A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation.

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4 ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB4 in 25 % overall yield in just 10 steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4 , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.

One-pot, multicomponent synthesis of 2,3-disubstituted quinazolin-ones with potent and selective activity against Toxoplasma gondii.

The discovery of two quinazolinones with selective, single-digit micromolar activity (IC50 = 6-7 µM) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites.

Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-activity relationship studies.

The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed structure-activity relationship (SAR) generation revealing synergistic structural features required for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir against acute HSV-1 infections in neurons and minimal toxicity to the host.

Enol ethers as carbonyl surrogates in a modification of the Povarov synthesis of 3-aryl quinolines and their anti-Toxoplasma activity.

A novel method for the preparation of 2-carboxyl-3-aryl quinoline derivatives from anilines, ethyl glyoxalate and enol ethers as phenylacetaldehyde surrogates is reported. The three-component coupling reaction occurs rapidly under mild conditions in dichloromethane catalysed by TFA. The method allows a more direct access to 3-aryl quinolines, sidestepping issues encountered with phenylacetaldehyde derivatives. This chemistry was used to prepare quinolines with 3-diarylether functionality that showed low micromolar efficacy (IC50 range: 5-26 µM) against in vitro Toxoplasma gondii coupled with little or no cytotoxicity (TD50≥ 320 µM) towards the host cells.

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

Investigation of aryl halides as ketone bioisosteres: refinement of potent and selective inhibitors of human cytochrome P450 19A1 (aromatase).

Bioisosteric replacement of cyclic ketone functionality with aryl halides was investigated on a centrally-flexible, five-component 1,2,3-triazole-containing pharmacophore, resulting in enhanced inhibition of aromatase (CYP450 19A1). Structure-activity data generated from both syn- and anti-aldol precursors provides significant insights into the requirements for enhanced potency, validating this novel ketone-to-aryl halide bioisostere hypothesis.

Effects of Transcendental Meditation on Academic Physician Burnout and Depression: A Mixed Methods Randomized Controlled Trial.

INTRODUCTION: Burnout is pervasive among physicians and has widespread implications for individuals and institutions. This research study examines, for the first time, the effects of the Transcendental Meditation (TM) technique on academic physician burnout and depression. METHODS: A mixed methods randomized controlled trial was conducted with 40 academic physicians representing 15 specialties at a medical school and affiliated VA hospital using the TM technique as the active intervention. Physicians were measured at baseline, 1 month, and 4 months using the Maslach Burnout Inventory, Beck Depression Inventory, Insomnia Severity Index, Perceived Stress Scale, and Brief Resilience Scale. Repeated measures analysis of covariance was used to assess adjusted mean change scores for the 1- and 4-months posttests. Qualitative interviews were conducted at baseline and 4 months and compared with the quantitative measurements. RESULTS: Significant improvements were found for the TM group compared with controls at 4 months in total burnout ( p = .020) including the Maslach Burnout Inventory dimensions of emotional exhaustion ( p = .042) and personal accomplishment ( p = .018) and depression ( p = .016). Qualitative interviews supported quantitative outcomes. Physicians reported classic burnout and depression symptoms in baseline interviews. Those regularly practicing the TM technique reported relief from those symptoms. The control group did not state similar changes. DISCUSSION: Mixed methods findings suggest the TM technique is a viable and effective intervention to decrease burnout and depression for academic physicians. Larger longitudinal studies with a wider range of health care providers are needed to validate these findings for extrapolation to the greater medical community.

A novel combination of mutations leading to congenital ichthyosis and ichthyosis vulgaris.

Coexistence of TGM1 and FLG mutations in a newborn with congenital ichthyosis is not well described in the literature. Early genetic testing and counseling are crucial for accurate diagnosis and appropriate management. Further exploration of associated problems, including hearing loss and developmental delay, is warranted in patients with these mutations.

Colicin-like bacteriocins as novel therapeutic agents for the treatment of chronic biofilm-mediated infection.

The emergence of pan-resistant strains of Gram-negative pathogens and the ability of many bacteria to form multidrug-resistant biofilms during chronic infection poses the grave threat of bacterial infections that are truly untreatable with our current armoury of antibiotics. Despite obvious clinical need, few new antibiotics have entered clinical practice in recent years. For 'difficult to treat' Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli, where the presence of outer membrane and multidrug-efflux pumps severely limit the effectiveness of whole classes of antibiotics, the need is particularly pressing. An alternative approach to antimicrobial treatment is to use the well-characterized species-specific colicin-like bacteriocins which are produced by a wide range of Gram-negative bacteria, including Pseudomonas aeruginosa and Escherichia coli. Our current work on colicin-like bacteriocins aims to determine whether these potent antimicrobial agents are effective at killing bacteria growing in the biofilm state and during infection.

The perception and identification of facial emotions in individuals with autism spectrum disorders using the Let's Face It! Emotion Skills Battery.

BACKGROUND: Although impaired social-emotional ability is a hallmark of autism spectrum disorder (ASD), the perceptual skills and mediating strategies contributing to the social deficits of autism are not well understood. A perceptual skill that is fundamental to effective social communication is the ability to accurately perceive and interpret facial emotions. To evaluate the expression processing of participants with ASD, we designed the Let's Face It! Emotion Skills Battery (LFI! Battery), a computer-based assessment composed of three subscales measuring verbal and perceptual skills implicated in the recognition of facial emotions. METHODS: We administered the LFI! Battery to groups of participants with ASD and typically developing control (TDC) participants that were matched for age and IQ. RESULTS: On the Name Game labeling task, participants with ASD (N = 68) performed on par with TDC individuals (N = 66) in their ability to name the facial emotions of happy, sad, disgust and surprise and were only impaired in their ability to identify the angry expression. On the Matchmaker Expression task that measures the recognition of facial emotions across different facial identities, the ASD participants (N = 66) performed reliably worse than TDC participants (N = 67) on the emotions of happy, sad, disgust, frighten and angry. In the Parts-Wholes test of perceptual strategies of expression, the TDC participants (N = 67) displayed more holistic encoding for the eyes than the mouths in expressive faces whereas ASD participants (N = 66) exhibited the reverse pattern of holistic recognition for the mouth and analytic recognition of the eyes. CONCLUSION: In summary, findings from the LFI! Battery show that participants with ASD were able to label the basic facial emotions (with the exception of angry expression) on par with age- and IQ-matched TDC participants. However, participants with ASD were impaired in their ability to generalize facial emotions across different identities and showed a tendency to recognize the mouth feature holistically and the eyes as isolated parts.

Discovery of a novel class of aldol-derived 1,2,3-triazoles: potent and selective inhibitors of human cytochrome P450 19A1 (aromatase).

The discovery of a novel five-component 1,2,3-triazole-containing pharmacophore that exhibits potent and selective inhibition of aromatase (CYP 450 19A1) is described. All compounds are derived from an initial aldol reaction of a phenylacetate derivative with an aromatic aldehyde. Structure-activity data generated from both syn- and anti-aldol adducts provides initial insights into the requirements for both potency and selectivity.

Echogenic Bowel as an Indicator of Necrotizing Enterocolitis in a Term Newborn.

A 3.5-kilogram infant was born at 40 weeks gestation with an uncomplicated delivery. Prenatal ultrasounds showed echogenic bowel and a ventricular septal defect (VSD), of no clinical significance. Abdominal radiographs showed pneumatosis at 21, 36, and 48 hours of life (HOL). She was treated for necrotizing enterocolitis (NEC) with intravenous antibiotics and parenteral nutrition for 7 days, before working up on feeds and discharging home with breast milk. The only prenatal finding in this case was hyperechogenic bowel, which is a soft marker and often disregarded in the absence of other signs. Chronic intrauterine gut ischemia can cause hyperechogenicity of the bowel. That same intrauterine gut ischemia may have been responsible for NEC in our patient. If a patient has persistent echogenic bowel on prenatal imaging, a critical need exists to make sure NEC is not present.

A Unique Presentation of Amniotic Band Syndrome: A Newborn With a Tail.

A 1-day-old late preterm, small-for-gestational-age female presented with a caudal appendage-a rare finding-and abnormalities in all 4 limbs most consistent with amniotic band syndrome. The caudal appendage was lateral to midline, measured 3 cm × 0.5 cm, and had no bony abnormalities or spinal cord tethering. Limb abnormalities consisted of brachydactyly, oligodactyly, and syndactyly. Renal and head ultrasounds and an echocardiogram were normal. Chromosomal microarray showed deletion of EPHA3, which is not associated with a known phenotype. The multidisciplinary approach of managing this infant with the rare finding of a caudal appendage and limb abnormalities is presented.

A Case of Consanguinity.

A newborn of unknown gestational age and unknown chronological age was admitted to the neonatal intensive care unit after presenting to the emergency department for evaluation and concern for neglect. The infant was found at home by authorities with no adult caretaker. As part of routine newborn care, this infant was noted to have an abnormal newborn metabolic screen. Subsequent genetic testing confirmed an inborn error of metabolism. When family and social history became available, it was determined that the mother and putative father were genetically related. This case report discusses newborn metabolic screening and inborn errors of metabolism and their relationship to consanguinity.

The NLRP3 Inflammasome in the Pathogenesis and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no "curative" disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets.

Using computerized games to teach face recognition skills to children with autism spectrum disorder: the Let's Face It! program.

BACKGROUND: An emerging body of evidence indicates that relative to typically developing children, children with autism are selectively impaired in their ability to recognize facial identity. A critical question is whether face recognition skills can be enhanced through a direct training intervention. METHODS: In a randomized clinical trial, children diagnosed with autism spectrum disorder were pre-screened with a battery of subtests (the Let's Face It! Skills battery) examining face and object processing abilities. Participants who were significantly impaired in their face processing abilities were assigned to either a treatment or a waitlist group. Children in the treatment group (N = 42) received 20 hours of face training with the Let's Face It! (LFI!) computer-based intervention. The LFI! program is comprised of seven interactive computer games that target the specific face impairments associated with autism, including the recognition of identity across image changes in expression, viewpoint and features, analytic and holistic face processing strategies and attention to information in the eye region. Time 1 and Time 2 performance for the treatment and waitlist groups was assessed with the Let's Face It! Skills battery. RESULTS: The main finding was that relative to the control group (N = 37), children in the face training group demonstrated reliable improvements in their analytic recognition of mouth features and holistic recognition of a face based on its eyes features. CONCLUSION: These results indicate that a relatively short-term intervention program can produce measurable improvements in the face recognition skills of children with autism. As a treatment for face processing deficits, the Let's Face It! program has advantages of being cost-free, adaptable to the specific learning needs of the individual child and suitable for home and school applications.

Teacher and Student Views on the Feasibility of Peer to Peer Education as a Model to Educate 16-18 Year Olds on Prudent Antibiotic Use-A Qualitative Study.

Peer education (PE) has been used successfully to improve young peoples' health-related behaviour. This paper describes a qualitative evaluation of the feasibility of university healthcare students delivering PE, covering self-care and antibiotic use for infections, to biology students in three UK schools (16-18 years), who then educated their peers. Twenty peer educators (PEds) participated in focus groups and two teachers took part in interviews to discuss PE feasibility. Data were analysed inductively. All participants reported that teaching students about antibiotic resistance was important. PE was used by PEds to gain communication skills and experience for their CV. PEds confidence increased with practice and group delivery. Interactive activities and real-life illness scenarios facilitated enjoyment. Barriers to PE were competing school priorities, no antibiotic content in the non-biology curriculum, controlling disruptive behaviour, and evaluation consent and questionnaire completion. Participation increased PEds' awareness of appropriate antibiotic use. This qualitative study supports the feasibility of delivering PE in schools. Maximising interactive and illness scenario content, greater training and support for PEds, and inclusion of infection self-care and antibiotics in the national curriculum for all 16-18-year olds could help facilitate greater antibiotic education in schools. Simplifying consent and data collection procedures would facilitate future evaluations.

International promotion of e-Bug, an infection prevention and control educational intervention: survey of partners across 14 countries.

BACKGROUND: Antimicrobial resistance (AMR) is a global threat to public health. e-Bug is an educational resource developed and promoted by a network of international partners. e-Bug seeks to reduce the spread of infection and use of antimicrobials in young people and the community, so helping to control AMR. This study aimed to explore how e-Bug is promoted by international partners and observe barriers to promotion, including the extent of education about antibiotics in schools. METHODS: A total of 29 e-Bug partners were invited to complete online questionnaires on (i) methods they use to promote e-Bug; and (ii) antibiotic topics covered in the national curriculum in their countries. RESULTS: Fourteen and 15 of 29 e-Bug partners across Europe and Palestine completed the promotional activities and curriculum questionnaires respectively. The most frequently reported methods of promotion included endorsement and collaboration with government and non-government sectors and involvement in national and global health awareness campaigns. Barriers to promotion included a lack of time and funding. The curriculum survey data showed variation in antibiotic education across Europe and Palestine, lack of antibiotic education for children under 11 years of age and little change in antibiotic topics included in the curriculum since 2006. CONCLUSIONS: Future and existing e-Bug partners should be encouraged to follow promotional activities reported in this paper, including ministry endorsement, educator training, international campaigns and youth programmes. We encourage all countries to increase antibiotic topics in the school curriculum across all ages.

Peer-Education as a Tool to Educate on Antibiotics, Resistance and Use in 16-18-Year-Olds: A Feasibility Study.

Peer education (PE) interventions may help improve knowledge and appropriate use of antibiotics in young adults. In this feasibility study, health-care students were trained to educate 16-18 years old biology students, who then educated their non-biology peers, using e-Bug antibiotic lessons. Knowledge was assessed by questionnaires, and antibiotic use by questionnaire, SMS messaging and GP record searches. Five of 17 schools approached participated (3 PE and 2 control (usual lessons)). 59% (10/17) of university students and 28% (15/54) of biology students volunteered as peer-educators. PE was well-received; 30% (38/127) intervention students and 55% (66/120) control students completed all questionnaires. Antibiotic use from GP medical records (54/136, 40% of students' data available), student SMS (69/136, 51% replied) and questionnaire (109/136, 80% completed) data showed good agreement between GP and SMS (kappa = 0.72), but poor agreement between GP and questionnaires (kappa = 0.06). Median knowledge scores were higher post-intervention, with greater improvement for non-biology students. Delivering and evaluating e-Bug PE is feasible with supportive school staff. Single tiered PE by university students may be easier to regulate and manage due to time constraints on school students. SMS collection of antibiotic data is easier and has similar accuracy to GP data.

Three new polyketides from fruiting bodies of the endophytic ascomycete Xylaria polymorpha.

The isolation of three new secondary metabolites from the fruiting body of Xylaria polymorpha is described. The new compounds are of mixed biosynthetic origin consisting of a polyketide starter, extended with a methyl orsellinate unit and terminated hydrolytically or with an amine-containing terminal unit.