Publications by authors named "Daniel Kerr"

87 Publications

The association of child maltreatment and systemic inflammation in adulthood: A systematic review.

PLoS One 2021 8;16(4):e0243685. Epub 2021 Apr 8.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.

Introduction: Child maltreatment (CM) is associated with mental and physical health disorders in adulthood. Some studies have identified elevated markers of systemic inflammation in adult survivors of CM, and inflammation may mediate the association between CM and later health problems. However, there are methodological inconsistencies in studies of the association between CM and systemic inflammation and findings are conflicting. We performed a systematic review to examine the association of CM with systemic inflammation in adults.

Methods: A pre-registered systematic review was performed following PRISMA guidelines. Medline, Embase, Scopus and PsychInfo were searched for studies of the association of CM with blood markers of inflammation in adults. Quality was assessed using the Crowe Critical Appraisal Tool. We had intended to perform a meta-analysis, but this was not possible due to variation in study design and reporting.

Results: Forty-four articles met criteria for inclusion in the review. The most widely reported biomarkers were C-Reactive Protein (CRP) (n = 27), interleukin-6 (IL-6) (n = 24) and Tumour Necrosis Factor-alpha (TNF-a) (n = 17). Three studies were prospective (all relating to CRP) and the remainder were retrospective. 86% of studies were based in high income countries. In the prospective studies, CM was associated with elevated CRP in adulthood. Results of retrospective studies were conflicting. Methodological issues relating to the construct of CM, methods of analysis, and accounting for confounding or mediating variables (particularly Body Mass Index) may contribute to the uncertainty in the field.

Conclusions: There is some robust evidence from prospective studies that CM is associated with elevated CRP in adulthood. We have identified significant methodological inconsistencies in the literature and have proposed measures that future researchers could employ to improve consistency across studies. Further prospective, longitudinal, research using robust and comparable measures of CM with careful consideration of confounding and mediating variables is required to bring clarity to this field.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031439PMC
April 2021

Genetic polymorphisms of the serotonin transporter are not related with depression in temporal lobe epilepsy caused by hippocampal sclerosis.

Epilepsy Behav 2021 04 25;117:107854. Epub 2021 Feb 25.

Laboratory of Clinical Neurophysiology, Institute and Department of Psychiatry, Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Rua Dr. Ovidio Pires de Campos, 785, Cerqueira Cesar, Sao Paulo, SP 05403-010, Brazil. Electronic address:

Background: Mood disorders are the most frequent psychiatric disorders in patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS). The pathophysiological mechanisms in common between TLE and mood disorders include abnormalities in the serotonergic pathway. We aimed to evaluate the association between serotonin transporter genetic polymorphisms - 5-HTTLPR and 5-HTTVNTR - and the presence of mood disorders in patients with TLE-HS.

Methods: We evaluated 119 patients with TLE-HS, with and without psychiatric disorder; 146 patients diagnosed with major depressive disorder (MDD), and 113 healthy volunteers. Individuals were genotyped for the 5-HTTLPR and 5-HTTVNTR polymorphisms.

Results: No difference was observed between the TLE-HS groups, healthy controls, and MDD without epilepsy. There was a correlation between the 12-allele of the 5-HTTVNTR and the family history of patients with epilepsy with TLE-HS (p = 0.013).

Conclusions: In this study conducted in two Brazilian centers, the serotonin transporter polymorphisms evaluated cannot be associated with depressive disorder in patients with TLE-HS. Still, they do have some influence over some clinical characteristics of epilepsy in TLE-HS. These data may not be reproduced in other populations with distinct ethnic characteristics.
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http://dx.doi.org/10.1016/j.yebeh.2021.107854DOI Listing
April 2021

PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice.

Biochim Biophys Acta Mol Basis Dis 2021 Apr 23;1867(4):166048. Epub 2020 Dec 23.

CUNY Doctoral Programs in Biology, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America; Department of Chemistry, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America. Electronic address:

Fragile X Syndrome (FXS) is an inherited developmental disorder caused by the non-expression of the Fmr1 gene. FXS is associated with abnormal social and anxiety behavior that is more prominent among males. Given that oxytocin (OXT) regulates both social and anxiety behavior, we studied the effect of FXS in the hypothalamic paraventricular nucleus (PVN), the major central source of OXT. We observed a significant suppression of protein kinase C epsilon (PKCε) (34%) in the ventral hippocampal CA1 region of postnatal day-18 (P18) male Fmr1 knockout (KO) mice, which displayed social behavior deficits and hyper-anxiety in adulthood. These mice also displayed a 39% increase in cell surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) at P18 (measured by the surface level of the AMPAR subunit GluR2), thereby indicating excitation of the CA1 neurons. It is known that neuronal activation at CA1 is linked to an inhibition of the PVN neurons. As expected, these mice also displayed a 25% suppression of oxytocin+ (OXT+) cells in the PVN at P20. Stimulating PKCε during postnatal days 6-,14 (P6-14) mice using a selective activator, dicyclopropyl-linoleic acid (DCP-LA), corrected AMPAR externalization in CA1 and suppression of OXT+ cell number in PVN in a PKCε dependent manner. Most notably, neonatal DCP-LA treatment rescued social behavior deficits and hyper-anxiety, displayed by adult (≥P60) male but not female KO mice. Thus, neonatal stimulation of PKCε could be a strategy to correct endophenotypic anomalies during brain development and aberrant adult behavior of the FXS males to the wild-type levels.
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http://dx.doi.org/10.1016/j.bbadis.2020.166048DOI Listing
April 2021

The hallmarks of childhood abuse and neglect: A systematic review.

PLoS One 2020 8;15(12):e0243639. Epub 2020 Dec 8.

University of Glasgow, Glasgow, United Kingdom.

Background: Studies on the impacts of child maltreatment (CM) have been conducted in diverse areas. Mechanistic understanding of the complex interplay between factors is lacking. Hallmarking is an approach which identifies common factors across studies and highlights the most robust findings.

Objectives: In a review of systematic reviews and meta-analyses, we addressed the following questions: 1) What are the hallmarks associated with exposure to CM across the bio-ecological spectrum? 2) What is the strength of evidence to support each hallmark? 3) What are the gaps that future research should address?

Methods: A comprehensive literature search was carried out to find relevant systematic reviews or meta-analyses. 269 articles were read in full and 178 articles, encompassing more than 6000 original papers, were included in the final synthesis. All reviews were independently rated for quality by at least 2 reviewers using AMSTAR-2.

Results: Of 178 review articles, 6 were rated as high quality (all meta-analyses) and 46 were rated as medium quality. Most were from high income countries.

Conclusions: Based on the most commonly reported high-quality research findings we propose that the hallmarks of exposure to child maltreatment are: Increased risk of psychopathology; Increased risk of obesity; Increased risk of high- risk sexual behaviours, Increased risk of smoking; and Increased risk of child maltreatment in children with disabilities. Research gaps include a lack of focus on complexity and resilience. Little can be concluded about directions of causality or mechanisms. Adequately powered prospective studies are required to move the field forward.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723263PMC
February 2021

Lower limb MSK injuries among school-aged rugby and football players: a systematic review.

BMJ Open Sport Exerc Med 2020 28;6(1):e000806. Epub 2020 Oct 28.

Institute of Nursing and Health Research, School of Health Sciences, Ulster University - Jordanstown Campus, Newtownabbey, UK.

Objective: The objective of this systematic review was to explore the incidence of lower limb musculoskeletal (MSK) injuries sustained by rugby union, rugby league, soccer, Australian Rules and Gaelic football players under 18 years. The review sought to identify the mechanisms and types of injury sustained and to compare between sports.

Design: This systematic review focused on the incidence of lower limb injury in adolescent team sports that involved running and kicking a ball. A literature search of studies published prior to January 2020 was conducted using SportDiscus, Medline and PubMed databases. The Standard Quality Assessment Criteria appraisal tool was used to assess the quality of each article included in the review. Two or more authors independently reviewed all papers.

Results: Sixteen papers met the inclusion criteria; prospective cohort (N=14), retrospective (n=1) and longitudinal (n=1). These studies investigated injuries in rugby union and rugby league (n=10), football (soccer) (n=3), Australian Rules (n=2) and Gaelic football (n=1). There were a total of 55 882 participants, aged 7-19 years old, who reported 6525 injuries. The type, site and mechanisms of injury differed across sports.

Summary: Lower limb injuries were common in adolescent rugby, soccer, Gaelic football and Australian Rules football players, however these studies may not fully reflect the true injury burden where recurrent and overuse injuries have not been considered. There were differences between sports in the mechanisms, types and severity of injury.
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http://dx.doi.org/10.1136/bmjsem-2020-000806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642221PMC
October 2020

Acceptability of online exercise-based interventions after breast cancer surgery: systematic review and narrative synthesis.

J Cancer Surviv 2021 Apr 15;15(2):281-310. Epub 2020 Sep 15.

School of Nursing and Midwifery, Queen's University Belfast, Belfast, Northern Ireland, UK.

Purpose: eHealth and mHealth approaches are increasingly used to support cancer survivors. This review aimed to examine adherence, acceptability and satisfaction with Internet-based self-management programmes for post-surgical cancer rehabilitation and to identify common components of such interventions.

Methods: Nine electronic databases were searched from inception up to February 15, 2020, for relevant quantitative and qualitative studies evaluating Internet-based cancer rehabilitation interventions. Studies were required to include an exercise or physical activity-based self-management intervention and a measure of adherence, acceptability or user satisfaction with the programme. Two independent reviewers performed all data extraction and quality assessment procedures. Data were synthesized using a narrative approach.

Results: Six hundred ninety-six potential papers were identified and screened. Eleven met the inclusion criteria. Interventions had wide variations in levels of adherence, but the majority were reported as being acceptable to the users. Increased acceptability and user satisfaction were associated with interventions which were seen as time and cost-efficient, requiring acquisition of minimal or no new skills, which used coherent language, or which provided tailored information. The majority contained behaviour change components such as goal setting.

Conclusions: Despite high levels of heterogeneity between studies, Internet-based approaches may be an acceptable method for the delivery of self-management interventions in post-surgical cancer rehabilitation.

Implications For Cancer Survivors: There is a need for further studies exploring factors associated with increased user engagement and usage of digital interventions in cancer rehabilitation settings. These findings should be used to help develop interventions prior to testing their effectiveness in adequately powered randomized controlled trials.
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http://dx.doi.org/10.1007/s11764-020-00931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966228PMC
April 2021

Dietary Interventions in the Management of Fibromyalgia: A Systematic Review and Best-Evidence Synthesis.

Nutrients 2020 Aug 31;12(9). Epub 2020 Aug 31.

School of Health Sciences, Ulster University, Shore Road, Newtownabbey BT37 0QB, UK.

Fibromyalgia syndrome (FMS) is characterised by chronic widespread pain alongside fatigue, poor sleep quality and numerous comorbidities. It is estimated to have a worldwide prevalence of 1.78%, with a predominance in females. Treatment interventions for fibromyalgia have limited success, leading to many patients seeking alternative forms of treatment, including modifications to their diet and lifestyle. The effectiveness of dietary changes in fibromyalgia has not been widely researched or evaluated. This systematic review identified twenty-two studies, including 18 randomised control trials (RCTs) and four cohort studies which were eligible for inclusion. In total these studies investigated 17 different nutritional interventions. Significant improvements in reported pain were observed for those following a vegan diet, as well as with the low fermentable oligo di-mono-saccharides and polyols (FODMAP) diets. Supplementation with green algae, coenzyme Q10, acetyl-l-carnitine or a combination of vitamin C and E significantly improved measures of pain. Interpretation of these studies was limited due to the frequent poor quality of the study design, the wide heterogeneity between studies, the small sample size and a high degree of bias. Therefore, there is insufficient evidence to recommend any one particular nutritional intervention for the management of fibromyalgia and further research is needed.
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http://dx.doi.org/10.3390/nu12092664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551150PMC
August 2020

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System.

Molecules 2020 Aug 23;25(17). Epub 2020 Aug 23.

Physiology, School of Medicine, National University of Ireland Galway, H91W5P7 Galway, Ireland.

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB) receptor expression following LPS/GalN. CB antagonism with AM6545 or CB agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.
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http://dx.doi.org/10.3390/molecules25173834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504576PMC
August 2020

Kappa Opioid Receptor-mediated Modulation of Social Responding in Adolescent Rats and in Rats Prenatally Exposed to Valproic Acid.

Neuroscience 2020 09 5;444:9-18. Epub 2020 Aug 5.

Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address:

The kappa opioid receptor (KOP) system modulates social play responding, however a paucity of studies have examined effects on social motivation and cognition in the absence of play. Prenatal exposure to the anti-epileptic and mood stabiliser valproic acid (VPA) is associated with impaired social responding and altered gene expression of KOP (oprk1) and dynorphin (pdyn) in several brain regions. The present study examined if pharmacological modulation of KOP altered social motivation and cognition, immediate early gene (IEG) and oprk1-pdyn expression in adolescent male rats and rats prenatally exposed to VPA. In control rats, the KOP antagonist DIPPA enhanced sociability, while both DIPPA and the KOP agonist U50488 decreased social novelty preference. In rats exposed prenatally to VPA, neither U50488 nor DIPPA altered sociability or social novelty preference. Analysis of IEG expression revealed that DIPPA reduced expression of egr-1 expression in the prefrontal cortex of control rats and U50488 increased junb expression in the PFC of both control and VPA-exposed rats. VPA-exposed rats exhibited increased expression of oprk1 and pdyn in the prefrontal cortex and amygdala compared with control rats. DIPPA and U50488 increased oprk1 expression in the amygdala of control rats and decreased oprk1 expression in the prefrontal cortex of VPA-exposed rats. Taken together, these data demonstrate that pharmacological modulation of the KOP system alters social motivation and cognition in control rats, an effect not observed in rats prenatally exposed to VPA. These data provide support that prenatal exposure to VPA is associated with alterations in the expression and functionality of KOP system.
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http://dx.doi.org/10.1016/j.neuroscience.2020.07.055DOI Listing
September 2020

Survival outcomes in blastic plasmacytoid dendritic cell neoplasm by first-line treatment and stem cell transplant.

Blood Adv 2020 07;4(14):3435-3442

Department of Malignant Hematology and.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies such cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose cytarabine and methotrexate (CVAD) have been commonly used for the BPDCN treatment until a recent study showed promising outcomes in patients treated with SL-401 (Tagraxofusp). In this single-institution retrospective study, we identified a total of 49 consecutive BPDCN patients. Among 42 patients who received treatment, hyper-CVAD regimen was associated with higher complete response rate compared with CHOP-based regimens or SL-401 (91% vs 50% vs 50%), although the difference did not achieve statistical significance. Furthermore, there was no significant overall survival (OS) difference between patients treated with SL-401 vs other chemotherapies as their first-line treatment (hazard ratio = 1.597; 95% CI, 0.460-5.548; P = .431). Of note, patients who received allogeneic stem cell transplant (allo-SCT) had significantly longer OS (hazard ratio = 0.160; 95% CI, 0.0453-0.56; P = .041). Extent of disease (skin vs bone marrow vs both) or younger age (<60 years old) did not have significant prognostic impact on OS. Collectively, our study confirmed the survival benefit of allo-SCT and suggests that conventional and intensive chemotherapies such as CHOP and hyper-CVAD as well as SL-401 would be comparable first-line choice for the BPDCN patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391135PMC
July 2020

Offshore telementored ultrasound: a quality assessment study.

Ultrasound J 2020 Jul 2;12(1):33. Epub 2020 Jul 2.

Faculty of Health Sciences, Department of Quality and Health Technology, University of Stavanger, Stavanger, Norway.

Background: Telementored ultrasound (US) connects experts to novices through various types of communication and network technologies with the overall aim to bridge the medical imaging gap between patients' diagnostic needs and on-site user experience. The recurrent theme in previous research on remote telementored US is the limited access to US machines and experienced users. This study was conducted to determine whether telementored US was feasible in a remote offshore setting. The aim was to assess if an onshore US expert can guide an offshore nurse through focused US scanning protocols by connecting an US machine to existing videoconference units at the offshore hospitals and to evaluate the diagnostic quality of the images and cineloops procured.

Results: The diagnostic quality of cineloops was scored on a five-point scale. The percentage of cineloops suitable for interpretation (score 3 ≥) for the FATE and e-FAST protocols was 96.4 and 79.1. Lung sliding and seashore sign could be identified in all volunteers. The scan time for the FAST protocol (n = four scanning positions), FATE protocol (n = six scanning positions) and both lungs (n = two scanning positions) was 1 min 20 s, 4 min 15 s and 32 s, respectively.

Conclusion: A novice US user can be guided by a remote expert through focused US protocols within an acceptable time frame and with good diagnostic quality using existing communication and network systems found onboard offshore oil rigs.
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http://dx.doi.org/10.1186/s13089-020-00180-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329972PMC
July 2020

Maternal presence or absence alters nociceptive responding and cortical anandamide levels in juvenile female rats.

Behav Brain Res 2020 08 30;392:112712. Epub 2020 May 30.

Physiology, School of Medicine, National University of Ireland Galway, Ireland; Centre for Pain Research, National University of Ireland Galway, Ireland; Galway Neuroscience Centre, National University of Ireland Galway, Ireland. Electronic address:

The influence of parental support on child pain experiences is well recognised. Accordingly, animal studies have revealed both short- and long-term effects of early life stress on nociceptive responding and neural substrates such as endocannabinoids. The endocannabinoid system plays an important role in mediating and modulating stress, social interaction, and nociception. This study examined the effects of maternal support or acute isolation on nociceptive responding of female rats to a range of stimuli during the juvenile pre-adolescent period and accompanying changes in the endocannabinoid system. The data revealed that juvenile female Sprague Dawley rats (PND21-24) isolated from the dam for 1 h prior to nociceptive testing exhibited increased latency to withdraw in the hot plate test and increased mechanical withdrawal threshold in the Von Frey test, compared to rats tested in the presence of the dam. Furthermore, isolated rats exhibited reduced latency to respond in the acetone drop test and enhanced nociceptive responding in the formalin test when compared to dam-paired counterparts. Anandamide, but not 2-AG, levels were reduced in the prefrontal cortex of dam-paired, but not isolated, juvenile rats following nociceptive testing. There was no change in the expression of CB, FAAH or MAGL; however, CB receptor expression was reduced in both dam-paired and isolated rats following nociceptive testing. Taken together the data demonstrate that brief social isolation or the presence of the dam modulates nociceptive responding of juvenile rat pups in a modality specific manner, and suggest a possible role for the endocannabinoid system in the prefrontal cortex in sociobehavioural pain responses during early life.
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http://dx.doi.org/10.1016/j.bbr.2020.112712DOI Listing
August 2020

Endocannabinoid modulation of inflammatory hyperalgesia in the IFN-α mouse model of depression.

Brain Behav Immun 2019 Nov 7;82:372-381. Epub 2019 Sep 7.

Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address:

Depression is a well-recognised effect of long-term treatment with interferon-alpha (IFN-α), a widely used treatment for chronic viral hepatitis and malignancy. In addition to the emotional disturbances, high incidences of painful symptoms such as headache and joint pain have also been reported following IFN-α treatment. The endocannabinoid system plays an important role in emotional and nociceptive processing, however it is unknown whether repeated IFN-α administration induces alterations in this system. The present study investigated nociceptive responding in the IFN-α-induced mouse model of depression and associated changes in the endocannabinoid system. Furthermore, the effects of modulating peripheral endocannabinoid tone on inflammatory pain-related behaviour in the IFN-α model was examined. Repeated IFN-α administration (8000 IU/g/day) to male C57/Bl6 mice increased immobility in the forced swim test and reduced sucrose preference, without altering body weight gain or locomotor activity, confirming development of the depressive-like phenotype. There was no effect of repeated IFN-α administration on latency to respond in the hot plate test on day 4 or 7 of treatment, however, formalin-evoked nociceptive behaviour was significantly increased in IFN-α treated mice following 8 days of IFN-α administration. 2-Arachidonoyl glycerol (2-AG) levels in the periaqueductal grey (PAG) and rostroventromedial medulla (RVM), and anandamide (AEA) levels in the RVM, were significantly increased in IFN-α-, but not saline-, treated mice following formalin administration. There was no change in endocannabinoid levels in the prefrontal cortex, spinal cord or paw tissue between saline- or IFNα-treated mice in the presence or absence of formalin. Furthermore, repeated IFN-α and/or formalin administration did not alter mRNA expression of genes encoding the endocannabinoid catabolic enzymes (fatty acid amide hydrolase or monoacylglycerol lipase) or endocannabinoid receptor targets (CB CB or PPARs) in the brain, spinal cord or paw tissue. Intra plantar administration of PF3845 (1 μg/10 μl) or MJN110 (1 μg/10 μl), inhibitors of AEA and 2-AG catabolism respectively, attenuated formalin-evoked hyperalgesia in IFN-α, but not saline-, treated mice. In summary, increasing peripheral endocannabinoid tone attenuates inflammatory hyperalgesia induced following repeated IFN-α administration. These data provide support for the endocannabinoid system in mediating and modulating heightened pain responding associated with IFNα-induced depression.
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http://dx.doi.org/10.1016/j.bbi.2019.09.006DOI Listing
November 2019

Blastic Plasmacytoid Dendritic Cell Neoplasm.

Curr Treat Options Oncol 2019 02 4;20(1). Epub 2019 Feb 4.

Department of Hematology and Medical Oncology, Moffitt Cancer Center/University of South Florida, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA.

Opinion Statement: While there is a high initial response rate with standard chemotherapeutic regimens for blastic plasmacytoid dendritic cell neoplasm (BPDCN), the responses are typically not durable and this remains a very aggressive disease with generally poor outcomes. For this reason, the standard approach for eligible patients has been high-dose induction chemotherapy preferably with acute lymphoblastic leukemia (ALL)-based regimens followed by consolidation with allogeneic hematopoietic stem cell transplantation (alloHSCT). Unfortunately, many patients with this disease are elderly and/or frail and cannot tolerate this therapy, and the low-dose regimens being used in this population are generally not as effective. However, this paradigm may be changing with the advent of newer targeted therapies, particularly the exploitation of CD123. SL-401 has shown very promising results with manageable toxicities and durable responses and appears to be a viable option for elderly or frail patients who are not eligible for transplant. The other CD123-directed therapies, especially chimeric antigen receptor-therapy (CAR-T), may also give promising results in trials that are currently underway. CAR-T has shown promise in a number of other hematologic malignancies, and toxicities have become more manageable as its use is becoming more widespread. While SL-401 has shown potential to provide durable responses even without transplant, we do not yet know whether it will be effective as a means to avoid transplant in patients who are otherwise eligible. All transplant-eligible patients should undergo alloHSCT consolidation given the current available data indicating this is the optimal approach to achieve a long-term remission. Once the CD123-directed therapies are established as standard regimens, future studies may be designed to investigate whether these therapies can be utilized without the use of transplant. Furthermore, combination therapy using anti-CD123 agents with high-dose induction chemotherapy or other low-dose regimens for elderly/frail patients should be investigated. Given the promising results in early clinical trials, it appears CD123 is the most viable target for BPDCN, and future studies should continue to exploit its expression on BPDCN cells.
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http://dx.doi.org/10.1007/s11864-019-0605-xDOI Listing
February 2019

Formation of Highly Substituted Indenes through Acid Promoted Cyclodehydration with Nucleophile Incorporation.

J Org Chem 2019 03 12;84(5):2756-2767. Epub 2019 Feb 12.

Monash Institute of Pharmaceutical Sciences , Monash University , 381 Royal Parade , Parkville 3052 , Victoria , Australia.

Readily accessible 3-aryl-2-carboxypropenones (by Knoevenagel condensation) undergo acid promoted cyclodehydration with nucleophile incorporation to form highly substituted indenes. For stronger nucleophiles, nucleophile incorporation precedes cyclodehydration in a nucleophilic-addition-cyclodehydration (NAC) sequence. For weaker nucleophiles, cyclodehydration precedes nucleophile incorporation in a cyclodehydrative-nucleophilic-trapping (CNT) sequence, involving a reactive allyl cation intermediate. The substrate scope and preferred cyclization pathway (NAC or CNT) has been studied with respect to 3-aryl-2-carboxypropenone and the nature of the nucleophile. Also, for 1,3-diaryl-2-carboxypropenones, which can also undergo Nazarov cyclization, delineation between competing Nazarov and CNT pathways is controlled by the nature of the acid catalyst.
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http://dx.doi.org/10.1021/acs.joc.8b03042DOI Listing
March 2019

Higher transcription alleles of the MAOA-uVNTR polymorphism are associated with higher seizure frequency in temporal lobe epilepsy.

Epilepsy Res 2019 01 12;149:26-29. Epub 2018 Nov 12.

Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. Electronic address:

Background: There is evidence of an imbalance in the neuromodulatory system mediated by serotonin (5-HT) in patients with drug-resistant temporal lobe epilepsy (TLE). This study analyzed the monoamine oxidase A promoter variable number of tandem repeats (MAOA-uVNTR) polymorphism in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Therefore, we assessed the association between this genetic variant and seizure predisposition and severity in patients with TLE-HS.

Methods: One hundred nineteen patients with TLE-HS and 113 healthy volunteers were assessed. First, we genotyped all individuals for the MAOA-uVNTR genetic polymorphism. Second, we compared patients and controls and evaluated clinical variants of epilepsy.

Results: There was no difference between the TLE-HS and control groups regarding genotypic and allelic distributions of MAOA-uVNTR polymorphism (p = 1.000). Higher transcription alleles of the MAOA-uVNTR were associated with higher seizure frequency (p = 0.032) and bilateral tonic-clonic seizures (p = 0.016).

Conclusions: In a selected group of patients with TLE-HS, the polymorphism MAOA-uVNTR was associated with some aspects of epilepsy severity, namely seizure frequency and bilateral tonic-clonic seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.11.003DOI Listing
January 2019

The advances in therapy of blastic plasmacytoid dendritic cell neoplasm.

Expert Opin Investig Drugs 2018 09 27;27(9):733-739. Epub 2018 Aug 27.

a Department of Malignant Hematology , Moffitt Cancer Center/University of South Florida , Tampa , FL , USA.

Introduction: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy that contributes to <1% of all hematologic neoplasms. Before the introduction of various targeted agents, the therapeutic approach was based on regimens used for acute lymphoblastic or myeloid leukemia and non-Hodgkin's lymphoma (e.g. hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) -based regimens) followed by allogeneic stem cell transplantation for eligible patients. Given that this disease primarily affects older patients, there is a significant barrier to using these highly toxic regimens, even though these regimens are usually associated with the most durable response.

Areas Covered: In this review, we briefly discuss outcomes with the use of leukemia-based induction regimens as well as the use of stem cell transplant. We also review low-intensity chemotherapeutic regimens. Finally, we will describe both preclinical and early clinical data regarding novel targeted strategies for treating BPDCN without the use of cytotoxic chemotherapy, with a focus on the use of CD123 directed therapy.

Expert Opinion: While the current standard treatment for BPDCN is acute leukemia-based regimen followed by hematopoietic stem cell transplantation for transplant-eligible patients, there are very promising results for CD123 directed therapies. The future of BPDCN treatment may include targeted therapies without the need for cytotoxic chemotherapy.
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http://dx.doi.org/10.1080/13543784.2018.1512970DOI Listing
September 2018

BDNF Val66Met polymorphism is not related with temporal lobe epilepsy caused by hippocampal sclerosis in Brazilian population.

Seizure 2018 Aug 7;60:159-162. Epub 2018 Jul 7.

Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Brazil; Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Brazil. Electronic address:

Purpose: Some variants of the brain derived neurotrophic factors (BDNF) gene, namely the Val66Met (rs6265), may contribute the risk for epilepsy development. We aimed to investigate if this polymorphism was associated with the risk for epilepsy development in TLE-HS and its correlation with epilepsy-related factors and the presence of psychiatric disorders.

Methods: We assessed 119 patients with unequivocal TLE-HS and 112 healthy controls. Individuals were genotyped for the polymorphisms of the gene encoding BDNF Val66Met.

Results: There was no difference between TLE-HS and healthy controls, for the genotypic distribution (p = 0.636) and allelic distribution (p = 0.471). There was no correlation between Val66Met and epilepsy-related factors and for psychiatric comorbidities (p = 0.888).

Conclusions: Our findings demonstrated that polymorphism Val66Met is not associated with TLE-HS, epilepsy-related factors and psychiatric comorbidities in this selected group of patients.
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http://dx.doi.org/10.1016/j.seizure.2018.07.004DOI Listing
August 2018

FAAH inhibition attenuates TLR3-mediated hyperthermia, nociceptive- and anxiety-like behaviour in female rats.

Behav Brain Res 2018 11 25;353:11-20. Epub 2018 Jun 25.

Physiology, School of Medicine, National University of Ireland Galway, Ireland; NCBES Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, Ireland. Electronic address:

Aberrant activation of toll-like receptor (TLR)s results in persistent and prolonged neuroinflammation and has been implicated in the pathogenesis and exacerbation of psychiatric and neurodegenerative disorders. TLR3 coordinates the innate immune response to viral infection and recent data have demonstrated that inhibiting fatty acid amide hydrolase (FAAH), the enzyme that primarily metabolizes anandamide, modulates TLR3-mediated neuroinflammation. However, the physiological and behavioural consequences of such modulation are unknown. The present study examined the effect of URB597, a selective FAAH inhibitor, on neuroinflammation, physiological and behavioural alterations following administration of the TLR3 agonist and viral mimetic poly I:C to female rats. URB597 attenuated TLR3-mediated fever, mechanical and cold allodynia, and anxiety-like behaviour in the elevated plus maze and open field arena. There was no effect of URB597 on TLR3-mediated decreases in body weight and no effect in the sucrose preference or forced swim tests. URB597 attenuated the TLR3-mediated increase in the expression of CD11b and CD68, markers of microglia/macrophage activation. In summary, these data demonstrate that enhancing FAAH substrate levels suppresses TLR3-mediated microglia/macrophage activation and associated changes in fever, nociceptive responding and anxiety-related behaviour. These data provide further support for FAAH as a novel therapeutic target for neuroinflammatory disorders.
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http://dx.doi.org/10.1016/j.bbr.2018.06.030DOI Listing
November 2018

Sensitivity of peripheral membrane proteins to the membrane context: A case study of phosphatidylserine and the TIM proteins.

Biochim Biophys Acta Biomembr 2018 10 18;1860(10):2126-2133. Epub 2018 Jun 18.

Program in Biophysical Sciences, Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, United States of America; Department of Chemistry, The University of Chicago, Chicago, IL, United States of America; James Franck Institute, The University of Chicago, Chicago, IL, United States of America. Electronic address:

There is a diverse class of peripheral membrane-binding proteins that specifically bind phosphatidylserine (PS), a lipid that signals apoptosis or cell fusion depending on the membrane context of its presentation. PS-receptors are specialized for particular PS-presenting pathways, indicating that they might be sensitive to the membrane context. In this review, we describe a combination of thermodynamic, structural, and computational techniques that can be used to investigate the mechanisms underlying this sensitivity. As an example, we focus on three PS-receptors of the T-cell Immunoglobulin and Mucin containing (TIM) protein family, which we have previously shown to differ in their sensitivity to PS surface density.
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http://dx.doi.org/10.1016/j.bbamem.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290684PMC
October 2018

Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice.

J Alzheimers Dis 2018 ;63(1):93-101

Laboratory of Neuroscience (LIM-27), Instituto de Psiquiatria do Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL.
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http://dx.doi.org/10.3233/JAD-170838DOI Listing
August 2019

Case Report: CEA Elevation Can Be a Marker of Increased Inflammation During Treatment with Oxaliplatin.

Anticancer Res 2018 03;38(3):1711-1713

Department of Hematology, Morsani School of Medicine, University of South Florida, Tampa, FL, U.S.A.

Oxaliplatin is a platinum-based chemotherapy that is an integral part of several regimens for colorectal cancer. We present the case of a patient, a 58-year-old male, who had initially presented aged 56 years with rectal bleeding for several months. His serum carcinoembryonic antigen (CEA) level at the time of diagnosis was 4.6 ng/ml. His CEA level increased significantly during oxaliplatin-based chemotherapy and declined to a near normal level after completion of therapy. There was no evidence of disease during this time and he remains disease-free. Oxaliplatin has been shown to cause an inflammatory response which appears to be one of the mechanisms of toxicity and high CEA levels have been correlated with increased inflammation. We postulate that this patient's rising CEA level was secondary to an inflammatory response to oxaliplatin-based therapy, which is further supported by the subsequent decrease after completion of chemotherapy. To our knowledge, this is the first published case of oxaliplatin-induced rising CEA level.
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http://dx.doi.org/10.21873/anticanres.12405DOI Listing
March 2018

Plasma N-acylethanolamine and endocannabinoid levels in burning mouth syndrome: Potential role in disease pathogenesis.

J Oral Pathol Med 2018 Apr 2;47(4):440-442. Epub 2018 Mar 2.

Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland.

Objective: The objective was to measure endocannabinoid (eCB) ligands and non-cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS) and to determine whether plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort.

Study Design: Plasma content of the eCBs, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and the NAE molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were assessed in healthy subjects (n = 8) and in a cohort of newly diagnosed BMS patients (n = 9) using liquid chromatography-tandem mass spectrometry. Plasma eCBs and NAE profiles were correlated with self-rated oral cavity pain intensities, depressive symptomatology and plasma IL-8 levels.

Results: Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology.

Conclusions: This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS.
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http://dx.doi.org/10.1111/jop.12692DOI Listing
April 2018

Coupling X-Ray Reflectivity and In Silico Binding to Yield Dynamics of Membrane Recognition by Tim1.

Biophys J 2017 Oct;113(7):1505-1519

Program in Biophysical Sciences, Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois; Department of Chemistry, The University of Chicago, Chicago, Illinois; James Franck Institute, The University of Chicago, Chicago, Illinois. Electronic address:

The dynamic nature of lipid membranes presents significant challenges with respect to understanding the molecular basis of protein/membrane interactions. Consequently, there is relatively little known about the structural mechanisms by which membrane-binding proteins might distinguish subtle variations in lipid membrane composition and/or structure. We have previously developed a multidisciplinary approach that combines molecular dynamics simulation with interfacial x-ray scattering experiments to produce an atomistic model for phosphatidylserine recognition by the immune receptor Tim4. However, this approach requires a previously determined protein crystal structure in a membrane-bound conformation. Tim1, a Tim4 homolog with distinct differences in both immunological function and sensitivity to membrane composition, was crystalized in a closed-loop conformation that is unlikely to support membrane binding. Here we have used a previously described highly mobile membrane mimetic membrane in combination with a conventional lipid bilayer model to generate a membrane-bound configuration of Tim1 in silico. This refined structure provided a significantly improved fit of experimental x-ray reflectivity data. Moreover, the coupling of the x-ray reflectivity analysis with both highly mobile membrane mimetic membranes and conventional lipid bilayer molecular dynamics simulations yielded a dynamic model of phosphatidylserine membrane recognition by Tim1 with atomic-level detail. In addition to providing, to our knowledge, new insights into the molecular mechanisms that distinguish the various Tim receptors, these results demonstrate that in silico membrane-binding simulations can remove the requirement that the existing crystal structure be in the membrane-bound conformation for effective x-ray reflectivity analysis. Consequently, this refined methodology has the potential for much broader applicability with respect to defining the atomistic details of membrane-binding proteins.
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http://dx.doi.org/10.1016/j.bpj.2017.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627149PMC
October 2017

Donepezil effects on cholesterol and oxysterol plasma levels of Alzheimer's disease patients.

Eur Arch Psychiatry Clin Neurosci 2018 Aug 31;268(5):501-507. Epub 2017 Aug 31.

Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos, 785, 3º andar, São Paulo, SP, 05403-010, Brazil.

Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease.
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http://dx.doi.org/10.1007/s00406-017-0838-2DOI Listing
August 2018

FAAH, but not MAGL, inhibition modulates acute TLR3-induced neuroimmune signaling in the rat, independent of sex.

J Neurosci Res 2018 06 20;96(6):989-1001. Epub 2017 Jul 20.

Physiology, School of Medicine, National University of Ireland, Galway, Ireland.

Toll-like receptor (TLR)3 is a key component of the innate immune response to viral infection. The present study firstly examined whether sex differences exist in TLR3-induced inflammatory, endocrine, and sickness responses. The data revealed that TLR3-induced expression of interferon- or NFkB-inducible genes (IFN-α/β, IP-10, or TNF-α), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3-induced IFN-α expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight - effects independent of sex. Thus, the acute-phase inflammatory, endocrine, and sickness responses to TLR3 activation exhibit minimal sex-related differences. A further aim of this study was to examine whether enhancing endocannabinoid tone - namely, 2-arachidonylglycerol (2-AG) or N-arachidonoylethanolamine (AEA), exhibited similar effects on TLR3-induced inflammatory responses in male versus female rats. Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2-AG levels did not alter the TLR3-induced increase in IP-10, IRF7, or TNF-α expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N-acylethanolamines, an effect associated with the attenuation of TLR3-induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats. These data support a role for FAAH, but not MAGL, substrates in the modulation of TLR3-induced neuroinflammatory responses, effects independent of sex.
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http://dx.doi.org/10.1002/jnr.24120DOI Listing
June 2018

Multistereocenter-Containing Cyclopentanoids from Ynamides via Oxazolidinone-Controlled Nazarov Cyclization.

J Org Chem 2017 07 13;82(13):6511-6527. Epub 2017 Jun 13.

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.

Achieving ready-enantioselective access to multistereocenter-containing cyclopentyl rings is an area of great significance to organic synthesis. In this work, we describe a general protocol for accessing multistereocenter-containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated divinyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio-, and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both in the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a "coupled-torque" mechanism in which rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation, favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated lone-pair stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates, broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereo- and regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multistereocenter containing cyclopentanoids. Finally, the Ox group is readily removed and recovered or can be converted into other amine functionalities.
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http://dx.doi.org/10.1021/acs.joc.7b00082DOI Listing
July 2017

Quantitative analysis of total reflection X-ray fluorescence from finely layered structures using XeRay.

Rev Sci Instrum 2017 Mar;88(3):033112

James Franck Institute, The University of Chicago, Chicago, Illinois 60637, USA.

Total reflection x-ray fluorescence (TXRF) is a widely applicable experimental technique for studying chemical element distributions across finely layered structures at extremely high sensitivity. To promote and facilitate scientific discovery using TXRF, we developed a MATLAB-based software package with a graphical user interface, named XeRay, for quick, accurate, and intuitive data analysis. XeRay lets the user model any layered system, each layer with its independent chemical composition and thickness, and enables fine-tuned data fitting. The accuracy of XeRay has been tested in the analysis of TXRF data from both air/liquid interface and liquid/liquid interfacial studies and has been compared to literature results. In an air/liquid interface study, Ca sequestration was measured at a Langmuir monolayer of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidic acid (SOPA) on a buffer solution of 1 mM CaCl at pH 7.5. Data analysis with XeRay reveals that each 1 nm of interfacial area contains 2.38 ± 0.06 Ca ions, which corresponds to a 1:1 ratio between SOPA headgroups and Ca ions, consistent with several earlier reports. For the liquid/liquid interface study of Sr enrichment at the dodecane/surfactant/water interface, analysis using XeRay gives a surface enrichment of Sr at 68 Å per ion, consistent with the result published for the same dataset.
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http://dx.doi.org/10.1063/1.4978654DOI Listing
March 2017

Pharmacological inhibition of FAAH modulates TLR-induced neuroinflammation, but not sickness behaviour: An effect partially mediated by central TRPV1.

Brain Behav Immun 2017 May 22;62:318-331. Epub 2017 Feb 22.

Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address:

Aberrant activation of toll-like receptors (TLRs), key components of the innate immune system, has been proposed to underlie and exacerbate a range of central nervous system disorders. Increasing evidence supports a role for the endocannabinoid system in modulating inflammatory responses including those mediated by TLRs, and thus this system may provide an important treatment target for neuroinflammatory disorders. However, the effect of modulating endocannabinoid tone on TLR-induced neuroinflammation in vivo and associated behavioural changes is largely unknown. The present study examined the effect of inhibiting fatty acid amide hydrolyase (FAAH), the primary enzyme responsible for the metabolism of anandamide (AEA), in vivo on TLR4-induced neuroimmune and behavioural responses, and evaluated sites and mechanisms of action. Systemic administration of the FAAH inhibitor PF3845 increased levels of AEA, and related FAAH substrates N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), in the frontal cortex and hippocampus of rats, an effect associated with an attenuation in the expression of pro- and anti-inflammatory cytokines and mediators measured 2hrs following systemic administration of the TLR4 agonist, lipopolysaccharide (LPS). These effects were mimicked by central i.c.v. administration of PF3845, but not systemic administration of the peripherally-restricted FAAH inhibitor URB937. Central antagonism of TRPV1 significantly attenuated the PF3845-induced decrease in IL-6 expression, effects not observed following antagonism of CB CB, PPARα, PPARγ or GPR55. LPS-induced a robust sickness-like behavioural response and increased the expression of markers of glial activity and pro-inflammatory cytokines over 24hrs. Systemic administration of PF3845 modulated the TLR4-induced expression of neuroimmune mediators and anhedonia without altering acute sickness behaviour. Overall, these findings support an important role for FAAH substrates directly within the brain in the regulation of TLR4-associated neuroinflammation and highlight a role for TRPV1 in partially mediating these effects.
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http://dx.doi.org/10.1016/j.bbi.2017.02.016DOI Listing
May 2017

Pharmacological inhibition of fatty acid amide hydrolase attenuates social behavioural deficits in male rats prenatally exposed to valproic acid.

Pharmacol Res 2016 11 31;113(Pt A):228-235. Epub 2016 Aug 31.

Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Galway Neuroscience Centre and Centre for Pain Research, National University of Ireland, Galway, Ireland. Electronic address:

Autism spectrum disorders are a group of neurodevelopmental disorders characterised by impaired social interaction, deficits in communication and repetitive stereotyped behaviours. The endocannabinoid system plays an important role in modulating emotionality and social responding, however there have been a paucity of studies investigating this system in autistic animal models. This study investigated the effect of inhibiting fatty acid amide hydrolyase (FAAH), the anandamide catabolic enzyme, on behavioural responding in the valproic acid (VPA) rat model of autism. Male rats prenatally exposed to VPA exhibit an autistic-like behavioural phenotype exemplified as thermal hypoalgesia, reduced social and exploratory behaviour, and enhanced repetitive behaviour. Systemic administration of the FAAH inhibitor PF3845 (10mg/kg) attenuated the deficit in social behaviour observed in VPA exposed male animals without altering nociceptive, repetitive or exploratory behaviour. In comparison, female VPA exposed rats displayed enhanced repetitive and reduced exploratory behaviour, but no change in social behaviour or thermal nociceptive responding. PF3845 did not alter social, repetitive or thermal nociceptive responding, but reduced exploratory behaviour in a social context in VPA-, but not saline-, exposed females. These data indicate that FAAH inhibition elicits sexual dimorphic effects on behavioural responding in VPA exposed rodents, and support an important role for FAAH in the regulation of social behavioural deficits in autistic males.
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http://dx.doi.org/10.1016/j.phrs.2016.08.033DOI Listing
November 2016