during vocalization. A synthetic voice with pitch shifts was used as auditory pseudo-feedback. The upward and downward shifts evoked very similar vocal F0 response patterns with polarity reversal. Attention to the auditory feedback caused a reduction in the grand-average response amplitude. By decomposing the F0 responses with principal component analysis (PCA), three principal components (PCs) with different peak latencies were found to have contributions above the criterion of 5%, totaling to 74%. All three PCs contributed to a compensatory response under the "ignore" condition. The slowest PC changed its polarity and the intermediate PC was reduced to almost zero under the "count" condition. Thus, the task-dependency of the F0 response to auditory feedback can be described in terms of different sensitivities of components to attention.


Mechanisms of Ca(2+)-independent contraction in single permeabilized ferret aorta cells.
The mechanisms by which prostaglandin F2 alpha (PGF2 alpha) can cause contractions at constant intracellular Ca2+ were investigated by the direct measurement of force from single saponin-permeabilized smooth muscle cells from the ferret aorta. The size of PGF2 alpha contractions did not change between pCa 9.0 and pCa 6.6. The remainder of the experiments were carried out at pCa 7.0. At pCa 7.0, PGF2 alpha (0.1-100 microM) induced sustained force in a dose-dependent manner, reaching a maximum (2.61 +/- 0.20 microN, n = 14) in 10 minutes. Both protein kinase C pseudosubstrate inhibitor (3 microM) and staurosporine (1 microM) significantly inhibited PGF2 alpha (100 microM)-induced contractions, but staurosporine was more effective. Staurosporine caused 88.8 +/- 13.3% inhibition, whereas protein kinase C pseudosubstrate inhibitor inhibited 62.3 +/- 9.6% of the PGF2 alpha-induced contraction. An inhibitor of type-1 and type-2A protein phosphatases, microcystin-LR, at a concentration of 1 microM induced a gradual and sustained contraction (1.53 +/- 0.21 microN). A lower concentration of microcystin-LR (100 nM) also induced a small but significant contraction (0.36 +/- 0.26 microN). Pretreatment with both 1 microM and 100 nM microcystin-LR caused significant inhibition of the PGF2 alpha-induced contraction from 2.61 +/- 0.20 microN (n = 14) to 0.32 +/- 0.20 microN (n = 6) (p < 0.01) and 1.52 +/- 0.21 microN (n = 6) (p < 0.01), respectively. These results indicate that the part of the PGF2 alpha-induced contraction that occurs at a constant, low intracellular Ca2+ is the combined result of activation of protein kinase C and phosphatase inhibition.


Experimental infection of calves with two strains of bovine virus diarrhoea virus: certain immunological reactions.
Certain immunological responses of 4-6 month old calves experimentally inoculated with either cytopathic or non-cytopathic bovine virus diarrhoea virus (BVDV) were compared with those of uninfected control calves. The tests used to demonstrate the immunological responses were the transformation of lymphocytes by PHA mitogen, the percentage of lymphocytes with surface immunoglobulin, and the antibody titres induced by an intravenous inoculation of killed Brucella abortus. There were no significant differences between the two groups of calves and therefore, the mild experimental disease produced by BVDV did not appear to affect adversely the immunological response.


CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study.
The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort. A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (± 5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62-1·59; OR = 1·13, 95% CI: 0·40-3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76-1·96; OR = 0·96, 95% CI: 0·60-1·52, respectively) compared with non-null genotypes. This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.


Efficacy of telaprevir-based therapy in stable liver transplant patients with chronic genotype 1 hepatitis C.
Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 ?g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE - consistent with the post-liver transplant population and the co-administered immunosuppressants. Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.


Design and use of organic nanoparticles prepared from star-shaped polymers with reactive end groups.
Star-shaped poly(isobornyl acrylate) (PiBA) was prepared by atom transfer radical polymerization (ATRP) using multifunctional initiators. The optimal ATRP conditions were determined to minimize star-star coupling and to preserve high end group functionality (>90%). Star-shaped PiBA with a narrow polydispersity index was synthesized with 4, 6, and 12 arms and of varying molecular weight (10,000 to 100,000 g x mol(-1)) using 4 equiv of a Cu(I)Br/PMDETA catalyst system in acetone. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis, NMR spectroscopy, and size exclusion chromatography (SEC) confirmed their controlled synthesis. The bromine end group of each arm was then transformed to a reactive end group by a nucleophilic substitution with methacrylic acid or cinnamic acid (conversion >90%). These reactive star polymers were used to prepare PiBA nanoparticles by intramolecular polymerization of the end groups. The successful preparation of this new type of organic nanoparticles on a multigram scale was proven by NMR spectroscopy and SEC. Subsequently, they have been used as additives for linear, rubbery poly(n-butyl acrylate). Rheology measurements indicated that the viscoelastic properties of the resulting materials can be fine-tuned by changing the amount of incorporated nanoparticles (1-20 wt %), as a result of the entanglements between the nanoparticles and the linear polymers.


Reliability and interrelations of seven proxy measures of cochlear synaptopathy.
Investigations of cochlear synaptopathy in living humans rely on proxy measures of auditory nerve function. Numerous procedures have been developed, typically based on the auditory brainstem response (ABR), envelope-following response (EFR), or middle-ear-muscle reflex (MEMR). Validation is challenging, due to the absence of a gold-standard measure in humans. Some metrics correlate with synaptic survival in animal models, but translation between species is not straightforward; measurements in humans are likely to reflect greater error and greater variability from non-synaptopathic sources. The present study assessed the reliability of seven measures, as well as testing for correlations between them. Thirty-one young women with normal audiograms underwent repeated measurements of ABR wave I amplitude, ABR wave I growth, ABR wave V latency shift in noise, EFR amplitude, EFR growth with stimulus modulation depth, MEMR threshold, and an MEMR across-frequency difference measure. Intraclass correlation coefficients for ABR wave I amplitude, EFR amplitude, and MEMR threshold ranged from 0.85 to 0.93, suggesting that such tests can yield highly reliable results, given careful measurement techniques. The ABR and EFR difference measures exhibited only poor-to-moderate reliability. No significant correlations, nor any consistent trends, were observed between the various measures, providing no indication that these metrics reflect the same underlying physiological processes. Findings suggest that many proxy measures of cochlear synaptopathy should be regarded with caution, at least when employed in young adults with normal audiograms.


Use of the PROMIS Mobility score in assessing function in adolescents and adults previously affected by childhood hip disease.
The Patient-Reported Outcomes Measurement Information System (PROMIS) has demonstrated faster administration, lower burden of data capture and reduced floor and ceiling effects compared to traditional Patient Reported Outcomes Measurements (PROMs). We investigated the suitability of PROMIS Mobility score in assessing physical function in the sequelae of childhood hip disease. In all, 266 adolscents (aged ≥ 12 years) and adults were identified with a prior diagnosis of childhood hip disease (either Perthes' disease (n = 232 (87.2%)) or Slipped Capital Femoral Epiphysis (n = 34 (12.8%)) with a mean age of 27.73 years (SD 12.24). Participants completed the PROMIS Mobility Computer Adaptive Test, the Non-Arthritic Hip Score (NAHS), EuroQol five-dimension five-level questionnaire, and the Numeric Pain Rating Scale. We investigated the correlation between the PROMIS Mobility and other tools to assess use in this population and any clustering of outcome scores. There was a strong correlation between the PROMIS Mobility and other established PROMs; NAHS (rs = 0.79; p < 0.001). There was notable clustering in PROMIS at the upper end of the distribution score (42.5%), with less seen in the NAHS (20.3%). However, the clustering was broadly similar between PROMIS Mobility and the comparable domains of the NAHS; function (53.6%), and activity (35.0%). PROMIS Mobility strongly correlated with other tools demonstrating convergent construct validity. There was clustering of physical function scores at the upper end of the distributions, which may reflect truncation of the data caused by participants having excellent outcomes. There were elements of disease not captured within PROMIS Mobility alone, and difficulties in differentiating those with the highest levels of function. Cite this article: Bone Jt Open 2021;2(12):1089-1095.