Classics in Chemical Neuroscience: Dextromethorphan (DXM).

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N-methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.

Time of dehairing alters pork quality development.

Studies investigating the effect of scald time on pork quality are confounded with time of dehairing. To understand better pork quality development and two-toning in hams, twenty-four carcasses were assigned to an 8- or 16-min dwell time prior to the dehairing, with or without scalding (n = 6 per trt). Semimembranosus (SM) muscles were collected following dehairing and at 24 h postmortem. Protracted time to dehair improved ultimate pH (pHu; P < 0.005) and reduced (P < 0.05) color variation. One hundred forty-two carcasses were then subjected to protracted (control, 10-min) dwell times (15-min, or 20-min) in an industrial setting. Lightness was improved with 15-min dwell times compared to control, however 20-min dwell decreased the pHu (P < 0.001), increased lightness (P < 0.05), and percent purge (P < 0.001) in the SM. Also, lightness of the longissimus muscle (LM) increased (P < 0.001) with dwell time. These data show time to dehairing impacts pork quality development and suggest dehairing may be critical to quality development in a muscle-dependent manner.

Reservoir computing using networks of memristors: effects of topology and heterogeneity.

Reservoir computing (RC) has attracted significant interest as a framework for the implementation of novel neuromorphic computing architectures. Previously attention has been focussed on software-based reservoirs, where it has been demonstrated that reservoir topology plays a role in task performance, and functional advantage has been attributed to small-world and scale-free connectivity. However in hardware systems, such as electronic memristor networks, the mechanisms responsible for the reservoir dynamics are very different and the role of reservoir topology is largely unknown. Here we compare the performance of a range of memristive reservoirs in several RC tasks that are chosen to highlight different system requirements. We focus on percolating networks of nanoparticles (PNNs) which are novel self-assembled nanoscale systems that exhibit scale-free and small-world properties. We find that the performance of regular arrays of uniform memristive elements is limited by their symmetry but that this symmetry can be broken either by a heterogeneous distribution of memristor properties or a scale-free topology. The best perfomance across all tasks is observed for a scale-free network with uniform memistor properties. These results provide insight into the role of topology in neuromorphic reservoirs as well as an overview of the computational performance of scale-free networks of memristors in a range of benchmark tasks.

Reduced scald time does not influence ultimate pork quality.

Fresh pork color is a function of pigment, and the pH and temperature conditions in the carcass postmortem. To explore the role of scald on color development, carcasses (n = 16) were subjected to either a 4- or 8-min scald. Semimembranosus (SM) muscle samples were collected before and after scalding, and at 24 h postmortem. A 50% reduction in scald time resulted in lighter color (L*) across the muscle early postmortem (P < 0.001), yet the 8-min scald treatment was lighter (P = 0.001) at 24 h. An interaction between scald time and sampling time showed in an increase in L* values at 4-min immediately following scald (P < 0.001). Two-hundred carcasses were then subjected to a modified scald time (6.5 min, or 7.5 min) in an industrial setting. Lowering scald time failed to recapitulate results. In fact, darker meat (L* value; P = 0.0166) was noted in the SM across longer scalds. These data suggest modest changes in scald time may not be responsible for changes in pork quality development.

Reservoir computing with 3D nanowire networks.

Networks of nanowires are currently being explored for a range of applications in brain-like (or neuromorphic) computing, and especially in reservoir computing (RC). Fabrication of real-world computing devices requires that the nanowires are deposited sequentially, leading to stacking of the wires on top of each other. However, most simulations of computational tasks using these systems treat the nanowires as 1D objects lying in a perfectly 2D plane - the effect of stacking on RC performance has not yet been established. Here we use detailed simulations to compare the performance of perfectly 2D and quasi-3D (stacked) networks of nanowires in two tasks: memory capacity and nonlinear transformation. We also show that our model of the junctions between nanowires is general enough to describe a wide range of memristive networks, and consider the impact of physically realistic electrode configurations on performance. We show that the various networks and configurations have a strikingly similar performance in RC tasks, which is surprising given their radically different topologies. Our results show that networks with an experimentally achievable number of electrodes perform close to the upper bounds achievable when using the information from every wire. However, we also show important differences, in particular that the quasi-3D networks are more resilient to changes in the input parameters, generalizing better to noisy training data. Since previous literature suggests that topology plays an important role in computing performance, these results may have important implications for future applications of nanowire networks in neuromorphic computing.

Inherent factors influence color variations in semimembranosus muscle of pigs.

Variations in color, though a quality frustration, are common across the face of fresh and processed hams. Herein, we measured objective color across the semimembranosus (SM) muscle early postmortem and at 1440 min, then compared these differences against biochemical and metabolic characteristics responsible for pork quality development. Color (L*, a*) differed (P < 0.001) by zone and time but no interaction was evident. Lactate content and pH were highly correlated (R2 = 0.92) at 30 min, but weakened (R2 = 0.161412) by 1440 min. Lactate anaplerosis was not responsible for this lack of relationship. Glycolytic potential also differed across zone (P < 0.001) and time (P < 0.005). Differences in myoglobin expression and abundance, as well as mitochondrial DNA were notable (P < 0.05) across zone. These data suggest inherent differences in SM muscle are key determinants of ham color variation, while postmortem metabolism may play a lesser role in driving this quality attribute.

Classics in Chemical Neuroscience: Amitriptyline.

Amitriptyline was the second tricyclic antidepressant to appear on the market for major depressive disorder under the brand name Elavil in 1961. Since its emergence, amitriptyline has been an effective therapeutic in various disease states and disorders but has also been a concerning source of cardiotoxicity. Amitriptyline inhibits serotonin and norepinephrine reuptake as well as produces off-target activity at histaminergic, muscarinic, and various other receptors. Its role as a modulator of monoamines helped further establish the monoamine theory to understand various mood disorders, paving the way for the now more common selective serotonin/norepinephrine reuptake inhibitors. In this review, we will discuss amitriptyline's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, and its history and importance in therapy to present amitriptyline as a true classic in chemical neuroscience.

Classics in Chemical Neuroscience: Pramipexole.

Pramipexole was first manufactured by Pharmacia and Upjohn in July 1997 under the United States brand names of Mirapex and Mirapex ER. Pramipexole is classified as a nonergoline aminobenzothiazole compound that selectively agonizes the dopamine D2-like receptor subfamily, which includes the D2, D3, and D4 receptor subtypes. Pramipexole is a unique compound in its therapeutic potential because it has D3-preferring properties. The D3 receptor target has implications in both motor and psychiatric symptoms of Parkinson's disease, restless leg syndrome, and bipolar and unipolar depression. Currently, pramipexole is approved to treat signs and symptoms of idiopathic Parkinson's disease and moderate to severe symptoms of primary restless leg syndrome. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, gait disorders, and a disturbance of posture due to a decrease in dopamine stores in the substantia nigra with the consequent presence of Lewy bodies. Restless leg syndrome is a neurologic sensorimotor disorder characterized by a compelling urge to move the body/limb to relieve this uncomfortable sensation. In this Review, we will discuss the synthesis, drug metabolism, pharmacology, adverse effects, history, and the importance of pramipexole to neuroscience and describe its role in therapy.

Development of the FAST-M maternal sepsis bundle for use in low-resource settings: a modified Delphi process.

OBJECTIVE: To develop a sepsis care bundle for the initial management of maternal sepsis in low resource settings. DESIGN: Modified Delphi process. SETTING: Participants from 34 countries. POPULATION: Healthcare practitioners working in low resource settings (n = 143; 34 countries), members of an expert panel (n = 11) and consultation with the World Health Organization Global Maternal and Neonatal Sepsis Initiative technical working group. METHODS: We reviewed the literature to identify all potential interventions and practices around the initial management of sepsis that could be bundled together. A modified Delphi process, using an online questionnaire and in-person meetings, was then undertaken to gain consensus on bundle items. Participants ranked potential bundle items in terms of perceived importance and feasibility, considering their use in both hospitals and health centres. Findings from the healthcare practitioners were then triangulated with those of the experts. MAIN OUTCOME MEASURE: Consensus on bundle items. RESULTS: Consensus was reached after three consultation rounds, with the same items deemed most important and feasible by both the healthcare practitioners and expert panel. Final bundle items selected were: (1) Fluids, (2) Antibiotics, (3) Source identification and control, (4) Transfer (to appropriate higher-level care) and (5) Monitoring (of both mother and neonate as appropriate). The bundle was given the acronym 'FAST-M'. CONCLUSION: A clinically relevant maternal sepsis bundle for low resource settings has been developed by international consensus. TWEETABLE ABSTRACT: A maternal sepsis bundle for low resource settings has been developed by international consensus.

Maternal omega-3 polyunsaturated fatty acid supplementation on offspring hip joint conformation.

Unsaturated omega-3 fatty acids, especially docosahexaenoic acid (DHA), when fed to dogs improves cognitive and neurological development. Supplementation with omega-3 fatty acids such as DHA and eicosapentaenoic acid (EPA) has also been associated with lipid peroxidation, which in turn has been implicated in reduced body weight and altered bone formation. To assess the impact of omega-3 fatty acid supplementation on skeletal growth, diets containing three levels of DHA and EPA (0.01 and 0.01%, 0.14 and 0.12%, and 0.21 and 0.18%, respectively) were fed to bitches during gestation and lactation with puppies also supplemented through weaning. Thus, the subjects studied were the puppies supplemented with DHA and EPA through gestation and early postnatal life. The hip joint conformation of the puppies (n = 676) was recorded at adulthood using two radiographic, non-invasive evaluations. In this population, females had higher hip distraction indices (DI) than males. Males from the lower two levels of DHA and EPA supplementation had significantly smaller hip DI than all females and males from the highest DHA and EPA supplementation. In contrast, there were no diet effects on anatomical indicators of hip joint conformation and no visible arthritic changes. These data suggest that dietary supplementation of DHA and EPA during gestation and the perinatal period to weaning does not adversely influence hip joint formation of dogs.

Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib.

Sunitinib is a multitargeted tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity. The mechanisms of this toxicity are unknown. We hypothesized that sunitinib undergoes metabolic activation to form chemically reactive, potentially toxic metabolites which may contribute to development of sunitinib-induced hepatotoxicity. The purpose of this study was to define the role of cytochrome P450 (P450) enzymes in sunitinib bioactivation. Metabolic incubations were performed using individual recombinant P450s, human liver microsomal fractions, and P450-selective chemical inhibitors. Glutathione (GSH) and dansylated GSH were used as trapping agents to detect reactive metabolite formation. Sunitinib metabolites were analyzed by liquid chromatography-tandem mass spectrometry. A putative quinoneimine-GSH conjugate (M5) of sunitinib was detected from trapping studies with GSH and dansyl-GSH in human liver microsomal incubations, and M5 was formed in an NADPH-dependent manner. Recombinant P450 1A2 generated the highest levels of defluorinated sunitinib (M3) and M5, with less formation by P450 3A4 and 2D6. P450 3A4 was the major enzyme forming the primary active metabolite N-desethylsunitinib (M1). In human liver microsomal incubations, P450 3A inhibitor ketoconazole reduced formation of M1 by 88%, while P450 1A2 inhibitor furafylline decreased generation of M5 by 62% compared to control levels. P450 2D6 and P450 3A inhibition also decreased M5 by 54 and 52%, respectively, compared to control. In kinetic assays, recombinant P450 1A2 showed greater efficiency for generation of M3 and M5 compared to that of P450 3A4 and 2D6. Moreover, M5 formation was 2.7-fold more efficient in human liver microsomal preparations from an individual donor with high P450 1A2 activity compared to a donor with low P450 1A2 activity. Collectively, these data suggest that P450 1A2 and 3A4 contribute to oxidative defluorination of sunitinib to generate a reactive, potentially toxic quinoneimine. Factors that alter P450 1A2 and 3A activity may affect patient risk for sunitinib toxicity.

Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2T202/Y204 protein levels at higher compound concentrations.

DARK Classics in Chemical Neuroscience: Psilocybin.

Psilocybin is found in a family of mushrooms commonly known as "magic mushrooms" that have been used throughout history to induce hallucinations. In the late 1950s Albert Hofmann, of Sandoz Laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. Psilocybin was marketed by Sandoz as Indocybin for basic psychopharmacological and therapeutic clinical research. Psilocybin saw a rapid rise in popularity during the 1960s and was classed as a Schedule I drug in 1970. This led to a significant decrease in psilocybin research. Recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. This review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.

Patient-reported outcome measurement compared with professional judgment of cosmetic results after breast-conserving therapy.

Background: In the present study, we set out to compare patient-reported outcomes with professional judgment about cosmesis after breast-conserving therapy (bct) and to evaluate which items (position of the nipple, color, scar, size, shape, and firmness) correlate best with subjective outcome. Methods: Dutch patients treated with bct between 2008 and 2009 were analyzed. Exclusion criteria were prior amputation or bct of the contralateral breast, metastatic disease, local recurrence, or any prior cosmetic breast surgery. Structured questionnaires and standardized six-view photographs were obtained with a minimum of 3 years' follow-up. Cosmetic outcome was judged by the patients and, based on photographs, by 5 different medical professionals using 3 different scoring systems: the Harvard scale, the Sneeuw questionnaire, and a numeric rating scale. Agreement was scored using the intraclass correlation coefficient (icc). The association between items of the Sneeuw questionnaire and a fair-poor Harvard score was estimated using logistic regression analysis. Results: The study included 108 female patients (age: 40-91 years). Based on the Harvard scale, agreement on cosmetic outcome between the professionals was good (icc: 0.78). In contrast, agreement between professionals as a group compared with the patients was found to be fair to moderate (icc range: 0.38-0.50). The items "size" and "shape" were identified as the strongest determinants of cosmetic outcome. Conclusions: Cosmetic outcome was scored differently by patients and professionals. Agreement was greater between the professionals than between the patients and the professionals as a group. In general, size and shape were the most prominent items on which cosmetic outcome was judged by patients and professionals alike.

[Basic therapeutics : What are the features of modern personal care products to protect and regenerate the skin barrier?] / Basistherapeutika : Was zeichnet moderne Pflegeprodukte zum Schutz und zur Wiederherstellung der Hautbarriere aus?

It is international consensus that the daily use of properly selected products for the maintenance therapy is a must in the adjuvant treatment of most chronic skin diseases. In a first step, the selection of an adequate product can be guided by the classical triangle of the dermal vehicles. However, modern skin care products use diverse excipients, e. g. emulsifiers and viscosity enhancers, to improve the galenical and haptic properties of the formulations. It is thus no longer sufficient to simply have knowledge about the oil and water content of a cream in order to make a proper selection. A very positive effect on the skin barrier can be achieved using biomimetic lipids which can be incorporated into the epidermal lipid barrier. The application of such products as a foam cream is the most convenient way especially favorable when inflamed or hardly accessible skin areas have to be treated.

Comprehensive phytochemical characterization of St. John's wort (Hypericum perforatum L.) oil macerates obtained by different extraction protocols via analytical tools applicable in routine control.

The aim of the present study was to investigate the impact of crucial process parameters, i.e. of light and temperature conditions, during the preparation of St. John's wort (SJW, Hypericum perforatum L.) Arachis oil macerates. Extracts were prepared according to a standardized protocol over a period of 28 days. For this purpose, flowering tops of H. perforatum were macerated with Arachis oil (drug extract ratio, DERnative 1:4) under different light and temperature conditions. Spectrophotometric measurements were carried out to quantitate naphthodianthrones and to characterize extract color in the CIE L*C*h° system. Moreover, individual plant secondary metabolites were screened by UHPLC-DAD-MSn measurements following liquid-liquid extraction of the oil macerates with methanol. For quantitation purposes, the chromatographic method was validated using reference standards. This methodology allowed the separation of up to 25 constituents in oily and methanolic SJW extracts, covering hydroxycinnamic acids, flavanols, proanthocyanidins, flavonol glycosides, flavonol aglyca, biflavones, bisanthraquinone glycosides, naphthodianthrones and phloroglucinols. Lowest naphthodianthrone contents were determined in oil macerates recovered at 5 °C, whereas highest amounts were detected upon extraction at 50 °C (both under the exclusion of light). Color shades of the oil macerates differed markedly, revealing e. g. a*-values ranging from -4.6±0.3 to 42.5±0.3. The flavonoids quercetin, kaempferol and I3, II8-biapigenin as well as the phloroglucinols hyperforin and adhyperforin could be simultaneously detected and quantitated in all oil macerates. Contents of these constituents varied noticeably between macerates prepared under different conditions (quercetin 14.7±1.2 to 21.8±0.6 µg/g, kaempferol 3.0±0.1 to 5.4±0.4 µg/g, I3, II8-biapigenin 4.4±0.2 to 7.4±0.4 µg/g, hyperforin 52.6±46.0 to 451.4±24.9 µg/g, adhyperforin 6.9±5.7 to 74.5±7.1 µg/g). These results confirm that the quality of the resulting plant extracts is largely determined by the respective process parameters, i.e. especially temperature and light conditions, and thus must be thoroughly chosen and monitored to obtain tailor-made preparations.

Influenza virus surveillance in Argentina during the 2012 season: antigenic characterization, genetic analysis and antiviral susceptibility.

The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses.

Future directions for the European influenza reference laboratory network in influenza surveillance.

By defining strategic objectives for the network of influenza laboratories that have national influenza centre status or national function within European Union Member States, Iceland and Norway, it is possible to align their priorities in undertaking virological surveillance of influenza. This will help maintain and develop the network to meet and adapt to new challenges over the next 3-5 years and underpin a longer-term strategy over 5-10 years. We analysed the key activities undertaken by influenza reference laboratories in Europe and categorised them into a framework of four key strategic objectives areas: enhancing laboratory capability, ensuring laboratory capacity, providing emergency response and translating laboratory data into information for public health action. We make recommendations on the priority areas for future development.