Synthesis of fused 1,2-naphthoquinones with cytotoxic activity using a one-pot three-step reaction.

A method for the synthesis of fused 1,2-naphthoquinones, as analogues of biologically active natural terpene quinones, is described. The intermediate polycyclic naphthalenes were prepared by a one-pot palladium-catalysed process from simple alkynes, one of which was made from an optically pure biomass-derived levoglucosenone. The prepared methoxy-substituted naphthalenes were subsequently transformed in one step to 1,2-naphthoquinones by a trivalent-iodine-mediated oxidation. The naphthoquinone products were found to have cytotoxic properties.

Enantioselective Synthesis of All-Carbon Quaternary Centers Structurally Related to Amaryllidaceae Alkaloids.

Enantioselective synthesis of all-carbon quaternary centers remains a considerable challenge for synthetic organic chemists. Here, we report a two-step protocol to synthesize such centers including tandem cyclization/Suzuki cross-coupling followed by halocarbocyclization. During this process, two rings, three new C-C bonds and a stereochemically defined all-carbon quaternary center are formed. The absolute configuration of this center is controlled by the stereochemistry of the adjacent stereocenter, which derives from an appropriate enantioenriched starting material. Using this method, we synthesized polycyclic compounds structurally similar to Amaryllidaceae alkaloids in high enantiomeric excesses. Because these products resemble naturally occurring compounds, our protocol can be used to synthesize various potentially bioactive compounds.

Bioinspired total synthesis of tetrahydrofuran lignans by tandem nucleophilic addition/redox isomerization/oxidative coupling and cycloetherification reactions as key steps.

A very short three-step approach to trans,trans,trans-2,5-diaryl-3,4-dimethyltetrahydrofuran lignans is reported. The carbon skeleton is assembled in a single step based on an unprecedented tandem reaction consisting of 1,2-addition of aryllithium reagents to α,ß-unsaturated aldehydes, ruthenium-catalyzed redox isomerization of the resulting alkoxides to enolates and their dimerization triggered by single electron oxidation. The resulting 2,3-dialkyl-1,4-diketones form with moderate to good d/l-diastereoselectivity and are transformed to the target tetrahydrofuran lignans by reduction and diastereoselective cycloetherification.

Adult ADHD and comorbid disorders: clinical implications of a dimensional approach.

Attention-deficit/hyperactivity disorder (ADHD) in the adult population is frequently associated with comorbid psychiatric diseases that complicate its recognition, diagnosis and management.The prevalence of ADHD in the general adult population is 2.5% and it is associated with substantial personal and individual burden. The most frequent comorbid psychopathologies include mood and anxiety disorders, substance use disorders, and personality disorders. There are strong familial links and neurobiological similarities between ADHD and the various associated psychiatric comorbidities. The overlapping symptoms between ADHD and comorbid psychopathologies represent challenges for diagnosis and treatment. Guidelines recommend that when ADHD coexists with other psychopathologies in adults, the most impairing condition should generally be treated first.Early recognition and treatment of ADHD and its comorbidities has the potential to change the trajectory of psychiatric morbidity later in life. The use of validated assessment scales and high-yield clinical questions can help identify adults with ADHD who could potentially benefit from evidence-based management strategies.

Scientific Misconduct in India: Causes and Perpetuation.

Along with economic strength, space technology and software expertise, India is also a leading nation in fraudulent scientific research. The problem is worsened by vested interests working in concert for their own benefits. These self-promoting cartels, together with biased evaluation methods and weak penal systems, combine to perpetuate scientific misconduct. Some of these issues are discussed in this commentary, with supporting examples and possible solutions.

Highly functionalized and potent antiviral cyclopentane derivatives formed by a tandem process consisting of organometallic, transition-metal-catalyzed, and radical reaction steps.

A simple modular tandem approach to multiply substituted cyclopentane derivatives is reported, which succeeds by joining organometallic addition, conjugate addition, radical cyclization, and oxygenation steps. The key steps enabling this tandem process are the thus far rarely used isomerization of allylic alkoxides to enolates and single-electron transfer to merge the organometallic step with the radical and oxygenation chemistry. This controlled lineup of multiple electronically contrasting reactive intermediates provides versatile access to highly functionalized cyclopentane derivatives from very simple and readily available commodity precursors. The antiviral activity of the synthesized compounds was screened and a number of compounds showed potent activity against hepatitis C and dengue viruses.

Nerve fibre organisation in the human optic nerve and chiasm: what do we really know?

A recent anatomical study of the human optic chiasm cast doubt on the widespread assumption that nerve fibres travelling in the human optic nerve and chiasm are arranged retinotopically. Accordingly, a scoping literature review was performed to determine what is known about the nerve fibre arrangement in these structures. Meta-analysis suggested that the average number of fibres in each optic nerve was 1.023 million with an inter-individual range of approximately 50% of the mean. Loss of nerve fibres with age (approximately 3,400 fibres/year) could not account for this variability. The review suggested that there might be a retinotopic arrangement of nerve fibres in the orbital portion of the optic nerve but that this arrangement is most likely to be lost posteriorly with a more random distribution of nerve fibres at the chiasm. Limited studies have looked at nerve fibre arrangement in the chiasm. In summary, the chiasm is more 'H-shaped' than 'X-shaped': nerve fibre crossings occur paracentrally with nerves in the centre of the chiasm travelling coronally and in parallel. There is interaction between crossed and uncrossed fibres which are widely distributed. The review supports the non-existence of Wilbrand's knee. Considerable further work is required to provide more precise anatomical information, but this review suggests that the assumed preservation of retinotopy in the human optic nerve and chiasm is probably not correct.

Screening for Adulthood ADHD and Comorbidities in a Tertiary Mental Health Center Using EarlyDetect: A Machine Learning-Based Pilot Study.

Screening for adult Attention-Deficit/Hyperactivity Disorder (ADHD) and differentiating ADHD from comorbid mental health disorders remains to be clinically challenging. A screening tool for ADHD and comorbid mental health disorders is essential, as most adult ADHD is comorbid with several mental health disorders. The current pilot study enrolled 955 consecutive patients attending a tertiary mental health center in Canada and who completed EarlyDetect assessment, with 45.2% of patients diagnosed with ADHD. The best ADHD classification model using composite scoring achieved a balanced accuracy of 0.788, showing a 2.1% increase compared to standalone ADHD screening, detecting four more patients with ADHD per 100 patients. The classification model including ADHD with comorbidity was also successful (balanced accuracy = 0.712). The results suggest the novel screening method can improve ADHD detection accuracy and inform the risk of ADHD with comorbidity, and may further inform specific comorbidity including MDD and BD.

Individualized identification of sexual dysfunction of psychiatric patients with machine-learning.

Sexual dysfunction (SD) is prevalent in patients with mental health disorders and can significantly impair their quality of life. Early recognition of SD in a clinical setting may help patients and clinicians to optimize treatment options of SD and/or other primary diagnoses taking SD risk into account and may facilitate treatment compliance. SD identification is often overlooked in clinical practice; we seek to explore whether patients with a high risk of SD can be identified at the individual level by assessing known risk factors via a machine learning (ML) model. We assessed 135 subjects referred to a tertiary mental health clinic in a Western Canadian city using health records data, including age, sex, physician's diagnoses, drug treatment, and the Arizona Sexual Experiences Scale (ASEX). A ML model was fitted to the data, with SD status derived from the ASEX as target outcomes and all other variables as predicting variables. Our ML model was able to identify individual SD cases-achieving a balanced accuracy of 0.736, with a sensitivity of 0.750 and a specificity of 0.721-and identified major depressive disorder and female sex as risk factors, and attention deficit hyperactivity disorder as a potential protective factor. This study highlights the utility of SD screening in a psychiatric clinical setting, demonstrating a proof-of-concept ML approach for SD screening in psychiatric patients, which has marked potential to improve their quality of life.

Clinical and functional outcomes in patients with major depressive disorder and painful physical symptoms switched to treatment with duloxetine.

OBJECTIVE: This post hoc analysis of a multicenter, single-arm, open-label trial (the Attributes of Response in Depressed Patients Switched to Treatment with Duloxetine [ARDENT] study) assessed the relationship between functional improvement in the Sheehan Disability Scale (SDS) and clinical outcomes of mood, pain, and anxiety over 8 weeks after switching treatment to duloxetine in patients with major depressive disorder. METHODS: Analyses included all 195 patients who completed the study. Pearson's correlation and multivariate regression analyses were used to evaluate the relationship between change from baseline in SDS total score and 17-item Hamilton Rating Scale for Depression (HAMD(17)) Maier score (mood), Brief Pain Inventory-Short Form average pain score (pain), and Hamilton Anxiety Rating Scale total score (anxiety) at week 8. RESULTS: At week 8, change in SDS total score was positively correlated with change in mood (r = 0.49), anxiety (r = 0.44), and pain (r = 0.40). Multivariate linear regression coefficients for mood and pain were estimated at 1.21 (standard error [SE] = 0.184) and 1.16 (SE = 0.180), respectively (both p < 0.0001) compared with 0.02 (SE = 0.097; p = 0.82) for anxiety. Overall, 43% of patients achieved both HAMD(17) and SDS total remission. CONCLUSIONS: Functional improvement at 8 weeks was positively correlated with mood, pain, and anxiety in patients with major depressive disorder switched to duloxetine. Change in mood and pain exerted a relatively stronger joint effect on functioning than did anxiety in this patient population. Copyright © 2011 John Wiley & Sons, Ltd.

Prevalence of Bipolar Disorder symptoms in Primary Care (ProBiD-PC): A Canadian study.

Objective To describe the prevalence of patients who screen positive for symptoms of bipolar disorder in primary care practice using the validated Mood Disorders Questionnaire (MDQ). Design Prevalence survey. Setting Fifty-four primary care practices across Canada. Participants Adult patients presenting to their primary care practitioners for any cause and reporting, during the course of their visits, current or previous symptoms of depression, anxiety, substance use disorders, or attention deficit hyperactivity disorder. Main outcome measures Subjects were screened for symptoms suggestive of bipolar disorder using the MDQ. Health-related quality of life, functional impairment, and work productivity were evaluated using the 12-Item Short-Form Health Survey and Sheehan Disability Scale. Results A total of 1416 patients were approached to participate in this study, and 1304 completed the survey. Of these, 27.9% screened positive for symptoms of bipolar disorder. All 13 items of the MDQ were significantly associated with screening positive for bipolar disorder (P < .05). Patients screening positive were significantly more likely to report depression, anxiety, substance use, attention deficit hyperactivity disorder, family history of bipolar disorder, or suicide attempts than patients screening negative were (P < .001). Health-related quality of life, work or school productivity, and social and family functioning were all significantly worse in patients who screened positive (P < .001). Conclusion This prevalence survey suggests that more than a quarter of patients presenting to primary care with past or current psychiatric indices are at risk of bipolar disorder. Patients exhibiting a cluster of these symptoms should be further questioned on family history of bipolar disorder and suicide attempts, and selectively screened for symptoms suggestive of bipolar disorder using the quick and high-yielding MDQ.

The long-term impact of the Leprosy Post-Exposure Prophylaxis (LPEP) program on leprosy incidence: A modelling study.

BACKGROUND: The Leprosy Post-Exposure Prophylaxis (LPEP) program explored the feasibility and impact of contact tracing and the provision of single dose rifampicin (SDR) to eligible contacts of newly diagnosed leprosy patients in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. As the impact of the programme is difficult to establish in the short term, we apply mathematical modelling to predict its long-term impact on the leprosy incidence. METHODOLOGY: The individual-based model SIMCOLEP was calibrated and validated to the historic leprosy incidence data in the study areas. For each area, we assessed two scenarios: 1) continuation of existing routine activities as in 2014; and 2) routine activities combined with LPEP starting in 2015. The number of contacts per index patient screened varied from 1 to 36 between areas. Projections were made until 2040. PRINCIPAL FINDINGS: In all areas, the LPEP program increased the number of detected cases in the first year(s) of the programme as compared to the routine programme, followed by a faster reduction afterwards with increasing benefit over time. LPEP could accelerate the reduction of the leprosy incidence by up to six years as compared to the routine programme. The impact of LPEP varied by area due to differences in the number of contacts per index patient included and differences in leprosy epidemiology and routine control programme. CONCLUSIONS: The LPEP program contributes significantly to the reduction of the leprosy incidence and could potentially accelerate the interruption of transmission. It would be advisable to include contact tracing/screening and SDR in routine leprosy programmes.

Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme.

BACKGROUND: Innovative approaches are required for leprosy control to reduce cases and curb transmission of Mycobacterium leprae. Early case detection, contact screening, and chemoprophylaxis are the most promising tools. We aimed to generate evidence on the feasibility of integrating contact tracing and administration of single-dose rifampicin (SDR) into routine leprosy control activities. METHODS: The leprosy post-exposure prophylaxis (LPEP) programme was an international, multicentre feasibility study implemented within the leprosy control programmes of Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania. LPEP explored the feasibility of combining three key interventions: systematically tracing contacts of individuals newly diagnosed with leprosy; screening the traced contacts for leprosy; and administering SDR to eligible contacts. Outcomes were assessed in terms of number of contacts traced, screened, and SDR administration rates. FINDINGS: Between Jan 1, 2015, and Aug 1, 2019, LPEP enrolled 9170 index patients and listed 179 769 contacts, of whom 174 782 (97·2%) were successfully traced and screened. Of those screened, 22 854 (13·1%) were excluded from SDR mainly because of health reasons and age. Among those excluded, 810 were confirmed as new patients (46 per 10 000 contacts screened). Among the eligible screened contacts, 1182 (0·7%) refused prophylactic treatment with SDR. Overall, SDR was administered to 151 928 (86·9%) screened contacts. No serious adverse events were reported. INTERPRETATION: Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers. The programme has also invigorated local leprosy control through the availability of a prophylactic intervention; therefore, we recommend rolling out SDR in all settings where contact tracing and screening have been established. FUNDING: Novartis Foundation.

Liquid chromatographic-tandem mass spectrometry assay for quantitation of a novel antidiabetic S002-853 in rat plasma and its application to pharmacokinetic study.

A sensitive and selective LC-MS/MS method has been developed and validated for the estimation of novel antidiabetic synthetic flavonoid S002-853 in rat plasma using centchroman as an internal standard. The method involves a simple two-step liquid-liquid extraction with diethyl ether. The analyte was chromatographed on a Pierce Spheri-5, guard cyano column (30 x 4.6 mm i.d., 5 microm) with isocratic mobile phase consisting of methanol-ammonium acetate buffer (pH 4.6, 10 mm; 90 : 10, v/v) at a flow rate of 0.75 mL/min. The API 4000 triple-quadrupole LC-MS/MS system was operated under multiple reaction-monitoring mode. The ionization was performed by electrospray ionization technique in positive ion mode. The chromatographic run time was 6 min and the weighted (1/x(2)) calibration curves were linear over the range 0.78-400 ng/mL. The limit of detection and lower limit of quantification were 0.195 and 0.78 ng/mL, respectively. The intra- and inter-batch accuracy (%bias) and precision (%RSD) were found to be less than 8.47 and 11.6% respectively. The average absolute recoveries of S002-853 and internal standard from spiked plasma samples were >90%. S002-853 was stable for 8 h at ambient temperature, 4 weeks at -60 degrees C and after three freeze-thaw cycles. The assay was successfully applied to determine the pharmacokinetic parameters in male Sprague-Dawley rats after an oral dose administration at 25 mg/kg.

Transient response analysis of the eukaryotic chemosensory system to intra-cellular fluctuations.

Like prokaryotic cells, those of eukaryotes are also subjected to noise from within the cells. While the cells have a built-in mechanism to attenuate the noise, conditions may arise where this is beyond the cell's ability to regulate. Start-up perturbations and those induced by metabolic shifts are examples of such situations. Then, it becomes useful to understand how the cells respond. For a eukaryotic chemosensory system, this has been studied by applying response coefficient analysis to a recent model. With even three dependent variables - an activator, an inhibitor, and a response element - the response coefficients differ widely with time and from one variable to another. These differences are interpreted in terms of the chemosensory mechanism and its robustness. The results complement similar recent studies of Escherichia coli chemotaxis, thus supporting their credibility and versatility.

Vagal nerve stimulator implantation: the otolaryngologist's perspective.

Vagal nerve stimulation (VNS) is a recognised and effective measure in treating refractory epilepsy and depression. VNS implantation is a widely accepted surgical procedure, most commonly performed by neurosurgeons. Otolaryngologists, in particular those with an interest in head and neck surgery, are very familiar with the surgical anatomy and dissection of the vagus nerve in the carotid sheath. We present a retrospective analysis of the first 12 patients to be implanted in our department. Our series suggests that otolaryngologists can safely and effectively perform VNS implantation. Otolaryngologists can assess and treat the most common post-operative complication of dysphonia and help the neurologist set the correct level of stimulation in such a way as to minimise laryngeal complications.

Cognitive optimization of microbial PHB production in an optimally dispersed bioreactor by single and mixed cultures.

Cognitive (or intelligent) models are often superior to mechanistic models for nonideal bioreactors. Two kinds of cognitive models--cybernetic and neural--were applied recently to fed-batch fermentation by Ralstonia eutropha in a bioreactor with optimum finite dispersion. In the present work, these models have been applied in simulation studies of co-cultures of R. eutropha and Lactobacillus delbrueckii. The results for both cognitive and mechanistic models have been compared with single cultures. Neural models were the most effective for both types of cultures and mechanistic models the least effective. Simulations with co-culture fermentations predicted more PHB than single cultures with all three types of models. Significantly, the predicted enhancements in PHB concentration by cognitive methods for mixed cultures were four to five times larger than the corresponding increases in biomass concentration. Further improvements are possible through a hybrid combination of all three types of models.

Robustness analysis of the E. coli chemosensory system to perturbations in chemoattractant concentrations.

MOTIVATION: Cells of Escherichia coli sense and move toward chemical attractants. This is done through an intricate sensory system that eventually directs the movements of flagellae which regulate the 'runs' and 'tumbles' of the cells. Under realistic conditions, chemical stimuli often fluctuate due to noise from the environment. The effect of noise on the chemosensory system has been investigated here through the sensitivity coefficients of the concentrations of four key proteins--the phosphorylated forms of CheA, CheB and CheY, and the FliM-CheY-P complex--that govern chemotactic motility. The letter P denotes phosphorylation. RESULTS: All sensitivities increased with time and then stabilized. However, the four sets of sensitivities differed in their magnitudes and the durations of their transient phases before stabilization. CheA-P was the least sensitive and CheY-P the most sensitive. Moreover, while the sensitivities of CheA-P, CheB-P and CheY-P increased with chemoattractant concentration, that of the FliM complex decreased. These differences have been interpreted in terms of the mechanism of the chemosensory system and they have important implications for practical applications of chemotaxis.