Growth pattern evaluation of the Edinburgh and Gothenburg cohorts by QEPS height model.
The QEPS-growth-model, developed and validated in GrowUp-Gothenburg cohorts, used for developing growth references and investigating healthy/pathological growth, lacks external validation from other longitudinal cohorts of healthy individuals. To investigate if the QEPS-model can fit the longitudinal Edinburgh growth study of another design than GrowUp-Gothenburg cohorts, and to compare growth patterns in the individuals born in mid-1970s in North-Western Europe. Longitudinal growth data were obtained from the Edinburgh and the GrowUp1974Gothenburg cohorts. The QEPS-model was used to describe length/height from birth to adult height with confidence interval, and the multivariable regression model for estimating the contribution of the different QEPS-functions to adult height. The QEPS-model fitted the Edinburgh cohort well, with high accuracy, and low confidence intervals indicating high precision. Despite 3 cm shorter stature (less QE-function growth) in Scottish children, the growth patterns of the cohorts were similar, especially for specific pubertal growth. The contribution to adult height from different QEPS functions was similar. The QEPS-model is validated for the first time in a longitudinal study of healthy individuals of another design and found to fit with high accuracy and precision. The Scottish and Western-Swedish cohorts born in mid-1970s showed similar growth patterns for both sexes, especially pubertal growth. For the first time, the QEPS height model was used and found to fit another longitudinal cohort of healthy individuals other than the Swedish longitudinal cohorts. With large numbers of individual measurements in each growth phase, the QEPS model calculates growth estimates with narrow confidence intervals (high precision) and high accuracy. The two different cohorts born in the mid-1970s from Scotland and Western Sweden have similar growth patterns, despite a 3 cm difference in adult height.


Justification of recommender systems results: a service-based approach.
With the increasing demand for predictable and accountable Artificial Intelligence, the ability to explain or justify recommender systems results by specifying how items are suggested, or why they are relevant, has become a primary goal. However, current models do not explicitly represent the services and actors that the user might encounter during the overall interaction with an item, from its selection to its usage. Thus, they cannot assess their impact on the user's experience. To address this issue, we propose a novel justification approach that uses service models to (i) extract experience data from reviews concerning all the stages of interaction with items, at different granularity levels, and (ii) organize the justification of recommendations around those stages. In a user study, we compared our approach with baselines reflecting the state of the art in the justification of recommender systems results. The participants evaluated the Perceived User Awareness Support provided by our service-based justification models higher than the one offered by the baselines. Moreover, our models received higher Interface Adequacy and Satisfaction evaluations by users having different levels of Curiosity or low Need for Cognition (NfC). Differently, high NfC participants preferred a direct inspection of item reviews. These findings encourage the adoption of service models to justify recommender systems results but suggest the investigation of personalization strategies to suit diverse interaction needs.


Ultrasonic wavefield inversion and migration in complex heterogeneous structures: 2D numerical imaging and nondestructive testing experiments.
Delaminations, cracks and other defects in engineered structures often lie close to the theoretical resolution limit for ultrasonic waves. While ultrasonic waveform tomography has succeeded in detecting such features, recovery is difficult because it requires computationally expensive high-frequency numerical wave simulations and an accurate understanding of large-scale background variations of the engineered structure. Without such knowledge, small defects may be incorrectly imaged or go undetected altogether. To reduce computational cost and improve detection of small defects, a useful approach is to divide the waveform tomography procedure into two steps: first, a low-frequency model-building step aimed at recovering background structure, and second, a high-frequency imaging step targeting defects. The first is naturally formulated as waveform inversion for wavespeed parameters and the second as time reversal migration for reflectivity. Through synthetic test cases, we show that the two-step workflow appears more promising in most cases than a single-step inversion. In particular, we find that new workflow succeeds in the challenging scenario where the defect lies along preexisting layer interface in a composite bridge deck and in related experiments involving noisy data or inaccurate source parameters.


Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments.
Human fetal and placental compartments have all the enzymatic systems necessary to produce steroid hormones. However, their activities are different and complementary: the fetus is very active in converting acetate into cholesterol, in transforming pregnanes to androstanes, various hydroxylases, sulfotransferases, whilst all these transformations are absent or very limited in the placenta. This compartment can transform cholesterol to C21-steroids, convert 5-ene to 4-ene steroids, and has a high capacity to aromatize C19 precursors and to hydrolyse sulfates. Steroid hormone receptors are present at an early stage of gestation and are functional for important physiological activities. The production rate of some steroids increases drastically with fetal evolution (e.g. estriol increases 500-1000 times in relation to non-pregnant women). We can hypothesize that the control of active steroid hormones could be carried out by fetal and placental factors, which act by stimulating or inhibiting the enzymes involved in their formation and transformation during pregnancy evolution and, consequently, limiting the high levels of the biologically active hormone.


Preparation of purified perikaryal and synaptosomal mitochondrial fractions from relatively small hypothalamic brain samples.
In order to measure the activity of neuronal mitochondria, a representative proof of neuronal processes, physiologically relevant mitochondrial samples need to be gained as simply as possible. Existing methods are, however, either for tissue samples of large size and/or homogenous microstructures only, or are not tested for mitochondrial function measurements. In the present article we describe a gradient fractionation method to isolate viable and well-coupled mitochondria from relatively heterogeneous histological microstructures such as the hypothalamus. With this new method, we are able to isolate a sufficient amount of functional mitochondria for determination of respiratory activity, in a short period of time, using affordable equipment. •Verified by electron microscopy, our method separates highly enriched and well-preserved perikaryal and synaptosomal mitochondria. Both fractions contain minimal cell debris and no myelin. Respiratory measurements (carried out by Clark-type electrode) confirmed undisturbed mitochondrial function providing well-evaluable records. The demonstrated protocol yields highly viable mitochondrial subfractions within 3 h from small brain areas for high-precision examinations. Using this procedure, brain regions with relatively heterogeneous histological microstructure (hypothalamus) can also be efficiently sampled.•Up to our present knowledge, our method is the shortest available procedure with the lowest sample size to gain debris-free, fully-viable mitochondria.


The affective origins of the Industrial Revolution.
We suggest in this commentary an emotional origin of the Industrial Revolution. Specifically, increased living standards directly preceding the Industrial Revolution produced increased happiness and subjective well-being that, in turn, fueled the explosion of innovation and economic growth experienced in industrial England.


Risk perception and its role in attitudes toward blood transfusion: a qualitative systematic review.
Despite improvements in blood safety making transfusion a much safer clinical procedure, the general public still perceives it as risky. We systematically reviewed available literature to examine evidence regarding the reasons and causes behind this perception. Electronic databases including PubMed, Cochrane Library, and EMBASE for literature dating back to the 1980s were searched. Eligible studies collected information on blood recipients' demographics, measures of risk domains (sets of values that risks encompass), and general knowledge of blood transfusion in terms of risks and benefits. Each study was assessed for quality of data, research method, and relevant findings. A scoring system was used to subjectively rate the overall quality of each study. Each study was reviewed for its method of data collection and information abstracted on hazards and conceptual dimensions used to measure risk. Risk perception between blood transfusion and other hazards including alternatives to transfusion were compared. Fifteen studies met the inclusion criteria, all of which were conducted outside the United States, with most of the studies published more than 10 years ago and conducted by only 3 research groups. Five studies were rated as being very good, four good, five fair, and one of poor quality. The finding of the studies consistently show that objective or raw knowledge is not correlated with risk perception, but subjective or calibrated knowledge is. Thus, it is what people think they know rather than what they actually do know that influences risk perception of transfusion. Of the 3 common conceptual domains-dread, unknown risk, and benefits-blood transfusion was found to be of intermediate dread, intermediate unknown risk, and most beneficial compared with other hazards. Donated blood was found to have lower perceived risk than all other alternatives to transfusion, except for use of autologous blood. There is a lack of recent studies on allogeneic transfusion. However, the more recent studies show that perceived high risk is still prevalent in the general public. The available risk perception studies suggest that although blood transfusion is safe, elevated risk perception of infections persists. Studies of the US population are needed to better understand the influence of both psychological and scientific factors.


Successful bridge therapy of gilteritinib to cord blood transplantation in relapsed acute myeloid leukemia after bone marrow transplantation.
The FMS-related tyrosine kinase 3 (FLT3) internal tandem duplication mutations (FLT3-ITD) positive acute myeloid leukemia (AML) is a disease with a dismal outcome. Gilteritinib is a second-generation FLT3 inhibitor with activity against ITD and high affinity toward the FLT3 receptor, thereby showing therapeutic potential for relapsed/refractory FLT3-mutated AML. Bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) identical sibling donor was performed in a 38-year-old Japanese male with FLT3-ITD positive AML. Neutrophil engraftment (>0.5 × 109/L) was achieved on day 16, and bone marrow remission was revealed on day 32. The patient's AML relapsed hematologically four months after BMT and was resistant to salvage chemotherapy. Gilteritinib was administered and the patient achieved non-remission but 'stable disease' status according to the response criteria. During administration, liver damage was observed but controllable. The patient received cord blood transplantation (CBT) as the second hematopoietic stem cell transplantation (HSCT) three months after relapse and achieved second remission. There was no evidence of recurrence of AML four months after CBT. This case demonstrates that gilteritinib can control FLT3-ITD positive AML that relapsed early after initial HSCT and can bridge to second HSCT.


Relationship between cognitive and non-cognitive symptoms of delirium.
To study relationship between the cognitive and the non-cognitive symptoms of delirium. Eighty-four patients referred to psychiatry liaison services and met DSM-IVTR criteria of delirium were assessed using the Delirium Rating Scale Revised-1998 (DRSR-98) and Cognitive Test for Delirium (CTD). The mean DRS-R-98 severity score was 17.19 and DRS-R-98 total score was 23.36. The mean total score on CTD was 11.75. The mean scores on CTD were highest for comprehension (3.47) and lowest for vigilance (1.71). Poor attention was associated with significantly higher motor retardation and higher DRS-R-98 severity scores minus the attention scores. There were no significant differences between those with and without poor attention. Higher attention deficits were associated with higher dysfunction on all other domains of cognition on CTD. There was significant correlation between cognitive functions as assessed on CTD and total DRS-R-98 score, DRS-R-98 severity score and DRS-R-98 severity score without the attention item score. However, few correlations emerged between CTD domains and CTD total scores with cognitive symptom total score of DRS-R-98 (items 9-13) and non-cognitive symptom total score of DRS-R-98 (items 1-8). Our study suggests that in delirium, cognitive deficits are quite prevalent and correlate with overall severity of delirium. Attention deficit is a core symptom of delirium.


Rural/urban background, depression and suicidal ideation in Chinese college students: a cross-sectional study.
The objective of this study was to examine, first, the relationship of having a rural vs. urban background with suicidal ideation in Chinese college students, and second, whether a potential relationship was mediated by depression. A survey was conducted among 1,145 undergraduate students at a university in China. Suicidal ideation and depressive symptoms were measured by the revised Hopkins' Symptom checklist (SCL-90-R). Associations between rural vs. urban background, depression and suicidal ideation were estimated by multivariable linear regression-based β coefficients, logistic regression-based odds ratios (ORs), and corresponding 95% confidence intervals (CIs). The magnitude of indirect effect and bias-corrected 95% CIs were obtained through bootstrap techniques. Rural background was positively associated with depression, which was in turn associated with suicidal ideation. The OR for rural status and suicidal ideation equaled 2.15 (95% CI = 1.36-3.41). This OR was slightly, though significantly (p<0.05) attenuated by additional adjustment for depressive symptoms (OR = 1.99, 95% CI = 1.15-3.44). Having a rural background is a determinant of suicidal ideation in Chinese college students. Depression may only marginally mediate this association.


Expansion of MIR482/2118 by a class-II transposable element in cotton.
Some plant microRNA (miRNA) families contain multiple members generating identical or highly similar mature miRNA variants. Mechanisms underlying the expansion of miRNA families remain elusive, although tandem and/or segmental duplications have been proposed. In this study of two tetraploid cottons, Gossypium hirsutum and Gossypium barbadense, and their extant diploid progenitors, Gossypium arboreum and Gossypium raimondii, we investigated the gain and loss of members of the miR482/2118 superfamily, which modulates the expression of nucleotide-binding site leucine-rich repeat (NBS-LRR) disease resistance genes. We found significant expansion of MIR482/2118d in G. barbadense, G. hirsutum and G. raimondii, but not in G. arboreum. Several newly expanded MIR482/2118d loci have mutated to produce different miR482/2118 variants with altered target-gene specificity. Based on detailed analysis of sequences flanking these MIR482/2118 loci, we found that this expansion of MIR482/2118d and its derivatives resulted from an initial capture of an MIR482/2118d by a class-II DNA transposable element (TE) in G. raimondii prior to the tetraploidization event, followed by transposition to new genomic locations in G. barbadense, G. hirsutum and G. raimondii. The 'GosTE' involved in the capture and proliferation of MIR482/2118d and its derivatives belongs to the PIF/Harbinger superfamily, generating a 3-bp target site duplication upon insertion at new locations. All orthologous MIR482/2118 loci in the two diploids were retained in the two tetraploids, but mutation(s) in miR482/2118 were observed across all four species as well as in different cultivars of both G. barbadense and G. hirsutum, suggesting a dynamic co-evolution of miR482/2118 and its NBS-LRR targets. Our results provide fresh insights into the mechanisms contributing to MIRNA proliferation and enrich our knowledge on TEs.


Bolus administration of cladribine in the treatment of Waldenström macroglobulinaemia.
This phase II clinical trial evaluated bolus cladribine as a single agent in Waldenstrom macroglobulinaemia (WM). Cladribine was administered to 20 patients at a dose of 0.12 mg/kg/d by 2 h intravenous infusion for 5 consecutive days at monthly intervals for three courses. Partially responding patients were continued on therapy until maximal response and/or prohibitive toxicity, to a maximum of eight courses. Complete responders were treated with one additional course of cladribine. After a median of three courses of cladribine, all 20 patients were evaluable; one achieved a complete response (CR) (5%) and 10 achieved a partial response (PR) (50%). The median duration of response follow-up was 28 months (range 1-37 months). Four of 7 (57%) untreated and 7/13 (54%) previously treated patients responded. The major toxicity encountered was myelosuppression with 60% of patients demonstrating grade 3 or 4 neutropenia. Non-haematological toxicities included two patients with herpes zoster and two patients with non-melanoma skin cancers. At a median follow-up duration of 20 months, 17 patients remain alive and three have died. We confirm that bolus cladribine is an effective and safe method of drug delivery in WM patients. Recommendations regarding the equivalence of the continuous infusion and bolus methods in untreated patients requires further study. Bolus cladribine is more convenient and less costly than infusional cladribine since it obviates the need for central catheters and infusional devices.


Dysphagia after laparoscopic antireflux surgery: a problem of hiatal closure more than a problem of the wrap.
Postoperative dysphagia after laparoscopic antireflux surgery usually is transient and resolves within weeks after surgery. Persistent dysphagia develops in a small percentage of patients after surgery. There still is debate about whether postoperative dysphagia is caused by the type or placement of the fundic wrap or by mechanical obstruction of the hiatal crura. This study aimed to investigate patients who experienced recurrent or persistent dysphagia after laparoscopic antireflux surgery, and to identify the morphologic reason for this complication. A sample of 50 patients consecutively referred to the authors' unit with recurrent, persistent, or new-onset of dysphagia after laparoscopic antireflux surgery were prospectively reviewed to identify the morphologic cause of postoperative dysphagia. According to their radiologic findings, these patients were divided into three groups: patients with signs of obstruction at or above the gastroesophageal junction suspicious of crural stenosis (group A; n = 18), patients with signs of total or partial migration of the wrap intrathoracically (group B; n = 27), and patients in whom the hiatal closure was radiologically assessed to be correct with a supposed stenosis of the wrap (group C; n = 5). The exact diagnosis of a too tight (group A) or too loose (group B) hiatus in contrast to a too tight wrap (group C) was established during laparoscopic redo surgery (groups B and C) or by x-ray during pneumatic dilation (group A). For all 18 group A patients, intraoperative x-ray during pneumatic dilation showed the typical signs of hiatal tightness. Of these, 15 were free of symptoms after dilation, and 3 had to undergo laparoscopic redo surgery because of persistent dysphagia. In all these patients, the hiatal closure was narrowing the esophagus. All the group B patients underwent laparoscopic redo surgery because of intrathoracic wrap migration. Intraoperatively, all the patients had an intact fundoplication, which slipped above the diaphragm. Definitely, only in 10% of all 50 patients (group C) presenting with the symptom of dysphagia, was the morphologic reason for the obstruction a problem of the fundic wrap. In most patients, postoperative dysphagia is more a problem of hiatal closure than a problem of the fundic wrap.


Dynamics and stability in coevolutionary ecological systems. I. Community stability and coevolutionarily stable states.
An extension of J. Roughgarden's [1979, Theor. Pop. Biol. 9, 388; 1979, "An Introduction to Evolutionary Ecology and Population Genetic Theory," Macmillan, New York] formalism for investigating the effects of coevolution on community structure is presented. The extension assumes the result that a coevolved community is asymptotically stable when coevolution takes place at a genetically noninvasible boundary. This is proved for the general case of n interacting species. From this a community persistence function, phi (P), is defined that allows measuring the domain of attraction for the community as well as the resilience time, that is, the time taken for a perturbation to decay to 1-1/e (63%) of its initial value.


Aggressive Cranial Osteoblastoma of the Parietotemporo-Occipital Bone: A Case Report and Review of Literature with Special Emphasis on Recurrence/Residue.
Osteoblastoma is a rare nonfibroblastic osteoid tissue-forming primary bony tumor usually arising in the medullary cavity/diploic space of any bone. The calvarium is an extremely rare site of its origin. Clinically, 2 types of osteoblastoma are noted: benign/conventional/typical and aggressive/high grade. Their imaging features are nondifferentiating and nonspecific, histopathologic features have a few subtle but nonspecific differences, and they have highly distinct clinical behavior. We report an extremely rare case of a patient with large aggressive cranial osteoblastoma, who developed massive inoperable multifocal recurrence 15 months after total en bloc resection with wide margins. A concise review of cases of aggressive osteoblastomas involving the cranium available in the English literature is also presented as an update.


Intrarenal and carotid hemodynamics in patients with essential hypertension.
The pulsatility index (PI) and resistive index (RI) are used as markers of peripheral vascular resistance. Recently intrarenal PI and RI were introduced for the evaluation of the severity of acute and chronic renal failure, as well as for the diagnosis of renal artery stenosis and kidney graft rejection. In the present study, we evaluated intrarenal PI and RI in patients with essential hypertension. Fifty-one patients with essential hypertension participated. The intima-media thickness (IMT) and mean diastolic (Vd) and systolic velocity (Vs) in the common carotid artery (CCA) were measured using ultrasound and Doppler flow methods. Relative diastolic flow velocity (Vd/Vs) was calculated as an assessment of CCA hemodynamics. Renal Doppler flow was obtained from the interlobar arteries in each of two kidneys. The mean PI ([peak systolic velocity--end-diastolic velocity]/mean velocity) and mean RI ([peak systolic velocity--end-diastolic velocity]/peak systolic velocity) were calculated. Intrarenal PI and RI were positively correlated with IMT and negatively correlated with Vd/Vs in CCA, indicating that renal vascular resistance is related to carotid stiffness. A stepwise regression analysis revealed that age and pulse pressure were independently associated with intrarenal PI and RI. These results suggest that the measurement of PI and RI is useful for the evaluation of arterial stiffness in patients with essential hypertension.


Localization of coenzyme Q10 in the center of a deuterated lipid membrane by neutron diffraction.
Quinones (e.g., coenzyme Q, CoQ10) are best known as carriers of electrons and protons during oxidative phosphorylation and photosynthesis. A myriad of mostly more indirect physical methods, including fluorescence spectroscopy, electron-spin resonance, and nuclear magnetic resonance, has been used to localize CoQ10 within lipid membranes. They have yielded equivocal and sometimes contradictory results. Seeking unambiguous evidence for the localization of ubiquinone within lipid bilayers, we have employed neutron diffraction. CoQ10 was incorporated into stacked bilayers of perdeuterated dimyristoyl phosphatidyl choline doped with dimyristoyl phosphatidyl serine containing perdeuterated chains in the natural fluid-crystalline state. Our data show CoQ10 at the center of the hydrophobic core parallel to the membrane plane and not, as might be expected, parallel to the lipid chains. This localization is of importance for its function as a redox shuttle between the respiratory complexes and, taken together with our recent result that squalane is in the bilayer center, may be interpreted to show that all natural polyisoprene chains lie in the bilayer center. Thus ubiquinone, in addition to its free radical scavenging and its well-known role in oxidative phosphorylation as a carrier of electrons and protons, might also act as an inhibitor of transmembrane proton leaks.


LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase.
In response to brain injury, microglia rapidly extend processes that isolate lesion sites and protect the brain from further injury. Here we report that microglia carrying a pathogenic mutation in the Parkinson's disease (PD)-associated gene, G2019S-LRRK2 (GS-Tg microglia), show retarded ADP-induced motility and delayed isolation of injury, compared with non-Tg microglia. Conversely, LRRK2 knockdown microglia are highly motile compared with control cells. In our functional assays, LRRK2 binds to focal adhesion kinase (FAK) and phosphorylates its Thr-X-Arg/Lys (TXR/K) motif(s), eventually attenuating FAK activity marked by decreased pY397 phosphorylation (pY397). GS-LRRK2 decreases the levels of pY397 in the brain, microglia and HEK cells. In addition, treatment with an inhibitor of LRRK2 kinase restores pY397 levels, decreased pTXR levels and rescued motility of GS-Tg microglia. These results collectively suggest that G2019S mutation of LRRK2 may contribute to the development of PD by inhibiting microglial response to brain injury.


Development, validation and application of a multi-mycotoxin method for the analysis of whole wheat plants.
Mycotoxins are known to affect the health of humans and husbandry animals. In contrast to wheat grains used for food and feed, whole wheat plants are rarely analysed for mycotoxins, although contaminated straw could additionally expose animals to these toxic compounds. Since the entire wheat plant may also act as source of mycotoxins emitted into the environment, an analytical method was developed, optimised and validated for the analysis of 28 different mycotoxins in above-ground material from whole wheat plants. The method comprises solid-liquid extraction and a clean-up step using a Varian Bond Elut Mycotoxin(®) cartridge, followed by liquid chromatography with electrospray ionisation and triple quadrupole mass spectrometry. Total method recoveries for 26 out of 28 compounds were between 69 and 122% and showed limits of detection from 1 to 26 ng/gdry weight (dw). The overall repeatability for all validated compounds was on average 7%, and their mean ion suppression 65%. Those rather high matrix effects made it necessary to use matrix-matched calibrations to quantify mycotoxins within whole wheat plants. The applicability of this method is illustrated with data from a winter wheat test field to examine the risks of environmental contamination by toxins following artificial inoculation separately with four different Fusarium species. The selected data originate from samples of a part of the field which was inoculated with Fusarium crookwellense. In the wheat samples, various trichothecenes (3-acetyl-deoxynivalenol, deoxynivalenol, diacetoxyscirpenol, fusarenone-X, nivalenol, HT-2 toxin, and T-2 toxin) as well as beauvericin and zearalenone were identified with concentrations ranging from 32 ng/gdw to 12 × 10(3) ng/gdw.


Association between WDR21A polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients.
Genetic polymorphism is partially responsible for the wide variation in the response of moderate-to-severe asthmatic patients to inhaled corticosteroids. The goal of the study was to examine polymorphisms in WDR21A, which encodes a putative glucocorticoid receptor (GR)-interacting protein, for their possible association with corticosteroid responsiveness. The change in forced expiratory volume in 1 s [FEV(1) (ΔFEV(1))] induced by 4 weeks of inhaled treatment with fluticasone propionate (1000 µg daily) was measured in 230 asthmatic patients. Fifteen single nucleotide polymorphisms (SNPs) of WDR21A were genotyped using a TaqMan assay, and 11 SNPs were used for further analysis. WDR21A transcripts were analyzed for variant splicing using reverse transcriptase-PCR. The WDR21A protein structure was predicted using a template-based modeling method and docked to a GR using Zdock. Of the 11 SNPs and three haplotypes of WDR21A analyzed, only the intronic SNP -10073G>C appeared to affect ΔFEV(1). The ΔFEV(1) of the -10073C/C homozygous genotype was twice that of the -10073G/G and -10073C/G genotypes (P(corr)=0.04 in recessive model). No splicing variant of WDR21A was observed, regardless of genotype. The predicted WDR21A protein structure was similar to the Gβ(1) protein structure (template modeling-score=0.93). The minor allele -10073C of WDR21A may induce a good response to inhaled corticosteroids possibly through competition with the Gβ(1) proteins for binding to GRs.


Effect of a vegetable oil factory effluent on in vitro lipid and protein synthesis by the liver of the freshwater teleost Heteropneustes fossilis (Bloch).
Following exposure to three sublethal concentrations (5, 10, and 15% v/v) of vegetable oil factory effluent for 30 days (March 1 through March 30, 1984), during the preparatory phase of the annual reproductive cycle of Heteropneustes fossilis, the in vitro incorporation, of [14C]glucose/[14C]/acetate into the lipids and of [14C]leucine into the proteins by the liver declined when compared with the control. In the three concentrations of the effluent used, the decline in the incorporation of radiolabelled substances increased with increase in the concentration.


Effects of novel subtype selective M-current activators on spinal reflexes in vitro: Comparison with retigabine.
The activation of Kv7 channels and the resulting M-current is a powerful mechanism to control neuronal excitability with profound effects in pain pathways. Despite the lack of specific data on the expression and role of these channels in nociceptive processing, much attention has been paid at exploring their potential value as targets for analgesia. Here we have characterized the spinal actions of two novel subunit selective Kv7 activators, ICA-069673 and ML213, and compared their effects to those of retigabine that acts with similar affinity on all neuronal Kv7 channels. Spinal reflexes were recorded in a mouse spinal cord in vitro preparation to allow the testing of the compounds on native spinal pathways at known concentrations. As retigabine, novel compounds depressed spinal segmental transmission with particularly strong effects on wind up, showing an adequate pro-analgesic profile. ML213 presented the highest potency. In contrast to retigabine, the effects of ICA-069673 and ML213 were blocked by XE-991 even at the highest concentrations used, suggesting specific effect on Kv7 channels. In addition, the effects of ICA-069673 on repetitive stimulation are consistent with a mode of action involving state or activity dependent interaction with the channels. Compared to retigabine, novel Kv7 openers maintain strong depressant effects on spinal nociceptive transmission showing an improved specificity on Kv7 channels. The differential effects obtained with these Kv7 openers may indicate the existence of several Kv7 conformations in spinal circuits.


Round window stimulation with the floating mass transducer at constant pretension.
Mechanical stimulation of the round window (RW) of the cochlea is successfully done with the Vibrant Soundbridge (Med-El), but clinical outcomes show a substantial degree of variability. One source of variability is variation in the static force applied by the stimulator to the round window (Maier et al., 2013). In this study we investigated other sources of variability by maintaining a constant pre-load testing the effect of a coupler device and the interposition of soft tissue between the stimulator and the RW. Experimental. The stapes footplate displacement produced by stimulation of the round window was determined in fresh human temporal bones. The response to sound and actuator stimulation was measured with a Laser Doppler Velocimeter at the stapes footplate. The RW was stimulated by a Floating Mass Transducer (FMT) with/without (1) an additional RW coupler (supplied by the manufacturer), and (2) the interposition of TUTOPATCH between the stimulator and the RW, while maintaining a pre-load of ∼1.96 mN. In 8 temporal bones with normal stapes footplate response to sound, we found an average 11.9 dB increase (500 Hz-2 kHz) under controlled conditions by using the coupler together with the interposition. The increase was statistically significant at 500 Hz (p < 0.01). Additionally, the coupler/interposition combination reduced the variability between experiments (FMT alone SD = 10.9 dB; FMT with TUTOPATCH & coupler: SD = 3.4 dB @ 500 Hz) and increased the repeatability. At controlled static force an improved output level, inter-subject variability and repeatability were found by using a coupler/TUTOPATCH combination in RW stimulation with the FMT. The high variability found in clinical experience is not solely due to inter-subject variability, but to coupling conditions and can be optimized further.


Brachial plexus lesions: 10 years of experience in a center for microsurgery in Germany.
Brachial plexus lesions are commonly associated with complete or partial plegia of affected muscles even after microsurgical treatment. This study provides an overview of strategies and outcomes of 42 patients operated in a center for peripheral nerve surgery in Germany. Postsurgically, the patients were followed up and examined for strength in various muscle groups by applying a standard clinical classification (M0-M5). Sensitivity was estimated by differentiation between blunt and sharp touch. The patients were asked via questionnaire about their postsurgical daily life. Most of the patients received a grafting procedure using the sural nerve. Different microsurgical techniques were applied according to the underlying pathology: Intercostal nerve transfer, end-to-side coaptation, and direct grafting to different recipient nerves. Only the 27 patients, who had a follow-up time of at least 36 months, presented a measurable function in the affected extremity. Elbow-flexion was restored in 15 cases. Triceps function was reconstructed in 7 patients of 27. One patient was able to move digits toward the palm without completing a full fist. Ten patients were able to flex the wrist and 4 could extend it. The results were estimated as acceptable for biceps reconstruction but poor for the other muscle groups. Some treatment strategies, which are presently under frequent discussion (contralateral C7-transfer, banked autografts, Oberlin procedure), were not applied. However, some of these techniques may provide a key to improve the results.


[Screening sensory and developmental disorders in nursery school children by the Maternal and Infant Protection Service in the Vaucluse (France) department: results, orientations, limits].
The aim of this study was to determine whether to continue the recommendations given by the doctors of the Maternal and Infant Protection (PMI) service within the medical check-ups given to nursery school children in the Vaucluse department in France. This was a longitudinal study conducted based on an observation grid from January to June 2009. A total of 2079 files were retained. This study revealed that more than one-quarter of the children for whom recommendations had been given no longer had care 3 months later; the main cause was the absence of adherence on the part of the family. This result emphasizes the limitation of the mass screenings conducted by the PMI in nursery schools: it raises the problem of access to healthcare for certain children and opens an opportunity for reflection on professional practices to optimize the mission of prevention and the promotion of health.


The role of termites in an equatorial rain forest ecosystem of West Malaysia : II. Leaf litter consumption on the forest floor.
To estimate the rate of consumption of leaf litter by termites on the forest floor of Pasoh Forest Reserve, Negeri Sembilan, West Malaysia, newly fallen leaves were marked and distributed on the ground. The loss of leaf area due to termites was determined either photometrically or visually. An average of 1.70% of the total surface area of the leaf litter disappeared per week in experiment 1 and 1.25% in experiment 2 in Plot 1, and 2.9% per day in other plots located near the mounds of Macrotermes carbonarius. The amount of leaf litter accumulation in the Ao layer was estimated at about 2.3 t/ha at Plot 1, so it was likely that an amount equivalent to about 32% of the daily leaf-litter fall was transported by M. carbonarius to their mounds in experiment 1 and 22% in experiment 2. It was considered that the termites had an important role in the detritus food chain of the ecosystem.


Complete genome sequence of Streptococcus agalactiae strain GBS85147 serotype of type Ia isolated from human oropharynx.
Streptococcus agalactiae, also referred to as Group B Streptococcus, is a frequent resident of the rectovaginal tract in humans, and a major cause of neonatal infection. The pathogen can also infect adults with underlying disease, particularly the elderly and immunocompromised ones. In addition, S. agalactiae is a known fish pathogen, which compromises food safety and represents a zoonotic hazard. This study provides valuable structural, functional and evolutionary genomic information of a human S. agalactiae serotype Ia (ST-103) GBS85147 strain isolated from the oropharynx of an adult patient from Rio de Janeiro, thereby representing the first human isolate in Brazil. We used the Ion Torrent PGM platform with the 200 bp fragment library sequencing kit. The sequencing generated 578,082,183 bp, distributed among 2,973,022 reads, resulting in an approximately 246-fold mean coverage depth and was assembled using the Mira Assembler v3.9.18. The S. agalactiae strain GBS85147 comprises of a circular chromosome with a final genome length of 1,996,151 bp containing 1,915 protein-coding genes, 18 rRNA, 63 tRNA, 2 pseudogenes and a G + C content of 35.48 %.


Underreporting of behavioral problems in older hospitalized patients.
This descriptive study examined reports of behavioral problems among older patients hospitalized in acute care medical settings. Greater numbers of behavioral problems were reported by nursing staff on the Neuropsychiatric Inventory-Questionnaire than were documented in medical charts over the same time period. Such underreporting may have clinical and administrative implications.


Game changers for meat and masculinity? Male athletes' perspectives on mixed and plant-based diets.
The dietary choices of male athletes are increasingly a topic of moral and nutritional debate. Though it has long been a consensus that athletes require animal products to advance their athletic goals, this understanding is now challenged in academic and popular sources based on nutritional evidence and concern about the environmental impacts of animal products. In order to better understand how (semi-)professional male athletes perceive plant-based diets and diets containing animal products, thirteen semi-structured interviews were conducted with male athletes competing nationally and internationally, including mixed and plant-based eaters. Interviews were analysed through reflexive thematic analysis, in line with a critical, qualitative research methodology. Justifications for meat, situated knowledge and masculinity were used as theoretical lenses. Our analysis shows how athletes reproduce nutritional claims about the necessity of protein for athletes, but disagree on the suitability of plant-based sources. This nutritional discourse derives from a broad range of sources, including professional nutritionists, friends, online influencers, and media. Second, when explaining their own food practices, food being 'nice' and 'normal' - common justifications for meat as evidenced in the 4N theory - often supersede necessity. Embedding these views in their everyday lives as athletes shows that food environments and shared eating practices fortify a mixed diet as normal, and plant-based diets as anomalous. It further shows how the view of meat being normal is subject to shifting masculinity norms. Interviewees reject meat eating as normal and masculine for men, while male athletes who show dedication, constraint, and knowledge in a plant-based diet are viewed positively. As role models for diet and masculinity, this has implications for a potential role of athletes in a societal transition towards lower consumption of animal products.


Age-Based Outcomes in Patients Who Underwent Septal Reduction Therapy.
There are no national data on age-based outcomes of septal reduction therapy. Using the National Inpatient Sample, we included all adult patients who underwent septal myectomy (SM) or alcohol septal ablation (ASA) from 2005 to 2019. The primary objective was to evaluate the in-hospital mortality and new permanent pacemaker (PPM) placement after SM and ASA in 3 age groups. In total, 9,564 patients underwent SM and 5,084 underwent ASA. Compared with the age group 18 to 39 years, the odds of in-hospital mortality after SM were similar in age group 40 to 64 years and 4.46 times higher than in age group ≥65 years; the higher mortality in the older group was explained by higher co-morbidity burden on the risk-adjusted analysis. Furthermore, compared with age group 18 to 39 years, the odds of new PPM placement after SM were higher in the age groups 40 to 64 years and ≥65 years, despite the risk adjustment (adjusted odds ratio [AOR] 3.17, 95% confidence interval [CI] 1.33 to 7.58 and AOR 4.39, 95% CI 1.78 to 10.8, respectively). The odds of in-hospital mortality after ASA were similar in age groups 65 to 79 years and 18 to 64 years. However, the odds of in-hospital mortality were higher in the age group ≥80 years than in the age group 18 to 64 years, although this difference were not present after risk adjustment. The odds of new PPM after ASA were higher for the age groups 65 to 79 years and ≥80 years than age group 18 to 64 years, despite the risk adjustment (AOR 1.78, 95% CI 1.22 to 2.60 and AOR 3.10, 95% CI 2.09 to 6.57, respectively). Finally, we also estimated these absolute risks in different age groups. In conclusion, this national data will inform health care providers to better understand the aged-based risks of outcomes after septal reduction therapy.


Chain mediating effect of insomnia, depression, and anxiety on the relationship between nightmares and cognitive deficits in adolescents.
The study explored the differences in nightmare, insomnia, depression, anxiety, and cognitive deficits among adolescents and the chain mediating effects of insomnia, depression, and anxiety on the relationship between nightmares and cognitive deficits in adolescents. An online survey was used to collect demographic data of 6014 adolescents and assess nightmare, insomnia, depression, anxiety, and cognitive deficits using the Chinese Version of Nightmare Distress Questionnaire, Insomnia Severity Index, Patient Health Questionnaire 9, Generalized Anxiety Disorder 7, and Perceived Deficits Questionnaire-Depression. Spearman correlation analysis and the SPSS function "PROCESS macro" were used for correlation and mediation analyses, respectively. Female adolescents, senior high school, and poor academic performance had higher nightmare, insomnia, and cognitive deficit scores; those living in the city had higher depression and anxiety scores. Cognitive deficits were positively correlated with nightmares, insomnia, depression, and anxiety. Further, insomnia, depression, and anxiety had a chain mediating effect between nightmares and cognitive deficits in adolescents. Nightmares indirectly affect cognition deficits by affecting insomnia and then depression and anxiety symptoms. As this was a cross-sectional study, the causal relationship between the variables could not be determined. Moreover, reporting bias and volunteer bias might be present. These findings suggest that clinicians should identify adolescents with frequent nightmares early and provide timely treatment to minimize negative outcomes and possibly limit the chronicity of nightmare disorder. It is significant to maintain the physical and mental health development of adolescents to reduce the risk of insomnia, depression, anxiety, and cognitive deficits.


Suppression of human ovarian SKOV-3 cancer cell growth by Duchesnea phenolic fraction is associated with cell cycle arrest and apoptosis.
Duchesnea indica (Andr.) Focke has been commonly used to treat cancer in Asian countries of centuries, and more recently, has been shown to possess anticancer properties in vivo and in vitro. However, little is known about the underlying mechanism of its anticancer action. In the present study, we investigated the effect of Duchesnea phenolic fraction (DPF) on SKOV-3 ovarian cancer cells to provide insights into the mechanisms of growth suppression involved in DPF-mediated apoptosis and cell cycle arrest. Cytotoxic activity of DPF on SKOV-3 cells was determined using MTT assay, apoptosis (AO/EB staining, DNA fragmentation, FACS), caspase-3 activation and cell cycle analysis studies. The role of the molecules in apoptosis and cell cycle regulation was analyzed by Western blot and RT-PCR. DPF significantly inhibited SKOV-3 cell proliferation in a dose-dependent manner and markedly induced apoptosis evidenced by characteristic apoptotic morphological changes, nuclear DNA fragmentation and sub-G1 peak. DPF suppressed Bcl-2 levels, enhanced Bax levels and Bax/Bcl-2 ratio, and simultaneously translocated Bax to mitochondria followed by mitochondrial release of cytochrome c into the cytosol and activation of effector caspase-3. Furthermore, DPF provoked S phase arrest in SKOV-3 cells with down-regulation of cyclin A, E, D1 and CDK2. DPF exhibits cytotoxicity towards human ovarian cancer SKOV-3 cells through induction of apoptosis via mitochondrial pathway and arresting cell cycle progression in S phase. All together, these data sustain our contention that DPF has anticancer properties and merits further investigation as a potential therapeutic agent.


Novel bioorthogonal reaction-mediated particle counting sensing platform using phage for rapid detection of Salmonella.
Bacterial detection in foods have to overcome the hindrance of complex matrices, resulting in more sophisticated pre-treatment steps and low sensitivity and reproductivity. Therefore, it remains a challenge to develop simple, rapid, accurate, and low-cost pathogen detection methods which were applicable for detection in turbid or complex food matrices. In this study, a novel bioorthogonal reaction-amplified microparticle counting sensing based on phages has been developed for the rapid detection of viable Salmonella in different foods. Phage not only acted as a bioreceptor to recognize viable Salmonella, but also used as an effective carrier for signal amplifiers due to its large specific surface area. The bioorthogonal reaction was introduced to further amplify the signal, the presence of Salmonella can specifically induce a quantitative change in the functionalized polystyrene microspheres, and thus can be monitored by the microporous resistance particle counter. Under the optimized conditions, this sensor could achieve a limit of detection of 33.58 CFU/mL and a linear range from 102 CFU/mL to 106 CFU/mL. This phage-mediated microporous resistance particle sensor can specifically recognize viable Salmonella in 1 h, providing a powerful platform for rapid and low-cost Salmonella quantification.


Illustrated multiple choice examinations.
Interpretation of visual data is an essential component of clinical competence. Illustrated multiple choice items have been used to measure interpretation, but the effects of introducing visual material into multiple choice items has not been critically assessed. A series of problem-sequenced multiple choice items containing, in the stem, a description of visual data such as a radiologist's report, was selected and matched with identical items where the description was replaced by reproductions of the original data. These two series of items were arranged into two parallel examinations which were taken by groups of final year medical students. From a comparison of the performance of the students in these two examinations it is concluded that substitution of actual visual data for the written description increases the difficulty of items, but is without consistent effect on discrimination. The illustrated format was commended by students for its clinical relevance but certain problems with the reproduction of radiographs and the selection of data have been revealed.


The emotionally disturbed child: disturbed or disturbing?
The notion that a child's behavior may be more "disturbing" than disturbed has been of interest to educators of behaviorally deviant children. Behavior indicative of deviance in child was studied with respect to the relating degree of "disturbingness" which each was judged to reflect. Four factor dimensions of disturbingness were identified and discussed with regard to future research and educational implications.


The need for ecological nested models as emerging theoretical frameworks in the investigation of affective variables in L2 education.
As an emotionally dynamic process, language learning is marked by fluctuations in students' affective constructs (e.g., enjoyment, playfulness, boredom). Thus, clues supporting an ecological perspective on behavioral trends and changes in language learners' emotional constructs driven by relational person and contextual components may be discovered. Therefore, an ecological approach enriched with the nested ecosystems model and complex dynamic system theory (CDST) can facilitate the investigation of dynamics of language students' affective constructs. These are first categorized and analyzed on the microsystem scale concerning students' motivation, beliefs, linguistic factors, cognitive factors, affective factors, and classroom context. Then, they are analyzed in 3 ecosystems including meso-, exo-, and macrosystems, each revealing an invaluable dimension of the reality of the emergent dynamicity of the variables. The present paper first draws attention to the dynamic nature of L2 learners' emotional factors and raises awareness of the ecological dynamic system theory. Then, it reviews the existing ecological studies of L2 affective variables and summarizes the findings. It ends with several conclusive remarks and suggestions for the future line of research.


Pentaerythritol tetranitrate (PETN) profiling in post-explosion residues to constitute evidence of crime-scene presence.
Pentaerythritol tetranitrate (PETN) and its degradation products are analyzed to discriminate between residues originating from PETN explosions and residues obtained under other circumstances, such as natural degradation on textile, or after handling intact PETN. The degradation products observed in post-explosion samples were identified using liquid chromatography-mass spectrometry as the less-nitrated analogues of PETN: pentaerythritol trinitrate (PETriN), pentaerythritol dinitrate (PEDiN) and pentaerythritol mononitrate (PEMN). Significant levels of these degradation products were observed in post-explosion samples, whereas only very low levels were detected in a variety of intact PETN samples and naturally degraded PETN. No significant degradation was observed after 12 weeks of storage at room temperature and the influence of high relative humidity (90%) was found to be small. Natural degradation was accelerated by storage of small amounts of PETN on different types of textile, resembling the clothing of a suspect, at elevated temperature (333K). This resulted in significant levels of PETN degradation products, but the relative amounts remained much lower than in post-explosion PETN. For PETriN the peak area relative to PETN was 0.014 (SD=0.0051) and 0.39 (SD=0.19) respectively. Based on the peak areas of PETriN, PEDiN and PEMN relative to PETN, it was possible to fully distinguish the post-explosion profiles from the profiles obtained from intact PETN or after (accelerated) natural degradation. Although more data are required to accurately assess the strength of the evidence, this work illustrates that PETN profiling may yield valuable evidence when investigating a possible link between a suspect and post-explosion PETN found on a crime scene. Due to the substantial variation in the degradation pattern between explosion experiments and even between sampling positions in one experiment, the method is not able to distinguish different PETN explosion events.


Mutation of the extracellular domain of tumour necrosis factor receptor 1 causes reduced NF-kappaB activation due to decreased surface expression.
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) results from point mutations in the extracellular domain of TNF receptor 1 (TNFRSF1A), but the effects of the mutations are controversial. This study shows that reduced NF-kappaB signalling is a feature of four TRAPS mutations. Reduced signalling correlates with reduced surface expression, measured by flow cytometry and microscopy. This suggests that correct formation of the extracellular domain of TNFRSF1A is important for localisation and receptor function. Importantly, our data provides a mechanism for the reduced TNFRSF1 signalling observed in a patient cell line.


Extracellular superoxide dismutase in biology and medicine.
Accumulated evidence has shown that reactive oxygen species (ROS) are important mediators of cell signaling events such as inflammatory reactions (superoxide) and the maintenance of vascular tone (nitric oxide). However, overproduction of ROS such as superoxide has been associated with the pathogenesis of a variety of diseases including cardiovascular diseases, neurological disorders, and pulmonary diseases. Antioxidant enzymes are, in part, responsible for maintaining low levels of these oxygen metabolites in tissues and may play key roles in controlling or preventing these conditions. One key antioxidant enzyme implicated in the regulation of ROS-mediated tissue damage is extracellular superoxide dismutase (EC-SOD). EC-SOD is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. In addition, EC-SOD is likely to play an important role in mediating nitric oxide-induced signaling events, since the reaction of superoxide and nitric oxide can interfere with nitric oxide signaling. This review will discuss the regulation of EC-SOD and its role in a variety of oxidant-mediated diseases.


Malassezia furfur colonization of neonates in an intensive care unit.
We studied Malassezia furfur colonization of neonates in the neonatal intensive care unit (NICU) and found that the rate was astonishingly high as compared to the previous studies. In very low birth weight (less than 1,000 g) infants we recorded a colonization rate of 80%, and 4% infants with a birth weight greater than 2,000 g. Under 10 day's hospitalization the rate was 11%, and it was 70% after 20 days spent in the unit. Among the infants with the birth weight less than 1,700 g, antibiotic therapy was recorded as a significant risk factor for colonization. In the infants with a greater birth weight, the colonization rate was independent from the risk factors studied. M. furfur colonization could not be linked with occurrence of any symptoms of signs recorded and colonization by M. furfur was so common in NICU that the predictive value of surveillance cultures is poor.


Improving Patient and Caregiver New Medication Education Using an Innovative Teach-back Toolkit.
Patients and caregivers are often not adequately informed about new medications. Nurses can lead innovations that improve new medication education. Healthcare Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores on medication questions trailed state and national levels in one Midwestern hospital. This quality improvement project, guided by the Ottawa Model of Research Use and the Always Use Teach-back! innovative toolkit, used a 1-group pre- and posteducation design with RNs, patients, and caregivers. RNs (n = 25) were observed in patient/caregiver education and surveyed in confidence/con-viction in the teach-back method before and after education. Patients' (n = 74) and caregivers' (n = 33) knowledge was assessed. RNs reported significant increases in conviction in the importance of (P < .0001), confidence in using (P < .0001), and frequency in using (P < .0001) teach-back. With teach-back, both patients and caregivers recalled the purpose and side effects of new medications. Specific HCAHPS scores increased from 6% to 10%. The teach-back method strengthened safe nursing practice and enhanced quality in new medication education.


Cytosolic lipid droplets increase in size by microtubule-dependent complex formation.
Adipocyte differentiation-related protein (ADRP)-containing lipid droplets have an essential role in the development of insulin resistance and atherosclerosis. Such droplets form in a cell-free system with a diameter of 0.1 to 0.4 microm, while the droplets present in cells vary in size, from small to very large, suggesting that the droplets can increase in size after being assembled. We have addressed this possibility. Experiments in NIH 3T3 cells demonstrated that the lipid droplets could increase in size independently of triglyceride biosynthesis. NIH 3T3 cells were either microinjected with ADRP-GFP (green fluorescent protein) or stained with Nile Red and followed by confocal microscopy and time-lapse recordings. The results showed that lipid droplets formed complexes with each other, with a volume equal to the sum of the merging particles. The formation of complexes could be inhibited by the nocodazole-induced depolymerization of the microtubules; thus, the process is dependent on microtubules. The presence of dynein on ADRP-containing droplets supports a role for this motor protein. Lipid droplets can grow after they have been assembled. This increase in size is independent of triglyceride biosynthesis and involves formation of complexes, which requires intact microtubules.


Sinomenine decreases MyD88 expression and improves inflammation-induced joint damage progression and symptoms in rat adjuvant-induced arthritis.
Sinomenine (SIN) is the active principle of the Chinese medical plant Sinomenium acutum which is widely used for the treatment of rheumatoid arthritis (RA) in China. Recently, several groups indicated that myeloid differentiation primary response protein 88 (MyD88) might be associated with disease progression of RA. Here, we observed the effect of SIN on MyD88 expression and showed its therapeutic role in RA. First, immunohistochemical staining in clinical specimens showed that MyD88 was mainly located in characteristic pathological structures of RA synovial tissues. Second, we found that MyD88 was overexpressed in the synovial tissues of the rats with adjuvant-induced arthritis (AIA). Treatment with SIN markedly decreased the expression of MyD88 in AIA rats. Finally, we provided evidences that SIN suppressed inflammation response and inflammation-induced joint destructive progression and arthritis symptoms in AIA rats. Therefore, SIN is an effective therapeutic agent for RA. Targeting MyD88 signaling may provide new methods for the treatment of RA.


Factors associated with non-specific low back pain in children aged 10-12 from Bucaramanga, Colombia: A cross-sectional study.
There are no Colombian studies published that assess non-specific low back pain (NSLBP) risk factors in children. To determine the factors associated with NSLBP in 73 children (19.2% girls) aged 10-12 years in one military school in Bucaramanga, Colombia. A questionnaire was used to obtain information of risk factors. Subsequently, children's weight and height were measured. The backpack was weighed at the beginning of each day from Monday to Friday. Crude and adjusted prevalence ratios were calculated, with their respective 95% confidence interval (CI). The one-month prevalence of NSLBP was 39.7% (95% CI 28.4-51.9). In the multivariate analysis, carrying backpacks wearing between 12% and 20% of body weight, having a perception that the backpack is very heavy, and being a passive smoker increase the likelihood of NSLBP, while being 11-year-old compared to 10-year-old decreases the likelihood of having NSLBP, adjusted for gender, body mass index, and history of LBP in parents. High prevalence of low back pain was found in children between 10 and 12 years old. The study of the decisive factors of low back pain is important to identify children at risk, as well as to develop efficient primary prevention programs.


Strength reliability and in vitro degradation of three-dimensional powder printed strontium-substituted magnesium phosphate scaffolds.
Strontium ions (Sr(2+)) are known to prevent osteoporosis and also encourage bone formation. Such twin requirements have motivated researchers to develop Sr-substituted biomaterials for orthopaedic applications. The present study demonstrates a new concept of developing Sr-substituted Mg3(PO4)2 - based biodegradable scaffolds. In particular, this work reports the fabrication, mechanical properties with an emphasis on strength reliability as well as in vitro degradation of highly biodegradable strontium-incorporated magnesium phosphate cements. These implantable scaffolds were fabricated using three-dimensional powder printing, followed by high temperature sintering and/or chemical conversion, a technique adaptable to develop patient-specific implants. A moderate combination of strength properties of 36.7MPa (compression), 24.2MPa (bending) and 10.7MPa (tension) were measured. A reasonably modest Weibull modulus of up to 8.8 was recorded after uniaxial compression or diametral tensile tests on 3D printed scaffolds. A comparison among scaffolds with varying compositions or among sintered or chemically hardened scaffolds reveals that the strength reliability is not compromised in Sr-substituted scaffolds compared to baseline Mg3(PO4)2. The micro-computed tomography analysis reveals the presence of highly interconnected porous architecture in three-dimension with lognormal pore size distribution having median in the range of 17.74-26.29μm for the investigated scaffolds. The results of extensive in vitro ion release study revealed passive degradation with a reduced Mg(2+) release and slow but sustained release of Sr(2+) from strontium-substituted magnesium phosphate scaffolds. Taken together, the present study unequivocally illustrates that the newly designed Sr-substituted magnesium phosphate scaffolds with good strength reliability could be used for biomedical applications requiring consistent Sr(2+)- release, while the scaffold degrades in physiological medium. The study investigates the additive manufacturing of scaffolds based on different strontium-substituted magnesium phosphate bone cements by means of three-dimensional powder printing technique (3DPP). Magnesium phosphates were chosen due to their higher biodegradability compared to calcium phosphates, which is due to both a higher solubility as well as the absence of phase changes (to low soluble hydroxyapatite) in vivo. Since strontium ions are known to promote bone formation by stimulating osteoblast growth, we aimed to establish such a highly degradable magnesium phosphate ceramic with an enhanced bioactivity for new bone ingrowth. After post-processing, mechanical strengths of up to 36.7MPa (compression), 24.2MPa (bending) and 10.7MPa (tension) could be achieved. Simultaneously, the failure reliability of those bioceramic implant materials, measured by Weibull modulus calculations, were in the range of 4.3-8.8. Passive dissolution studies in vitro proved an ion release of Mg(2+) and PO4(3-) as well as Sr(2+), which is fundamental for in vivo degradation and a bone growth promoting effect. In our opinion, this work broadens the range of bioceramic bone replacement materials suitable for additive manufacturing processing. The high biodegradability of MPC ceramics together with the anticipated promoting effect on osseointegration opens up the way for a patient-specific treatment with the prospect of a fast and complete healing of bone fractures.


Red not dead: signaling in and from erythrocytes.
The oxygen required to meet metabolic needs of all tissues is delivered by the erythrocyte, a small, flexible cell which, in mammals, is devoid of a nucleus and mitochondria. Despite its simple appearance, this 'bag of hemoglobin' has an important role in its own distribution, enabling the delivery of oxygen to precisely meet localized metabolic need. When an erythrocyte enters an area in which tissue oxygen demand exceeds supply, a signaling pathway is activated resulting in the release of adenosine 5'-triphosphate (ATP). This ATP acts in a paracrine fashion to increase vascular caliber resulting in increased oxygen delivery. Defects in this pathway are found in erythrocytes of humans with type 2 diabetes (DM2) and could contribute to the perfusion abnormalities in skeletal muscle associated with this disease.


En Bloc Versus Conventional Resection of Primary Bladder Tumor (eBLOC): A Prospective, Multicenter, Open-label, Phase 3 Randomized Controlled Trial.
En bloc transurethral resection of the bladder (eTURB) might improve the surgical management of non-muscle-invasive bladder cancer (NMIBC) in comparison to conventional TURB (cTURB). To evaluate whether eTURB is superior to cTURB in resection of NMIBC and specimen retrieval. This was a randomized, multicenter trial in patients with up to three cTa-T1 NMIBC tumors of 1-3 cm in size, who were enrolled from January 2019 to January 2022. Participants were randomized 1:1 to undergo eTURB (n = 192) or cTURB (n = 192). The primary outcome was the prevalence of detrusor muscle (DM) in the specimen retrieved. Secondary endpoints included bladder perforation, persistent disease at second-look TURB, positive lateral resection margin, positive deep resection margin, operation time, perforation rate, obturator reflex, conversion from eTURB to cTURB, recurrence-free survival, and disease recurrence at 3 mo. A total of 384 patients were randomized to undergo eTURB or cTURB. A total of 452 tumors were resected and analyzed for the primary outcome. eTURB was superior to cTURB in retrieval of DM (80.7% vs 71.1%; mixed-model p = 0.01). Bladder perforation (5.6% vs 12%; difference -6.4%; 95% confidence interval [CI] -12.2% to -0.6%) and obturator reflex (8.4% vs 16%; difference -7.6%; 95% CI -14.3% to -0.9%) were less frequent in the eTURB arm than in the cTURB arm. Operation time did not differ between the two techniques (26 min, interquartile range [IQR] 20-38 for eTURB vs 25 min, IQR 17-35 for cTURB; difference 1 min, 95% CI -25.9 to 4.99). Second-look TURB was performed in 24 patients in the eTURB arm and 34 in the cTURB arm, with no difference in the rate of residual papillary disease (pTa/pT1: 56% vs 55.9%; difference 0.1%, 95% CI -25.5% to 25.7%). At median follow-up of 13 mo (IQR 7-20), 18.4% of the patients in the eTURB arm and 16.7% in the cTURB arm had experienced bladder cancer recurrence (Cox hazard ratio 0.87, 95% CI 0.49-1.52; p = 0.6). In patients with clinical NMIBC with up to three tumors of 1-3 cm in size, tumor removal via eTURB resulted in a higher rate of DM in the pathologic specimen in comparison to cTURB. Moreover, eTURB was associated with lower frequency of obturator reflex and bladder perforation than cTURB was. While improving on the quality indicators for NMIBC, the long-term differential oncologic benefits of eTURB remain uncertain. We compared two techniques for removal of bladder tumors and found that tumor removal in a single piece, called en bloc resection, provides a better-quality specimen for pathology analysis and fewer complications in comparison to the conventional method. This trial is registered at ClinicalTrials.gov as NCT03718754.


Efficient generation of functional hepatocyte-like cells from menstrual blood-derived stem cells.
In recent years, the advantages of menstrual blood-derived stem cells (MenSCs), such as minimal ethical considerations, easy access and high proliferative ability, have inspired scientists to investigate the potential of MenSCs in cell therapy of different diseases. In order to characterize the potency of these cells for future cell therapy of liver diseases, we examined the potential of MenSCs to differentiate into hepatocytes, using different protocols. First, the immunophenotyping properties and potential of MenSCs to differentiate into osteoblasts, adipocytes and chondrocytes were evaluated. Thereafter, the differentiation protocols developed by two concentrations of hepatocyte growth factor (HGF) and oncostatin M (OSM), in combination with other components in serum-supplemented or serum-free culture media, were also investigated. The sequential differentiation was monitored by real-time PCR, immunostaining and functional assays. Our primary data revealed that the isolated MenSCs exhibited mesenchymal stem cell markers in parallel to OCT-4 as an embryonic marker. Regardless of differentiation procedures, the developed cells expressed mature hepatocyte markers, such as albumin, tyrosine aminotransferase and cytokeratin-18 at the mRNA and protein levels. They also showed functional properties of hepatocytes, including albumin secretion, glycogen storage and cytochrome P450 7A1 expression. However, the degree of differentiation was dependent on the concentrations of HGF and OSM. Indeed, omission of serum during the differentiation process caused typical improvement in hepatocyte-specific functions. This study is a novel report demonstrating the differentiation potential of MenSCs into hepatocyte-like cells. We recommend a complementary serum-free differentiation protocol for enrichment of in vitro production of functional MenSC-derived hepatocyte-like cells that could lead to a major step toward applied stem cell therapy of chronic liver diseases.


Factors associated with time of diagnosis and habilitation of congenital hearing loss in Indonesia: A multicenter study.
To investigate factors associated with time of diagnosis and habilitation of congenital hearing loss in Indonesia. A retrospective cohort study was conducted from January to December 2020 by collecting data on patients with congenital hearing loss using validated questionnaires. Among 535 children with congenital hearing loss, 2.7% had a family history of congenital hearing loss, 11.2% and 37.4% had a maternal history of ototoxic drugs and herbal medicine use during pregnancy, respectively, and 17.8% had prenatal exposure to TORCH infection. Lower maternal education level was shown to be associated with older age at diagnosis (p = 0.045), while older maternal age (p < 0.001), non-housewife mothers (p = 0.029), and out-of-pocket payment scheme (p = 0.027) were associated with a higher rate of habilitation. The present study showed that the presence of family history, the use of certain medications during pregnancy, and prenatal TORCH infection are prevalent in children with congenital hearing loss in Indonesia. Several factors such as maternal education level, age, occupation, and habilitation payment scheme may be associated with time of diagnosis and habilitation of congenital hearing loss.


Midinfrared Laser Pancorneal Coagulation as a Method of Treatment for Painful Bullous Keratopathy.
To evaluate the efficacy of midinfrared laser pancorneal coagulation (PCC) for the management of secondary painful bullous keratopathy (PBK) with poor visual potential. A single-center, nonrandomized, retrospective observational study was performed on 137 eyes (137 patients) with PBK that underwent midinfrared laser PCC and were followed up in our clinic during 2000 to 2010. Preoperatively and at follow-up visits, all the eyes underwent a standard ophthalmologic examination; concurrently, 36 of these underwent corneal optical coherence tomography (OCT) and Scheimpflug camera examination (SCE). The main criteria for the efficacy of the treatment included a profile of the patients' corneal syndrome-related complaints (pain, dryness, etc), presence of bullae and deepithelization, and changes in the corneal thickness (CT) and transparency, based on OCT and SCE data, respectively, whereas additional ones included visual acuity changes. During the 24-month follow-up period, 69.3% of the patients had no complaints (complete epithelization), whereas 10.9% and 3.6% complained of having dryness and residual pain, respectively; the rest exhibited a recurrent corneal syndrome with isolated blister and/or corneal erosion areas, which was successfully managed with an additional focal-pattern laser coagulation session. In the OCT and SCE subgroup, on the day-3, day-7, and month-24 visits, the mean CT statistically significantly decreased from baseline (1027.1 ± 239.5) to 737.6 ± 157.4 μm, 592.3 ± 96.4 μm, and was 617 ± 95.9 μm, respectively, whereas the mean optical density decreased from the baseline (72.5 ± 9.5) to 62.3 ± 7.8, 58.5 ± 8.7, and was 56.33 ± 8.1 Scheimpflug densitometry units, respectively. PCC is a simple procedure that provides prompt relief from pain for eyes that have PBK with poor visual potential due to the reduction in CT and significant resolution of bullae and edema.


The Emerging Role of FDG PET/CT in Diagnosing Endocarditis and Cardiac Device Infection.
Infective endocarditis and cardiac implantable electronic device infection (CIEDI) have witnessed an increasing incidence in clinical practice and associated with increasing health care expenditure. Expanding indications of CIED in various cardiovascular conditions have also contributed to the surge of these infections. Early diagnosis of these infections is associated with a favorable prognosis. Given the lack of a single definitive diagnostic method and the limitations of echocardiography, which is considered a central diagnostic imaging modality, additional imaging modalities are required. Recent studies have highlighted the diagnostic utility of FDG PET and CT. In this review article, we discuss the existing limitations of echocardiography, acquisition protocols of PET/CT, and indications of these advanced imaging modalities in infective endocarditis and CIEDI diagnosis.


Renal clearance of perfluorooctane sulfonate and perfluorooctanoate in humans and their species-specific excretion.
Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are detected in the environment, as well as more specifically in wildlife and humans. However, the toxicokinetic aspects of perfluorochemicals in humans are unclear. In this study, we measured concentrations of PFOA and PFOS in subjects who had lived in Kyoto city for more than 10 years. The serum concentrations of PFOA and PFOS were higher in females who menstruated than those who did not menstruation (P<0.01), but in males this did not change by age; the levels in females reached those in males at an age of 60 years. We then determined the renal clearances of PFOA and PFOS in young (20-40 years old, N=5 for each sex) and old (60 years old, N=5 for each sex) subjects of both sexes. All young females were menstruating, while all old females were not. The renal clearances were 10(-5)-fold smaller than the glomerular filtration rate in humans, suggesting the absence of active excretion in human kidneys. The renal clearances of PFOA and PFOS were approximately one-fifth of the total clearance based on their serum half-lives, assuming a one-compartment model. The sex differences in renal clearance that have been reported in rats and Japanese macaques were not found in our human subjects. We tried to build a one-compartment pharmacokinetic model using the reported half-lives in human. The model was simple but could predict the serum concentrations in both males and females fairly well. We therefore suggest that an internal dose approach using a pharmacokinetic model should be taken because of the large species differences in kinetics that exist for PFOA and PFOS.


[Analysis of ANKRD11 gene variant in a family affected with KBG syndrome].
To explore the genetic basis for a pedigree affected with KBG syndrome. Clinical data of three patients from the pedigree (the proband, his mother and sister) was collected. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing (WES). Suspected variant was verified by Sanger sequencing. The proband was found to harbor a heterozygous c.4398_4401del (p.Glu1467AsnfsTer63) frameshift variant of the ANKRD11 gene by WES. Sanger sequencing confirmed that the same variant was also present in his mother and sister, but not in his father. The c.4398_4401de (p.Glu1467AsnfsTer63) variation of the ANKRD11 gene probably underlies the KBG syndrome in this pedigree.


Effects of core stabilization exercises on thickness and activity of trunk and hip muscles in subjects with nonspecific chronic low back pain.
Changes in trunk and hip muscles are believed to be important in subjects with nonspecific chronic low back pain (NSCLBP), but little is known about specific changes, or how they might be affected by core stabilization exercises. The aim of this study was to compare six key muscles before and after these exercises. Thirty two NSCLBP patients were assigned randomly into two groups: exercise (n = 17) and control (n = 15). On 5 days per week for 4 weeks, the Exercise group performed 16 core stabilization exercises and the Control group received transcutaneous electrical nerve stimulation and a 'hot-pack'. Surface electromyography (EMG) was used to assess maximum bilateral activity of transversus abdominis (TrA), multifidus (MF) and gluteus maximus (Gmax) muscles. Ultrasound imaging was used to measure the rest and contracted thickness of these muscles. Pain and disability were assessed using a visual analogue scale (VAS) and the Oswestry Disability Index. When left and right-side muscle data were combined, two-way ANOVAs showed a nonsignificant interaction effect for all dependent variables (P > 0.05), significant time effects on resting muscle thickness for TrA (P = 0.01), MF (P = 0.041) and Gmax (P = 0.003), EMG signals of TrA (P = 0.038), pain and disability (P = 0.000). There were a significant group effect on contracted thickness for TrA (P = 0.032) and Gmax (P = 0.026) and disability (P = 0.017). Core stabilization exercises increased contracted thickness of TrA and Gmax muscles and decreased disability in subjects with NSCLBP.


Cytokine production by human odontoblast-like cells upon Toll-like receptor-2 engagement.
Recent studies have suggested that odontoblasts are involved in the dental pulp immune response to oral pathogens that invade human dentin during the caries process. How odontoblasts regulate the early inflammatory and immune pulp response to Gram-positive bacteria, which predominate in shallow and moderate dentin caries, is still poorly understood. In this study, we investigated the production of pro- and anti-inflammatory cytokines by odontoblast-like cells upon engagement of Toll-like receptor (TLR) 2, a pattern recognition molecule activated by Gram-positive bacteria components. We used a highly sensitive Milliplex(®) kit for detecting cytokines released by cells stimulated with lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria, or with the potent TLR2 synthetic agonist Pam2CSK4. We found that odontoblasts produce the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8, as well as the immunosuppressive cytokine IL-10 in response to TLR2 agonists. GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-12(p70), IL-13 and TNF-α were not detected. These data indicate that TLR2 activation in human odontoblasts selectively induces production of mediators known to influence positively or negatively inflammatory and immune responses in pathogen-challenged tissues. We suggest that these molecules might be important in regulating the fine tuning of the pulp response to Gram-positive bacteria which enter dentin during the caries process.


Colonic MUC2 mucin regulates the expression and antimicrobial activity of β-defensin 2.
In this study we identified mechanisms at the colonic mucosa by which MUC2 mucin regulated the production of β-defensin in a proinflammatory milieu but functionally protected susceptible bacteria from its antimicrobial effects. The regulator role of MUC2 on production of β-defensin 2 in combination with the proinflammatory cytokine interleukin-1β (IL-1β) was confirmed using purified human colonic MUC2 mucin and colonic goblet cells short hairpin RNA (shRNA) silenced for MUC2. In vivo, Muc2(-/-) mice showed impaired β-defensin mRNA expression and peptide localization in the colon as compared with Muc2(+/-) and Muc2(+/+) littermates. Importantly, purified MUC2 mucin abrogated the antimicrobial activity of β-defensin 2 against nonpathogenic and enteropathogenic Escherichia coli. Sodium metaperiodate oxidation of MUC2 removed the capacity of MUC2 to stimulate β-defensin production and MUC2's inhibition of defensin antimicrobial activity. This study highlights that a defective MUC2 mucin barrier, typical in inflammatory bowel diseases, may lead to deficient stimulation of β-defensin 2 and an unbalanced microbiota that favor the growth of β-defensin-resistant microbes such as Clostridium difficile.


Correction of secondary cleft lip and nasal deformities.
Surgical techniques for the correction of commonly seen secondary cleft deformities of the lip and nose are reviewed. These techniques include revision of the vermilion, vermilion--cutaneous junction, philtrum, nasal base, and nasal tip. Timing of intervention and coordination with other orofacial therapies are emphasized.


Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin.
In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca(2+) channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca(2+) influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.


CT enterography in obscure gastrointestinal bleeding: a systematic review and meta-analysis.
The objective of this article is to provide a comprehensive and update overview of clinical application of CT enterography (CTE) in the evaluation of obscure gastrointestinal bleeding (OGIB). We performed a systematic review of relevant literatures in PubMed, EMBASE and The Cochrane Library and pooled the yield of CTE and the incremental yield (IY) of CTE over an alternate modality. A total of 18 studies (n = 660) reported the yield of CTE in evaluating OGIB and the pooled yield was 40% (95% confidence interval (CI): 33-49%). Seven studies (n = 279) compared the yield of CTE with capsule endoscopy (CE). The yield for CTE and CE for all findings was 34% and 53%, respectively (IY = -19%, 95% CI = -34% to -4%). When considering the types of identified lesions, the yield was significantly different for vascular and inflammatory lesions but not significantly different for neoplastic or other lesions. Two studies (n = 63) compared the yield of CTE with double-balloon enteroscopy (DBE). The yield for CTE and DBE was 38% and 78%, respectively (IY = -40%, 95% CI = -55% to -25%). Three studies (n = 49) compared the yield of CTE with digital subtraction angiography. The yield for CTE and digital subtraction angiography was 64% and 60%, respectively (IY = 4%, 95% CI = -40% to 47%). CTE is an excellent diagnostic tool in patients with OGIB. It may play a complementary role to CE and can be used as a triage tool prior to DBE in evaluating OGIB.


Management of immediate and sustained intraocular pressure rise associated with intravitreal antivascular endothelial growth factor injection therapy.
To summarize the findings of recent reports of short-term and sustained intraocular pressure (IOP) rise associated with intravitreal antivascular endothelial growth factor (VEGF) injections and to guide the management of this infrequent complication. Short-term increases in IOP are common immediately after intravitreal anti-VEGF injection. IOP takes longer to reach a safe level in patients with a history of glaucoma or ocular hypertension. Preinjection medicinal therapy and ocular decompression therapy may blunt this short-term IOP rise. Sustained increases in IOP are relatively infrequent, but are likely to necessitate intervention for IOP-lowering. A 'pro re nata' (PRN) injection protocol may obviate the need for intervention. The pathophysiology of sustained IOP rise is poorly understood, but may relate to repackaging processes undertaken by the pharmacies that compound these agents. Treating physicians should be aware of the potential for short-term and sustained IOP rise associated with intravitreal anti-VEGF injection therapy. Considerations for management include prophylactic IOP-lowering with medicinal therapy and/or preinjection ocular decompression for patients with a history of glaucoma or ocular hypertension and switching to a 'PRN' injection protocol in patients suffering a sustained rise in IOP.


Feasibility and Safety of Urgent Laparoscopic Cholecystectomy for Acute Cholecystitis After 4 Days from Symptom Onset.
It is preferable to perform laparoscopic cholecystectomy for acute cholecystitis in the acute phase, within 72 h of symptom onset. The feasibility and safety of performing urgent laparoscopic cholecystectomy in the late phase (4-7 days after symptom onset) are unclear. The aim of this study was to clarify the feasibility and safety of late phase urgent laparoscopic cholecystectomy. Between 2005 and 2014, 233 patients underwent urgent laparoscopic cholecystectomy for acute cholecystitis within 7 days. We compared clinical features and perioperative outcomes between patients who underwent laparoscopic cholecystectomy within 3 days (early phase group) and 4-7 days after symptom onset (late phase group). There were 193 patients in the early phase group and 40 patients in the late-phase group. Performing laparoscopic cholecystectomy in the late phase did not influence operation time, postoperative complications, or postoperative hospital stay. The rate of conversion to open surgery and blood loss were slightly higher in the late-phase group (8 % and 140 ml) compared with the early phase group (3 % and 69 ml) but were still acceptable. Late phase urgent laparoscopic cholecystectomy for acute cholecystitis was feasible and safe.


Loss of the mitochondrial cox2 intron 1 in a family of monocotyledonous plants and utilization of mitochondrial intron sequences for the construction of a nuclear intron.
The intron content of plant organellar genes is a useful marker in molecular systematics and evolution. We have tested representatives of a wide range of monocotyledonous plant families for the presence of an intron (cox2 intron 1) in one of the most conservative mitochondrial genes, the cox2 locus. Almost all species analyzed were found to harbor a group II intron at a phylogenetically conserved position. The only exceptions were members of a single monocot family, the Ruscaceae: representatives of all genera in this family were found to lack cox2 intron 1, but instead harbor an intron in the 3' portion of the cox2 coding region (cox2 intron 2). The presence of cox2 intron 1 in families of monocotyledonous plants that are closely related to the Ruscaceae suggests that loss of the intron is specific to this family and may have accompanied the evolutionary appearance of the Ruscaceae. Interestingly, sequences that are highly homologous to cox2 intron 2 are found in a nuclear intron in a lineage of monocotyledonous plants, suggesting that the originally mitochondrial group II intron sequence was transferred to the nuclear genome and reused there to build a spliceosomal intron.


ADAR1 is a prognostic biomarker and is correlated with immune infiltration in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer with high morbidity and mortality rates and is usually detected at advanced stages because of the early onset of metastasis. Adenosine deaminase RNA-specific 1 (ADAR1) is an RNA editing enzyme that catalyzes the important physiological process of adenosine-to-inosine editing and has been shown to participate in the progression of LUAD. Increasing evidence has suggested that immune infiltration of the tumor immune microenvironment has prognostic value for most human solid organ malignancies; however, much is unknown about the functions of ADAR1. The expression of ADAR1 was analyzed in The Cancer Genome Atlas -LUAD database and validated in our LUAD cohort. To assess the prognostic value of ADAR1, Kaplan-Meier survival analyses and Cox regression analyses were carried out in LUAD cohorts. The association between ADAR1 and LUAD immune infiltrates via analyses of cell-type identification by estimating relative subsets of known RNA transcripts. Furthermore, multiplex immunohistochemistry was used to confirm the relationship between ADAR1 expression and immune cells in the present cohort of patients with LUAD. ADAR1 was highly expressed in LUAD tissues and closely correlated with lymph node metastasis (LNM) (p < 0.01), advanced tumor stage (p < 0.05), and poor patient prognosis (p < 0.01), thus indicating that increased ADAR1 contributed to the progression of LUAD. LUAD with high ADAR1 expression can metastasize to lymph nodes that express more ADAR1 than the primary lesion. In addition, M0 macrophages and M2 macrophages increased and CD4+ T cells decreased in LUAD tissues with high ADAR1 expression. And the expression of ADAR1 in lymph node metastases was negatively correlated with the contents of CD4+ T cells (p = 0.0017) and M1 macrophages (p = 0.0037). The findings of our study suggested that ADAR1 may be useful in predicting prognosis and LNM in LUAD, and may serve as a promising immune-related molecular target for LUAD patients.


18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy.
Prostate cancer is highly prevalent worldwide. Androgen deprivation therapy (ADT) remains the treatment of choice for incurable prostate cancer, but majority of patients develop disease recurrence following ADT. There is therefore an urgent need for early detection of treatment resistance. Isogenic androgen-responsive (CWR22Res) and castration-resistant (22Rv1) human prostate cancer cells were implanted into the anterior lobes of the prostate in CD-1 Nu mice to generate prostate orthografts. Castrated mice bearing CWR22Res and 22Rv1 orthografts mimic clinical prostate cancer following acute and chronic ADT, respectively. 18F-Fluciclovine (1-amino-3-fluorocyclobutane-1-carboxylic acid) with a radiochemical purity of > 99% was produced on a FASTlab synthesiser. Ki67 staining in endpoint orthografts was studied. Western blot, quantitative RT-PCR and next-generation sequencing transcriptomic analyses were performed to assess the expression levels of amino acid transporters (including LAT1 and ASCT2, which have been implicated for Fluciclovine uptake). Longitudinal metabolic imaging with 18F-Fluciclovine-based positron emission tomography (PET) was performed to study tumour response following acute and chronic ADT. Both immunohistochemistry analysis of endpoint prostate tumours and longitudinal 18F-Fluciclovine imaging revealed tumour heterogeneity, particularly following ADT, with in vivo 18F-Fluciclovine uptake correlating to viable cancer cells in both androgen-proficient and castrated environment. Highlighting tumour subpopulation following ADT, both SUVpeak and coefficient of variation (CoV) values of 18F-Fluciclovine uptake are consistent with tumour heterogeneity revealed by immunohistochemistry. We studied the expression of amino acid transporters (AATs) for 18F-Fluciclovine, namely LAT1 (SLC7A5 and SLC3A2) and ASCT2 (SLC1A5). SLC7A5 and SLC3A2 were expressed at relatively high levels in 22Rv1 castration-resistant orthografts following chronic ADT (modelling clinical castration-resistant disease), while SLC1A5 was preferentially expression in CWR22Res tumours following acute ADT. Additional AATs such as SLC43A2 (LAT4) were shown to be upregulated following chronic ADT by transcriptomic analysis; their role in Fluciclovine uptake warrants investigation. We studied in vivo 18F-Fluciclovine uptake in human prostate cancer orthograft models following acute and chronic ADT. 18F-Fluciclovine uptakes highlight tumour heterogeneity that may explain castration resistance and can be exploited as a clinical biomarker.


Assessment of cytological features of glandular lesions of the cervix on conventional smear preparations-a comprehensive study from a tertiary care hospital.
Atypical glandular cells (AGC) as a diagnostic category in cervicovaginal cytology remains as a challenge to cytopathologists. The aim of the present study is to identify the cytological features helpful in categorizing AGC as reactive or neoplastic upon correlation with histology. The study was a retrospective review of cervical smears, with histopathological follow up, reported as glandular lesions for a period of 9 years. The architectural and nuclear features studied were adapted from The Bethesda System (TBS) to stratify the lesions as AGC, AGC-FN (atypical glandular cells favour neoplasia) and adenocarcinoma. The cytological categories were correlated with histology. A total of 89 cases of which 67 (AGC NOS = 34, AGC FN = 19, adenocarcinoma = 14) with histology were reviewed. Neoplastic lesions were encountered in 14 cases (34.6%). Of the cases diagnosed as AGC-NOS, AGC-FN and adenocarcinoma, 26.5%, 68.4% and 100% respectively were neoplastic on histopathology. Squamous lesions accounted for 14.9% of all the glandular lesions. Rosette or acinar formation and loss of polarity frequently observed in neoplastic lesions as compared to reactive changes (p = 0.0004, p = 0.001). Of the nuclear features, nuclear hyperchromasia or coarse clumping of chromatin along with nuclear membrane irregularity and nuclear pleomorphism was frequently associated with neoplastic lesions as compared to reactive conditions (p = 0.007, p = 0.001, p = 0.0002). A diagnosis of AGC at cytology harbors significant number of malignant lesions when confirmed on biopsy. Architectural features complemented with nuclear characteristics helps in differentiating between reactive and neoplastic conditions. Hence stratifying glandular lesions at cytology according to TBS helps in the management.


Alu element-containing RNAs maintain nucleolar structure and function.
Non-coding RNAs play a key role in organizing the nucleus into functional subcompartments. By combining fluorescence microscopy and RNA deep-sequencing-based analysis, we found that RNA polymerase II transcripts originating from intronic Alu elements (aluRNAs) were enriched in the nucleolus. Antisense-oligo-mediated depletion of aluRNAs or drug-induced inhibition of RNA polymerase II activity disrupted nucleolar structure and impaired RNA polymerase I-dependent transcription of rRNA genes. In contrast, overexpression of a prototypic aluRNA sequence increased both nucleolus size and levels of pre-rRNA, suggesting a functional link between aluRNA, nucleolus integrity and pre-rRNA synthesis. Furthermore, we show that aluRNAs interact with nucleolin and target ectopic genomic loci to the nucleolus. Our study suggests an aluRNA-based mechanism that links RNA polymerase I and II activities and modulates nucleolar structure and rRNA production.