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Parkinson's disease (PD) is a common neurological disorder characterized by gait impairment. PD has no cure, and an impediment to developing a treatment is the lack of any accepted method to predict disease progression rate. The primary aim of this study was to develop a model using clinical measures and biomechanical measures of gait and postural stability to predict an individual's PD progression over two years. Data from 160 PD subjects were utilized. Machine learning models, including XGBoost and Feed Forward Neural Networks, were developed using extensive model optimization and cross-validation. The highest performing model was a neural network that used a group of clinical measures, achieved a PPV of 71% in identifying fast progressors, and explained a large portion (37%) of the variance in an individual's progression rate on held-out test data. This demonstrates the potential to predict individual PD progression rate and enrich trials by analyzing clinical and biomechanical measures with machine learning.

Head motion during functional Magnetic Resonance Imaging acquisition can significantly contaminate the neural signal and introduce spurious, distance-dependent changes in signal correlations. This can heavily confound studies of development, aging, and disease. Previous approaches to suppress head motion artifacts have involved sequential regression of nuisance covariates, but this has been shown to reintroduce artifacts. We propose a new motion correction pipeline using an omnibus regression model that avoids this problem by simultaneously regressing out multiple artifacts using the best performing algorithms to estimate each artifact. We quantitatively evaluate its motion artifact suppression performance against sequential regression pipelines using a large heterogeneous dataset (n=151) which includes high-motion subjects and multiple disease phenotypes. The proposed concatenated regression pipeline significantly reduces the association between head motion and functional connectivity while significantly outperforming the traditional sequential regression pipelines in eliminating distance-dependent head motion artifacts.

Currently, the diagnosis of Autism Spectrum Disorder (ASD) is dependent upon a subjective, time-consuming evaluation of behavioral tests by an expert clinician. Non-invasive functional MRI (fMRI) characterizes brain connectivity and may be used to inform diagnoses and democratize medicine. However, successful construction of predictive models, such as deep learning models, from fMRI requires addressing key choices about the model's architecture, including the number of layers and number of neurons per layer. Meanwhile, deriving functional connectivity (FC) features from fMRI requires choosing an atlas with an appropriate level of granularity. Once an accurate diagnostic model has been built, it is vital to determine which features are predictive of ASD and if similar features are learned across atlas granularity levels. Identifying new important features extends our understanding of the biological underpinnings of ASD, while identifying features that corroborate past findings and extend across atlas levels instills model confidence. To identify aptly suited architectural configurations, probability distributions of the configurations of high versus low performing models are compared. To determine the effect of atlas granularity, connectivity features are derived from atlases with 3 levels of granularity and important features are ranked with permutation feature importance. Results show the highest performing models use between 2-4 hidden layers and 16-64 neurons per layer, granularity dependent. Connectivity features identified as important across all 3 atlas granularity levels include FC to the supplementary motor gyrus and language association cortex, regions whose abnormal development are associated with deficits in social and sensory processing common in ASD. Importantly, the cerebellum, often not included in functional analyses, is also identified as a region whose abnormal connectivity is highly predictive of ASD. Results of this study identify important regions to include in future studies of ASD, help assist in the selection of network architectures, and help identify appropriate levels of granularity to facilitate the development of accurate diagnostic models of ASD.

The application of deep learning to build accurate predictive models from functional neuroimaging data is often hindered by limited dataset sizes. Though data augmentation can help mitigate such training obstacles, most data augmentation methods have been developed for natural images as in computer vision tasks such as CIFAR, not for medical images. This work helps to fills in this gap by proposing a method for generating new functional Magnetic Resonance Images (fMRI) with realistic brain morphology. This method is tested on a challenging task of predicting antidepressant treatment response from pre-treatment task-based fMRI and demonstrates a 26% improvement in performance in predicting response using augmented images. This improvement compares favorably to state-of-the-art augmentation methods for natural images. Through an ablative test, augmentation is also shown to substantively improve performance when applied before hyperparameter optimization. These results suggest the optimal order of operations and support the role of data augmentation method for improving predictive performance in tasks using fMRI.

The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.

Extensive computational and neurobiological work has focused on how the training schedule, i.e., the duration and rate at which an environmental disturbance is presented, shapes the formation of motor memories. If long-lasting benefits are to be derived from motor training, however, retention of the performance improvements gained during practice is essential. Thus a better understanding of mechanisms that promote retention could lead to the design of more effective training procedures. The few studies that have investigated how retention depends on the training schedule have suggested that the gradual exposure of a perturbation leads to improved retention of motor memory compared with an abrupt exposure. However, several of these previous studies showed small effects, and although some controlled the training duration and others the level of learning, none have controlled both. In the present study we disambiguated both of these effects from exposure rate by systematically varying the duration of training, type of trained dynamics, and exposure rate for these dynamics in human force-field adaptation. After controlling for both training duration and the amount of learning, we found essentially identical retention when comparing gradual and abrupt training for two different types of force-field dynamics. By contrast, we found that retention was markedly higher for long-duration compared with short-duration training for both types of dynamics. These results demonstrate that the duration of training has a far greater effect on the retention of motor memory than the exposure rate during training. We show that a multirate learning model provides a computational mechanism for these findings. NEW & NOTEWORTHY Previous studies have suggested that a gradual, incremental introduction of a novel environment is helpful for improving retention. However, we used experimental and computational approaches to demonstrate that previously reported improvements in retention associated with gradual introductions fail to persist when other factors, including the duration of training and the degree of initial learning, are accounted for.

Background: A lower extremity venous duplex ultrasound (LEVDUS) examination positive for deep venous thrombosis (DVT) is an indication for anticoagulation. Incomplete examinations that fail to examine all lower extremity veins in patients not otherwise indicated for anticoagulation may be followed by repeated examination to exclude missed or progressing DVT. This study examined the frequency of incomplete LEVDUS studies, reasons for incomplete studies, veins incompletely examined, and follow-up LEVDUS after incomplete LEVDUS. The incidence of a positive finding of DVT was compared between initial complete LEVDUS and follow-up LEVDUS after an initial incomplete examination to determine whether improving rates of follow-up LEVDUS after an incomplete examination is a reasonable target for quality improvement., Methods: At a single academic medical center from January 2017 to December 2017, incomplete LEVDUS studies were prospectively identified in patients who did not otherwise have an identified indication for anticoagulation. Rate of DVT in complete LEVDUS was also determined during the same time frame. Incomplete LEVDUS reports were reviewed for clinical setting, patient demographics, examination indication, ordering providers, reasons for incomplete examinations, anatomic locations of veins not visualized, rates of follow-up LEVDUS examinations within 30 days of the initially incomplete study, and rates of DVT identified in follow-up examinations of initially incomplete examinations., Results: Of the 2843 LEVDUS examinations performed in 2017, 341 studies identified DVT and 197 incomplete examinations did not identify DVT. Veins not visualized on incomplete studies included tibial veins (n = 170 [86.3%]), femoral veins (n = 73 [37.1%]), and popliteal veins (n = 76 [38.6%]), with the most common reasons for incomplete studies being bandages or fixation devices (46.2%), intolerance of the patient for the study (14.7%), and body habitus or edema (17.4%). Only a minority of incomplete studies not identifying DVT (27.9%) had a follow-up examination performed. The majority of the repeated examinations were performed after incomplete LEVDUS examinations that were originally performed for high-risk screening (80%) as opposed to clinical suspicion for DVT (20%). There was no significant difference in demographic features of patients with initially incomplete studies who did or did not have a follow-up examination and no significant difference in the rates of DVT (13.1%) in complete LEVDUS examinations compared with the rate of DVT found in follow-up examinations of initially incomplete LEVDUS examinations (9.1%; P = .33)., Conclusions: The majority of patients with incomplete LEVDUS, even those with symptoms or signs suggestive of DVT, do not have a follow-up examination within 30 days of the incomplete study. The rate of DVT detected in initially complete studies was similar to that in patients with follow-up examinations whose initial study was incomplete and did not identify DVT. This suggests that to avoid missing DVT in patients with incomplete LEVDUS studies, quality assurance programs should be initiated to ensure that follow-up LEVDUS studies are performed after an incomplete LEVDUS examination., (Copyright © 2019 Society for Vascular Surgery. All rights reserved.)

Major depressive disorder is a primary cause of disability in adults with a lifetime prevalence of 6-21% worldwide. While medical treatment may provide symptomatic relief, response to any given antidepressant is unpredictable and patient-specific. The standard of care requires a patient to sequentially test different antidepressants for 3 months each until an optimal treatment has been identified. For 30-40% of patients, no effective treatment is found after more than one year of this trial-and-error process, during which a patient may suffer loss of employment or marriage, undertreated symptoms, and suicidal ideation. This work develops a predictive model that may be used to expedite the treatment selection process by identifying for individual patients whether the patient will respond favorably to bupropion, a widely prescribed antidepressant, using only pretreatment imaging data. This is the first model to do so for individuals for bupropion. Specifically, a deep learning predictor is trained to estimate the 8-week change in Hamilton Rating Scale for Depression (HAMD) score from pretreatment task-based functional magnetic resonance imaging (fMRI) obtained in a randomized controlled antidepressant trial. An unbiased neural architecture search is conducted over 800 distinct model architecture and brain parcellation combinations, and patterns of model hyperparameters yielding the highest prediction accuracy are revealed. The winning model identifies bupropion-treated subjects who will experience remission with the number of subjects needed-to-treat (NNT) to lower morbidity of only 3.2 subjects. It attains a substantially high neuroimaging study effect size explaining 26% of the variance ( R 2 = 0.26) and the model predicts post-treatment change in the 52-point HAMD score with an RMSE of 4.71. These results support the continued development of fMRI and deep learning-based predictors of response for additional depression treatments.

Humans rapidly adapt reaching movements in response to perturbations (e.g., manipulations of movement dynamics or visual feedback). Following a break, when reexposed to the same perturbation, subjects demonstrate savings, a faster learning rate compared with the time course of initial training. Although this has been well studied, there are open questions on the extent early savings reflects the rapid recall of previous performance. To address this question, we examined how the properties of initial training (duration and final adaptive state) influence initial single-trial adaptation to force-field perturbations when training sessions were separated by 24 h. There were two main groups that were distinct based on the presence or absence of a washout period at the end of day 1 (with washout vs. without washout). We also varied the training duration on day 1 (15, 30, 90, or 160 training trials), resulting in 8 subgroups of subjects. We show that single-trial adaptation on day 2 scaled with training duration, even for similar asymptotic levels of learning on day 1 of training. Interestingly, the temporal force profile following the first perturbation on day 2 matched that at the end of day 1 for the longest training duration group that did not complete the washout. This correspondence persisted but was significantly lower for shorter training durations and the washout subject groups. Collectively, the results suggest that the adaptation observed very early in reexposure results from the rapid recall of the previously learned motor recalibration but is highly dependent on the initial training duration and final adaptive state. NEW & NOTEWORTHY The extent initial readaptation reflects the recall of previous motor performance is largely unknown. We examined early single-trial force-field adaptation on the second day of training and distinguished initial retention from recall. We found that the single-trial adaptation following the 24-h break matched that at the end of the first day, but this recall was modified by the training duration and final level of learning on the first day of training.

The phytochemical investigation of Euphorbia tirucalli L. (Euphorbiaceae) yielded four new compounds, including a rare cadalene-type sesquiterpene (tirucadalenone), two tirucallane triterpenoids, euphorol L and euphorol M, with the latter being described as an epimeric mixture, and a euphane triterpene, namely, euphorol N, together with 7 known compounds. Their structures and absolute configurations were elucidated from analysis of 1D (1H, J-modulated 13 C) and 2D NMR (HSQC, HMBC and NOESY), high-resolution mass spectrometry (HRESIMS), optical rotation, and GIAO NMR shift calculation followed by CP3 analysis, along with comparison with literature reports. All these compounds were tested for cytotoxicity against K562, MCF-7 and/or and HepG2 tumor cell lines. Only tirucadalenone displayed a mild cytotoxic activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A phytochemical investigation of the foliose lichen Parmotrema tsavoense (Krog and Swinscow) Krog and Swinscow (Parmeliaceae) resulted in the isolation of a new trichlorinated xanthone, isodemethylchodatin. The structure elucidation of this new norlichexanthone derivative proved tricky owing to proton deficiency, and to the lack of NMR data of closely related analogues. The structure of this compound was determined based on an integrated interpretation of 13 C-NMR chemical shifts, MS spectra, and DP4-based computational chemistry was also performed to provide an independent and unambiguous validation of the determined structure. Isodemethylchodatin represents the first chlorinated lichexanthone/norlichexanthone derivative bearing a methoxy group at C-5.

When common software packages (CONN and SPM) are used to process fMRI, results such as functional connectivity measures can substantially differ depending on the versions of the packages used and the tools used to convert image formats such as DICOM to NIFTI. The significance of these differences are illustrated within the context of a realistic research application: finding moderators of antidepressant response from a large psychiatric study of 288 major depressive disorder (MDD) patients. Significant differences in functional connectivity measurements and discrepancies in derived moderators were found between nearly all software configurations. These results should encourage researchers to be vigilant of software versions during fMRI preprocessing, to maintain consistency throughout each project, and to carefully report versions to facilitate reproducibility.

Background: Topical methyl aminolevulinate photodynamic therapy (MAL-PDT) is highly effective for the treatment of superficial basal cell carcinoma (sBCC). Current European treatment protocol requires two hospital visits, which is costly and unpractical. The aim of this study was to evaluate the efficacy of fractionated MAL-PDT, using two light fractions at 3 and 4 h compared to illumination at 3 and 5 h after MAL-application., Methods: Thirty patients were randomized into two groups. The first group received illumination at 3 and 4 h (20 + 55 J/cm 2 ) after MAL-application (3/4 group). In the other group, two light fractions were performed at 3 and 5 h (20 + 55 J/cm 2 ) after MAL-application (3/5 group). The lesion response was evaluated at 3 and 12 months posttreatment., Results: In the 3/5 group, 70.0% showed a complete response (CR) at 3 months compared to 63.6% in the other group. At 12 months, 100% showed a CR in the 3/5 group compared to 80.0% in the other group. However, most failures/recurrences were eventually due to the presence of a more aggressive BCC subtype, mostly caused by sampling error of the primary punch biopsy., Conclusion: Single day protocol for MAL-PDT for sBCC is feasible and this study shows promising results.

To make decisions organisms often accumulate information across multiple timescales. However, most experimental and modeling studies of decision-making focus on sequences of independent trials. On the other hand, natural environments are characterized by long temporal correlations, and evidence used to make a present choice is often relevant to future decisions. To understand decision-making under these conditions we analyze how a model ideal observer accumulates evidence to freely make choices across a sequence of correlated trials. We use principles of probabilistic inference to show that an ideal observer incorporates information obtained on one trial as an initial bias on the next. This bias decreases the time, but not the accuracy of the next decision. Furthermore, in finite sequences of trials the rate of reward is maximized when the observer deliberates longer for early decisions, but responds more quickly towards the end of the sequence. Our model also explains experimentally observed patterns in decision times and choices, thus providing a mathematically principled foundation for evidence-accumulation models of sequential decisions.

Thrombosis of unusual venous sites encompasses a large part of consultative hematology and is encountered routinely by practicing hematologists. Contrary to the more commonly encountered lower extremity venous thrombosis and common cardiovascular disorders, the various thromboses outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review attempts to outline the most up to date literature on cerebral, retinal, upper extremity, hepatic, portal, splenic, mesenteric, and renal vein thrombosis, focusing on the incidence, pathophysiology, provoking factors, and current recommended treatments for each type of unusual thrombosis to provide a useful and practical review for the hematologist., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

While cardiovascular disease is common, occasionally hematologists and other practitioners will encounter patients with arterial thrombosis/infarction in unusual sites, without clear cause or obvious diagnostic and treatment paradigms. Contrary to the more commonly encountered cerebrovascular accident and cardiovascular disorders, the various infarctions outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review outlines the current literature on arterial thrombosis, with consideration given to anatomic sources and hypercoagulable associations, while focusing on the epidemiology, pathophysiology, provoking factors, and current recommended treatments for intracardiac thrombus, primary aortic mural thrombus, visceral infarctions, and cryptogenic limb ischemia to provide a useful and practical review for the practitioner., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Two new triterpenes, the seco-friedelane type secofriedelanophyllemblicine and the ursane-derived saponin ursophyllemblicoside were isolated from the roots of the edible fruit-producing Phyllanthus emblica. Their structures were unambiguously elucidated using extensive 1D and 2D NMR analyses, high resolution mass spectrometry and single-crystal X-ray crystallographic analyses along with comparison with literature data. Secofriedelanophyllemblicine represents the first 3,4-secofriedelane bearing a carboxylic acid group substituent at C-20. Ursophyllemblicoside, incorporating the rare 21α hydroxyursolic acid as a sapogenol represents the first example of saponin comprising this aglycone. Secofriedelanophyllemblicine displayed a moderate cytotoxicity against K562 and HepG2 cancer cell lines., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The objective of the study was to compare the outcomes of externally supported polytetrafluoroethylene (PTFE) grafts and femoral vein as conduits for femorofemoral crossover grafts., Methods: This is a retrospective review of consecutive femorofemoral crossover grafts at our institution between January 2005 and March 2016. Patient demographics, indications, complication rates, patency rates, and survival rates were compared between femorofemoral grafts created with either PTFE or femoral vein conduits, autogenous or cryopreserved., Results: One hundred nineteen femorofemoral crossover bypasses (89 PTFE, 30 vein [18 autogenous and 12 cryopreserved femoral veins]) were performed. Most patients underwent isolated femorofemoral bypass alone (76% isolated femorofemoral bypass versus 24% axillobifemoral bypass). A greater proportion of patients who received vein grafts were female (PTFE 37% vs. vein 60%, P = 0.028) and had prior bypasses (PTFE 33% vs. vein 73%, P < 0.001). PTFE bypasses were performed primarily for chronic limb ischemia (61.8%), while most venous bypasses were for infections (80%, P < 0.001). Femoral vein conduits were used in cases of infected aortic or extra-anatomical grafts (N = 20) or groin infection (N = 5). The 30-day complication rate was 38.7% and was not different between groups (36% for PTFE, 44.4% for autologous vein grafts and 50% for cryovein, P = 0.33) with wound complications being most frequent (18% PTFE, 27.8% autologous vein, 16.7% cryovein, P = 0.25). Patients receiving vein grafts were more likely to receive blood transfusion (34.8% PTFE vs. 70% vein, P = 0.001). Overall, median follow-up was 9.8 months (range 0-107). Primary patency rates at 1, 2, and 3 years were 83.7 %, 73.7% and 69.8%, respectively, for PTFE bypasses, and 100% for all time points for venous grafts, respectively (log rank, P = 0.03). Primary-assisted and secondary patency rates were not significantly different between the 2 groups (log rank, P = 0.16). Survival rates at 1, 2, and 3 years were 82%, 76.4% and 69.7%, respectively, for patients with PTFE grafts versus 76.7%, 73.3%, and 55%, respectively, for patients with vein grafts, respectively (log rank, P = 0.17)., Conclusions: While the indications for procedure differed in this series, femoral veins in femorofemoral bypasses have overall superior primary patency and similar complication rates compared with PTFE grafts. Based on this series, femoral vein, either autologous or cryopreserved, appears to be a suitable conduit for femorofemoral bypasses, and in some cases, it may be the preferred conduit., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clinical diagnosis of inflammatory skin disorders (ISD), including hair and nail disorders, is not always straightforward. Not uncommonly, a punch biopsy may be required. Dermoscopy and videodermoscopy (VD) are non-invasive techniques that are used for in vivo examination of the skin, hair, and nails. Both techniques can contribute to determining the accurate diagnosis of common ISD and can be useful for assessing treatment effects. However, the value of VD over conventional dermoscopy for ISD is undetermined. We systematically searched and reviewed the current published literature on ISD evaluated by VD and dermoscopy in the electronic databases, PubMed, Embase, the Cochrane Library, and Web of Science. All studies were assessed for quality using the Strengthening the Reporting of Observational studies in Epidemiology and Cochrane checklist. Finally, 82 studies were eligible for inclusion. An overview is presented of the (video)dermoscopic features for common ISD diagnoses, with details regarding the level of accuracy and features that should be monitored during treatment. Although both techniques are promising, studies of high methodological quality are necessary to determine the value of VD over conventional dermoscopy for common ISD.

Six new sulfonic acid-containing flavonoids, acidoflavanone (1), acidoauronol (2), 5- O-methylacidoauronol (3), acidoaurone (4), acidoisoflavone (5), and acidoflavonol (6), were isolated from the EtOH extract of the roots of Phyllanthus acidus. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data, single-crystal X-ray diffraction analysis, and comparison to the literature data. These new structures represent the first examples of sulfonic acid-containing flavanones, auronols, aurones, and isoflavones.

New racemic dispiranic polyketides, tsavoenones A (1), B (2) and C (3), having a novel 1,7-dioxadispiro[4.0.4.4]tetradecane scaffold were isolated from the foliose lichen Parmotrema tsavoense. These compounds were structurally elucidated by extensive NMR analyses, comparison between experimental and theoretical 13C NMR data and X-ray crystallography. A putative biosynthetic scenario for the formation of 1-3 from parmosidone D, a meta-depsidone previously isolated from the same lichen material, was proposed. Tested for its cytotoxicity, 1 displayed a moderate activity against human myelogenous leukemia K562 cell line with an IC50 value of 66 μg mL-1.

Rationale: Biological significance of c-Kit as a cardiac stem cell marker and role(s) of c-Kit+ cells in myocardial development or response to pathological injury remain unresolved because of varied and discrepant findings. Alternative experimental models are required to contextualize and reconcile discordant published observations of cardiac c-Kit myocardial biology and provide meaningful insights regarding clinical relevance of c-Kit signaling for translational cell therapy., Objective: The main objectives of this study are as follows: demonstrating c-Kit myocardial biology through combined studies of both human and murine cardiac cells; advancing understanding of c-Kit myocardial biology through creation and characterization of a novel, inducible transgenic c-Kit reporter mouse model that overcomes limitations inherent to knock-in reporter models; and providing perspective to reconcile disparate viewpoints on c-Kit biology in the myocardium., Methods and Results: In vitro studies confirm a critical role for c-Kit signaling in both cardiomyocytes and cardiac stem cells. Activation of c-Kit receptor promotes cell survival and proliferation in stem cells and cardiomyocytes of either human or murine origin. For creation of the mouse model, the cloned mouse c-Kit promoter drives Histone2B-EGFP (enhanced green fluorescent protein; H2BEGFP) expression in a doxycycline-inducible transgenic reporter line. The combination of c-Kit transgenesis coupled to H2BEGFP readout provides sensitive, specific, inducible, and persistent tracking of c-Kit promoter activation. Tagging efficiency for EGFP+/c-Kit+ cells is similar between our transgenic versus a c-Kit knock-in mouse line, but frequency of c-Kit+ cells in cardiac tissue from the knock-in model is 55% lower than that from our transgenic line. The c-Kit transgenic reporter model reveals intimate association of c-Kit expression with adult myocardial biology. Both cardiac stem cells and a subpopulation of cardiomyocytes express c-Kit in uninjured adult heart, upregulating c-Kit expression in response to pathological stress., Conclusions: c-Kit myocardial biology is more complex and varied than previously appreciated or documented, demonstrating validity in multiple points of coexisting yet heretofore seemingly irreconcilable published findings., (© 2018 American Heart Association, Inc.)

Objective: Ad libitum high-fat diets (HFDs) spontaneously increase caloric intake in rodents, which correlates positively with weight gain. However, it remains unclear why rodents overeat HFDs. This paper investigated how changing the proportion of diet that came from HFDs might alter daily caloric intake in mice., Methods: Mice were given 25%, 50%, or 90% of their daily caloric need from an HFD, along with ad libitum access to a low-fat rodent chow diet. Food intake was measured daily to determine how these HFD supplements impacted total daily caloric intake. Follow-up experiments addressed the timing of HFD feeding., Results: HFD supplements did not alter total caloric intake or body weight. In a follow-up experiment, mice consumed approximately 50% of their daily caloric need from an HFD in 30 minutes during the light cycle, a time when mice do not normally consume food., Conclusions: An HFD did not disrupt regulation of total daily caloric intake, even when up to 90% of total calories came from the HFD. However, HFDs increased daily caloric intake when provided ad libitum and were readily consumed by mice outside of their normal feeding cycle. Ad libitum HFDs appear to induce overconsumption beyond the mechanisms that regulate daily caloric intake., (© 2018 Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Background: The North American Pediatric Craniofacial Collaborative Group (PCCG) established the Pediatric Craniofacial Surgery Perioperative Registry to evaluate outcomes in infants and children undergoing craniosynostosis repair. The goal of this multicenter study was to utilize this registry to assess differences in blood utilization, intensive care unit (ICU) utilization, duration of hospitalization, and perioperative complications between endoscopic-assisted (ESC) and open repair in infants with craniosynostosis. We hypothesized that advantages of ESC from single-center studies would be validated based on combined data from a large multicenter registry., Methods: Thirty-one institutions contributed data from June 2012 to September 2015. We analyzed 1382 infants younger than 12 months undergoing open (anterior and/or posterior cranial vault reconstruction, modified-Pi procedure, or strip craniectomy) or endoscopic craniectomy. The primary outcomes included transfusion data, ICU utilization, hospital length of stay, and perioperative complications; secondary outcomes included anesthesia and surgical duration. Comparison of unmatched groups (ESC: N = 311, open repair: N = 1071) and propensity score 2:1 matched groups (ESC: N = 311, open repair: N = 622) were performed by conditional logistic regression analysis., Results: Imbalances in baseline age and weight are inherent due to surgical selection criteria for ESC. Quality of propensity score matching in balancing age and weight between ESC and open groups was assessed by quintiles of the propensity scores. Analysis of matched groups confirmed significantly reduced utilization of blood (26% vs 81%, P < .001) and coagulation (3% vs 16%, P < .001) products in the ESC group compared to the open group. Median blood donor exposure (0 vs 1), anesthesia (168 vs 248 minutes) and surgical duration (70 vs 130 minutes), days in ICU (0 vs 2), and hospital length of stay (2 vs 4) were all significantly lower in the ESC group (all P < .001). Median volume of red blood cell administered was significantly lower in ESC (19.6 vs 26.9 mL/kg, P = .035), with a difference of approximately 7 mL/kg less for the ESC (95% confidence interval for the difference, 3-12 mL/kg), whereas the median volume of coagulation products was not significantly different between the 2 groups (21.2 vs 24.6 mL/kg, P = .73). Incidence of complications including hypotension requiring treatment with vasoactive agents (3% vs 4%), venous air embolism (1%), and hypothermia, defined as <35°C (22% vs 26%), was similar between the 2 groups, whereas postoperative intubation was significantly higher in the open group (2% vs 10%, P < .001)., Conclusions: This multicenter study of ESC versus open craniosynostosis repair represents the largest comparison to date. It demonstrates striking advantages of ESC for young infants that may result in improved clinical outcomes, as well as increased safety.

Deep venous thrombosis (DVT) remains a common and serious cardiovascular problem with both fatal and long-term consequences. The consequences of DVT include the development of postthrombotic syndrome in 25% to 60% of DVT patients. Despite the clinical importance of venous thrombus resolution, the cellular and molecular mediators involved are poorly understood, and currently there is no molecular therapy to accelerate this process. Several lines of evidence suggest that a complex and interrelated array of molecular signaling processes are involved in the inflammatory vascular remodeling associated with the resolution of DVT. Here, we have identified a role for the tumor suppressor gene p53 in regulating venous thrombus resolution. Using the stasis model of venous thrombosis and resolution in mice, we found that genetic deficiency of p53 or pharmacologic inhibition by pifithrin impairs thrombus resolution and is associated with increased fibrosis and altered expression of matrix metalloproteinase-2. The effect of p53 loss was mediated by cells of the myeloid lineage, resulting in enhanced polarization of the cytokine milieu toward an M1-like phenotype. Furthermore, augmentation of p53 activity using the pharmacological agonist of p53, quinacrine, accelerates venous thrombus resolution in a p53-dependent manner, even after establishment of thrombosis. Together, these studies define mechanisms by which p53 regulates thrombus resolution by increasing inflammatory vascular remodeling of venous thrombi in vivo, and the potential therapeutic application of a p53 agonist as a treatment to accelerate this process in patients with DVT., (© 2017 by The American Society of Hematology.)

Motor adaptation paradigms provide a quantitative method to study short-term modification of motor commands. Despite the growing understanding of the role motion states (e.g., velocity) play in this form of motor learning, there is little information on the relative stability of memories based on these movement characteristics, especially in comparison to the initial adaptation. Here, we trained subjects to make reaching movements perturbed by force patterns dependent upon either limb position or velocity. Following training, subjects were exposed to a series of error-clamp trials to measure the temporal characteristics of the feedforward motor output during the decay of learning. The compensatory force patterns were largely based on the perturbation kinematic (e.g., velocity), but also showed a small contribution from the other motion kinematic (e.g., position). However, the velocity contribution in response to the position-based perturbation decayed at a slower rate than the position contribution to velocity-based training, suggesting a difference in stability. Next, we modified a previous model of motor adaptation to reflect this difference and simulated the behavior for different learning goals. We were interested in the stability of learning when the perturbations were based on different combinations of limb position or velocity that subsequently resulted in biased amounts of motion-based learning. We trained additional subjects on these combined motion-state perturbations and confirmed the predictions of the model. Specifically, we show that (1) there is a significant separation between the observed gain-space trajectories for the learning and decay of adaptation and (2) for combined motion-state perturbations, the gain associated to changes in limb position decayed at a faster rate than the velocity-dependent gain, even when the position-dependent gain at the end of training was significantly greater. Collectively, these results suggest that the state-dependent adaptation associated with movement velocity is relatively more stable than that based on position.

Food intake measurements are essential for many research studies. Here, we provide a detailed description of a novel solution for measuring food intake in mice: the Feeding Experimentation Device (FED). FED is an open-source system that was designed to facilitate flexibility in food intake studies. Due to its compact and battery powered design, FED can be placed within standard home cages or other experimental equipment. Food intake measurements can also be synchronized with other equipment in real-time via FED's transistor-transistor logic (TTL) digital output, or in post-acquisition processing as FED timestamps every event with a real-time clock. When in use, a food pellet sits within FED's food well where it is monitored via an infrared beam. When the pellet is removed by the mouse, FED logs the timestamp onto its internal secure digital (SD) card and dispenses another pellet. FED can run for up to 5 days before it is necessary to charge the battery and refill the pellet hopper, minimizing human interference in data collection. Assembly of FED requires minimal engineering background, and off-the-shelf materials and electronics were prioritized in its construction. We also provide scripts for analysis of food intake and meal patterns. Finally, FED is open-source and all design and construction files are online, to facilitate modifications and improvements by other researchers.

Background: Clinical differentiation between actinic keratosis (AK), squamous cell carcinoma (SCC) in situ, and invasive SCC and its variants may be difficult. Reflectance confocal microscopy (RCM) is a non-invasive technique for in vivo skin imaging., Objectives: To explicate the diagnostic and monitoring use of RCM within the spectrum of AK and SCC, and evaluate the accuracy of RCM for these diagnoses relative to histopathology., Materials & Methods: A systematic literature search was performed in PubMed, EMBASE, the Cochrane Library, and Web of Science databases. The quality was assessed using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist., Results: Twenty-five eligible studies were included. Different diagnostic RCM features have been described for AK, actinic cheilitis (AC), erythroplasia of Queyrat, Bowen disease, invasive SCC, and keratoacanthoma (KA). The overall range of sensitivity and specificity of RCM for the diagnosis of SCC, AK, SCC in situ, and KA was 79-100% and 78-100%, respectively., Conclusion: The current literature describes the use of RCM for diagnosing AK, AC, erythroplasia of Queyrat, Bowen disease, invasive SCC, and KA, as well as for monitoring treatments of AK, with good accuracy. Unfortunately, studies with high methodological quality are lacking. Pre-treatment of hyperkeratotic lesions and uniform definitions of RCM features are required to simplify the differentiation between AKs, SCC in situ, and SCC and its variants in clinical practice.

Background: Measuring food intake in rodents is a conceptually simple yet labor-intensive and temporally-imprecise task. Most commonly, food is weighed manually, with an interval of hours or days between measurements. Commercial feeding monitors are excellent, but are costly and require specialized caging and equipment., New Method: We have developed the Feeding Experimentation Device (FED): a low-cost, open-source, home cage-compatible feeding system. FED utilizes an Arduino microcontroller and open-source software and hardware. FED dispenses a single food pellet into a food well where it is monitored by an infrared beam. When the mouse removes the pellet, FED logs the timestamp to a secure digital (SD) card and dispenses a new pellet into the well. Post-hoc analyses of pellet retrieval timestamps reveal high-resolution details about feeding behavior., Results: FED is capable of accurately measuring food intake, identifying discrete trends during light and dark-cycle feeding. Additionally, we show the utility of FED for measuring increases in feeding resulting from optogenetic stimulation of agouti-related peptide neurons in the arcuate nucleus of the hypothalamus., Comparison to Existing Methods: With a cost of ∼$350 per device, FED is >10× cheaper than commercially available feeding systems. FED is also self-contained, battery powered, and designed to be placed in standard colony rack cages, allowing for monitoring of true home cage feeding behavior. Moreover, FED is highly adaptable and can be synchronized with emerging techniques in neuroscience, such as optogenetics, as we demonstrate here., Conclusions: FED allows for accurate, precise monitoring of feeding behavior in a home cage setting., (Published by Elsevier B.V.)

Background: Skin cancer, including basal cell carcinoma (BCC), has become a major health care problem. The limitations of a punch biopsy (at present the gold standard) as diagnostic method together with the increasing incidence of skin cancer point out the need for more accurate, cost-effective, and patient friendly diagnostic tools. In vivo reflectance confocal microscopy (RCM) is a noninvasive imaging technique that has great potential for skin cancer diagnosis., Objective: To investigate whether in vivo RCM can correctly identify the subtype of BCC and to determine the cost-effectiveness of RCM compared with punch biopsy (usual care)., Study Design: Randomized controlled multicenter trial., Methods: On the basis of 80% power and an alpha of 0.05, 329 patients with lesions clinically suspicious for BCC will be included in this study. Patients will be randomized for RCM or for a punch biopsy (usual care). When a BCC is diagnosed, surgical excision will follow and a follow-up visit will be planned 3 months later. Several questionnaires will be filled in (EQ-5D, EQ-5D VAS, iMTA PCQ, and TSQM-9). We will perform statistical analysis, cost-effectiveness, and patient outcome analysis after data collection., Results: This research started in January 2016 and is ethically approved. We expect to finish this study at the end of 2018., Conclusions: In this study, we will investigate whether RCM is at least as good in identifying BCC subtypes as conventional pathological investigation of skin biopsies. Anticipating that RCM is found to be a cost-effective alternative, it saves on direct medical consumption like labor of the pathologist and other medical personnel as well as materials related to treatment failure with at least equal effectiveness., Trial Registration: Clinicaltrials.gov NCT02623101; https://clinicaltrials.gov/ct2/show/NCT02623101 (Archived by WebCite at http://www.webcitation.org/6id54WQa2).

The operant conditioning chamber is a cornerstone of animal behavioral research. Operant boxes are used to assess learning and motivational behavior in animals, particularly for food and drug reinforcers. However, commercial operant chambers cost several thousands of dollars. We have constructed the Rodent Operant Bucket (ROBucket), an inexpensive and easily assembled open-source operant chamber based on the Arduino microcontroller platform, which can be used to train mice to respond for sucrose solution or other liquid reinforcers. The apparatus contains two nose pokes, a drinking well, and a solenoid-controlled liquid delivery system. ROBucket can run fixed ratio and progressive ratio training schedules, and can be programmed to run more complicated behavioral paradigms. Additional features such as motion sensing and video tracking can be added to the operant chamber through the array of widely available Arduino-compatible sensors. The design files and programming code are open source and available online for others to use.

Background: In the era of increasing endovascular approaches for aortoiliac disease, we sought to determine the role of axillofemoral bypass in contemporary practice., Methods: All axillofemoral bypasses performed at our institution from 2006 to 2013 were reviewed for indication, patency, and survival and compared with our prior published series before the widespread use of endovascular techniques (1996 to 2001)., Results: During the study period, 90 bypasses (29 axillofemoral and 61 axillobifemoral) bypasses were performed. The number of procedures performed decreased from an average of 24 to 12 procedures per year in historical and contemporary groups, respectively. Indications have changed significantly with more urgent or emergent procedures. Overall patency at 1 and 2 years was 74.6% and 67.8%, respectively. Median survival was 40.3 months, with overall survival 67.0% and 54.2% at 1 and 2 years, respectively., Conclusions: Axillofemoral bypass is an increasingly uncommon procedure and more likely performed for limb salvage in urgent or emergent settings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Nonpenetrating titanium surgical clips (clips) offer a theoretical advantage of inducing less intimal hyperplasia at an anastomosis because of less endothelial injury. Whether this translates into improved outcomes when used in the creation of arteriovenous fistulas (AVFs) remains unclear. We sought to compare the maturation, patency, and failure rates of anastomoses created using traditional continuous polypropylene suture and clips., Methods: All primary AVF created at a single Veterans Administration Medical Center were reviewed over a 6-year period. Anastomoses were created with either clips or suture based on surgeon preference. Patient characteristics and surgical outcomes were collected. Comparisons were made between the 2 groups., Results: Over a 6-year period, 334 fistulas were created (29% suture and 71% clips) in 326 patients. The mean age was 64.8 ± 11 years with 98% males. Comorbidities included diabetes (70%), hypertension (96.1%), and tobacco use (52.9% previous or current). Approximately half the patients were predialysis. Comparison of patient characteristics showed no differences between the suture and clip groups. There was no significant difference in maturation rate (suture 79% versus clips 72%, P = 0.25), median time to maturation (suture 62 ± 35 versus clips 71 ± 13 days, P = 0.07), 1 year primary patency rate (suture 37.4% versus clips 39.6, P = 0.72), 1 year assisted primary patency rate (suture 82.4% versus clips 76.3%, P = 0.31), or overall failure rates (suture 62% versus clips 58%, P = 0.56). Median time to initial failure or reintervention was not significantly different in the clip group (suture 615 [range, 239-991] versus clips 812 [range, 635-989] days, P = 0.72)., Conclusions: Compared to traditional polypropylene suture creation of upper extremity AVFs, nonpenetrating clips had equivalent maturation, 1-year patency, and overall failure rates. Neither clips nor suture offers any clear advantage in the creation of AVF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Deep venous thrombosis is a common vascular problem with long-term complications including post-thrombotic syndrome. Post-thrombotic syndrome consists of leg pain, swelling and ulceration that is related to incomplete or maladaptive resolution of the venous thrombus as well as loss of compliance of the vein wall. We examine the role of metalloproteinase-9 (MMP-9), a gene important in extracellular remodeling in other vascular diseases, in mediating thrombus resolution and biomechanical changes of the vein wall., Methods and Results: The effects of targeted deletion of MMP-9 were studied in an in vivo murine model of thrombus resolution using the FVB strain of mice. MMP-9 expression and activity significantly increased on day 3 after DVT. The lack of MMP-9 impaired thrombus resolution by 27% and this phenotype was rescued by the transplantation of wildtype bone marrow cells. Using novel biomechanical techniques, we demonstrated that the lack of MMP-9 significantly decreased thrombus-induced loss of vein wall compliance. Biomechanical analysis of the contribution of individual structural components showed that MMP-9 affected the elasticity of the extracellular matrix and collagen-elastin fibers. Biochemical and histological analyses correlated with these biomechanical effects as thrombi of mice lacking MMP-9 had significantly fewer macrophages and collagen as compared to those of wildtype mice., Conclusions: MMP-9 mediates thrombus-induced loss of vein wall compliance by increasing stiffness of the extracellular matrix and collagen-elastin fibers during thrombus resolution. MMP-9 also mediates macrophage and collagen content of the resolving thrombus and bone-marrow derived MMP-9 plays a role in resolution of thrombus mass. These disparate effects of MMP-9 on various aspects of thrombus illustrate the complexity of individual protease function on biomechanical and morphometric aspects of thrombus resolution.

Although neuromuscular block (NMB) allows immobility for airway management and surgical exposure, termination of its effect is limited by and associated with side effects of acetylcholinesterase inhibitors. Sugammadex is a selective relaxant binding agent that has been shown to reverse deep NMB, even when administered 3 minutes following a 1.2 mg/kg dose of rocuronium. This novel drug is a modified gamma cyclodextrin, that through encapsulation process terminates the effects of rocuronium and vecuronium (aminosteroid muscle relaxants), and enables the anesthesiologists rapidly to reverse profound NMB induced by rocuronium or vecuronium, in a "can't ventilate, can't intubate" crisis. In this review, data from published phase 1, 2, and 3 clinical trials are reviewed and presented. In addition, clinical trials on special patient populations (patients with pulmonary disease and renal insufficiency) are evaluated. Each article reviewed will conclude with a discussion of relevance, focus on adverse event profile, and clinical usefulness.

Background: Early recognition of squamous cell carcinoma (SCC) is difficult. Non-invasive reflectance confocal microscopic (RCM) imaging of the skin is a promising diagnostic technique. Although several RCM features for SCC and AK have been described, it is not determined whether RCM has the ability to distinguish between SCC and actinic keratosis (AK)., Objective: To determine in vivo reflectance confocal microscopic features that are specific for making a distinction between AK and SCC., Methods: In 24 patients, 30 lesions clinically suspicious for AK or SCC were selected for RCM imaging. Following the imaging procedure, a 3 mm skin biopsy was obtained for confirmation of the histopathological diagnosis. Two observers evaluated the RCM images according to a literature based list of RCM features. The obtained data were evaluated by an univariate and forward multivariate logistic regression analysis, kappa analysis and independent T-test., Results: The univariate logistic regression showed statistically significant odds ratios for several RCM features, including architectural disarray in the stratum granulosum, architectural disarray in the spinous layer and nest-like structures in the dermis. The forward multivariate logistic regression analysis showed that the combination of these features increased the ability to make the correct diagnosis AK and SCC non-invasively. The interobserver agreement between a starting and an experienced RCM observer ranged from poor to no agreement., Conclusion: This study revealed specific RCM features that can distinguish between AK and SCC, stimulating further prospective, large cohort research in this field. This will result in correct, efficient and adequate diagnosis and treatment of clinically difficult to distinguish AK and SCC lesions., (© 2014 European Academy of Dermatology and Venereology.)

Sonneratia ovata Backer, Sonneratiaceae, is a widespread plant in mangrove forests in Vietnam, Cambodia, Thailand, Indonesia. Sonneratia ovata's chemical composition remains mostly unknown. Therefore, we now report on the structural elucidation of three new phenolics, sonnerphenolic A (1), sonnerphenolic B (2), and sonnerphenolic C (23), a new cerebroside, sonnercerebroside (3) together with nineteen known compounds, including nine lignans (5-13), two steroids (14, 15), two triterpenoids (16, 17), three gallic acid derivatives (18-20), two phenolic derivatives (4, 22) and a 1-O-benzyl-β-d-glucopyranose (21) isolated from the leaves of Sonneratia ovata. Their chemical structures were established by spectroscopic data, as well as high resolution mass spectra and comparison with literature data. The in vitro acetylcholinesterase (AChE) inhibition and cytotoxic activities against HeLa (human epithelial carcinoma), NCI-H460 (human lung cancer), MCF-7 (human breast cancer) cancer cell lines and PHF (primary human fibroblast) cell were evaluated on some extracts and purified compounds at a concentration of 100 μg/mL. Compounds (5, 6, 23) exhibited cytotoxicity against the MCF-7 cell line with the IC50 values of 146.9±9.0, 114.5±7.2, and 112.8±9.4 μM, respectively, while they showed nontoxic with the normal cell (PHF) with IC50s >277 μM. Among 15 tested compounds, (S)-rhodolatouchol (22) showed inhibition against AChE with an IC50 value of 96.1±14.5 μM., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pain is a predictable consequence following operations, but the management of postoperative pain is another challenge for anesthesiologists and inappropriately controlled pain may lead to unwanted outcomes in the postoperative period. Opioids are indeed still at the mainstream of postoperative pain control, but solely using only opioids for postoperative pain management may be connected with risks of complications and adverse effects. As a consequence, the concept of multimodal analgesia has been proposed and is recommended whenever possible. Acetaminophen is one of the most commonly used analgesic and antipyretic drug for its good tolerance and high safety profiles. The introduction of intravenous form of acetaminophen has led to a wider flexibility of its use during peri- and postoperative periods, allowing the early initiation of multimodal analgesia. Many studies have revealed the efficacy, safety and opioid sparing effects of intravenous acetaminophen. Intravenous ibuprofen has also shown to be well tolerated and demonstrated to have significant opioid sparing effects during the postoperative period. However, the number of randomized controlled trials confirming the efficacy and safety is small and should be used in caution in certain group of patients. Intravenous acetaminophen and ibuprofen are important options for multimodal postoperative analgesia, improving pain and patient satisfaction.

Neutrophile elastase has the capacity to degrade elastin, a protein found in the connective tissue of the lungs. Unchecked elastase leads to pulmonary pathologies. Therefore, the development of elastase inhibitors is currently actively pursued in the therapeutic field. Several triterpenoids have been reported as inhibitors against elastase or its release. Such compounds could be valuable for the design of new drugs. This review is aimed at giving a comprehensive insight into the recent work performed in the field of triterpenoid-induced elastase inhibition.

Prior research has suggested that attention is determined by exploiting what is known about the most valid predictors of outcomes and exploring those stimuli that are associated with the greatest degree of uncertainty about subsequent events. Previous studies of human contingency learning have revealed evidence for one or other of these processes, but differences in the designs and procedures of these studies make it difficult to pinpoint the crucial determinant of whether attentional exploitation or exploration will dominate. Here we present two studies in which we systematically manipulated both the predictiveness of cues and uncertainty regarding the outcomes with which they were associated. This allowed us to demonstrate, for the first time, evidence of both attentional exploration and exploitation within the same experiment. Moreover, while the effect of predictiveness persisted to influence the rate of novel learning about the same cues in a second stage, the effect of uncertainty did not. This suggests that attentional exploration is more sensitive to a change of context than is exploitation. The pattern of data is simulated with a hybrid attentional model.

Three series of methyl 5-substituted 2-aminofuran-4-keto-3-carboxylates have been prepared following a multicomponent reaction strategy by the addition of an isocyanide to 4-oxo-2-butynoate in the presence of an aldehyde. The cycloaddition regioselectivity is generally high (>95%) but decreases when an electron-rich substituent is located at the butynoate 4-position.

Introduction: Biologic grafts have been shown to support tissue regeneration in various animal models. Very few reports in the literature exist to show tissue remodeling in patients after placement of a biologic graft., Case Presentation: We report the case of a 69-year-old Caucasian man with a history of small bowel carcinoid resection and concurrent recurrent ventral hernia repair with component separation and underlay biologic graft placement who underwent re-operation for metastatic carcinoid tumor to his liver. Complete incorporation of the biologic graft was observed. Tissue analysis of the incised midline fascia revealed tissue remodeling at the site of the previous abdominal wall defect., Conclusion: Placement of a biologic graft in ventral hernia repair supports tissue regeneration similar to that previously reported in animal models.

Whereas standard strong bases (n-BuLi, s-BuLi/TMEDA, n-BuLi/t-BuOK, TMPMgCl·LiCl, and LDA) reduce the N═N bond of the parent azobenzene (Y = H), aromatic H→Li permutation occurs with LTMP when a suitable director of lithiation (Y = OMe, CONEt2, F) is present in the benzene residue of the azo compound. The method allows direct access to new substituted azobenzenes.

Tithonia tagetiflora Desv. (Asteraceae) is a widespread plant in Vietnam, and the species of Tithonia are known as plants containing many biologically active compounds. However, T. tagetiflora's chemical composition remains mostly unknown. Therefore, we now report the structural elucidation of two new sesquiterpene lactones, 8-angeloyloxy-2,14-epoxygermacra-4,10(1),11(13)-trien-6,12-olide (1) and 6-angeloyloxy-1-hydroxy-3,4-epoxygermacra-9,11(13)-dien-8,12-olide (2), together with three known compounds, including two norisoprenoids, (6S,9S)-vomifoliol or (6R,9R)-vomifoliol (3) and (6S,9S)-roseoside (4), and one glutinane type triterpene, epi-glutinol (5), from the leaves of T. tagetiflora. Their structures are established by 1D and 2D NMR spectroscopy, as well as ESI-MS analysis and comparison with literature data., (Copyright © 2013 John Wiley & Sons, Ltd.)