Multi-Level Swin Transformer Enabled Automatic Segmentation and Classification of Breast Metastases.
Detection of metastatic breast cancer lesions is a challenging task in breast cancer treatment. The recent advancements in deep learning gained attention owing to its robustness, particularly in addressing automated segmentation and classification issues in medical images. In this paper, we proposed a modified Swin Transformer model (mST) integrated with a novel Multi-Level Adaptive Feature Fusion (MLAFF) Module. We constructed a modified Swin Transformer network comprising of a Local Transferable MSA (LT-MSA) and a Global Transferable MSA (GT-MSA) in addition to a Feed Forward Network (FFN). Our novel Multi-Level Adaptive Feature Fusion (MLAFF) module iteratively combines the features throughout multiple transformers. We utilized a pre-trained deep learning model U-Net and trained it on mammography utilizing Transfer Learning for automated segmentation. The proposed method, mST-MLAFF, is used for breast cancer classification into normal, benign, and malignant classes. Our model outperformed comparison methods based on U-Net and Swin Transformer in breast metastatic lesion segmentation on the seven benchmark datasets, namely INBreast, DDSM, MIAS, CBIS-DDSM, MIMBCD-UI, KAU-BCMD, and Mammographic Masses. Our model achieved 98% Dice-Similarity coefficient (DSC) for segmentation and an average of 94.5% accuracy for classification, whereas U-Net based model achieved 92% DSC and Swin Transformer achieved 93% DSC. Extensive performance evaluation of our model on benchmark datasets shows the potential of our model for breast cancer classification.Clinical relevance- This research work is focused on assisting the radiologist in the early detection and classification of breast cancer. A single mammography image is analyzed in less than a minute for automated segmentation and classification into malignant and benign classes.


The Yorkhill CHIRPP story: a qualitative evaluation of 10 years of injury surveillance at a Scottish children's hospital.
The Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) is an emergency department-based injury surveillance system that was devised in Canada and has been in operation since 1990. CHIRPP was imported to Glasgow's Royal Hospital for Sick Children at Yorkhill in 1996 and ran for 10 years. To critically review CHIRPP at Yorkhill (Y-CHIRPP). The following two key questions were posed. (1) Did Y-CHIRPP fail, and, if so, why? (2) What generalisable lessons can be learned about injury surveillance? A retrospective qualitative review of Y-CHIRPP was carried out. In gathering information, the aims were to: (a) describe the processes involved in running Y-CHIRPP; (b) identify changes made to that process over the 10 years; (c) determine the strengths and weaknesses of Y-CHIRPP. Taken together, and with reference to the WHO attributes of a good surveillance system, the findings suggest that Y-CHIRPP largely met the criteria of simplicity, flexibility, and acceptability. Criteria that were not, or only intermittently, met were reliability, utility, sustainability, and timeliness. Y-CHIRPP was, at best, a partial success. To maintain the viability of an injury surveillance system and to secure the long-term support of hospital staff, it is important that the system is perceived as an injury prevention service tool and not a research method. Experience with Y-CHIRPP suggests that injury surveillance requires three supporting posts: an emergency department staff member, a data analyst, and someone with responsibility for developing and/or lobbying for the implementation of preventive measures.


Human CYP2A6, CYP2B6, AND CYP2E1 Atropselectively Metabolize Polychlorinated Biphenyls to Hydroxylated Metabolites.
Exposure to chiral polychlorinated biphenyls (PCBs) has been associated with neurodevelopmental disorders. Their hydroxylated metabolites (OH-PCBs) are also potentially toxic to the developing human brain; however, the formation of OH-PCBs by human cytochrome P450 (P450) isoforms is poorly investigated. To address this knowledge gap, we investigated the atropselective biotransformation of 2,2',3,4',6-pentachlorobiphenyl (PCB 91), 2,2',3,5',6-pentachlorobiphenyl (PCB 95), 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132), and 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by different human P450 isoforms. In silico predictions with ADMET Predictor and MetaDrug software suggested a role of CYP1A2, CYP2A6, CYP2B6, CYP2E1, and CYP3A4 in the metabolism of chiral PCBs. Metabolism studies with recombinant human enzymes demonstrated that CYP2A6 and CYP2B6 oxidized PCB 91 and PCB 132 in the meta position and that CYP2A6 oxidized PCB 95 and PCB 136 in the para position. CYP2B6 played only a minor role in the metabolism of PCB 95 and PCB 136 and formed meta-hydroxylated metabolites. Traces of para-hydroxylated PCB metabolites were detected in incubations with CYP2E1. No hydroxylated metabolites were present in incubations with CYP1A2 or CYP3A4. Atropselective analysis revealed P450 isoform-dependent and congener-specific atropselective enrichment of OH-PCB metabolites. These findings suggest that CYP2A6 and CYP2B6 play an important role in the oxidation of neurotoxic PCBs to chiral OH-PCBs in humans.


[Postoperative complications in a case of iatrogenic hypothyroidism induced by diet drugs].
Oral thyroid preparations, which were first administered in 1892 to treat myxedema, are the oldest effective endocrine medications. Since thyroxin became available, such drugs have been dispensed without a physician's prescription and have come to be mistakenly referred to as "diet pills". Self-prescription of such products can cause changes in thyroid function, with systemic repercussions. We report the case of a woman who took thyroid extracts, among other diet drugs to enhance weight loss without medical supervision. The patient failed to report taking such drugs during the preanesthetic visit. Interrupting therapy several days before surgery produced a state of hypothyroidism that led to marked postoperative hemodynamic changes necessitating transfer to the intensive care unit.


Polar Nature of (CH3NH3)3Bi2I9 Perovskite-Like Hybrids.
High-quality single crystals of perovskite-like (CH3NH3)3Bi2I9 hybrids have been synthesized, using a layered-solution crystal-growth technique. The large dielectric constant is strongly affected by the polar ordering of its constituents. Progressive dipolar ordering of the methylammonium cation upon cooling below 300 K gradually converts the hexagonal structure (space group P63/mmc) into a monoclinic phase (C2/c) at 160 K. A well-pronounced, ferrielectric phase transition at 143 K is governed by in-plane ordering of the bismuth lone pair that breaks inversion symmetry and results in a polar phase (space group P21). The dielectric constant is markedly higher in the C2/c phase above this transition. Here, the bismuth lone pair is disordered in-plane, allowing the polarizability to be substantially enhanced. Density functional theory calculations estimate a large ferroelectric polarization of 7.94 μC/cm2 along the polar axis in the P21 phase. The calculated polarization has almost equal contributions of the methylammonium and Bi3+ lone pair, which are fairly decoupled.


Exploring the potential of ChatGPT for clinical reasoning and decision-making: a cross-sectional study on the Italian Medical Residency Exam.
This study aimed to assess the performance of ChatGPT, a large language model (LLM), on the Italian State Exam for Medical Residency (SSM) test to determine its potential as a tool for medical education and clinical decision-making support. A total of 136 questions were obtained from the official SSM test. ChatGPT responses were analyzed and compared to the performance of medical doctors who took the test in 2022. Questions were classified into clinical cases (CC) and notional questions (NQ). ChatGPT achieved an overall accuracy of 90.44%, with higher performance on clinical cases (92.45%) than on notional questions (89.15%). Compared to medical doctors' scores, ChatGPT performance was higher than 99.6% of the participants. These results suggest that ChatGPT holds promise as a valuable tool in clinical decision-making, particularly in the context of clinical reasoning. Further research is needed to explore the potential applications and implementation of large language models (LLMs) in medical education and medical practice.


Confirmation and certainty in toxicology screening.
Confirmation of presumptive positive urine drug screens, necessary to minimize the reporting of false-positive results, can be costly and time-consuming. The predictive value model can be used to select the confirming tests and to calculate the confidence of the result. The predictive value of a test result is the probability, based on the sensitivity and specificity of the test, that the result is a true positive or a true negative. The predictive value model applied to toxicology screening tests for drugs of abuse showed that prevalence, in addition to sensitivity and specificity, was the factor controlling the confidence level of a result. For example, the predictive value of a positive result for a screening test that has a sensitivity of 99% and a specificity of 99%, applied to screening in a population with a prevalence of 1% is 0.50; for a prevalence of 10%, it is 0.92. Confirmation with a second, chemically independent, test of equal sensitivity and specificity increases the predictive value to 0.99.


Electrophysiology of intestinal cholecystokinin secretion.
The control of gastrointestinal CCK secretion may occur at several points. A decrease in potassium conductance may depolarize the plasma membrane, activating calcium channels with a resultant stimulation in CCK release. The opposite may occur with increases in potassium conductance. The model presented in Fig. 8 suggests that the key control point in the understanding of CCK secretion is the regulation of L-type calcium channels. Whether a single second messenger pathway may regulate calcium channels stimulated by agents such as glucose, phenylalanine, bombesin and cAMP is an important area to pursue.


Performance of Multidrug-Resistant Tuberculosis Surveillance in Yemen: Interview Study.
Multidrug-resistant tuberculosis (MDR-TB) is a major challenge to ending TB occurrence by 2035. In Yemen, the 2011 survey showed an MDR-TB prevalence of 1.4% among new cases and 14.4% among previously treated cases. The National Tuberculosis Control Program (NTCP) established four MDR-TB sentinel surveillance sites in 2013 to monitor the MDR-TB situation. In Yemen, the 2011 survey showed an MDR-TB prevalence of 1.4% among new cases and 14.4% among previously treated cases. The NTCP established four MDR-TB sentinel surveillance sites in 2013 to monitor the MDR-TB situation. This study aimed to assess the performance of MDR-TB surveillance and determine its strengths and weaknesses. We used the updated Center for Diseases Control and Prevention guidelines for evaluating public health surveillance systems. Interviews were conducted with NTCP managers and Regional MDR-TB centers' staff using a semistructured questionnaire. We used a 5-point Likert scale to assess the usefulness and other attributes (eg, simplicity and flexibility). The mean percentage was calculated for each attribute and used for the final rank of the performance: poor (<60%), average (60%-80%), and good (>80%). The MDR-TB surveillance system achieved good performance in usefulness (87%), acceptability (82%), and data quality (91%); average performance in flexibility (61%) and simplicity (72%); and poor performance in stability (55%). The overall performance score was average (74%). Although strong commitment, good monitoring, and well-trained staff are the main strengths, depending on an external fund is a major weakness along with unavailability of the MDR-TB unit at the governorate level. Although the MDR-TB surveillance system has achieved an average overall performance, more efforts are required to improve its stability by ensuring constant power supply to enable laboratories to perform necessary diagnostic and follow-up tests. Gradual replacement of donors' funds by the government is recommended. Scaling up of MDR-TB services and removing access barriers are crucial.


Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells.
The aim of the current study was to investigate the anticancer potential of arctigenin, a natural lignan compound, in malignant gliomas. The U87MG and T98G human glioma cell lines were treated with various concentrations of arctigenin for 48 h and the effects of arctigenin on the aggressive phenotypes of glioma cells were assessed. The results demonstrated that arctigenin dose-dependently inhibited the growth of U87MG and T98G cells, as determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays. Arctigenin exposure also induced a 60-75% reduction in colony formation compared with vehicle-treated control cells. However, arctigenin was not observed to affect the invasiveness of glioma cells. Arctigenin significantly increased the proportion of cells in the G0/G1 phase and reduced the number of cells in the S phase, as compared with the control group (P<0.05). Western blot analysis demonstrated that arctigenin increased the expression levels of p21, retinoblastoma and p53 proteins, and significantly decreased the expression levels of cyclin D1 and cyclin-dependent kinase 4 proteins. Additionally, arctigenin was able to induce apoptosis in glioma cells, coupled with increased expression levels of cleaved caspase-3 and the pro-apoptotic BCL2-associated X protein. Furthermore, arctigenin-induced apoptosis was significantly suppressed by the pretreatment of cells with Z-DEVD-FMK, a caspase-3 inhibitor. In conclusion, the results suggest that arctigenin is able to inhibit cell proliferation and may induce apoptosis and cell cycle arrest at the G0/G1 phase in glioma cells. These results warrant further investigation of the anticancer effects of arctigenin in animal models of gliomas.


Split cord malformation - A study of 300 cases at AIIMS 1990-2006.
Split cord malformation (SCM) is a rare condition. With decreasing incidence of neural tube defect (NTD) in the West, the reports of SCM are getting lesser and lesser. However, in India, spinal dysraphism is still a major problem encountered by the neurosurgeons. Our aim was to analyze 300 patients of SCM for their clinical features, radiological findings and outcome of surgery, which can throw light on the subject to others, who have less scope of finding these cases frequently. Over a 16-year period, we encountered 300 cases of SCM at AIIMS. Over the same period, more than 1500 cases of NTD were managed. SCM was noticed in 20% of cases with NTD. Skin stigmata were noted in two-third of the cases, and scoliosis and foot deformity were observed in 50% and 48% cases, respectively. Motor and sensory deficits were observed in 80% and 70% cases, respectively. Commonest site affected was lumbar or dorsolumbar (55% and 23%, respectively). In 3% cases, it was cervical in location. Magnetic resonance imaging (MRI) scan revealed a large number of anomalies like lipoma, neuroenteric cyst, thick filum and dermoid or epidermoid cysts. All the patients were surgically treated. In type I, bony spurs were excised, and in type II, bands tethering the cord were released. Associated anomalies were managed in the same sitting. Patients were followed up from 3 months to 3 years. Overall improvement was noticed in 50% and stabilization in 44% cases and deterioration of neurological status was recorded in 6% cases. However, 50% of those who deteriorated improved to preop status prior to discharge, 7-10 days following surgery. SCM is rare and not many large series are available. We operated 300 cases and noticed a large number of associated anomalies and also multilevel and multisite splits. Improvement or stabilization was noted in 94% and deterioration in 6% cases. We recommended prophylactic surgery for our asymptomatic patients.


Chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.
The purpose of this study was to determine whether chronic exercise alters sensitivity to the conditioned rewarding effects of cocaine. Female rats were obtained at weaning and randomly assigned to either sedentary or exercise conditions. After 6 weeks under these conditions, the effects of cocaine were examined in the conditioned place preference procedure. Cocaine produced a dose-dependent conditioned place preference in both groups of rats. Exercising rats were more sensitive than sedentary rats to cocaine in this procedure, and this effect was most pronounced at the highest dose of cocaine. These data suggest that chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.


A new stratified risk assessment tool for whiplash injuries developed from a prospective observational study.
An initial stratification of acute whiplash patients into seven risk-strata in relation to 1-year work disability as primary outcome is presented. The design was an observational prospective study of risk factors embedded in a randomised controlled study. Acute whiplash patients from units, general practitioners in four Danish counties were referred to two research centres. During a 2-year inclusion period, acute consecutive whiplash-injured (age 18-70 years, rear-end or frontal-end car accident and WAD (whiplash-associated disorders) grades I-III, symptoms within 72 h, examination prior to 10 days postinjury, capable of written/spoken Danish, without other injuries/fractures, pre-existing significant somatic/psychiatric disorder, drug/alcohol abuse and previous significant pain/headache). 688 (438 women and 250 men) participants were interviewed and examined by a study nurse after 5 days; 605 were completed after 1 year. A risk score which included items of initial neck pain/headache intensity, a number of non-painful complaints and active neck mobility was applied. The primary outcome parameter was 1-year work disability. The risk score and number of sick-listing days were related (Kruskal-Wallis, p<0.0001). In stratum 1, less than 4%, but in stratum 7, 68% were work-disabled after 1 year. Early work assessment (p<0.0001), impact of the event questionnaire (p<0.0006), psychophysical pain measures being McGill pain questionnaire parameters (p<0.0001), pressure pain algometry (p<0.0001) and palpation (p<0.0001) showed a significant relationship with risk stratification. Findings confirm previous studies reporting intense neck pain/headache and distress as predictors for work disability after whiplash. Neck-mobility was a strong predictor in this study; however, it was a more inconsistent predictor in other studies. Application of the risk assessment score and use of the risk strata system may be beneficial in future studies and may be considered as a valuable tool to assess return-to-work following injuries; however, further studies are needed.


Direct diverticular peroral endoscopic myotomy for the treatment of thoracic esophageal diverticula: technique and outcomes.
Diverticular peroral endoscopic myotomy (POEM) is an alternative to surgery for the management of symptomatic thoracic esophageal diverticula. Conventionally, this requires proximal tunnel formation but a direct approach may simplify the technique. Herein, we report the outcomes of direct diverticular-POEM (DD-POEM). We conducted a single-center prospective observational study evaluating DD-POEM. This involved a direct approach to the diverticulum. Success was defined as an Eckardt score of ≤ 3 without the need for reintervention. 10 patients underwent DD-POEM (median age 72 years; interquartile range [IQR] 14.3; male 60 % [n = 6]). Median diverticulum size was 40 mm (IQR 7.5) and median location was 35 cm from the incisors (IQR 8.3). Five patients (50 %) had an underlying dysmotility disorder. The median procedure duration was 60 minutes (IQR 28.8). There were no adverse events. The median hospital stay was 1 day (IQR 0.75). The pre-procedure median Eckardt score of 6 (IQR 4) significantly improved to 0 (IQR 0.75; P < 0.001) at a median follow-up of 14.5 months (IQR 13.8). Success was achieved in all patients. DD-POEM was a safe technique for the management of thoracic esophageal diverticula. Owing to its simplicity and excellent performance it should be further evaluated for the treatment of this disorder.


Ultra-Fast Recyclable and Value-Added Desulfation Method for Spent Lead Paste via Dual Intensification Processes.
The new low-cost clean pre-desulfation technology is very important in pyrometallurgy and hydrometallurgy. However, traditional reactors have low space-time yield and desulfation rate, resulting in high energy consumption and SO2 emissions in the industrial desulfation processes. Herein, dual rotating liquid film reactors (RLFRs) and lime are proposed to construct a recyclable, ultra-fast, and value-added desulfation method. Parameter optimization and kinetic calculations prove that the above reactions are controlled by internal diffusion, revealing that RLFR promotes the mass transfer and reaction rate. The new process greatly shortens the desulfation time of lead paste from 40 min to 10 s with a high desulfation rate of 99.7%, and the sulfation time of lime from 30 min to 30 s with a sulfation rate of 98.6% with a net profit of 55.99 ¥/ton by cost accounting. Moreover, ten batches of continuous scale-up experiments demonstrate the stability of processes, the desulfation and sulfation rates are kept at 99.7% and 98.2%, which greatly reduces the emissions of waste desulfate liquor. This work provides a new universal strategy for a sustainable, low-cost, and clean desulfation method of waste resources to achieve technical and economic feasibility.


Elucidating Non-aqueous Solvent Stability and Associated Decomposition Mechanisms for Mg Energy Storage Applications From First-Principles.
Rational design of novel electrolytes with enhanced functionality requires fundamental molecular-level understanding of structure-property relationships. Here we examine the suitability of a range of organic solvents for non-aqueous electrolytes in secondary magnesium batteries using density functional theory (DFT) calculations as well as experimental probes such as cyclic voltammetry and Raman spectroscopy. The solvents considered include ethereal solvents (e.g., glymes) sulfones (e.g., tetramethylene sulfone), and acetonitrile. Computed reduction potentials show that all solvents considered are stable against reduction by Mg metal. Additional computations were carried out to assess the stability of solvents in contact with partially reduced Mg cations (Mg2+ → Mg+) formed during cycling (e.g., deposition) by identifying reaction profiles of decomposition pathways. Most solvents, including some proposed for secondary Mg energy storage applications, exhibit decomposition pathways that are surprisingly exergonic. Interestingly, the stability of these solvents is largely dictated by magnitude of the kinetic barrier to decomposition. This insight should be valuable toward rational design of improved Mg electrolytes.


New perspectives on the mechanisms for orientation selectivity.
Since the discovery of orientation selectivity by Hubel and Wiesel, the mechanisms responsible for this remarkable operation in the visual cortex have been controversial. Experimental studies over the past year have highlighted the contribution of feedforward thalamo-cortical afferents, as proposed originally by Hubel and Wiesel, but they have also indicated that this contribution alone is insufficient to account for the sharp orientation tuning observed in the visual cortex. Recent advances in understanding the functional architecture of local cortical circuitry have led to new proposals for the involvement of intracortical recurrent excitation and inhibition in orientation selectivity. Establishing how these two mechanisms work together remains an important experimental and theoretical challenge.


Prenatal childbearing motivations, parenting styles, and child adjustment: A longitudinal study.
To have a child is among individuals' most important and meaningful decisions, with far-reaching implications. Despite evidence linking this decision to a wide variety of consequences, little is known about what motivates people to have children, and even less so about the long-term effects of different childbearing motivations on parenting and child adjustment. This study took a self-determination theory (SDT) perspective, examining how prenatal maternal autonomous and controlled childbearing motivations are related to child behavior problems through parenting styles. The rationale was that prenatal autonomous (sense of volition and self-fulfillment) and controlled (feeling pressured) childbearing motivations would shape later parental styles (autonomy-supportive vs. controlling, respectively) and, consequently, child adjustment. Over a period of 2 years beginning at pregnancy, 326 Israeli mothers reported their prenatal childbearing motivations, as well as parental styles and child behavior problems 20 months postpartum. Results of a path analysis revealed that prenatal autonomous childbearing motivation predicted autonomy-supportive parenting, yet the latter was not associated with children's behavior problems. Prenatal controlled motivation predicted controlling parenting, which, in turn, predicted children's internalizing and externalizing problems. No direct effects of childbearing motivation on children's behavior problems are observed, suggesting that childbearing motivation is a distal antecedent operating through more proximal factors such as parenting style. Findings were robust to children's temperamental tendencies and sociodemographic risk factors such as maternal age, high-risk pregnancy, and preterm birth. These findings have theoretical and practical implications for the discourse on motivations underlying the childbearing decision and their effects on parenting and child adjustment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Kinetic effects of sangivamycin in sarcoma 180 in vitro.
The lethal and sublethal effects of sangivamycin (SGM) were studied in sarcoma 180 in vitro in relation to drug concentration and duration of drug exposure. SGM lethality was found to be dependent on both drug concentration and duration of drug exposure. Pronounced effects on cell survival were observed only when SGM exposure was prolonged; with prolonged drug exposure, small increments in SGM concentration resulted in large increases in cell killing. Log-phase cells were more susceptible to the lethal effects of SGM than were early-plateau-phase cells. Measurements of incorporation of [3H]thymidine and [3H]uridine into the acid-insoluble cell fraction demonstrated inhibition of both DNA and RNA synthesis by SGM which was also dependent on drug concentration and duration of drug exposure, reflecting the lethality characteristics of SGM. As SGM concentration was increased, DNA synthesis was inhibited more rapidly than was RNA synthesis. Flow cytometry demonstrated a concentration- and time-dependent accumulation of cells in the late S and G2-M region of the DNA histogram. Our findings indicate that maximum lethality is obtained by prolongation of SGM exposure, and they suggest that pharmacokinetic studies may be important for determining regimens which provide such exposure in humans.


Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer.
The aim of this study was to evaluate the activity and safety of oxaliplatin/5-fluorouracil-based chemo-radiotherapy in patients with not radically resectable locally advanced esophageal cancer. Fifty-nine patients with adeno or squamous-cell carcinoma received oxaliplatin (60 mg/m(2)), and leucovorin (20 mg/m(2) on days 1,8,15,29,36,43,50,57) followed by continuous infusion fluorouracil (200 mg/m(2) per day on days 1-22 and 29-64) with radiotherapy (1.8 Gy daily fractions to a total dose of 45 Gy, from days 29 to 64). When feasible, surgery was scheduled 6-8 weeks after chemo-radiotherapy completion. The primary endpoint was 1-year progression-free survival. Forty (68%) patients completed treatment without modifications. An objective clinical response was seen in 35 patients (59%). Esophagectomy was possible in 33 patients and a complete resection (R0) was achieved in 26 (79%) with 6 pathologic complete responses (pCR) and 3 near pCR. At a median follow-up of 39.7 months for the surviving patients, the median progression-free and overall survivals were 11 months (95% CI 6.5-14) and 18.5 months (95% CI 13-29). The 1-year progression-free and overall survivals were 47.5% (95% CI 34-59.5%) and 63% (95% CI 49-74%). Major toxicities were esophagitis (20% G3 and 5% G4) and diarrhea (8.5% G3 and 8.5% G4). Hematological toxicity (7% G3 and 3% G4) was less common; severe neurotoxicity (3% G3) was infrequent. Concurrent oxaliplatin, leucovorin, fluorouracil and radiotherapy followed or not by esophagectomy has a tolerable toxicity and promising activity in locally advanced esophageal cancer.


Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database.
The Cardiac Safety Research Consortium (CSRC) provides both "learning" and blinded "testing" digital electrocardiographic (ECG) data sets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This article reports the first results from a blinded testing data set that examines developer reanalysis of original sponsor-reported core laboratory data. A total of 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 181 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer-measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Developer and sponsor-reported baseline-adjusted data were similar with average differences <1 ms for all intervals. Both developer- and sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject SD for triplicate QTcF measurements was significantly lower for developer- than sponsor-reported data (5.4 and 7.2 ms, respectively; P < .001). The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared with the sponsor-reported study, without the use of a manual core laboratory. These findings indicate that CSRC ECG data sets can be useful for evaluating novel methods and algorithms for determining drug-induced QT/QTc prolongation. Although the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG technologies applied for QT/QTc measurement is illustrated.


A simple method for assessing free brain/free plasma ratios using an in vitro model of the blood brain barrier.
Historically, the focus has been to use in vitro BBB models to optimize rate of drug delivery to the CNS, whereas total in vivo brain/plasma ratios have been used for optimizing extent. However, these two parameters do not necessarily show good correlations with receptor occupancy data or other pharmacological readouts. In line with the free drug hypothesis, the use of unbound brain concentrations (Cu,br) has been shown to provide the best correlations with pharmacological data. However, typically the determination of this parameter requires microdialysis, a technique not ideally suited for screening in early drug development. Alternative, and less resource-demanding methodologies to determine Cu,br employ either equilibrium dialysis of brain homogenates or incubations of brain slices in buffer to determine fraction unbound brain (fu,br), which is subsequently multiplied by the total brain concentration to yield Cu,br. To determine Cu,br/Cu,pl ratios this way, still requires both in vitro and in vivo experiments that are quite time consuming. The main objective of this study was to explore the possibility to directly generate Cu,br/Cu,pl ratios in a single in vitro model of the BBB, using a co-culture of brain capillary endothelial and glial cells in an attempt to mimick the in vivo situation, thereby greatly simplifying existing experimental procedures. Comparison to microdialysis brain concentration profiles demonstrates the possibility to estimate brain exposure over time in the BBB model. A stronger correlation was found between in vitro Cu,br/Cu,pl ratios and in vivo Cu,br/Cu,pl obtained using fu,br from brain slice than with fu,br from brain homogenate for a set of 30 drugs. Overall, Cu,br/Cu,pl ratios were successfully predicted in vitro for 88% of the 92 studied compounds. This result supports the possibility to use this methodology for identifying compounds with a desirable in vivo response in the CNS early on in the drug discovery process.


Coordination Driven Capture of Nicotine Inside a Mesoporous MOF.
Metal organic frameworks (MOFs) are a wide class of crystalline porous polymers studied in many fields, ranging from catalysis to gas storage. In the past few years, MOFs have been studied for the encapsulation of organic or organometallic molecules and for the development of potential drug carriers. Here, we report on the study of two structurally-related mesoporous Cu-MOFs, namely PCN-6 and PCN-6' (PCN stands for Porous Coordination Network), for nicotine trapping. Nicotine is a well-known alkaloid liquid molecule at room temperature, whose crystalline structure is still unknown. In this work, the loading process was monitored by electron ionization mass spectrometry by using a direct insertion probe (DIP-EI/MS), infrared (IR), and ultraviolet/visible (UV/VIS) analysis. Both nuclear magnetic resonance (NMR) spectroscopy and thermogravimetric (TGA) analysis showed evidence that nicotine trapping reaches remarkable uptakes up to 40 wt %. In the case of PCN-6@nicotine, X-ray structural resolution revealed that the guest uptake is triggered by coordination of the pyridine ring of nicotine to the copper nuclei of the paddle-wheel units composing the framework of PCN-6.


[Protein granules and spheres in the nuclei of reptile oocytes].
The morphology, the time and place of formation of the protein granules and spheres in nuclei of reptiles 11 species of oocytes are described. The problem of the place of protein synthesis forming the granules and spheres is discussed. Examples are cited showing presence of protein bodies in nuclei of primary sex cell, oogonies, spermatocytes, and in macronuclei of protozoa as well as in oocytes at the diplotene state of some invertebrae and vertebrae. The description of their chemical composition and ultrastructure is given. With regard to the nucleus programming role. the significance of these structures for accumulation of proteins necessary for meiotic division and cleavage of oocytes, was suggested.


Orthographic processing of polysyllabic words by native and nonnative English speakers.
How polysyllabic English words are analyzed in silent reading was examined in three experiments by comparing lexical decision responses to words physically split on the screen. The gap was compatible either with the Maximal Onset Principle or the Maximal Coda Principle. The former corresponds to the spoken syllable (e.g., ca det), except when the word has a stressed short first vowel (e.g., ra dish), while the reverse is true for the latter (giving cad et and rad ish). Native English speakers demonstrated a general preference for the Max Coda analysis and a correlation with reading ability when such an analysis did not correspond with the spoken syllable. Native Japanese speakers, on the other hand, showed a Max Onset preference regardless of the type of word, while native Mandarin Chinese speakers showed no preference at all. It is concluded that a maximization of the coda is the optimal representation of polysyllabic words in English and that poorer native readers are more influenced by phonology than are better readers. The way that nonnative readers mentally represent polysyllabic English words is affected by the way such words are structured in their native language, which may not lead to optimal English processing.


Recruiting participants for an international mHealth study via Facebook Ads: Experiences from the Untire App RCT.
Social media recruitment via Facebook Ads seems to be a promising method for large-scale international trials examining the effectiveness of mHealth interventions. However, little is known about this method in terms of strategy, reach, and costs in the context of psycho-oncology. This paper presents the results of the recruitment strategy that was applied in the Untire app study and shows how many participants could be reached using advertisements (i.e., Ads) on Facebook, who participated, and what it cost. The Untire app study is a randomized controlled trial targeted at cancer patients and survivors across four English-speaking countries (i.e., Australia, Canada, the U.K., and the U.S.A.). Reach was assessed by the number of people who were shown the Ads, who clicked on the Ads, and completed study assessments. Demographic characteristics were gathered from Facebook Ads Manager and from online study assessments to describe who was reached. Costs were assessed by the budget spent and the cost per click for Ads, for reaching the study's landing page, and for completing study assessments. To conduct a powered RCT, we needed 164 12-weeks assessments in both the intervention and the control group. From March till October 2018, we used 76 Ads, which were presented to 1.2 million people. 37.376 persons clicked on the study link in the Ads, resulting in 755 baseline completers. Most participants were female (92%), middle-aged (55.5 ± 9.79), and came from the U.K. (72%). The total Facebook advertisement costs from March till October 2018 were €17 k, resulting in an average cost of €0.45 per click on the Ads, €5.55 on average for a person reaching the study's landing page, and €14.89 on average per eligible participant. The costs for every baseline and 12-weeks completer were €22.42 and €47.69, respectively. Reaching participants for international mHealth studies in psycho-oncology via Facebook Ads has potential but is costly. The key to reducing costs lies in constant optimization and testing of Ads and refinement of target audience characteristics.


Placing epidemiological results in the context of multiplicity and typical correlations of exposures.
Epidemiological studies evaluate multiple exposures, but the extent of multiplicity often remains non-transparent when results are reported. There is extensive debate in the literature on whether multiplicity should be adjusted for in the design, analysis, and reporting of most epidemiological studies, and, if so, how this should be done. The challenges become more acute in an era where the number of exposures that can be studied (the exposome) can be very large. Here, we argue that it can be very insightful to visualize and describe the extent of multiplicity by reporting the number of effective exposures for each category of exposures being assessed, and to describe the distribution of correlation between exposures and/or between exposures and outcomes in epidemiological datasets. The results of new proposed associations can be placed in the context of this background information. An association can be assigned to a percentile of magnitude of effect based on the distribution of effects seen in the field. We offer an example of how such information can be routinely presented in an epidemiological study/dataset using data on 530 exposure and demographic variables classified in 32 categories in the National Health and Nutrition Examination Survey (NHANES). Effects that survive multiplicity considerations and that are large may be prioritized for further scrutiny.


Identification of the alpha-aminoadipic semialdehyde dehydrogenase-phosphopantetheinyl transferase gene, the human ortholog of the yeast LYS5 gene.
In mammals, L-lysine is first catabolized to alpha-aminoadipate semialdehyde by the bifunctional enzyme alpha-aminoadipate semialdehyde synthase (AASS), followed by a conversion to alpha-aminoadipate by alpha-aminoadipate semialdehyde dehydrogenase. In Saccharomyces cerevisiae, which synthesize rather than degrade lysine, the latter activity requires two distinct genes. LYS2 encodes the alpha-aminoadipate reductase activity, while LYS5 encodes a phosphopantetheinyl transferase activity that is required to activate Lys2p. We have identified a full-length human cDNA homologous to the yeast LYS5 gene. The cDNA contains an open-reading frame of 930 bp predicted to encode 309 amino acids, and the human protein is 26% identical and 44% similar to its yeast counterpart. In Northern blot analysis the cDNA hybridizes to a single transcript of approximately 3 kb in all tissues except testis, where there is an additional transcript of 1.5 kb. Expression is highest in brain followed by heart and skeletal muscle, and to a lesser extent in liver. We further identified three human genomic BAC clones containing the human gene. Fluorescence in situ hybridization (FISH) analysis using the BAC clones mapped the gene to chromosome 11q22 while alignment of the cDNA and genomic sequences allowed partial identification of the intron-exon boundaries. Finally, using one-step homologous recombination in S. cerevisiae we generated a lys5 knockout strain. Complementation studies in the yeast knockout demonstrate that the human homolog encodes alpha-aminoadipate dehydrogenase phosphopantetheinyl transferase activity. We hypothesize that defects in this gene may result in pipecolic acidemia.


Risk of insomnia attributable to β-blockers in elderly patients with newly diagnosed hypertension.
Use of β-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among β-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with β-blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35-0.63) for non-propranolol users, 0.31 (0.19-0.50) for bisoprolol, and 0.46 (0.33-0.66) for atenolol. Compared to the patients using non-selective β-blockers, the adjusted odds ratio was 0.48 (0.36-0.34) for those using selective β(1)-blockers. Additionally, the adjusted odds ratio was 0.72 (0.53-0.96) for β-blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. β-Blockers with high selectivity in β(1)-receptors and/or low lipophilicity were associated with a lower risk of insomnia.


Advancements in minimally invasive total hip arthroplasty.
Orthopedic surgeons have successfully performed total hip arthroplasty (THA) for more than 40 years. During this time it has continued to evolve into a more predictable and refined procedure. Minimally invasive surgery represents one of the most recent techniques to have emerged within THA. In conventional THA, the incision typically measures 20-30 cm depending on the patient. Although conventional THA affords wide exposure of the hip joint, it also leads to a predictably large blood loss and significant rehabilitation time. Minimally invasive approaches, defined as less invasive to the skin, muscles, or bone, may reduce complications and potentially improve recovery time. Minimizing the recovery process is becoming increasingly desirable in a society that demands an individual to return to normal activities after a short recovery. There are a number of potential approaches and methods that may improve the results of THA. Complications of minimally invasive surgery may include sciatic or femoral nerve palsy, component malpositioning, intraoperative fracture, leg length discrepancy, and damage to muscles or skin by excessive retraction.


Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects.
Therapeutic peptides have become very successful drugs due to their specificity, potency and low toxicity, but they show challenges for their delivery, due to their short half-life and rapid plasma clearance. For these reasons, peptides are usually administered using injectable sustained-release formulations. Oral peptide route is highly compelling from a patient and commercial point of view. However, poor peptide stability and low permeability across the intestinal epithelium still make it very challenging to effectively deliver peptides by the oral route. In this paper, biopharmaceutical and formulation features of oral peptides, as well as key clinical outcomes, are reviewed and discussed in the perspective of designing next generation of oral peptide formulations for a true paradigm shift.


CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents.
Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective. Citron kinase protein (CITK) has been proposed as a promising target for SHH MB, whose inactivation leads to DNA damage and apoptosis. D283 and D341 cell lines (Group 3/Group 4 MB) were silenced with established siRNA sequences against CITK, to assess the direct effects of its loss. Next, D283, D341, ONS-76 and DAOY cells were treated with ionizing radiation (IR) or cisplatin in combination with CITK knockdown. CITK depletion impaired proliferation and induced cytokinesis failure and apoptosis of G3/G4 MB cell lines. Furthermore, CITK knockdown produced an accumulation of DNA damage, with reduced RAD51 nuclear levels. Association of IR or cisplatin with CITK depletion strongly impaired the growth potential of all tested MB cells. These results indicate that CITK inactivation could prevent the expansion of G3/G4 MB and increase their sensitivity to DNA-damaging agents, by impairing homologous recombination. We suggest that CITK inhibition could be broadly associated with IR and adjuvant therapy in MB treatment.


Non-convulsive status epilepticus: a treatable cause of confusion in pituitary apoplexy.
Confusion occurring in pituitary apoplexy is well described. We describe a case of pituitary apoplexy associated with confusion, occurring as a result of non-convulsive status epilepticus. Electroencephalography should be performed in pituitary apoplexy associated with confusion if this treatable and potentially serious complication is not to be missed.


The Relationships between Sibling Characteristics and Motor Performance in 3- to 5-Year-Old Typically Developing Children.
Siblings have been hypothesized to positively impact the motor performance of children by acting as examples and by providing a safe environment, but they may also negatively impact motor performance because they could compete for the parent's time and care. Therefore, this study investigates the relationship between several sibling characteristics and motor performance in 3- to 5-year-old children. The sample consisted of 205 3- to 5-year-old children (mean age 50.9 ± 10.0 months, 52.2% boys). The Movement Assessment Battery for Children-2 was used to measure motor performance. The sibling variable was operationalized as the number of siblings present, the age difference between a child and its siblings, and the birth order position of a child. The confounding variables that were taken into account were the age, sex, and behavioral problems of the child and maternal education level. None of the investigated sibling variables were related to the total motor performance of a child after controlling for possible confounding variables. The absence of any associations between the sibling variables and motor performance might be explained by the characteristics of the study sample, the possibility that there is no linear relationship, or the presence of still unknown moderating or mediating factors.


Divergent effects of leptin in mice susceptible or resistant to obesity.
Consumption of a high-fat diet decreases hypothalamic neuropeptide Y (NPY) and increases proopiomelanocortin (POMC) and brown adipose uncoupling protein (UCP)-1 mRNA in obesity-resistant SWR/J but not obesity-prone C57Bl/6J mice. Although leptin was elevated in both strains in response to a high-fat diet, its role in the development of diet-induced obesity has remained unclear since insulin and other factors that affect similar tissue targets are altered. Thus, we administered recombinant leptin by subcutaneous infusion to chow-fed mice to mimic the changes in plasma leptin across its broad physiologic range. We observed strain differences in responsiveness to reduced and elevated leptin levels. A reduction in leptin during fasting evoked a greater response in C57Bl/6J mice by decreasing energy expenditure and thyroxin, increasing corticosterone and stimulating food intake and weight gain during refeeding. However, C57Bl/6J mice were less responsive to an increase in leptin in the fed state. Conversely, the leptin-mediated response to fasting was blunted in SWR/J mice, whereas an increase in leptin profoundly reduced food intake and body weight in SWR/J mice fed ad libitum. Sensitivity to fasting in C57Bl/6J mice was associated with higher hypothalamic NPY mRNA and reduced POMC and UCP-1 mRNA expression, while the robust response to high leptin levels in SWR/J mice was associated with suppression of NPY mRNA. These results indicate that differences in leptin responsiveness between strains might occur centrally or peripherally, leading to alteration in the patterns of food intake, thermogenesis and energy storage.


Drosophila rae1 is required for male meiosis and spermatogenesis.
Previous studies of RAE1, a conserved WD40 protein, in Schizosaccharomyces pombe and mouse revealed a role in mRNA export and cell cycle progression in mitotic cells. Studies of RAE1 in Drosophila showed that the protein localizes to the nuclear envelope and is required for progression through the G1 phase of the cell cycle but not RNA export in tissue culture cells. Drosophila RAE1 also plays an essential developmental role, as it is required for viability and synaptic growth regulation as a component of an E3 ubiquitin ligase complex. Here we describe characterization of a new Drosophila rae1 mutant that is viable but results in male sterility. The mutant showed striking defects in primary spermatocyte nuclear integrity, meiotic chromosome condensation, segregation, and spindle morphology. These defects led to a failure to complete meiosis but allowed several aspects of spermatid differentiation to proceed, including axoneme formation and elongation. A GFP-RAE1 fusion protein that rescued most of the cytological defects showed a dynamic localization to the nuclear envelope, chromatin and other structures depending on the stage of spermatogenesis. A role for RAE1 in male meiosis, as well as mitotic cells, was also indicated by the defects induced by expression of rae1-RNAi. These studies in Drosophila provide the first evidence for an essential meiotic role of RAE1, and thus define RAE1 as a protein required for both meiotic and mitotic cell cycles.


Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.
To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. F Hoffmann-La Roche.


X-ray microanalysis of Plasmodium falciparum and infected red blood cells: effects of qinghaosu and chloroquine on potassium, sodium, and phosphorus composition.
Cryosections of human red blood cells infected by Plasmodium falciparum were analyzed by energy dispersive x-ray microanalysis to determine the elemental composition of the parasites and their red cell hosts separately. The effects of two antimalarial drugs, qinghaosu and chloroquine, on potassium, sodium, and phosphorus concentrations were studied. Malarial infection causes a decrease in potassium concentration and an increase in sodium concentration in the host red cells. The drastic change in the cation composition, however, occurs only in red cells infected by late stage parasites (late trophozoite and schizont). Red cells infected by early stage parasites (ring stage) show only small changes in sodium concentration. Furthermore, the noninfected red cells in parasitized cultures show no difference in composition from those of normal red cells. Treatment of the parasitized cultures with qinghaosu (10(-6) M) or chloroquine (10(-6) M) for 8 hr causes phosphorus concentration of both early and late parasites to decrease. An 8 hr treatment with qinghaosu also produces a reduction in potassium and an increase in sodium concentrations in early and late parasites. In contrast, 8 hr treatment with chloroquine only causes a change in the sodium and potassium concentrations of the late stage parasites and does not affect the early stage parasites.


Mycolactone gene expression is controlled by strong SigA-like promoters with utility in studies of Mycobacterium ulcerans and buruli ulcer.
Mycolactone A/B is a lipophilic macrocyclic polyketide that is the primary virulence factor produced by Mycobacterium ulcerans, a human pathogen and the causative agent of Buruli ulcer. In M. ulcerans strain Agy99 the mycolactone polyketide synthase (PKS) locus spans a 120 kb region of a 174 kb megaplasmid. Here we have identified promoter regions of this PKS locus using GFP reporter assays, in silico analysis, primer extension, and site-directed mutagenesis. Transcription of the large PKS genes mlsA1 (51 kb), mlsA2 (7 kb) and mlsB (42 kb) is driven by a novel and powerful SigA-like promoter sequence situated 533 bp upstream of both the mlsA1 and mlsB initiation codons, which is also functional in Escherichia coli, Mycobacterium smegmatis and Mycobacterium marinum. Promoter regions were also identified upstream of the putative mycolactone accessory genes mup045 and mup053. We transformed M. ulcerans with a GFP-reporter plasmid under the control of the mls promoter to produce a highly green-fluorescent bacterium. The strain remained virulent, producing both GFP and mycolactone and causing ulcerative disease in mice. Mosquitoes have been proposed as a potential vector of M. ulcerans so we utilized M. ulcerans-GFP in microcosm feeding experiments with captured mosquito larvae. M. ulcerans-GFP accumulated within the mouth and midgut of the insect over four instars, whereas the closely related, non-mycolactone-producing species M. marinum harbouring the same GFP reporter system did not. This is the first report to identify M. ulcerans toxin gene promoters, and we have used our findings to develop M. ulcerans-GFP, a strain in which fluorescence and toxin gene expression are linked, thus providing a tool for studying Buruli ulcer pathogenesis and potential transmission to humans.


Distinctive regulation of v-Src-associated phosphatidylinositol 3-kinase during PC12 cell differentiation.
In chicken embryo fibroblasts, the binding of v-Src to PtdIns 3-kinase requires Src homology domains, SH3, SH2 and the SH1 or kinase domain, which induces the cytoskeletal disruption associated with fibroblast transformation. In the rat phaeochromocytoma PC12 cell line, v-Src has a different effect on the cytoskeleton, inducing neurite extension rather than cytoskeletal disruption. Here we show that v-Src-induced neurite outgrowth is suppressed by the selective PtdIns 3-kinase inhibitor LY294002, suggesting that this effect of v-Src in PC12 cells also requires the activity of the lipid kinase. However, in contrast with chicken embryo fibroblasts, the association of PtdIns 3-kinase with v-Src in PC12 cells is delayed until several hours after activating the v-Src tyrosine kinase. Furthermore the v-Src-associated p85 regulatory subunit of PtdIns 3-kinase is not phosphorylated on tyrosine in PC12 cells and associates only weakly with isolated v-Src homology domains (SH3/SH2) in a Src kinase-independent manner. However, p85 and v-Src both associate with an unidentified protein (of molecular mass approx. 68 kDa; termed p68), which becomes tyrosine phosphorylated concomitantly with the association of both p85 and PtdIns 3-kinase with v-Src in PC12 cells. Thus we conclude that the mode of regulation of v-Src-associated PtdIns 3-kinase is cell-context-dependent and that p68 might act as an adaptor protein to mediate the association of p85 and v-Src in PC12 cells. The different regulation of PtdIns 3-kinase in PC12 and in chicken embryo fibroblasts in response to v-Src activity might reflect the different cytoskeletal rearrangements induced by this oncoprotein in the two cell types.


Ribosomal localization of translation initiation factor IF2.
Bacterial translation initiation factor IF2 is a GTP-binding protein that catalyzes binding of initiator fMet-tRNA in the ribosomal P site. The topographical localization of IF2 on the ribosomal subunits, a prerequisite for understanding the mechanism of initiation complex formation, has remained elusive. Here, we present a model for the positioning of IF2 in the 70S initiation complex as determined by cleavage of rRNA by the chemical nucleases Cu(II):1,10-orthophenanthroline and Fe(II):EDTA tethered to cysteine residues introduced into IF2. Two specific amino acids in the GII domain of IF2 are in proximity to helices H3, H4, H17, and H18 of 16S rRNA. Furthermore, the junction of the C-1 and C-2 domains is in proximity to H89 and the thiostrepton region of 23S rRNA. The docking is further constrained by the requisite proximity of the C-2 domain with P-site-bound tRNA and by the conserved GI domain of the IF2 with the large subunit's factor-binding center. Comparison of our present findings with previous data further suggests that the IF2 orientation on the 30S subunit changes during the transition from the 30S to 70S initiation complex.


Therapy in gout.
The effective management of patients with gout is outlined. The treatment of the acute attack, the prevention of recurrent episodes, and the dissolution of tophi, when present, are generally straightforward and associated with relatively few complications. Patients with a resistant acute attack, with extensive tophaceous deposition, or with allergy or toxicity to any of the standard drugs, present more complex treatment decisions. All agents must be used in an individualized manner for each patient with appropriate concern for risks as well as for benefit.


Herpes virus and Ménière's disease.
The main goal of this study was to examine the vestibular ganglia from patients with intractable classic Ménière's disease (MD) for the presence or absence of DNA from three neurotropic viruses herpes simplex virus 1 and 2 (HSV1, HSV2) and varicella zoster virus (VZV) and to investigate the hypothesis that MD is associated with virus reactivation within Scarpa's ganglion. Polymerase chain reaction (PCR) was performed with nested primer sets specific for viral genomic DNA of HSV1, HSV2 and VZV in biopsies of the ganglion scarpae of patients with MD who underwent vestibular neurectomy. Included were patients with MD classified as definite MD according to American Academy of Otolaryngology/Head and Neck Surgery criteria. The ganglion scarpae and ganglion geniculi harvested at autopsy from patients without history of MD or facial palsy served as control specimens. No viral DNA was detected in the vestibular ganglion of 7 patients with definite MD. In 34% of the vestibular ganglia of the control group we detected either HSV1 or VZV. Only one Scarpa's ganglion had both viruses present at the same time. Thirty-two out of 34 ganglia from the geniculate segment of the facial nerve contained either HSV1 and/or VZV genomic DNA. Eight specimens contained both viruses simultaneously. Altogether viral DNA was found in 94% of ganglia. Viral genomic DNA of HSV2 was not detected. Although HSV and VZV appear to be present in many ganglion cells throughout the human body, we were unable to find genomic DNA of these viruses in patients with definite MD and disabling vertigo, who underwent vestibular neurectomy. Based on these results, reactivation of HSV1 and VZV in the vestibular ganglion does not seem to play a role in the pathogenesis of MD.


Effects of processing delay, temperature, and transport tube type on results of quantitative bacterial culture of canine urine.
To determine the impact of processing delay, temperature, and transport tube type on results of quantitative bacterial culture (QBC) of canine urine. Diagnostic test evaluation. 60 mL of pooled urine from 4 dogs, divided into six 10-mL aliquots. Urine aliquots were spiked with bacteria from 1 of 6 independent Escherichia coli cultures to achieve a target bacterial concentration of 10(5) CFUs/mL. One milliliter from each aliquot was transferred into 5 silicone-coated clot tubes (SCTs) and 5 urine transport tubes (UTTs). Samples were stored at 4°C (39°F) and 25°C (77°F) for 0, 8, and 24 hours, and then standard QBCs were performed. Median bacterial concentration for urine samples stored in a UTT for 24 hours at 4°C was lower than that for samples stored in an SCT under the same conditions. Conversely, a substantial decrease in median bacterial concentration was identified for samples stored for 24 hours in an SCT at 25°C, compared with the median concentration for samples stored in a UTT under the same conditions. Median bacterial concentration in samples stored in an SCT at 25°C for 24 hours (275 CFUs/mL) was less than the cutoff typically used to define clinically important bacteriuria by use of urine samples obtained via cystocentesis (ie, > 1,000 CFUs/mL). Canine urine samples submitted for immediate QBC should be transported in plain sterile tubes such as SCTs. When prolonged (24-hour) storage at room temperature is anticipated, urine samples should be transported in UTTs.


Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer.
Colorectal cancer (CRC) is the most common carcinoma of the digestive tract. The slow growing nature of CRC offers a great opportunity for prevention strategies. The concept of chemoprevention of colorectal cancer using plant derived natural products is gaining substantial attention because it is an inherently safe and cost-effective alternative to conventional cancer therapies. Piperlongumine (PL), a natural alkaloid present in Piper longum Linn has been reported to exhibit notable anticancer effects in various in vitro studies. Nonetheless, the chemopreventive potential of PL has not been studied in experimentally induced colon cancer yet. Ras/PI3K/Akt/mTOR signaling axis plays a central role in promoting tumor cell growth, proliferation and survival by inhibiting apoptosis. In the present study, we demonstrated, for the first time, the chemopreventive effects of PL in DMH + DSS induced colon carcinogenesis animal model. We showed that PL displayed potent antineoplastic activity against colon cancer cell growth by targeting Ras proteins and PI3K/Akt signaling cascade. PL mediated inhibition of tumor cell growth was associated with inhibition of Ras protein levels and its preferred companion protein PI3K levels that led to suppressed activity of Akt/NF-κB, c-Myc and cyclin D1. It was also found that PL arrested the cell cycle progression at G2/M phase and induced mitochondrial apoptotic pathway by downregulating Bcl-2 levels. Furthermore, the results of liver and kidney toxicity suggested that PL exhibit no toxicity in animals. Our results suggest that PL may be an effective chemopreventive agent for colon cancer.


The Integrated Clinical Education Strategic Initiatives Project-Development of Parameters to Guide Harmonization in Clinical Education: A Scoping Review.
Clinical education curricular models specifically related to integrated clinical education (ICE) vary across physical therapist education programs. The interconnectedness of ICE to the advancement of a shared vision for clinical education in professional physical therapist education needs investigating. The purpose of this scoping review was to: (1) define ICE, (2) define baseline expectations and parameters of ICE, and (3) discern and describe current ICE models. Databases accessed included Medline, MedlinePlus with Full, CINAHL, and CINAHL Plus with full text. A multimodal data collection scoping review was completed. Data collection included survey research, a systematic review of the literature, and a series of focus groups. The McMaster Critical Appraisal Tool assessed methodological study quality. A qualitative, metasynthesis approach was used for data synthesis. Consensus agreement produced results. Twenty-two articles were included in the literature review from the health disciplines of medicine, nursing, physical therapy, occupational therapy, and speech-language pathology. Data synthesis produced 8 parameters defining the factors essential to categorizing clinical education experiences as ICE in physical therapist education. The 8 parameters and ICE definition are supported by a description of models of ICE that currently exist within health profession curricula. Data synthesis followed a qualitative, metasynthesis approach. Themes emerged from the surveys, literature review, and focus group data. Patterns were compared, analyzed, and synthesized to generate the themes and ICE parameters. Selection bias from the literature search could have limited the richness of the model descriptions by unintentional exclusion of articles, and might limit the applicability of results beyond the United States. Sampling bias from survey and focus groups, although purposeful, might have limited a broader description of current viewpoints about ICE. However, the data sources, including multiple health profession perspectives coupled with consensus agreement, provide sound evidence in development of profession-based parameters. The results of this scoping review provide the profession with a standard definition of ICE and parameters that can guide a program in designing a curriculum using ICE experiences as a foundation. A recommended next step is to design education research studies using reliable and valid outcome measures across programs to determine impact and effectiveness of ICE as an educational intervention.


Multilayer perceptron-based DFE with lattice structure.
The severely distorting channels limit the use of linear equalizers and the use of the nonlinear equalizers then becomes justifiable. Neural-network-based equalizers, especially the multilayer perceptron (MLP)-based equalizers, are computationally efficient alternative to currently used nonlinear filter realizations, e.g., the Volterra type. The drawback of the MLP-based equalizers is, however, their slow rate of convergence, which limit their use in practical systems. In this work, the effect of whitening the input data in a multilayer perceptron-based decision feedback equalizer (DFE) is evaluated. It is shown from computer simulations that whitening the received data employing adaptive lattice channel equalization algorithms improves the convergence rate and bit error rate performances of multilayer perceptron-based DFE. The adaptive lattice algorithm is a modification to the one developed by Ling and Proakis (1985). The consistency in performance is observed in both time-invariant and time-varying channels. Finally, it is found in this work that, for time-invariant channels, the MLP DFE outperforms the least mean squares (LMS)-based DFE. However, for time-varying channels comparable performance is obtained for the two configurations.


Single-Cell Atlas of Neonatal Mouse Hearts Reveals an Unexpected Cardiomyocyte.
Single-cell RNA sequencing is widely used in cancer research and organ development because of its powerful ability to analyze cellular heterogeneity. However, its application in cardiomyocytes is dissatisfactory mainly because the cardiomyocytes are too large and fragile to withstand traditional single-cell approaches. Through designing the isolation procedure of neonatal mouse cardiac cells, we provide detailed cellular atlases of the heart at single-cell resolution across 4 different stages after birth. We have obtained 10 000 cardiomyocytes; to our knowledge, this is the most extensive reference framework to date. Moreover, we have discovered unexpected erythrocyte-like cardiomyocyte-terminal cardiomyocytes, comprising more than a third of all cardiomyocytes. Only a few genes are highly expressed in these cardiomyocytes. They are highly differentiated cardiomyocytes that function as contraction pumps. In addition, we have identified 2 cardiomyocyte-like conducting cells, lending support to the theory that the sinoatrial node pacemaker cells are specialized cardiomyocytes. Notably, we provide an initial blueprint for comprehensive interactions between cardiomyocytes and other cardiac cells. This mouse cardiac cell atlas improves our understanding of cardiomyocyte heterogeneity and provides a valuable reference in response to varying physiological conditions and diseases.


Detailed structure of integrons and transposons carried by large conjugative plasmids responsible for multidrug resistance in diverse genomic types of Salmonella enterica serovar Brandenburg.
To evaluate the incidence, molecular basis and distribution among genomic types of antimicrobial drug resistance in Salmonella enterica (S.) serovar Brandenburg isolates recorded in the Principality of Asturias, Spain. Thirty-seven S. Brandenburg isolates were tested for susceptibility to antimicrobial agents and typed by random amplified polymorphic DNA (RAPD) and pulsed-field gel electrophoresis (PFGE). PCR amplifications, together with DNA cloning and sequencing, were used to identify resistance genes, integrons and transposons and to establish the structure and physical associations between them. Conjugation experiments were applied to establish the location of the identified elements. Twenty-one isolates were resistant to one or more unrelated drugs. Resistances to streptomycin, tetracycline, kanamycin, chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole, encoded by aadA1, tet(A) or tet(B), aphA1, catA1, bla(TEM) and dfrA1-sul1-sul3, respectively, were most frequently observed. Multidrug resistance (32.4%) was mainly mediated by mobile genetic elements. These included: (i) class 1 integrons (with dfrA1-aadA1 gene cassettes in their variable region), which were part of Tn21-related transposons associated with Tn9; (ii) a Tn1721-derivative containing tet(A); (iii) a defective Tn10 that carried tet(B), and was linked to an integron; and (iv) large conjugative plasmids carrying a class 1 integron-Tn21-Tn9-like structure, together with the Tn1721- or the Tn10-related element. Two-way-RAPD and XbaI-PFGE discriminated the isolates into 15 and 12 profiles, respectively. Complex genetic elements have apparently been responsible for the recruitment, assembly and dispersion of resistance genes among the highly diverse genomic types of S. Brandenburg, identified as causal agents of human salmonellosis in the Principality of Asturias, over recent years.


Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study.
To investigate the association between physician-documented diagnoses of maternal autoimmune diseases, allergies, and asthma around the time of pregnancy and subsequent diagnoses of autism in children. A case-control study nested within a cohort of infants born between January 1995 and June 1999. Northern California Kaiser Permanente Medical Care Program. Cases (n = 420) were children with at least 1 diagnosis of an autism spectrum disorder (ASD) recorded in Kaiser Permanente outpatient clinical databases. Controls (n = 2100) were children without an ASD diagnosis who were frequency matched to cases on sex, birth year, and hospital of birth. Frequencies of maternal immunologic disorders were compared between cases and controls with a chi2 statistic, and relative risks were estimated by crude and adjusted odds ratios and 95% confidence intervals using logistic regression. The final study population included 407 cases and 2095 controls. A similar proportion of case and control mothers had a diagnosis of any autoimmune disease in the 4-year period surrounding pregnancy (10.3% vs 8.2%, P = .15). After adjustment for maternal factors, only 1 autoimmune condition, psoriasis, was significantly associated with ASDs (adjusted odds ratio, 2.7; 95% confidence interval, 1.3-5.8). A greater than 2-fold elevated risk of ASD was observed for maternal asthma and allergy diagnoses recorded during the second trimester of pregnancy. These findings suggest that maternal autoimmune disorders present in women around the time of pregnancy are unlikely to contribute significantly to autism risk. Further etiologic investigations are needed to confirm these results and should include objective documentation of diagnoses and consider a larger set of maternal immune-related conditions, including asthma and allergies.


Cannabidiol enhances verbal episodic memory in healthy young participants: A randomized clinical trial.
Cannabis contains a multitude of different compounds. One of them, cannabidiol - a non-psychoactive substance - might counteract negative effects of Δ-9-Tetrahydrocannabinol on hippocampus-dependent memory impairment. The aim of the present study was to investigate the effect of vaping cannabidiol on verbal episodic memory in healthy young subjects. We used a double-blind, placebo-controlled, randomized crossover trial in 39 healthy young subjects. Participants received once a single dose of cannabidiol e-liquid (0.25 ml, 5% cannabidiol, 12.5 mg cannabidiol) and once placebo for vaping after learning 15 unrelated nouns. The primary outcome measure was the short delay verbal memory performance (number of correctly free recalled nouns) 20 min after learning. 34 participants (mean age: 22.26 [3.04]) completed all visits and entered analyses (17 received cannabidiol and 17 received placebo first). Cannabidiol enhanced verbal episodic memory performance (placebo: 7.03 [2.34]; cannabidiol 7.71 [2.48]; adjusted group difference 0.68, 95% CI 0.01 to 1.35; R2β = .028, p = .048). Importantly, we did not detect medication effects on secondary outcome measures attention or working memory performance, suggesting that CBD has no negative impact on these basic cognitive functions. The results are in line with the idea that vaping cannabidiol interacts with the central endocannabinoid system and is capable to modulate memory processes, a phenomenon with possible therapeutic potential. Further studies are needed to investigate optimal dose-response and time-response relationships.


Distribution of bacterial proteins in biofilms formed by non-typeable Haemophilus influenzae.
The ability to preserve the fragile ultrastructural organization of bacterial biofilms using cryo-preparation methods for electron microscopy has enabled us to probe sections through non-typeable Haemophilus influenzae (NTHi) biofilms and determine the localization of NTHi-specific lipooligosaccharide (LOS) and proteins within these structures. Some of the proteins we examined are currently being considered as candidates for vaccine development, so it is important that their distribution and accessibility within the biofilms formed by NTHi be determined. We have localized LOS to the extracellular matrix (ECM) of the biofilm and the P6 outer membrane protein to the membrane of what appear to be viable bacteria within the biofilm. The Hap and HWM1/HMW2 adhesive proteins were associated with bacteria within the biofilm and were present in the biofilm ECM. The IgA1 protease is a secreted protein that was also associated with NTHi in the biofilm and was in the ECM, but was more concentrated in the top region of the biofilm, suggesting a role in protecting biofilm bacteria from antibody attack.


Inhibition of return to successively cued spatial locations: commentary on Pratt and Abrams (1995).
J. Pratt and R.A. Abrams (1995) reported that the inhibition of return of attention is found only for the most recently attended of 2 cued locations. This study does not dispute their findings, but suggests that a more ecologically valid experiment would have more than 2 possible target locations. Twelve male students participated in an experiment in which the target may occur in 1 of 4 possible locations, after 3 of those locations have been cued exogenously in sequence. Inhibition of return was found for each of the cued locations. This result suggests that inhibition may be an important mechanism for aiding visual search in complex environments.


How are visual words represented? Insights from EEG-based visual word decoding, feature derivation and image reconstruction.
Investigations into the neural basis of reading have shed light on the cortical locus and the functional role of visual-orthographic processing. Yet, the fine-grained structure of neural representations subserving reading remains to be clarified. Here, we capitalize on the spatiotemporal structure of electroencephalography (EEG) data to examine if and how EEG patterns can serve to decode and reconstruct the internal representation of visually presented words in healthy adults. Our results show that word classification and image reconstruction were accurate well above chance, that their temporal profile exhibited an early onset, soon after 100 ms, and peaked around 170 ms. Further, reconstruction results were well explained by a combination of visual-orthographic word properties. Last, systematic individual differences were detected in orthographic representations across participants. Collectively, our results establish the feasibility of EEG-based word decoding and image reconstruction. More generally, they help to elucidate the specific features, dynamics, and neurocomputational principles underlying word recognition.


Use of tunable, pulsed dye laser for quantitative fluorescence in syphilis serology (FTA-ABS test).
A pulsed dye laser was used as an excitation source in a fluorescent treponemal antibody absorption (FTA-ABS) test. A high precision in quantitative fluorescence was obtained with this high-power excitation source coupled to an electronic detection system and a storage oscilloscope by standardization of fluorescence evaluation and through elimination of human error. One 0.4-mus pulse exposure was sufficient to record fluorescence intensity data on the oscilloscope. Absence of fading of fluorescence after repeated excitation permitted multiple readings of the same microscope field. Almost 100% reproducible results were obtained for the FTA-ABS test with 40 samples. Electronic detection of fluorescence and the high sensitivity obtained with laser excitation raise doubts about the relative value of quantitative immunofluorescence in the FTA-ABS test.


In vitro study on the immunological effect of bromelain and trypsin on mononuclear cells from humans.
Proteolytic enzymes such as bromelain and trypsin are used as an adjuvant therapeutic approach in the treatment of chronic inflammatory, malignant and autoimmune diseases. In vitro studies have shown that proteolytic enzymes modulate surface adhesion molecules on T-cells. In this study we analysed the influence of bromelain and trypsin on the cytokine production and proliferation of peripheral blood mononuclear cells (PBMC) from patients with a classical cellular mediated autoimmune disorder, namely encephalomyelitis disseminata (ED) as well as from healthy controls. - PBMC from patients with ED (n=12) and healthy controls (n=12) were cultured for seven days at 37 degrees C under three different conditions: without antigen, with bromelain and with trypsin (final concentrations 10-1000 microg/ml). Proliferation was determined by superset3H-thymidine incorporation. Secretion of cytokines into the supernatant was measured by a double sandwich ELISA. Intracellular cytokines were determined by flow cytometric analysis. - PBMC from patients with ED and healthy controls showed a significantly increased proliferative response to bromelain (ED: 14053+/- 7585 cpm with bromelain vs. spontaneous proliferation of 430+/- 255 cpm; healthy controls: 10689+/- 4607 cpm vs. 327+/-193) but not to trypsin. Bromelain induced in all 24 individuals a significant increase of the macro-phage/monocyte associated cytokines interleukin (IL)-6, granulocyte-macrophage-colony stimulating factor (GM-CSF), tumour necrosis factor alpha (TNFa) (p<0.01) as well as of the type 1 cytokine gamma-interferon (IFNgamma). In contrast, the type 2 cytokines IL-4 and IL-5 were not induced. Flow cytometric analysis revealed a significant increase of IFNgamma-producing CD4+ T-cells. There were no differences in cytokine production between ED patients and healthy controls. - These results indicate that bromelain - but not trypsin - activates macrophages/monocytes and type 1 cells independently from the underlying disease and may stimulate, therefore, the innate as well as the adaptive immune system.


Melanoma: Last call for radiotherapy.
Melanoma is traditionally considered to be a radioresistant tumor. However, radiotherapy and immunotherapy latest developments might upset this radiobiological dogma. Stereotactic radiotherapy allows high dose per fraction delivery, with high dose rate. More DNA lethal damages, less sublethal damages reparation, endothelial cell apoptosis, and finally clonogenic cell dysfunction are produced, resulting in improved local control. Radiotherapy can also enhance immune responses, inducing neoantigens formation, tumor antigen presentation, and cytokines release. A synergic effect of radiotherapy with immunotherapy is expected, and might lead to abscopal effects. If hadrontherapy biological properties seem able to suppress hypoxia-induced radioresistance and increase biological efficacy, ballistic advantages over photon radiations might also improve radiotherapy outcomes on usually poor prognosis locations. The present review addresses biological and clinical effects of high fraction dose, bystander effect, abscopal effect, and hadrontherapy features in melanoma. Clinical trials results are warranted to establish indications of innovative radiotherapy in melanoma.


Acupuncture decreased the risk of coronary heart disease in patients with rheumatoid arthritis in Taiwan: a Nationwide propensity score-matched study.
Patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease (CHD). Acupuncture, a commonly used treatment for patients with RA, has not been reported to prevent CHD in patients with RA. We aimed to assess the risk of developing CHD in acupuncture users and non-users of patients with RA. We identified 29,741 patients with newly diagnosed RA from January 1997 to December 2010 from the Registry of Catastrophic Illness Patients Database from the Taiwanese National Health Insurance Research Database. Among them, 10,199 patients received acupuncture (acupuncture users), and 19,542 patients did not receive acupuncture (no-acupuncture users). After performing 1:1 propensity score matching by sex, age, baseline comorbidity, conventional treatment, initial diagnostic year, and index year, there were 9932 patients in both the acupuncture and no-acupuncture cohorts. The main outcome was the diagnosis of CHD in patients with RA in the acupuncture and no-acupuncture cohorts. Acupuncture users had a lower incidence of CHD than non-users (adjusted HR = 0.60, 95% CI = 0.55-0.65). The estimated cumulative incidence of CHD was significantly lower in the acupuncture cohort (log-rank test, p < .001). Subgroup analysis showed that patients receiving manual acupuncture of traditional Chinese medicine style, electroacupuncture, or combination of both all had a lower incidence of CHD than patients never receiving acupuncture treatment. The beneficial effect of acupuncture on preventing CHD was independent of age, sex, diabetes mellitus, hypertension, hyperlipidemia, and statins use. This is the first large-scale study to reveal that acupuncture might have beneficial effect on reducing the risk of CHD in patients with RA. This study may provide useful information for clinical utilization and future studies.


An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia.
Dysplastic lesions of the oral epithelium are known precursors of oral cancer. A significant proportion of oral dysplastic lesions have functional defects in p53 response pathways. The ONYX-015 adenovirus is selectively cytotoxic to cells carrying defects in p53-dependent signaling pathways. The current study sought to establish the feasibility and activity of ONYX-015 administered topically as a mouthwash to patients with clinically apparent and histologically dysplastic lesions of the oral mucosa. A total of 22 patients (19 assessable patients) were enrolled onto the study. ONYX-015 was administered on three different schedules to consecutive cohorts. Biopsies of the involved mucosa were performed to evaluate histologic response and changes in expression of putative markers of malignant potential, including p53, cyclin D1, and Ki-67. Serology was performed to measure antiadenoviral titers. Histologic resolution of dysplasia was seen in seven (37%) of 19 patients, and the grade of dysplasia improved in one additional patient. The majority of responses were transient. No toxicity greater than grade 2 (febrile episode in one patient) was observed. Only one of seven patients demonstrated an increase in circulating antiadenoviral antibody titer while on therapy. Although responding and resistant lesions had similar mean p53 staining at baseline, histologic response correlated with a decrease in p53 positivity over time. Significant changes in cyclin D1 or Ki-67 were not observed. Viral replication was confirmed in two of three lesions examined. This novel approach to cancer prevention is tolerable, feasible, and has demonstrable activity.


Inactivation of bacteria via photosensitization of vitamin K3 by UV-A light.
This study investigated inactivation of bacteria with ultraviolet light A irradiation in combination with vitamin K3 as a photosensitizer. Six bacteria including Bacillus cereus, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, and Escherichia coli suspended in vitamin K3 aqueous solution were exposed to ultraviolet light A. Five of six bacteria, with the exception of Pseudomonas aeruginosa, were reduced by eight logs with 1600 μM of vitamin K3 and 5.8 J cm(-2) UV-A irradiation. Pseudomonas aeruginosa was reduced by four logs under these conditions. Reactive oxygen species including singlet oxygen, hydroxyl radical and superoxide anion radical were generated in vitamin K3 aqueous solution under UV-A irradiation. These results suggest that vitamin K3 and UV-A irradiation may be effective for bacterial inactivation in environmental and medical applications.


Preparation of pod-shaped TiO2 and Ag@TiO2 nano burst tubes and their photocatalytic activity.
The pod-shaped TiO2 nano burst tubes (TiO2 NBTs) were prepared by the combination of electrospinning and impregnation calcination with oxalic acid (H2C2O4), polystyrene (PS) and tetrabutyl titanate. The silver nanoparticles (AgNPs) were loaded onto the surface of TiO2 NBTs by ultraviolet light reduction method to prepare pod-shaped Ag@TiO2 NBTs. In this work, we analysed the effect of the amount of oxalic acid on the cracking degree of TiO2 NBTs; the effect of the concentration of AgNO3 solution on the particle size and loading of AgNPs on the surface of TiO2 NBTs. Scanning electron microscopy and transmission electron microscopy investigated the surface morphology of samples. X-ray diffraction and X-ray photoelectron spectroscopy characterized the structure and composition of samples. Rhodamine B (RhB) solution was used to evaluate the photocatalytic activity of pod-shaped TiO2 NBTs and Ag@TiO2 NBTs. The results showed that TiO2 NBTs degraded 91.0% of RhB under ultraviolet light, Ag@TiO2 NBTs degraded 95.5% under visible light for 75 and 60 min, respectively. The degradation process of both samples was consistent with the Langmuir-Hinshelwood first-order kinetic equation. Therefore, the catalytic performance of the sample is: Ag@TiO2 NBTs > TiO2 NBTs > TiO2 nanotubes.


Resveratrol inhibits angiotensin II- and epidermal growth factor-mediated Akt activation: role of Gab1 and Shp2.
trans-Resveratrol (RV), a polyphenolic stilbene derivative found in grape skin and other food products, has been proposed to exert beneficial effects in cardiovascular disease. Our group has shown previously that RV inhibits angiotensin II (Ang II)-induced Akt activation and, consequently, vascular smooth muscle cell (VSMC) hypertrophy. In this work, to identify the molecular target of RV, we investigated the impact of RV on early signaling cascades in rat aortic VSMCs triggered by Ang II and epidermal growth factor (EGF). We show that RV does not influence Ang II-mediated transactivation of EGF-receptor but potently inhibits EGF-induced phosphorylation of Akt kinase, suggesting that RV acts downstream of EGF-receptor transactivation in VSMCs. Recent evidence indicates that the adapter molecule Gab1, together with the protein tyrosine phosphatase Shp2, is critically involved in regulating the strength and duration of phosphatidylinositol-3-kinase (PI3K) and Akt activation upon EGF stimulation in fibroblasts. Our results show that stimulation of VSMCs with EGF as well as Ang II leads to a rapid tyrosine phosphorylation of Gab1 and its association with the p85 subunit of PI3K. RV attenuates these processes. Experiments performed in Shp2-deficient fibroblasts revealed that RV does not inhibit EGF-stimulated Akt activation in these cells, suggesting that Shp2 is necessary for the inhibitory effect of RV on the PI3K/Akt pathway. Furthermore, RV treatment activates Shp2. We therefore propose that RV blocks Akt activation in Ang II- and EGF-stimulated VSMCs by activating Shp2, thus preventing interaction between Gab1 and PI3K that is necessary for further signal transduction.


[Cytoreductive surgery of liver metastasis from colorectal cancer: principles of intra-arterial regional chemotherapy].
A significant number of patients with colorectal cancer have metastases (MTS) to the liver. Cytoreductive surgery (CRS) and new antitumor drugs provide promising results. The aim of the study was to evaluate clinical results of CRS in combination with modern antitumor drug irinotekan (kampto). Forty-seven patients suffering from colorectal cancer with MTS to the liver were treated. Primary focus was resected. All the patients were divided into 4 groups depending on combination of surgical treatment and chemotherapy: with liver resection and complete removal (or devitalization) of metastatic lesions in combination with postoperative intravenous (group 1) or intraarterial regional (group 2) injection of Irinotekan and without resection of the liver with implantation of a catheter to the hepatic artery with postoperative intraarterial (group 3) or systemic intravenous (group 4) therapy with Irinotekan. Mean dose of kampto was 350 mg per 1 m2 of body surface. It was demonstrated that intraarterial infusion was highly effective. The follow-up in group 1 was 9.5 +/- 3.75 months, in group 2--11.3 +/- 4.2, in group 3--6.5 +/- 5.3, in group 4--4.6 +/- 2.3 months. It is concluded that cytoreduction of the the liver with intraarterial intrahepatic regional chemotherapy is an effective method of treatment of patients with metastatic colorectal cancer of the liver.


Population pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in ill cows.
This study was performed in 105 ill cows to determine the best practical individualized dose of enrofloxacin after i.m. (2.5 mg/kg) single-dose administration. Samples were collected from each cow at random time to ensure the percentage of samples distributed equally in the absorption phase, distribution phase, and elimination phase of the drug. Drug concentrations were determined by high-performance liquid chromatography with fluorometric detector, analyzed by population pharmacokinetic (PPK) modeling with NONMEM. The concentration-time data for enrofloxacin in plasma and ciprofloxacin were fitted to the one-compartment model with first-order absorption and elimination. The final covariate model indicated that body weight and daily milk productions have significant influence on clearance (CL) of enrofloxacin and ciprofloxacin, and the volume (V) of distribution of enrofloxacin. The typical PPK parameters were K(a) = 3.33 h(-1), CL = 1.25 L/h/kg, and V = 2.98 L/kg of enrofloxacin, and the interindividual variability for CL and V were 20.2% and 24.3%, respectively, the population mean estimates of K(a), CL, and V for ciprofloxacin were 1.12 h(-1), 2.36 L/h/kg, 8.20 L/kg, respectively, and their interindividual variability was 36.9%, 15.8% and 14.1%, respectively.


Is Emergency Medical Services (EMS) in Islamic Republic of Iran Practical and Efficient in Facing Ebola?
To evaluate the efficacy and preparedness of Emergency Medical Services (EMS) in Islamic Republic of Iran to face Ebola. The present study is cross-sectional and somehow descriptive. We used a standard questionnaire that was designed by "center for disease control and prevention". This questionnaire was captioned "Emergency Medical Services (EMS) checklist for Ebola preparedness". We collected a lot of data by studying that questionnaire and every manager in every province of Iran were informed about that info in 2016. This data was analyzed by using SSPP software version 16. Findings have showed the average score related to preparation level of EMS in facing Ebola in Iran was 63.73±12.77 percent. There was no significant difference between the country regions regarding the preparedness of to detect (p=0.975), protect (p=0.275) and respond (p=0.344) to ebola outbreaks.The highest score had been achieved by region number 5 and the lowest score belonged to region number 7. Although the acquired average score in this study is higher than standards, considering the increased threat of breaking out biologic threats especially Ebola infection, using and practicing some measures in order to enhance preparation level of Emergency Medical Services counter this infection and similar infectious diseases is inevitable.