MRI arterial spin labeling in evaluating hemorrhagic transformation following endovascular recanalization of subacute ischemic stroke.
To investigate the value of the MRI arterial spin labeling (ASL) in evaluating the blood-brain barrier permeability of anterior circulation ischemic lesions in subacute ischemic stroke (SIS) and the risk of hemorrhage transformation (HT) after endovascular recanalization. Patients with anterior circulation SIS treated with endovascular recanalization were prospectively enrolled. The imaging presentations in the MRI ASL sequences, dynamic contrast-enhanced (DCE) sequence, and Xper CT were studied. The relative cerebral blood flow (rCBF), volume transfer constant (Ktrans), and the weighted Kappa coefficient (rKtrans) were analyzed. Among 27 eligible patients, HT occurred in 7 patients (25.92%). Patients with HT had significantly higher rCBF value (1.56 ± 0.16 vs. 1.16 ± 0.16), Ktrans, (0.08 ± 0.03 min vs. 0.03 ± 0.01 min) and rKtrans (3.02 ± 0.89 vs. 1.89 ± 0.56). The ASL imaging sequence had a high consistency with the DCE sequence and Xper CT with a high weighted Kappa coefficient of 0.91 for the DCE sequence and 0.70 for the Xper CT imaging. The DCE sequence was also highly consistent with the Xper CT in imaging classification with a high weighted Kappa coefficient of 0.78. The rCBF value in the 21 patients with the subcortical and basal ganglia infarction was significantly lower than that in the other 6 patients with the cortical infarction (1.222 ± 0.221 vs. 1.413 ± 0.259, t = 1.795, P = 0.004). The MRI ASL sequence has an important role in evaluating the blood-brain barrier permeability and the risk of hemorrhagic transformation of anterior circulation SIS following endovascular recanalization.


Physiological responses during simulated competition.
Laboratory studies with competitive athletes often use graded exercise protocols to elicit physiologic responses. This pattern of power output is different than ordinarily employed by athletes during competition. To understand the physiologic responses during competition, we studied 24 athletes (speed skaters, cyclists, triathletes) during simulated competition, a 5-km time trial on a racing bicycle attached to a windload simulator, and during cycle ergometer graded exercise testing (N = 8). During the time trial the velocity pattern was similar to real world competitions, and the subjects indicated that the time trial was perceptually similar to competition. Physiologic responses were of significantly greater magnitude vs graded exercise (VO2max: 3.46 +/- 0.73 vs 3.27 +/- 0.79 l.min-1; VEmax: 138 +/- 27 vs 119 +/- 22 l.min-1; HRmax 184 +/- 11 vs 175 +/- 11 beats x min-1; HLa 14.8 +/- 3.7 vs 11.9 +/- 2.1 mM). All physiologic measures increased steadily throughout the time trial (km 0, 1, 2, 3, 4, and 5: VO2 = 1.03, 2.95, 3.42, 3.69, 3.82, and 3.92 l.min-1; HR = 93, 175, 181, 185, 189, and 194 beats.min-1; VE = 31, 99, 120, 129, 145, and 156 l.min-1; HLa = 2.9, 5.6, 7.2, 9.2, 10.6, and 13.5 mM). In six subjects (speed skaters), the peak values observed during time trial for HR (188 +/- 6 vs 191 +/- 5 beats.min-1) and HLa (16.4 +/- 3.1 vs 17.0 +/- 4.2 mM) were not significantly different than observed during real world competition.(ABSTRACT TRUNCATED AT 250 WORDS)


Impulsive control of stochastic systems with applications in chaos control, chaos synchronization, and neural networks.
Real systems are often subject to both noise perturbations and impulsive effects. In this paper, we study the stability and stabilization of systems with both noise perturbations and impulsive effects. In other words, we generalize the impulsive control theory from the deterministic case to the stochastic case. The method is based on extending the comparison method to the stochastic case. The method presented in this paper is general and easy to apply. Theoretical results on both stability in the pth mean and stability with disturbance attenuation are derived. To show the effectiveness of the basic theory, we apply it to the impulsive control and synchronization of chaotic systems with noise perturbations, and to the stability of impulsive stochastic neural networks. Several numerical examples are also presented to verify the theoretical results.


An efficient synthesis of epoxydiynes and a key fragment of neocarzinostatin chromophore.
[reaction: see text] A key structural feature of the Neocarzinostatin chromophore is a reactive epoxydiyne. We present here a new method for the preparation of epoxydiynes by the addition of an allenyl zinc bromide to a propargylic ketone.


Contact thermography in idiopathic trigeminal neuralgia and other facial pains.
Contact thermography is a useful tool in the differential diagnosis of facial pain and can be used to differentiate idiopathic trigeminal neuralgia from atypical facial pain and anaesthesia dolorosa. The increase in sympathetic activity found in idiopathic trigeminal neuralgia has not previously been reported. The basis for this finding is discussed.


Quantitative flow ratio-guided versus angiography-guided operation for valve disease accompanying coronary heart disease.
Valve replacement combined with coronary artery bypass graft (CABG) operation (VR + CABG) is usually associated with higher mortality and complication rates. Currently, angiography remains the most commonly used approach to guide CABG. The aim of this study is to investigate whether a quantitative flow ratio (QFR)-guided strategy can improve the clinical outcomes of VR + CABG. Patients (n = 536) treated by VR + CABG between January 2018 and December 2021 were retrospectively assessed. In 116 patients, all lesions were revascularized entirely based on QFR (the QFR-guided group), whereas in 420 patients, all lesions were revascularized entirely based on angiography (the angiography-guided group). To minimize selection bias between the 2 groups, propensity score matching was performed at a ratio of 1:2. The primary endpoint of the study was the rate of major adverse cardiac and cerebrovascular events (MACCE) at 1-year, which was defined as a composite of cardiac mortality, myocardial infarction (MI), any repeat revascularization, and stroke. No statistically significant differences were observed in the baseline clinical characteristics between the QFR-guided and angiography-guided groups after propensity score matching. The mean age of all patients was 66.2 years [standard deviation (SD) = 8.3], 370 (69%) were men, the mean body-mass index of the population was 24.8 kg/m2 (SD = 4.5), 129 (24%) had diabetes, and 229 (43%) had angina symptoms. When compared with the angiography-guided group, the QFR-guided group had a significantly shorter operative time (323 ± 60 min vs. 343 ± 71 min, P = 0.010), extra corporal circulation time (137 ± 38 min vs. 155 ± 62 min, P = 0.004), clamp time (73 ± 19 min vs. 81 ± 18 min, P < 0.001), and less intraoperative bleeding volume (640 ± 148 ml vs. 682 ± 166 ml, P = 0.022). Compared with the angiography-guided group, the 1-year MACCE was significantly lower in the QFR-guided group (6.9% vs. 14.7%, P = 0.036, hazard ratio = 0.455, 95% confidence interval: 0.211-0.982). Our results raise the hypothesis that among patients who undergo VR + CABG, QFR-guided strategy is associated with optimized surgical procedure and a superior clinical outcome, as evidenced by a lower rate of MACCE at 1-year compared with conventional angiography-guided strategy.


Stages: sub-Fourier dynamic shim updating using nonlinear magnetic field phase preparation.
Heterogeneity of the static magnetic field in magnetic resonance imaging may cause image artifacts and degradation in image quality. The field heterogeneity can be reduced by dynamically adjusting shim fields or dynamic shim updating, in which magnetic field homogeneity is optimized for each tomographic slice to improve image quality. A limitation of this approach is that a new magnetic field can be applied only once for each slice, otherwise image quality would improve somewhere to its detriment elsewhere in the slice. The motivation of this work is to overcome this limitation and develop a technique using nonlinear magnetic fields to dynamically shim the static magnetic field within a single Fourier-encoded volume or slice, called sub-Fourier dynamic shim updating. However, the nonlinear magnetic fields are not used as shim fields; instead, they impart a strong spatial dependence to the acquired MR signal by nonlinear phase preparation, which may be exploited to locally improve magnetic field homogeneity during acquisition. A theoretical description of the method is detailed, simulations and a proof-of-principle experiment are performed using a magnet coil with a known field geometry. The method is shown to remove artifacts associated with magnetic field homogeneity in balanced steady-state free-precession pulse sequences. We anticipate that this method will be useful to improve the quality of magnetic resonance images by removing deleterious artifacts associated with a heterogeneous static magnetic field.


N-Heterocyclic carbene-catalyzed [4 + 2] cyclization of 2-bromo-2-enal with 3-alkylenyloxindoles: efficient assembly of spirocarbocyclic oxindole.
A NHC-catalyzed [4 + 2] cyclization of 2-bromo-2-enal bearing γ-H with 3-alkylenyloxindoles under mild reaction conditions gives spirocarbocyclic oxindoles containing one quaternary carbon in moderate to good yields with high diastereoselectivities. The easy availability of the starting materials, the concise assembly and the potential utilization value of the products make this strategy attractive in molecular biology and pharmacy.


Asymmetric Synthesis of the Aromatic Fragment of Sespendole.
Sespendole is an indole sesquiterpene alkaloid bearing two isoprenyl groups, one of which is highly oxidized. Herein, we disclose an eight-step synthesis of the aromatic fragment of sespendole in an optically pure form, starting from 4-bromo-2-fluoronitrobenzene. The key steps were a Claisen rearrangement at room temperature for introduction of the prenyl group and a coupling between the dianion generated from prenylated bromo-N-tosylanilide and a chiral epoxy aldehyde.


Access to electron-rich arene-fused hexahydroquinolizinones through a gold-catalysis-initiated cascade process.
Golden Cascade: With a tethered, electron-rich arene as the internal nucleophile, a gold-catalyzed amide cyclization to an alkyne initiates a cascade process that ends with a Ferrier rearrangement. Electron-rich arene-bearing hexahydroquinolizin-2-ones are formed in good yields and can be converted into indole alkaloids in only a few steps.


RNA editing in the Wilms' tumor susceptibility gene, WT1.
Rat kidney WT1 cDNAs contain either a thymidine or a cytosine residue at position 839. Genomic WT1 DNA contains only T839. To explain these results, we propose the WT1 transcript undergoes RNA editing in which U839 is converted to C, resulting in the replacement of leucine 280 in WT1 by proline. RNA editing at the same nucleotide was observed in WT1 cDNAs from human testis. In functional assays, the WT1-leucine280 polypeptide repressed the EGR-1 promoter in in vitro assays approximately 30% more efficiently than WT1-proline. Edited WT1-C839 mRNA was barely detectable in neonatal kidney, whereas adult rat kidneys contained both U839 and C839-WT1 mRNA, suggesting a role for the two protein isoforms in growth and differentiation.


asymptoticMK: A Web-Based Tool for the Asymptotic McDonald-Kreitman Test.
The McDonald-Kreitman (MK) test is a widely used method for quantifying the role of positive selection in molecular evolution. One key shortcoming of this test lies in its sensitivity to the presence of slightly deleterious mutations, which can severely bias its estimates. An asymptotic version of the MK test was recently introduced that addresses this problem by evaluating polymorphism levels for different mutation frequencies separately, and then extrapolating a function fitted to that data. Here, we present asymptoticMK, a web-based implementation of this asymptotic MK test. Our web service provides a simple R-based interface into which the user can upload the required data (polymorphism and divergence data for the genomic test region and a neutrally evolving reference region). The web service then analyzes the data and provides plots of the test results. This service is free to use, open-source, and available at http://benhaller.com/messerlab/asymptoticMK.html We provide results from simulations to illustrate the performance and robustness of the asymptoticMK test under a wide range of model parameters.


Understanding the native Californian diet: Identification of condensed and hydrolyzable tannins in tanoak acorns (Lithocarpus densiflorus).
The tanoak (Lithocarpus densiflorus) acorn was a staple food in the Native American diet and is still used in traditional dishes. Acorns from the genus Quercus have been shown to contain a large range of hydrolyzable tannins. However, neither hydrolyzable nor condensed tannins have been characterized in tanoak acorns. The aim of this study was to identify the full range of hydrolyzable and condensed tannins in extracts of tanoak acorns using liquid chromatography/electrospray ionization-mass spectrometry/mass spectrometry. Condensed tannins were identified as B type oligomers of (epi)-catechin (procyanidins) with a degree of polymerization up to six. Oligomers up to and including tetramers were identified by UV spectra and MS detection whereas pentamers and hexamers were detected only by MS. The total concentration of condensed tannins was 464 mg/100 g acorn pericarp. The concentration of propocyanidin monomers, dimers, trimers, and tetramers in acorn pericarp (mg/100 g acorn pericarp) were 95 +/- 10.9, 148 +/- 35.0, 90 +/- 17.9, and 131 +/- 1.9, respectively. No procyanidins were found in the acorn cotyledon tissue. A total of 22 hydrolyzable tannins were identified in methanolic extracts of acorn cotyledon tissue. Gallic acid derivatives predominated and included galloylated esters of glucose, hexahydrodiphenoyl esters of glucose, and methylated gallates. Galloylated esters of glucose were present as isomers of galloyl glucose, digalloyl glucose, and trigalloyl glucose. Mass spectral fragmentation patterns indicate the presence of one gallic acid-galloyl glucose isomer and two gallic acid-digalloyl-glucose isomers. No isomers of tetragalloyl glucose and pentagalloyl glucose were identified. Ellagic acid and ellagic acid pentoside were also identified.


Association of Progression of Carotid Artery Wall Volume and Recurrent Transient Ischemic Attack or Stroke: A Magnetic Resonance Imaging Study.
This study aimed to investigate the association between carotid plaque progression and subsequent recurrent events using magnetic resonance imaging. Sixty-three symptomatic patients with ipsilateral carotid atherosclerotic stenosis (30%-69% stenosis) determined by ultrasound underwent first and second carotid artery magnetic resonance imaging for carotid artery at baseline and ≥6 months after the first scan, respectively. All the patients had clinical follow-up after the second magnetic resonance scan for ≤5 years until the onset of recurrent transient ischemic attack or stroke. Presence/absence of carotid plaque compositional features, particularly intraplaque hemorrhage and fibrous cap rupture was identified. The annual progression of carotid wall volume between 2 magnetic resonance scans was measured. Univariate and multivariate Cox regression was used to calculate the hazard ratio and corresponding 95% confidence interval of carotid plaque features in discriminating recurrent events. Receiver-operating-characteristic-curve analysis was conducted to determine the area-under-the-curve of carotid plaque features in predicting recurrent events. Sixty-three patients (mean age: 66.5±10.0 years old; 54 males) were eligible for final statistics analysis. During a mean follow-up duration of 55.1±13.6 months, 14.3% of patients (n=9) experienced ipsilateral recurrent transient ischemic attack/stroke. The annual progression of carotid wall volume was significantly associated with recurrent events before (hazard ratio, 1.14 per 10 mm3; 95% confidence interval, 1.02-1.27; P=0.019) and after (hazard ratio, 1.19 per 10 mm3; 95% confidence interval, 1.03-1.37; P=0.022) adjusted for confounding factors. In discriminating the recurrence of transient ischemia attack/stroke, receiver-operator curve analysis indicated that combined with annual progression of wall volume, there was a significant incremental improvement in the area-under-the-curve of intraplaque hemorrhage (area-under-the-curve: 0.69-0.81) and fibrous cap rupture (area-under-the-curve: 0.73-0.84). The annual progression of carotid wall volume is independently associated with recurrent ischemic cerebrovascular events, and this measurement has added value for intraplaque hemorrhage and fibrous cap rupture in predicting future events.


[The early results of the minimally invasive direct coronary artery bypass (MIDCAB)].
The clinical experiences of 29 consecutive MIDCAB procedures performed at our institution between October, 1996, and October, 1997, were analyzed. Preoperative patient's characteristics were as follows; LAD single vessel disease: 25, double vessel disease: 1, triple vessel disease: 1, RC single vessel disease: 1, LMT lesion: 1, concomitant procedures: 2 (ASO: 1, AAA: 1). LITA harvesting was performed using the video-assisted thoracoscopy in initial 4 patients, and in last 10 patients we used the specially designed retractor THORALIFT (Autosuture Co., Ltd.) for harvesting LITA by direct vision. LAD was stabilized mechanically using the stabilizer when we performed the anastomosis in last 10 patients to enhance the quality of the anastomosis. The patency rate was 96%, but there were two patients (6%) who had the stenosis of the anastomosis site. Coronary artery occlusion time was 13.2 minutes in the mean. We also studied the hemodynamics of blood flow in LITA grafts with the aid of 7.5 MHz transthoracic duplex imaging in these MIDCAB patients and compared with the LITA grafts in conventional CABG performed in same periods. There were no statistical differences between the two groups about the graft flow and velocity. We conclude that MIDCAB would be an alternative procedure that can be performed with low risk and acceptable early results in selected patients.


Pharmacist-manned drug information centers in the United States.
Pharmacist-manned drug information centers (DICs) were surveyed in early 1976 to obtain current information concerning the status, availability and scope of their services. Eight-six institutions believed to be active in disseminating drug information were surveyed; 74 responses were usable. Descriptive information on the respondents is tabulated. It appears that DICs make constructive contributions to enhancing drug therapy. Respondents at 63 of the centers believed, and 31 DICs said they have demonstrated, that physicians who used their services often changed their drug therapy based on answers supplied by the centers.


Application of a 3D Bioprinted Hepatocellular Carcinoma Cell Model in Antitumor Drug Research.
The existing in vitro models for antitumor drug screening have great limitations. Many compounds that inhibit 2D cultured cells do not exhibit the same pharmacological effects in vivo, thereby wasting human and material resources as well as time during drug development. Therefore, developing new models is critical. The 3D bioprinting technology has greater advantages in constructing human tissue compared with sandwich culture and organoid construction. Here, we used 3D bioprinting technology to construct a 3D model with HepG2 cells (3DP-HepG2). The biological activities of the model were evaluated by immunofluorescence, real-time quantitative PCR, and transcriptome sequencing. Compared with the traditional 2D cultured tumor cells (2D-HepG2), 3DP-HepG2 showed significantly improved expression of tumor-related genes, including ALB, AFP, CD133, IL-8, EpCAM, CD24, and β-TGF genes. Transcriptome sequencing analysis revealed large differences in gene expression between 3DP-HepG2 and 2D-HepG2, especially genes related to hepatocyte function and tumor. We also compared the effects of antitumor drugs in 3DP-HepG2 and 2D-HepG2, and found that the large differences in drug resistance genes between the models may cause differences in the drugs' pharmacodynamics.


Time Elapsed from onset of symptoms to antituberculosis treatment in children with central nervous system tuberculosis in a tertiary hospital in South India: A mixed-methods pilot study.
A pilot study with a mixed-methods design was conducted to estimate the time for tuberculosis (TB) treatment initiation and associated factors among children with central nervous system-TB (CNS-TB). A total of 38 children were enrolled for the quantitative component, and 20 in-depth interviews were conducted. The median duration (interquartile range) from onset of symptoms to treatment initiation was 23 (11, 55) days. About 44% and 31% of the children presented with Stage II and Stage III of CNS-TB, respectively. The major reasons for delay were symptoms not taken seriously (50%) and too many referrals (21%). About 89% of the families went into catastrophic health expenditure due to the disease. The treatment delay may be due to both patient delay and health system delay. Tailoring approaches to target the pediatric population could further improve early detection and treatment initiation of CNS-TB.


Early detection: the impact of genomics.
The field of genomics has shifted our view on disease development by providing insights in the molecular and functional processes encoded in the genome. In the case of cancer, many alterations in the DNA accumulate that enable tumor growth or even metastatic dissemination. Identification of molecular signatures that define different stages of progression towards cancer can enable early tumor detection. In this review, the impact of genomics will be addressed using early detection of colorectal cancer (CRC) as an example. Increased understanding of the adenoma-to-carcinoma progression has led to the discovery of several diagnostic biomarkers. This combined with technical advancements, has facilitated the development of molecular tests for non-invasive early CRC detection in stool and blood samples. Even though several tests have already made it to clinical practice, sensitivity and specificity for the detection of precancerous lesions still need improvement. Besides the diagnostic qualities, also the accuracy of the intermediate endpoint is an important issue on how the effectiveness of a novel test is perceived. Here, progression biomarkers may provide a more precise measure than the currently used morphologically based features. Similar developments in biomarker use for early detection have taken place in other cancer types.


Sibling Influences on Risky Behaviors from Adolescence to Young Adulthood: Vertical Socialization or Bidirectional Effects?
This study built on research on sibling influences to assess potential bidirectional effects of older and younger siblings' risky behaviors on one another's risky behaviors; our longitudinal design allowed us to test these effects when siblings were at about the same chronological age, at different points in time. We also tested whether the strength and/or direction of effects of siblings' risky behaviors changed from middle adolescence to young adulthood. Reports of risky behaviors (i.e., deviant behaviors and excessive alcohol use) were provided by firstborn and secondborn siblings from up to 201 families on five occasions spanning 10 years. In general, accounting for known covariates, multilevel models revealed bidirectional sibling effects and some evidence that secondborns' risky behaviors were stronger and more consistent predictors of firstborns' behaviors than the reverse. Sibling influence generally declined with age and sibling effects were not moderated by gender constellation. Findings indicate that both older and younger siblings are important socializers of risk behaviors across adolescence and continue to shape each other's alcohol use into early adulthood.


Curative resection of bladder cancer with pancreas head metastasis.
Bladder cancer is the 9th most frequent cancer worldwide. Its incidence is increasing. The pancreas is an infrequent site of metastasis in relation to any type of malignancy. In this study, we report our experience with a patient who has undergone a pancreaticoduodenectomy for metastatic bladder cancer. A 61-year-old male was admitted with jaundice and pancreas head mass. He underwent robot assisted-cystectomy and ileal conduit for bladder cancer 7 months ago. Initial diagnosis under the imaging study was a resectable pancreas head cancer. However, we did not rule-out a metastatic bladder cancer. He underwent a classic pancreaticoduodenectomy. Based on histologic findings and immunohistochemistry results, a pancreas tumor with 4.9-cm sized metastatic urothelial carcinoma was diagnosed. He experienced no complication. He was discharged 11 days after the surgery. Four cycles of gemcitabine and cisplatin were administered. He remained recurrence-free of tumors for 16 months. Although the benefit of pancreatectomy for patient survival has been reported for metastases from renal cell carcinoma, it is unknown for bladder cancer because of no report. We believe that curative resection for metastasis to pancreas of urothelial carcinoma might be helpful for its management.


Estrogen-induced cell multiplication: direct or indirect effect on rat uterine cells?
It has been previously demonstrated that the exposure of the liver to estradiol-17 beta (E2) is sufficient to produce cell multiplication in the oviduct of the quail. In this report we determine whether this can also be observed in the rat. Ovariectomized, primed, adult rats were infused over a 3-h period with 2 micrograms E2/kg BW via the jugular vein (systemically). Mitotic figures arrested by colchicine appeared in the uterine luminal epithelium 16-20 h later and remained at maximal levels for the subsequent 3 intervals of 4 h. The minimum dose required to induce a mitotic response was 1.25 micrograms E2/kg BW. There was no increase in response with larger doses. Plasma E2 levels increased linearly with the dose infused systemically. Under the same conditions, E2 infused via the spleen produced mitoses with a similar time course and dose response. However, the amplitude of the response and the plasma E2 levels were significantly depressed. To circumvent problems involved with the interpretation of the results obtained by splenic infusions, we infused 2 micrograms E2/kg BW via the superior mesenteric vein (hepatoportal system). There was no mitotic response and the plasma E2 levels were not elevated above controls. We conclude that a strictly liver mediated, indirect mechanism for the regulation of cell multiplication proposed for quail, is not operative in the rat. In an initial attempt to explain this difference between species, we injected 5 micrograms E2/kg BW sc into hypophysectomized rats. Hypophysectomy had no effect upon the proliferation of the uterine luminal epithelial cells.


Factors influencing diagnosis and treatment initiation for multidrug-resistant/rifampicin-resistant tuberculosis in six sub-Saharan African countries: a mixed-methods systematic review.
Drug-resistant tuberculosis burdens fragile health systems in sub-Saharan Africa (SSA), complicated by high prevalence of HIV. Several African countries reported large gaps between estimated incidence and diagnosed or treated cases. Our review aimed to identify barriers and facilitators influencing diagnosis and treatment for drug-resistant tuberculosis (DR-TB) in SSA, which is necessary to develop effective strategies to find the missing incident cases and improve quality of care. Using an integrative design, we reviewed and narratively synthesised qualitative, quantitative and mixed-methods studies from nine electronic databases: Medline, Global Health, CINAHL, EMBASE, Scopus, Web of Science, International Journal of Tuberculosis and Lung Disease, PubMed and Google Scholar (January 2006 to June 2019). Of 3181 original studies identified, 55 full texts were screened, and 29 retained. The studies included were from 6 countries, mostly South Africa. Barriers and facilitators to DR-TB care were identified at the health system and patient levels. Predominant health system barriers were laboratory operational issues, provider knowledge and attitudes and information management. Facilitators included GeneXpert MTB/RIF (Xpert) diagnosis and decentralisation of services. At the patient level, predominant barriers were patients being lost to follow-up or dying due to lengthy diagnostic and treatment delays, negative public sector care perceptions, family, work or school commitments and using private sector care. Some patient-level facilitators were HIV positivity and having more symptoms. Case detection and treatment for DR -TB in SSA currently relies on individual patients presenting voluntarily to the hospital for care. Specific interventions targeting identified barriers may improve rates and timeliness of detection and treatment.


Do the New FDA Guidance Documents Help Improving Performance of Blood Glucose Monitoring Systems Compared With ISO 15197?
Recently, the Food and Drug Administration (FDA) published guidance documents for point-of-care testing (POCT) and over-the-counter (OTC) blood glucose monitoring systems (BGMS). These are expected to improve weaknesses of the already established ISO 15197:2013 standard accuracy evaluation for OTC BGMS; however, the proposed criteria and procedures rather raise new questions. As an example, the OTC guidance stipulates tighter accuracy criteria in the low glycemic range than the POCT guidance for no obvious reason. Furthermore, a clear definition of requirements for the reference method is missing under consideration of the strict accuracy criteria. External surveillance of BGMS after introduction to the market is an issue that is addressed neither in the FDA documents, nor in ISO 15197, but in the Clinical and Laboratory Standards Institute (CLSI) guideline POCT12-A3.


Insulin-like growth factor-1, a component of serum that enables porcine cumulus cells to expand in response to follicle-stimulating hormone in vitro.
The present study was aimed at determining whether insulin-like growth factor-1 (IGF-1) is a component of fetal bovine serum (FBS) that enables porcine cumulus cells to expand in response to FSH in vitro. Cumulus-oocyte complexes (COC) obtained from 4- to 6-mm follicles of prepubertal gilts were cultured at 39 degrees C for 24 h in media that contained human recombinant IGF-1 (50 ng/ml), FBS (15% v:v), or their combination, with or without FSH (1.5 microg/ml), and cumulus expansion was scored microscopically. Expansion was FSH dependent and was observed only when IGF-1, FBS, or both were present. The proportion of FSH-stimulated COC exhibiting full expansion in response to IGF-1 alone did not differ significantly (p > 0.05) from the proportion in those cultured with FBS or IGF-1+FBS (79 +/- 2.8% vs. 84 +/- 2.2% or 76 +/- 6.2%, respectively). In a concentration-response study, FSH-stimulated expansion was observed in a significant proportion of COC (32 +/- 2.8% vs. 0% control) at 1 ng/ml IGF-1, with the proportions increasing dose-dependently to maximal values between 10 and 75 ng/ml IGF-1, and decreasing at higher IGF-1 concentrations. Exposure of COC to an IGF-1 receptor (IGF-1R)-neutralizing antibody (Ab) for 90 min before addition of FSH and FBS dose-dependently inhibited cumulus expansion, with maximal inhibition at 10 microg/ml (1 +/- 1.0% vs. 68 +/- 1.1% control). In the absence of FBS or IGF-1, some COC had a tendency toward slight expansion when cultured with FSH, and the Ab completely inhibited that effect, suggesting that this may be due to endogenous IGF-1 production by the COC. The Ab effect was reversible and was eliminated by washing twice with fresh medium followed by culture for an additional 24 h in the presence of FSH and FBS. Expression of IGF-1R mRNA in the isolated oocyte and cumulus cells was determined by reverse tramscriptase polymerase chain reaction using sequence-specific primers. The IGF-1R message was detected in both the oocyte and cumulus cells. Collectively, these observations suggest that IGF-1 is a component of serum that enables cumulus cells to expand in response to FSH in vitro, and that the effect is receptor mediated. Since IGF-1 is present in the follicle in vivo, it may have a physiological role during gonadotropin-induced cumulus expansion.


Hemifacial spasm in a patient with Marfan syndrome and Chiari I malformation. Case report.
Marfan syndrome, hemifacial spasm, and Chiari malformation are all relatively rare and seemingly separate entities. Marfan syndrome is caused by a defect in the gene that encodes fibrillin and leads to weakness of the artery wall. Hemifacial spasm results from compression of the facial nerve by an abnormal artery. Chiari malformation is characterized by a small posterior fossa. The authors report the case of a patient with Marfan syndrome who presented with hemifacial spasm and was also found to have a Chiari malformation Type I. The patient's Chiari malformation and hemifacial spasm were successfully treated by performing suboccipital and microvascular decompression surgeries, respectively. The pathophysiological characteristics of Marfan syndrome, hemifacial spasm, and Chiari malformation are discussed, and the authors propose a link between these conditions in this patient. The authors hypothesize that the patient's Marfan syndrome contributed to the abnormal shape of his vertebral artery and that, given the lack of space in his crowded posterior fossa due to the Chiari malformation, the artery caused compression of his facial nerve, resulting in hemifacial spasm.


Mitochondrial targeting of the human peptide methionine sulfoxide reductase (MSRA), an enzyme involved in the repair of oxidized proteins.
Peptide methionine sulfoxide reductase (MSRA) catalyzes the reduction of methionine sulfoxide to methionine. This widely expressed enzyme constitutes an important repair mechanism for oxidatively damaged proteins, which accumulate during the manifestation of certain degenerative diseases and aging processes. In addition, it is discussed to be involved in regulatory processes. Here we address the question of how the enzyme's diverse functions are reflected in its subcellular localization. Using fusions of the human version of MSRA with the enhanced green fluorescence protein expressed in various mammalian cell lines, we show a distinct localization at mitochondria. The N-terminal 23 amino acid residues contain the signal for this mitochondrial targeting. Activity tests showed that they are not required for enzyme function. Mitochondrial localization of native MSRA in mouse and rat liver slices was verified with an MSRA-specific antibody by using immunohistochemical methods. The protein was located in the mitochondrial matrix, as demonstrated by using pre-embedding immunostaining and electron microscopy. Mitochondria are the major source of reactive oxygen species (ROS). Therefore, MSRA has to be considered an important means for the general reduction of ROS release from mitochondria.


Assessment of microbial diversity in biofilms recovered from endotracheal tubes using culture dependent and independent approaches.
Ventilator-associated pneumonia (VAP) is a common nosocomial infection in mechanically ventilated patients. Biofilm formation is one of the mechanisms through which the endotracheal tube (ET) facilitates bacterial contamination of the lower airways. In the present study, we analyzed the composition of the ET biofilm flora by means of culture dependent and culture independent (16 S rRNA gene clone libraries and pyrosequencing) approaches. Overall, the microbial diversity was high and members of different phylogenetic lineages were detected (Actinobacteria, beta-Proteobacteria, Candida spp., Clostridia, epsilon-Proteobacteria, Firmicutes, Fusobacteria and gamma-Proteobacteria). Culture dependent analysis, based on the use of selective growth media and conventional microbiological tests, resulted in the identification of typical aerobic nosocomial pathogens which are known to play a role in the development of VAP, e.g. Staphylococcus aureus and Pseudomonas aeruginosa. Other opportunistic pathogens were also identified, including Staphylococcus epidermidis and Kocuria varians. In general, there was little correlation between the results obtained by sequencing 16 S rRNA gene clone libraries and by cultivation. Pyrosequencing of PCR amplified 16 S rRNA genes of four selected samples resulted in the identification of a much wider variety of bacteria. The results from the pyrosequencing analysis suggest that these four samples were dominated by members of the normal oral flora such as Prevotella spp., Peptostreptococcus spp. and lactic acid bacteria. A combination of methods is recommended to obtain a complete picture of the microbial diversity of the ET biofilm.


MAWRID: A Model of Arabic Word Reading in Development.
This article offers a model of Arabic word reading according to which three conspicuous features of the Arabic language and orthography shape the development of word reading in this language: (a) vowelization/vocalization, or the use of diacritical marks to represent short vowels and other features of articulation; (b) morphological structure, namely, the predominance and transparency of derivational morphological structure in the linguistic and orthographic representation of the Arabic word; and (c) diglossia, specifically, the lexical and lexico-phonological distance between the spoken and the standard forms of Arabic words. It is argued that the triangulation of these features governs the acquisition and deployment of reading mechanisms across development. Moreover, the difficulties that readers encounter in their journey from beginning to skilled reading may be better understood if evaluated within these language-specific features of Arabic language and orthography.


Linking extractables and leachables in container/closure applications.
Establishing a link between extractables and leachables may be necessary to understand, interpret, assess, quantify, or control the interaction between a drug product and its container/closure system. This paper considers the various factors that affect the rigor with which such a linkage is established and justified. Such an assessment considers the origin and/or genesis of the leachable or extractable, enumerates situations in which extractables/leachables linkages are useful, ties such situations to the drug product's lifecycle, defines a hierarchy of linkages based on the rigor with which the linkages are established and justified, and establishes guidelines for how to determine what kind of linkage is appropriate for certain circumstances and situations. Additionally, this paper gives several examples of linkages relevant to flexible plastic drug product containers.


Wrestling with the future: should we test children for adult-onset genetic conditions?
Genetics professionals have been reluctant to test children for adult-onset conditions because they believe this would create psychosocial harm to children not counterbalanced by significant benefits. An additional concern they express is that such testing would violate the autonomy of these children as adults. Yet weighing the harms and benefits of such testing results in a draw, with no substantial harms proven. Moreover, such testing can enhance, rather than violate the adult autonomy of these children. In deciding whether to proceed with predictive testing of children, parents, mature children, and health care professionals should consider a complex of factors relevant to the particular child. The importance of these factors will vary depending on the condition at issue, the age and stage of development of the child, family dynamics, and the concerns, values, and objectives of the parents and mature child. The final decision whether to test a child for an adult-onset condition should rest with the parents and the mature child.


Gonadotropin-releasing hormone does not directly stimulate luteinizing hormone biosynthesis in male African catfish.
Besides gonadotropin release, GnRH stimulates gonadotropin subunit gene transcription and translation in gonadotrophs. In the African catfish, Clarias gariepinus, chicken GnRH-II (cGnRH-II: [His5,Trp7,Tyr8]-GnRH) and catfish GnRH (cfGnRH: [His5,Asn8]-GnRH) are two endogenous forms of GnRH. Studying their effects on LH subunit steady-state mRNA levels, LH de novo synthesis, and LH release in primary pituitary cell cultures of adult males, we found that cGnRH-II hardly influenced the steady-state levels of LH subunit mRNAs or LH de novo synthesis, although it stimulated LH release. Although cfGnRH stimulated LH secretion as well, high concentrations-although apparently still within the physiologic range-reduced LH transcript levels and de novo synthesis in primary pituitary cell cultures. In vivo experiments demonstrated a biphasic response of LH subunit transcript levels after a single GnRH injection: a decrease after 2 h was followed by an increase at 8 h. When the testes were removed before GnRH treatment, however, LH transcript levels remained depressed at 8 h after GnRH injection, indicating that the secondary increase in LH transcript levels depends on the presence of the testes. We conclude that the up-regulation of LH production subsequent to GnRH stimulation in adult male African catfish is mediated by factors originating from the testis. Previous work suggests that aromatizable androgens may play an important role in this context. Under the present experimental conditions, however, GnRHs had no, or an inhibitory, direct effect on LH production in catfish gonadotrophs.


Expression-profiling of apoptosis induced by ablation of the long ncRNA TRPM2-AS in prostate cancer cell.
We recently identified the long non-coding RNA (ncRNA) TRPM2-AS as a key regulator of survival in prostate cancer [1]. This essential role, coupled to the TRPM2-AS low-expression levels in healthy tissues, makes this ncRNA a suitable therapeutic target for further clinical studies. To get insights into the survival mechanism controlled by this molecule, we ablated its expression in prostate cancer cells and performed a genome-wide analysis of the transcripts differentially regulated in dying cells. Here, we describe in detail the experimental system, methods and quality control for the generation of the microarray data associated with our recent publication [1]. The data are related to [1]. Data have been deposited to the Gene Expression Omnibus (GEO) database repository with the dataset identifier GSE40687.


INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR THE MANAGEMENT OF NEOVASCULARIZATION IN RETINOBLASTOMA AFTER INTRAVENOUS AND/OR INTRAARTERIAL CHEMOTHERAPY: Long-Term Outcomes in a Series of 35 Eyes.
To report the use of anti-vascular endothelial growth factor in the management of retinoblastoma. Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti-vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy. Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti-vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1-7.6). Intravitreal anti-vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment.


Antimicrobial Susceptibility and Virulence Surveillance of Campylobacter spp. Isolated From Patients in Two Tertiary Medical Centers in Taiwan.
Campylobacter spp. may cause fever, vomiting, and diarrhea in humans. Antibiotic treatment is suggested for patients with severe campylobacteriosis. However, the interpretative criteria for antibiotic susceptibility are inconsistent between Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing guidelines. The aim of the study is to investigate the antibiotic susceptibility and prevalence of cytolethal distending toxin genes and to evaluate antibiotic susceptibility testing methods in the clinical laboratories of two tertiary medical centers in Taiwan. In total, 236 bacterial isolates were collected between 2001 and 2014. The disk diffusion and E-test methods were used to evaluate the antibiotic susceptibility, and broth dilution results were used as a reference. The virulence genes cdtA, cdtB, cdtC, and ceuE were detected through polymerase chain reaction. The antimicrobial sensitivity rates for erythromycin, ciprofloxacin, and tetracycline using the broth dilution assay were 80.4, 5.4, and 3.4%, respectively. No significant differences were observed in the antibiotic susceptibility of the isolates obtained from southern and northern Taiwan. However, some differences were observed between species. The susceptibility test for erythromycin (disk diffusion) showed that the isolates with small inhibition zone diameters were all resistant, and five isolates (4.0%) with large IZDs were non-sensitive. The error rate of the disk diffusion method according to the CLSI M45-A3 guideline was 5.4% (8/148). The incompatibility rates between the E-test and broth dilution methods for erythromycin, ciprofloxacin, and tetracycline were 8.0, 5.3, and 1.3%, respectively. The positive rates of the genes cdtA and cdtC were considerably higher in Campylobacter jejuni than in C. coli. Erythromycin is recommended as the first choice of treatment for campylobacteriosis. The disk diffusion method is suitable for prescreening Campylobacter susceptibility by using the CLSI M45-A2 and EUCAST criteria (low error rate of 3.4%). If antibiotic treatment fails or IZDs are between 6 and 20 mm, minimum inhibitory concentration testing by using the E-test method is highly recommended because the results of the E-test and broth dilution methods exhibit high agreement. The error rate of disk diffusion method using CLSI M45-A3 criteria is only slightly higher than B, which is also a suitable criteria.


Development of U-Net Breast Density Segmentation Method for Fat-Sat MR Images Using Transfer Learning Based on Non-Fat-Sat Model.
To develop a U-net deep learning method for breast tissue segmentation on fat-sat T1-weighted (T1W) MRI using transfer learning (TL) from a model developed for non-fat-sat images. The training dataset (N = 126) was imaged on a 1.5 T MR scanner, and the independent testing dataset (N = 40) was imaged on a 3 T scanner, both using fat-sat T1W pulse sequence. Pre-contrast images acquired in the dynamic-contrast-enhanced (DCE) MRI sequence were used for analysis. All patients had unilateral cancer, and the segmentation was performed using the contralateral normal breast. The ground truth of breast and fibroglandular tissue (FGT) segmentation was generated using a template-based segmentation method with a clustering algorithm. The deep learning segmentation was performed using U-net models trained with and without TL, by using initial values of trainable parameters taken from the previous model for non-fat-sat images. The ground truth of each case was used to evaluate the segmentation performance of the U-net models by calculating the dice similarity coefficient (DSC) and the overall accuracy based on all pixels. Pearson's correlation was used to evaluate the correlation of breast volume and FGT volume between the U-net prediction output and the ground truth. In the training dataset, the evaluation was performed using tenfold cross-validation, and the mean DSC with and without TL was 0.97 vs. 0.95 for breast and 0.86 vs. 0.80 for FGT. When the final model developed with and without TL from the training dataset was applied to the testing dataset, the mean DSC was 0.89 vs. 0.83 for breast and 0.81 vs. 0.81 for FGT, respectively. Application of TL not only improved the DSC, but also decreased the required training case number. Lastly, there was a high correlation (R2 > 0.90) for both the training and testing datasets between the U-net prediction output and ground truth for breast volume and FGT volume. U-net can be applied to perform breast tissue segmentation on fat-sat images, and TL is an efficient strategy to develop a specific model for each different dataset.


Interactions of human replication protein A with oligonucleotides.
Replication protein A (RPA) is a heterotrimeric, single-stranded DNA binding protein that is essential for eukaryotic DNA replication. In order to gain a better understanding of the interactions between RPA and DNA, we have examined the interactions of human RPA with single-stranded oligonucleotides. Our analysis of RPA.DNA complexes demonstrated that RPA binds as a heterotrimer. Stoichiometric binding reactions monitored by fluorescence quenching indicated that the binding site size of human RPA is 30 nucleotides and that between 20-30 nucleotides of DNA directly interact with RPA. The binding of RPA to DNA of different lengths was systematically examined using deoxythymidine-containing oligonucleotides. We found that the binding affinity of RPA for short oligonucleotides was length dependent. The apparent association constant of RPA varied over 200-fold from approximately 7 x 10(7) M-1 for oligo(dT)10 to approximately 1.5 x 10(10) M-1 for oligo(dT)50. Human RPA binds to oligonucleotides with low cooperativity; the cooperativity parameter (omega) for RPA binding was estimated to be approximately 15.


Methionine metabolism and multiple sclerosis.
Methylation reactions are particularly important in the brain and their inhibition can lead to a number of serious pathologies. Multiple sclerosis is one of the most common neurological disorders caused by interaction of genetic and environmental factors, but little is known about its cause or factors that contribute to the disorder. Although multiple sclerosis is primarily regarded as demyelinating disorder, there are no many articles focusing on methionine determination. The aim of this work was to investigate whether serum methionine and its related compounds like homocysteine, cysteine, glutathione and asymmetric dimethylarginine were changed in multiple sclerosis patients. Sulphur-containing compounds were determined by using high-performance liquid chromatography with electrochemical detection in a single run for providing more complex view on methionine metabolism and asymmetric dimetylarginine was measured by a commercial enzyme-linked immunosorbent assay kit. Methionine and glutathione were decreased, but homocysteine, asymmetric dimethylarginine and cysteine were unchanged in patients with multiple sclerosis compared with controls. Methionine and glutathione seem to be potential biomarkers for prognosis of the disease.


Stimulation of thyroidal thiol endopeptidases by thyrotropin.
Rabbit thyroids contain cathepsin D (CD) and several thiol endopeptidases including cathepsin B and three newly described enzymes (cathepsins 180K, 110K, and 45K). The present paper assesses the relative physiological importance of these enzymes in thyroglobulin degradation in rabbits. Thyroidal thiol endopeptidase [thiol thyroglobulin hydrolase (thiol TgH)] activity increased in the absence of changes in CD activity in animals treated with 10 U bovine TSH. Peak enzyme activity occurred 24 h after injection of hormone. After 20 U bovine TSH, thiol endopeptidase activity increased by approximately 100%, whereas CD increased by 50%. The increase in thiol enzyme activity was attributed both to cathepsin B and to the other thiol endopeptidases. The lysosomal acid hydrolases acid phosphatase and dipeptidyl peptidase II were unaffected by TSH at either dose level. Thiol TgH activity, but not CD activity, was decreased in thyroids of rabbits treated with T4 [5 micrograms/(100 g BW X day)] for 1 week. All thyroidal acid hydrolases examined were suppressed in animals receiving T4 for 3 weeks. Thiol TgH activity was localized primarily to a lysosome-enriched fraction of thyroid homogenates. Our results suggest that the thiol proteases probably are the most important endopeptidases in thyroglobulin hydrolysis in vivo and that their activities are influenced by TSH.


Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior.
Three different cell markers were studied in rats to note changes in the immunoreactivity (IR) in the lumbar spinal cord 1 to 84 days following partial sciatic nerve ligation (PSNL). Alteration in average IR were studied for complement receptor C3bi (OX42; microglia), major histocompatibility complex II (OX6; microglia), and glia fibrillary acidic protein (GFAP; astroglia). Thirty-four female rats underwent ligation of approximately 1/2 of the sciatic nerve (PSNL). This injury resulted in the development of mechanical allodynia, which was quantitated by the measurement of foot withdrawal threshold to the application of Von Frey filaments. Ipsilateral increase in IR of OX42 and GFAP was observed to occur within 2 days, maximized by day 14, and did not return to contralateral spinal gray matter IR levels by day 84 (time period of study). Increases in OX42 IR and GFAP IR were observed within the spinal segments innervated by the sciatic nerve. GFAP IR was not expressed in all lumbar segments. OX42 staining with the upper portion of the dorsal horn was found to localize within the areas of deafferentation demonstrated by loss of thiamine monophosphatase activity within the substantia gelatinosa. OX6 IR was only seen in a few cells within the ipsilateral gray matter, indicating that microglia did not become phagocytic. Both GFAP IR and OX42 IR were found to linearly correlate with allodynic behavior with OX42 IR being more statistically significant. Correlation of OX42 IR in only the upper portion of the dorsal horn (not including the neck) resulted in an even a greater level of significance. These findings demonstrate that microglia and astroglia are activated following PSNL and that their increase in IR correlates with the development of allodynic behavior.


Comparison of CT and CMR for detection and quantification of carotid artery calcification: the Rotterdam Study.
Carotid artery atherosclerosis is an important risk factor for stroke. As such, quantitative imaging of carotid artery calcification, as a proxy of atherosclerosis, has become a cornerstone of current stroke research. Yet, population-based data comparing the computed tomography (CT) and cardiovascular magnetic resonance (CMR) for the detection and quantification of calcification remain scarce. A total of 684 participants from the population-based Rotterdam Study underwent both a CT and CMR of the carotid artery bifurcation to quantify the amount of carotid artery calcification (mean interscan interval: 4.9 ± 1.2 years). We investigated the correlation between the amount of calcification measured on CT and CMR using Spearman's correlation coefficient, Bland-Altman plots, and linear regression. In addition, using logistic regression modeling, we assessed the association of CT and CMR based calcification volumes with a history of stroke. We found a strong correlation between CT and CMR based calcification volumes (Spearman's correlation coefficient:0.86, p-value ≤0.01). Bland-Altman analyses showed a good agreement, though CT based calcification volumes were systematically larger. Finally, calcification volume assessed with either imaging modality was associated with a history of stroke with similar effect estimates (odds ratio (OR) per 1-SD increase in calcification volume: 1.52 (95% CI:1.00;2.30) for CT, and 1.47 (95% CI:1.01;2.14) for CMR. CT based and CMR based volumes of carotid artery calcification are highly correlated, but CMR based calcification is systematically smaller than those obtained with CT. Despite this difference, both provide comparable information with regard to a history of stroke.


ViVar: a comprehensive platform for the analysis and visualization of structural genomic variation.
Structural genomic variations play an important role in human disease and phenotypic diversity. With the rise of high-throughput sequencing tools, mate-pair/paired-end/single-read sequencing has become an important technique for the detection and exploration of structural variation. Several analysis tools exist to handle different parts and aspects of such sequencing based structural variation analyses pipelines. A comprehensive analysis platform to handle all steps, from processing the sequencing data, to the discovery and visualization of structural variants, is missing. The ViVar platform is built to handle the discovery of structural variants, from Depth Of Coverage analysis, aberrant read pair clustering to split read analysis. ViVar provides you with powerful visualization options, enables easy reporting of results and better usability and data management. The platform facilitates the processing, analysis and visualization, of structural variation based on massive parallel sequencing data, enabling the rapid identification of disease loci or genes. ViVar allows you to scale your analysis with your work load over multiple (cloud) servers, has user access control to keep your data safe and is easy expandable as analysis techniques advance. URL: https://www.cmgg.be/vivar/


Phylogeny of leafcutter ants in the genus Atta Fabricius (Formicidae: Attini) based on mitochondrial and nuclear DNA sequences.
Leafcutting ants of the genus Atta are the most conspicuous members of the tribe Attini, the fungus-growing ants. Atta species have long attracted the attention of naturalists, and have since become a common model system for the study of complex insect societies as well as for the study of coevolutionary dynamics due to their numerous interactions with fungi and other microbes. Nevertheless, systematics and taxonomy of the 15 species in the genus Atta have proven challenging, due in part to the extreme levels of worker polymorphism these species display, leading to disagreements about the validity of as many as five different subgenera and calling into question the monophyly of the genus. Here, we use DNA sequence information from fragments of three mitochondrial genes (COI, tRNA leucine and COII) and one nuclear gene (EF1-alphaF1), totaling 1070 base pairs, to reconstruct the phylogenetic relationships of Atta species using maximum parsimony, maximum likelihood and Bayesian inference techniques. Our results provide support for monophyly of the genus Atta, and suggest that the genus is divided into four monophyletic groups, which correspond to four of the five previously erected Atta subgenera: Atta sensu stricto and Archeatta, each with species composition identical to earlier proposals; Neoatta and Epiatta, with major differences in species composition from earlier proposals. The current geographic ranges of these species suggest that the historical separation of South America from Central and North America has played a role in speciation within this genus.


Safety of dilation in adults with eosinophilic esophagitis.
Esophageal dilation is an effective therapy for dysphagia in patients with stenosing eosinophilic esophagitis (EoE). Historically, there have been significant concerns of increased perforation rates when dilating EoE patients. More recent studies suggest that improved techniques and increased awareness have decreased complication rates. The aim of this study was to explore the safety of dilation in our population of EoE patients. A retrospective review of all adult EoE patients enrolled in a registry from 2006 to 2010 was performed. All patients who underwent esophageal dilation during this time period were identified and included in the analysis. Our hospital inpatient/outpatient medical records, radiology reports, and endoscopy reports were searched for evidence of any complication following dilation. Perforation, hemorrhage, and hospitalization were identified as a major complication, and chest pain was considered a minor complication. One hundred and ninety-six patients (41 years [12]; mean age [standard deviation], 80% white, 85% male) were identified. In this cohort, 54 patients (28%) underwent 66 total dilations (seven patients underwent two dilations, one patient underwent three dilations, and one patient underwent four dilations). Three dilation techniques were used (Maloney [24], Savary [29] and through-the-scope [13]). There were no major complications encountered. Chest pain was noted in two patients (4%). There were no endoscopic features (rings, furrows, plaques) associated with any complication. Type of dilator, size of dilator, number of prior dilations, and age of patient were also not associated with complications. Endoscopic dilation using a variety of dilators can be safely performed with minimal complications in patients with EoE.


Modulation of GABAA receptor activity by alphaxalone.
The modulation of the gamma-aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage-clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture. Alphaxalone (greater than 30 nM) reversibly and dose-dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 microM). The potentiation was not associated with a change in the reversal potential of GABA-evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15-1788 (300 nM). At relatively high concentrations (greater than 1 microM), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 microM), dose-dependently enhanced by phenobarbitone (100-500 microM), and had a similar reversal potential (approximately 0 mV) to currents elicited by GABA. Additionally, on outside-out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA. Alphaxalone (30 nM-1 microM) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 microM). However, higher concentrations of alphaxalone (10-100 microM) reversibly suppressed ACh-evoked currents, the IC50 for blockade being 20 microM. The beta-hydroxy isomer of alphaxalone, betaxalone (100 nM-1 microM), did not potentiate GABA-induced currents, nor did higher concentrations of the steroid (10-100 microM) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh. The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor.


Dacryoadenitis due to gonococcal conjunctivitis complicated by corneal perforation.
Adnexal and periocular involvement in Neisseria gonorrhoeae (NG) infection is rare. This report describes the case of a patient with a delayed diagnosis of gonococcal dacryoadenitis with contiguous conjunctivitis and corneal involvement. She underwent extensive inpatient laboratory and infectious workup but rapidly progressed to corneal perforation requiring emergent penetrating keratoplasty prior to a positive culture confirming the diagnosis. To date, this is the first reported case of ophthalmologic NG infection with associated conjunctivitis, dacryoadenitis, and corneal perforation.


Poisson-Boltzmann theory of the charge-induced adsorption of semi-flexible polyelectrolytes.
A model is suggested for the structure of an adsorbed layer of a highly charged semi-flexible polyelectrolyte on a weakly charged surface of opposite charge sign. The adsorbed phase is thin, owing to the effective reversal of the charge sign of the surface upon adsorption, and ordered, owing to the high surface density of polyelectrolyte strands caused by the generally strong binding between polyelectrolyte and surface. The Poisson-Boltzmann equation for the electrostatic interaction between the array of adsorbed polyelectrolytes and the charged surface is solved for a cylindrical geometry, both numerically, using a finite element method, and analytically within the weak curvature limit under the assumption of excess monovalent salt. For small separations, repulsive surface polarization and counterion osmotic pressure effects dominate over the electrostatic attraction and the resulting electrostatic interaction curve shows a minimum at nonzero separations on the Angstrom scale. The equilibrium density of the adsorbed phase is obtained by minimizing the total free energy under the condition of equality of chemical potential and osmotic pressure of the polyelectrolyte in solution and in the adsorbed phase. For a wide range of ionic conditions and charge densities of the charged surface, the interstrand separation as predicted by the Poisson-Boltzmann model and the analytical theory closely agree. For low to moderate charge densities of the adsorbing surface, the interstrand spacing decreases as a function of the charge density of the charged surface. Above about 0.1 M excess monovalent salt, it is only weakly dependent on the ionic strength. At high charge densities of the adsorbing surface, the interstrand spacing increases with increasing ionic strength, in line with the experiments by Fang and Yang [J. Phys. Chem. B 101, 441 (1997)].


Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls.
Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. To determine the best predictive model for detecting puberty in girls. Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls.


Computational mining of MHC class II epitopes for the development of universal immunogenic proteins.
The human leukocyte antigen (HLA) gene complex, one of the most diverse gene complexes found in the human genome, largely dictates how our immune systems recognize pathogens. Specifically, HLA genetic variability has been linked to vaccine effectiveness in humans and it has likely played some role in the shortcomings of the numerous human vaccines that have failed clinical trials. This variability is largely impossible to evaluate in animal models, however, as their immune systems generally 1) lack the diversity of the HLA complex and/or 2) express major histocompatibility complex (MHC) receptors that differ in specificity when compared to human MHC. In order to effectively engage the majority of human MHC receptors during vaccine design, here, we describe the use of HLA population frequency data from the USA and MHC epitope prediction software to facilitate the in silico mining of universal helper T cell epitopes and the subsequent design of a universal human immunogen using these predictions. This research highlights a novel approach to using in silico prediction software and data processing to direct vaccine development efforts.


Identification of a murine testis complementary DNA encoding a homolog to human A-kinase anchoring protein-associated sperm protein.
Using differential display reverse transcriptase-polymerase chain reaction (RT-PCR) we have cloned a cDNA that encodes a putative peptide with homology to a recently reported A-kinase anchoring protein-associated protein (ASP) in human sperm. The mouse cDNA was 864 bases in length and encoded for a putative protein of 230 amino acids that had 90% amino acid similarity with the human ASP. The N terminal amino acid sequence had 65% similarity to the rat, mouse, and human protein kinase A regulatory type II sequences. Expression of the gene encoding this ASP was specific to testicular germ cells. Northern blot analysis of testis RNA from 5-, 15-, 25-, and 40-day-old mice showed expression of the ASP gene, but similar analyses of busulfan-treated germ cell-deficient mice failed to detect its expression. In addition, Northern blot analysis did not detect expression of the ASP mRNA in cultured Sertoli cells or cultured interstitial cells. Northern blot and RT-PCR analyses did not detect the ASP mRNA in mouse spleen, brain, liver, lung, heart, kidney, skeletal muscle, ovary, or Sertoli cells. In situ hybridization analysis localized the ASP mRNA to the germ cell compartment of the seminiferous tubules in the testis.


Synthesis of diphenylamine macrocycles and their anti-inflammatory effects.
A collection of fourteen diphenylamine macrocyclic derivatives containing a peptide chain with different substituents was synthesized using a protocol of two Ugi four component reactions (Ugi-4CR) and a Buchwald-Hartwig macrocyclization. Their anti-inflammatory effects were assayed with an ear edema model using 12-O-tetradecanoylphorbol-13-acetate, while the activity of myeloperoxidase was determined to evaluate the index of leukocyte infiltration. Compound 5e had an ID50 of 0.18 μM per ear with a potency higher than that of the reference drugs indomethacin and celecoxib (0.24 and 0.91 μM per ear, respectively). Moreover, the cytotoxicity of the macrocycles was determined in two healthy cell lines, showing a low percentage of toxicity.


Diaqua-bis-(2-oxo-2H-chromene-3-carboxyl-ato)copper(II).
In the title compound, [Cu(C(10)H(5)O(4))(2)(H(2)O)(2)], the Cu(II) atom lies on a crystallographic inversion center and exhibits an octa-hedral coordination defined by two O atoms from water mol-ecules in the axial positions and by four O atoms from two deprotonated coumarin-3-carb-oxy-lic acid ligands in the equatorial positions. The angles around the Cu(II) atom vary between 85.32 (6) and 94.68 (6)°. The Cu-O bond distances between the Cu(II) atom and the O atoms vary between 1.9424 (14) and 2.3229 (15) Å. The layers inter-digitate via face-to-face aromatic inter-actions [3.6490 (8) Å] between coumarin moieties such that the inter-layer separation is 10.460 (2) Å, i.e. the length of the c axis. O-H⋯O hydrogen bonds between the H atoms of coordinated water mol-ecules and the O atoms of carboxyl-ate groups link the complex mol-ecules into layers parallel to the ab plane.


Concrescence of teeth: cemental union between the crown of an impacted tooth and the roots of an erupted tooth.
Concrescence of teeth is a condition showing a union of adjacent teeth by only cementum. In all the previously reported cases, the union has been observed between the roots of the affected teeth. Here, we describe the first case that showed a concrescence of the crown of an impacted tooth and the roots of the erupted tooth. In addition, we discuss how this condition, especially the deposition of acellular cementum on the crown, occurred.


Serious games for upper limb rehabilitation: a systematic review.
The aim of this research is to carry out a systematic review of the use of technological gaming platforms with serious games in the upper limb rehabilitation of patients with neuromotor disorders. Through a systematic review, the first two authors defined the inclusion criteria and extracted the data, resulting in 38 studies collected from B-On, PubMed and Medline. Ninety-two per cent of the selected articles were published since 2010. This review documents 35 different gaming platforms types. Twenty-one of the 38 articles included in this review conducted a clinical trial and of those only eight report improvements in the target population following the use of the games and platforms. This review concludes that a new paradigm is emerging in the rehabilitation field, characterized by the systematic use of technological gaming platforms with serious games in/for rehabilitation. The use of this approach seems to be beneficial. However, to facilitate the full integration of these platforms, it is necessary to conduct more research in this area, explore new approaches and carry out in-depth clinical studies into the benefits of these platforms. Implications for rehabilitation This review states that the use serious games and gaming platforms for upper limb rehabilitation are starting a new paradigm in the rehabilitation. For a full integration of this technologies in the rehabilitation field more studies are needed.


Detection of Two Biotypes of Liriomyza chinensis (Diptera: Agromyzidae) in Japan.
The larva of stone leek leafminer, Liriomyza chinensis (Kato), is known to infest alternately just below the epidermis and inner surface of hollow cylindrical leaves of allium crops, resulting in the formation of discontinuous linear mines (mine form: discontinuous). However, after the fall of 2016, a novel mine form of the same species (mine form: continuous) was detected in Welsh onion fields of Kyoto Prefecture, Japan. We hypothesized that these mine forms were associated with flies having different genetic backgrounds; hence, we compared the mine forms and the partial mtCOI gene of flies collected from Welsh onion fields from 2018 to 2019. The results demonstrated that the flies that emerged from different mine forms could be classified into two haplogroups, i.e., flies displaying a discontinuous mine form were of haplogroup A, whereas those that displayed continuous mines were of haplotype B. Additionally, using populations of these flies reared in the laboratory, we confirmed that the mine form of the larvae of haplotype A on Welsh onions was discontinuous, whereas that of haplotype B was continuous. We named the population that exhibited a discontinuous mine form as biotype A and the population displaying a continuous mine form as biotype B.


Standardization of Free Thyroxine Measurements Allows the Adoption of a More Uniform Reference Interval.
The IFCC Committee for Standardization of Thyroid Function Tests intended to standardize free thyroxine (FT4) immunoassays. We developed a Système International d'Unités traceable conventional reference measurement procedure (RMP) based on equilibrium dialysis and mass spectrometry. We describe here the latest studies intended to recalibrate against the RMP and supply a proof of concept, which should allow continued standardization efforts. We used the RMP to target the standardization and reference interval (RI) panels, which were also measured by 13 manufacturers. We validated the suitability of the recalibrated results to meet specifications for bias (3.3%) and total error (8.0%) determined from biological variation. However, because these specifications were stringent, we expanded them to 10% and 13%, respectively. The results for the RI panel were reported as if the assays were recalibrated. We estimated all but 1 RI using parametric statistical procedures and hypothesized that the RI determined by the RMP was suitable for use by the recalibrated assays. Twelve of 13 recalibrated assays had a bias, meeting the 10% specification with 95% confidence; for 7 assays, this applied even for the 3.3% specification. Only 1 assay met the 13% total error specification. Recalibration reduced the CV of the assay means for the standardization panel from 13% to 5%. The proof-of-concept study confirmed our hypothesis regarding the RI but within constraints. Recalibration to the RMP significantly reduced the FT4 immunoassays' bias, so that the RI determined by the RMP was suitable for common use within a margin of 12.5%.


A 7-Step Formal Asymmetric Total Synthesis of Strictamine via an Asymmetric Propargylation and Metal-Mediated Cyclization.
Herein is shown how a novel catalytic asymmetric propargylation of 3,4-dihydro-β-carboline, followed by a designed Au(I)/Ag(I)-mediated 6-endo-dig cyclization, can directly deliver the indolenine-fused methanoquinolizidine core of the akuammiline alkaloid strictamine in its native oxidation state, ultimately achieving a 7-step formal asymmetric total synthesis. Also demonstrated are how the cyclization products can rearrange into vincorine-type skeletons and a further use for the developed propargylation with the first catalytic asymmetric total synthesis of decarbomethoxydihydrogambirtannine.


[Long-term outcomes of percutaneous microwave ablation versus repeat hepatectomy for treatment of late recurrent small hepatocellular carcinoma: a retrospective study].
To compare the effectiveness of percutaneous microwave ablation with those of repeat hepatectomy in the treatment of late recurrent small hepatocellular carcinoma measuring ≤ 5 cm (interval of recurrence from initial hepatectomy was > 12 months). 66 patients who underwent initial hepatectomy for primary liver cancer in April 1998 to December 2010, and subsequent initial recurrent hepatocellular carcinoma treated with percutaneous microwave ablation or repeat hepatectomy, were enrolled in the study. Among these patients 39 were treated with percutaneous microwave ablation and 27 were treated with repeat hepatectomy. Technique effectiveness was evaluated by means of contrast enhanced techniques one month after ablation. The overall survival and disease-free survival were evaluated by using the Kaplan-Meier method. The technique effectiveness rate determined one month after ablation was 94.9%. The 1, 3, and 5 year overall survival rates were 86.2%, 73.3%, and 62.2%, respectively, for the microwave ablation group and 96.2%, 76.9%, and 61.2%, respectively, for the repeat hepatectomy group (P = 0.471). The corresponding recurrence-free survival rates were 65.8%, 28.0%, and 14.0%, respectively, for the microwave ablation group and 66.7%, 50.7%, and 43.4%, respectively, for the repeat hepatectomy group (P = 0.323). In patients with late recurrent small hepatocellular carcinoma, Percutaneous microwave ablation was efficient, and showed similar long-term survival and recurrence-free survival compared with repeat hepatectomy.


Transferrin overexpression alters testicular function in aged mice.
Many studies have shown a correlation between transferrin (Tf) concentration and sperm yield in several mammalian species. We have used transgenic mice expressing human Tf (hTf) to investigate if overexpression of Tf increases the efficiency of mouse spermatogenesis. We demonstrated that a 36% increase of Tf does not ameliorate the efficiency of mouse spermatogenesis but on the contrary resulted in a 36% decrease of testis sperm reserves. Tf overexpression had no effect on testicular determination and development, however testicular function of these transgenic mice was affected in an age-dependent manner. At 16 months of age, testicular and epididymal weights were significantly reduced. While spermatogenesis was qualitatively normal, testicular functions were perturbed. In fact, testosterone rate after human chorionic gonadotropin (hCG) stimulation was lower in Tf overexpressing mice. Intratesticular concentration of estradiol-17beta was increased and fluid accumulation after ligation of rete testis was more abundant in these transgenic mice. Surprisingly, we found that endogenous Tf levels were also increased in Tf overexpressing mice and we demonstrated for the first time that Tf may serve to upregulate its own expression in testis. Collectively, our data show that Tf overexpression has negative effects on testicular function and that Tf levels require strict regulation in the testis.


Multifactorial Activation of NLRP3 Inflammasome: Relevance for a Precision Approach to Atherosclerotic Cardiovascular Risk and Disease.
Chronic low-grade inflammation, through the specific activation of the NACHT leucine-rich repeat- and PYD-containing (NLRP)3 inflammasome-interleukin (IL)-1β pathway, is an important contributor to the development of atherosclerotic cardiovascular disease (ASCVD), being triggered by intracellular cholesterol accumulation within cells. Within this pathological context, this complex pathway is activated by a number of factors, such as unhealthy nutrition, altered gut and oral microbiota, and elevated cholesterol itself. Moreover, evidence from autoinflammatory diseases, like psoriasis and others, which are also associated with higher cardiovascular disease (CVD) risk, suggests that variants of NLRP3 pathway-related genes (like NLRP3 itself, caspase recruitment domain-containing protein (CARD)8, caspase-1 and IL-1β) may carry gain-of-function mutations leading, in some individuals, to a constitutive pro-inflammatory pattern. Indeed, some reports have recently associated the presence of specific single nucleotide polymorphisms (SNPs) on such genes with greater ASCVD prevalence. Based on these observations, a potential effective strategy in this context may be the identification of carriers of these NLRP3-related SNPs, to generate a genomic score, potentially useful for a better CVD risk prediction, and, possibly, for personalized therapeutic approaches targeted to the NLRP3-IL-1β pathway.


Cystathionine-β-synthase-derived hydrogen sulfide is required for amygdalar long-term potentiation and cued fear memory in rats.
Hydrogen sulfide (H2S) is an endogenous gaseous molecule that functions as a neuromodulator in the brain. We previously reported that H2S regulated amygdalar synaptic plasticity and cued fear memory in rats. However, whether endogenous H2S is required for amygdalar long-term potentiation (LTP) induction and cued fear memory formation remains unclear. Here, we show that cystathionine-β-synthase (CBS), the predominant H2S-producing enzyme in the brain, was highly expressed in the amygdala of rats. Suppressing CBS activity by inhibitor prevented activity-triggered generation of H2S in the lateral amygdala (LA) region. Incubating brain slices with CBS inhibitor significantly prevented the induction of NMDA receptors (NMDARs)-dependent LTP in the thalamo-LA pathway, and intra-LA infusion of CBS inhibitor impaired cued fear memory in rats. Notably, treatment with H2S donor, but not CBS activator, significantly reversed the impairments of LTP and fear memory caused by CBS inhibition. Mechanismly, inhibition of CBS activity led to a reduction in NMDAR-mediated synaptic response in the thalamo-LA pathway, and treatment with H2S donor restored the function of NMDARs. Collectively, these results indicate that CBS-derived H2S is required for amygdalar synaptic plasticity and cued fear memory in rats, and the effects of endogenous H2S might involve the regulation of NMDAR function.


Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia.
Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk. We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures. We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively. Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.


Preoperative radiation therapy for locally advanced rectal cancer: a comparison between two different time intervals to surgery.
Although it is now considered a standard treatment to irradiate an advanced mid or low rectal tumor before surgical total mesorectal excision (TME), the optimal time interval between radiation therapy and surgery remains controversial. Between 1995 and 2005, patients undergoing preoperative radiation therapy and TME for locally advanced mid and low rectal tumors treated in the VU Medical Center or the Zaans Medical Center were entered into this study. All patients received identical radiation treatment in the VU Medical Center and were subsequently operated on within 2 weeks in the Zaans Medical Center (SI group) and after 6-8 weeks in the VU Medical Center (LI group). Preoperative tumor staging, operative data, postoperative complications, pathology results, and follow-up were compared. The SI group (N=57) underwent surgery after a median delay of 4 days and the LI group (N=51) after 45 days. Operative data and short-term morbidity were comparable for both groups. However, significantly higher numbers of complete remissions (12 vs 0%), tumor downstaging (55 vs 26%), and less lymph-node metastases (22 vs 44%) were found in the LI group. No significant differences were found regarding local control or long-term survival after a median follow-up of 34 months. Several advantages, such as complete remissions and downstaging in the LI group, do not appear to have expression in a better survival or less local recurrences after a median follow-up of 34 months. Although larger (randomized) studies will be needed for definite conclusions, this may indicate that patients can be operated on within 2 weeks after radiation therapy.


A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing.
STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2'3'-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-β that dominantly inhibits innate nucleic acid sensing. STING-β without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-β correlated inversely with IFN-β production. The expression of STING-β declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-β suppressed the induction of IFNs, IFN-stimulated genes and other cytokines by various immunostimulatory agents including cyclic dinucleotides, DNA, RNA and viruses, whereas depletion of STING-β showed the opposite effect. STING-β interacted with STING-α and antagonized its antiviral function. STING-β also interacted with TBK1 and prevented it from binding with STING-α, TRIF or other transducers. In addition, STING-β bound to 2'3'-cGAMP and impeded its binding with and activation of STING-α, leading to suppression of IFN-β production. Taken together, STING-β sequesters 2'3'-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.


Late effects in survivors of Hodgkin and non-Hodgkin lymphoma treated with autologous hematopoietic cell transplantation: a report from the bone marrow transplant survivor study.
We determined the prevalence of self-reported late-effects in survivors of autologous hematopoietic cell transplantation (HCT) for Hodgkin lymphoma (HL, n = 92) and non-Hodgkin lymphoma (NHL, n = 184) using a 255-item questionnaire and compared them to 319 sibling controls in the Bone Marrow Transplant Survivor Study. Median age at HCT was 39 years (range: 13-69) and median posttransplant follow-up was 6 years (range: 2-17). Median age at survey was 46 years (range: 21-73) for survivors and 44 years (range: 19-79) for siblings. Compared to siblings, HCT survivors reported a significantly higher frequency of cataracts, dry mouth, hypothyroidism, bone impairments (osteoporosis and avascular necrosis), congestive heart failure, exercise-induced shortness of breath, neurosensory impairments, inability to attend work or school, and poor overall health. Compared to those receiving no total-body irradiation (TBI), patients treated with TBI-based conditioning had higher risks of cataracts (odds-ratio [OR] 4.9, 95% confidence interval [CI] 1.5-15.5) and dry mouth (OR 3.4, 95% CI 1.1-10.4). Females had a greater likelihood of reporting osteoporosis (OR 8.7, 95% CI: 1.8-41.7), congestive heart failure (OR 4.3, 95% CI 1.1-17.2), and abnormal balance, tremor, or weakness (OR 2.4, 95% CI 1.0-5.5). HL and NHL survivors of autologous HCT have a high prevalence of long-term health-related complications and require continued monitoring for late effects of transplantation.


Renal Abscess Caused by Salmonella Typhi.
Salmonella typhi is a true pathogen, which is capable of causing both intestinal and extraintestinal infections. Unusual presentations of Salmonella should always be kept in mind as this organism can cause disease in almost any organ of the body. S. typhi has been reported to cause the life-threatening infections such as meningitis, endocarditis, myocarditis, empyema, and hepatic abscess. Renal involvement by S. typhi is a relatively rare presentation. We report a case of renal abscess caused by S. typhi in an afebrile, 10-year-old child who did not have any clinical history of enteric fever. To our knowledge, this is the first reported case of isolation of S. typhi from the renal abscess, and interestingly this isolate was found to be resistant to quinolones.


Products of lipid peroxidation, but not membrane susceptibility to oxidative damage, are conserved in skeletal muscle following temperature acclimation.
Changes in oxidative capacities and phospholipid remodeling accompany temperature acclimation in ectothermic animals. Both responses may alter redox status and membrane susceptibility to lipid peroxidation (LPO). We tested the hypothesis that phospholipid remodeling is sufficient to offset temperature-driven rates of LPO and, thus, membrane susceptibility to LPO is conserved. We also predicted that the content of LPO products is maintained over a range of physiological temperatures. To assess LPO susceptibility, rates of LPO were quantified with the fluorescent probe C11-BODIPY in mitochondria and sarcoplasmic reticulum from oxidative and glycolytic muscle of striped bass (Morone saxatilis) acclimated to 7°C and 25°C. We also measured phospholipid compositions, contents of LPO products [i.e., individual classes of phospholipid hydroperoxides (PLOOH)], and two membrane antioxidants. Despite phospholipid headgroup and acyl chain remodeling, these alterations do not counter the effect of temperature on LPO rates (i.e., LPO rates are generally not different among acclimation groups when normalized to phospholipid content and compared at a common temperature). Although absolute levels of PLOOH are higher in muscles from cold- than warm-acclimated fish, this difference is lost when PLOOH levels are normalized to total phospholipid. Contents of vitamin E and two homologs of ubiquinone are more than four times higher in mitochondria prepared from oxidative muscle of warm- than cold-acclimated fish. Collectively, our data demonstrate that although phospholipid remodeling does not provide a means for offsetting thermal effects on rates of LPO, differences in phospholipid quantity ensure a constant proportion of LPO products with temperature variation.


A field study on Nakayama and Beijing strains of Japanese encephalitis vaccines.
A field study to compare the immune response of children aged 1-6 years to Nakayama and Beijing strains JE vaccines was carried out in Mae Hong Son Province, northwest Thailand, where there was low incidence of JEV infection. The first and second dose of each vaccine was given 1-2 weeks apart and the third dose was 1 year after the second dose. Seroconversion rate was similarly high, about 94% in both groups of vaccinees. At 6 and 12 months after 2 doses of vaccines, the seroconversion rates dropped in both groups of vaccinees, so there were 10-20% of children (50-65% if cross protection was considered) susceptible to JEV infections during this period. After the third dose of vaccine, the seroconversion rate rose to 100% in both groups. The GMT in Bejing strain vaccinees were slightly higher than Nakayama strain JE vaccines. To reduce the number of susceptible children during 6-12 months after the second dose and for longer protection, the primary JE immunization should be 3 doses and the timing for the third dose should be at 6 months after the second dose. Either Nakayama or Beijing strain vaccine could be used in Thailand.


Predictors of Long-Term Psychosocial Functioning and Health-Related Quality of Life in Children and Adolescents With Prior Concussions.
Individual differences in long-term psychosocial functioning after concussions in children and adolescents are poorly understood. The aim of the study was to investigate potential predictors of long-term psychosocial functioning and health-related quality of life in youth after prior concussion. Participants (N=75; mean age=14.3 years old; 52% girls) with one prior concussion (n=24), multiple prior concussions (n=24), or a prior orthopedic injury and no concussion (n=27) were seen on average 2.7 years after their most recent injury. Psychosocial functioning was assessed using the self-report versions of the Behavior Assessment System for Children (BASC-2; Anxiety and Depression scales only), the Strengths and Difficulties Questionnaire, and the Pediatric Quality of Life Inventory TM 4.0. Pre-existing conditions (attention problems, learning difficulties, mood concerns, anxiety concerns, and migraines) were reported by parents using a checklist and examined as predictors of long-term functioning. Other potential predictors included age at testing, sex, time between most recent injury and testing, and number of prior concussions. The groups did not differ significantly on long-term psychosocial functioning. Moreover, only pre-existing mood concerns or attention problems significantly predicted psychosocial adjustment. Children's functioning before a concussion is critical to understanding outcome. Pre-injury attention and mood concerns should be assessed in clinical settings to prevent and treat long-term psychosocial problems after concussion. (JINS, 2018, 24, 540-548).


Phylogenetic, Evolutionary and Structural Analysis of Canine Parvovirus (CPV-2) Antigenic Variants Circulating in Colombia.
Canine parvovirus (CPV-2) is the causative agent of haemorrhagic gastroenteritis in canids. Three antigenic variants-CPV-2a, CPV-2b and CPV-2c-have been described, which are determined by variations at residue 426 of the VP2 capsid protein. In Colombia, the CPV-2a and CPV-2b antigenic variants have previously been reported through partial VP2 sequencing. Mutations at residues Asn428Asp and Ala514Ser of variant CPV-2a were detected, implying the appearance of a possible new CPV-2a variant in Colombia. The purpose of the present study was to characterise the full VP2 capsid protein in samples from Antioquia, Colombia. We conducted a cross-sectional study with 56 stool samples from dogs showing clinical symptoms of parvoviral disease. Following DNA extraction from the samples, VP2 amplification was performed using PCR and positive samples were sequenced. Sequence and phylogenetic analyses were performed by comparison with the VP2 gene sequences of the different CPV-2 worldwide. VP2 was amplified in 51.8% of the analysed samples. Sequencing and sequence alignment showed that 93.1% of the amplified samples belonged to the new CPV-2a antigenic variant previously. Analysing the amino acid sequences revealed that all CPV-2a contain Ala297Asn mutations, which are related to the South America I clade, and the Ala514Ser mutation, which allows characterization as a new CPV-2a sub-variant. The Colombian CPV-2b variant presented Phe267Tyr, Tyr324Ile and Thr440Ala, which are related to the Asia-I clade variants. The CPV-2c was not detected in the samples. In conclusion, two antigenic CPV-2 variants of two geographically distant origins are circulating in Colombia. It is crucial to continue characterising CPV-2 to elucidate the molecular dynamics of the virus and to detect new CPV-2 variants that could be becoming highly prevalent in the region.