4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. METHODS: Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. RESULTS: Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. CONCLUSIONS: Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis.

BACKGROUND: Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate from the tricarboxylic acid cycle. Itaconate has recently emerged as a regulator of immune cell functions, especially in macrophages. Studies show that itaconate is required for the activation of anti-inflammatory transcription factor Nrf2 by LPS in mouse and human macrophages, and LPS-activated IRG1-/- macrophages that lack endogenous itaconate production exhibit augmented inflammatory responses. Moreover, dimethyl itaconate (DMI), an itaconate derivative, inhibits IL-17-induced IκBς activation in keratinocytes and modulates IL-17-IκBς pathway-mediated skin inflammation in an animal model of psoriasis. Currently, the effect of itaconate on regulating macrophage functions and peripheral inflammatory immune responses is well established. However, its effect on microglia (MG) and CNS inflammatory immune responses remains unexplored. Thus, we investigated whether itaconate possesses an immunomodulatory effect on regulating MG activation and CNS inflammation in animal models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). METHODS: Chronic C57BL/6 EAE was induced followed by DMI treatment. The effect of DMI on disease severity, blood-brain barrier (BBB) disruption, MG activation, peripheral Th1/Th17 differentiation, and the CNS infiltration of Th1/Th17 cells in EAE was determined. Primary MG was cultured to study the effect of DMI on MG activation. Relapsing-remitting SJL/J EAE was induced to assess the therapeutic effect of DMI. RESULTS: Our results show DMI ameliorated disease severity in the chronic C57BL/6 EAE model. Further analysis of the cellular and molecular mechanisms revealed that DMI mitigated BBB disruption, inhibited MMP3/MMP9 production, suppressed microglia activation, inhibited peripheral Th1/Th17 differentiation, and repressed the CNS infiltration of Th1 and Th17 cells. Strikingly, DMI also exhibited a therapeutic effect on alleviating severity of relapse in the relapsing-remitting SJL/J EAE model. CONCLUSIONS: We demonstrate that DMI suppresses neuroinflammation and ameliorates disease severity in EAE through multiple cellular and molecular mechanisms, suggesting that DMI can be developed as a novel therapeutic agent for the treatment of MS/EAE through its immunomodulatory and anti-inflammatory properties.

Disubstituted Dithiolethione ACDT Exerts Neuroprotective Effects Against 6-Hydroxydopamine-Induced Oxidative Stress in SH-SY5Y Cells.

Parkinson's disease (PD) is a prevalent, progressive, neurodegenerative disorder with no known cure. Oxidative stress has been found to play a significant role in its etiology, and the search for novel neuroprotective compounds that actively prevent disease progression is currently ongoing. Dithiolethiones are a group of sulfur-containing heterocyclic compounds found in cruciferous vegetables. Using the 6-hydroxydopamine (6-OHDA) model of PD, we tested a previously identified disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) for its neuroprotective potential. Pretreatment of SH-SY5Y cells with ACDT led to a time- and concentration-dependent induction of the antioxidant glutathione (GSH). ACDT also diminished 6-OHDA-induced cell death, lactate dehydrogenase release, elevation of caspase 3/7 activity, and increase in levels of reactive oxygen species. Inhibition of the GSH-synthesizing enzyme glutamate-cysteine ligase catalytic subunit (GCLC) led a corresponding dissipation of ACDT's neuroprotective effects, hence underlining the importance of GSH in ACDT's neuroprotective response. ACDT caused the stabilization and nuclear translocation of nuclear factor erythroid-2 related factor (Nrf2), resulting in increased protein expression of the phase II enzyme NADPH:quinone oxidoreductase 1 (NQO1), and the excitatory amino acid cysteine membrane transporter (EAAT3). Interestingly, no changes in the levels of other Nrf2-dependent molecules including GCLC were observed, indicating the possible involvement of additional alternate mechanisms behind ACDT's GSH-inducing property. Collectively, the data demonstrated ACDT to be a promising new dithiolethione for the treatment of PD, with two modifiable functional groups offering additional avenues for enhanced pharmacological application.

Dithiolethione ACDT suppresses neuroinflammation and ameliorates disease severity in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disorder characterized by the central nervous system (CNS) infiltration of myelin-specific pathogenic T cells followed by brain inflammation in association with demyelination. Similarly, experimental autoimmune encephalomyelitis (EAE), the animal model of MS, also exhibits increased CNS infiltration of pathogenic T cells, including Th1 and Th17, leading to detrimental effects of neuroinflammation and demyelination. We previously reported that 3H-1,2-dithiole-3-thione (D3T), the structurally-simplest of the sulfur-containing dithiolethiones, exerted a promising therapeutic effect in EAE. In the current study we report that 5-Amino-3-thioxo-3H-(1,2)dithiole-4-carboxylic acid ethyl ester (ACDT), a substituted derivative of D3T, exhibits anti-inflammatory properties in EAE. ACDT, administered post immunization, delayed disease onset and reduced disease severity in chronic C57BL/6 EAE, and ACDT, administered during disease remission, suppressed disease relapse in relapsing-remitting SJL/J EAE. Further analysis of the cellular and molecular mechanisms underlying the protective effects of ACDT in EAE revealed that ACDT inhibited pathogenic T cell infiltration, suppressed microglia activation, repressed neurotoxic A1 astrocyte generation, lessened blood-brain barrier disruption, and diminished MMP3/9 production in the CNS of EAE. In summary, we demonstrate that ACDT suppresses neuroinflammation and ameliorates disease severity in EAE through multiple cellular mechanisms. Our findings suggest the potential of developing ACDT as a novel therapeutic agent for the treatment of MS/EAE.

Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents.

A series of simplified berberine analogs was designed, synthesized, and evaluated for anti-inflammatory activity. SAR studies identified N-benzyltetrahydroisoquinoline 7d as a potent berberine analog. 7d suppressed LPS-induced inflammatory cytokine levels in both BV2 cells and primary microglia. Taken together, our results suggest that simplified BB analogs have therapeutic potential as a novel class of anti-neuroinflammatory agents.

3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway.

Cerebral ischemic stroke accounts for more than 80% of all stroke cases. During cerebral ischemia, reactive oxygen species produced in brain tissue induce oxidative stress and inflammatory responses. D3T, the simplest compound of the cyclic, sulfur-containing dithiolethiones, is found in cruciferous vegetables and has been reported to induce antioxidant genes and glutathione biosynthesis through activation of Nrf2. In addition to antioxidant activity, D3T was also reported to possess anti-inflammatory effects. In this study, we evaluated the therapeutic potential of D3T for the treatment of ischemic stroke and investigated the mechanisms underlying the protective effects of D3T in ischemic stroke. Mice subjected to transient middle cerebral artery occlusion/reperfusion (tMCAO/R) were administered with vehicle or D3T to evaluate the effect of D3T in cerebral brain injury. We observed D3T reduced infarct size, decreased brain edema, lessened blood-brain barrier disruption, and ameliorated neurological deficits. Further investigation revealed D3T suppressed microglia (MG) activation and inhibited peripheral inflammatory immune cell infiltration of CNS in the ischemic brain. The protective effect of D3T in ischemic stroke is mediated through Nrf2 induction as D3T-attenuated brain injury was abolished in Nrf2 deficient mice subjected to tMCAO/R. In addition, in vitro results indicate the induction of Nrf2 by D3T is required for its suppressive effect on MG activation and cytokine production. In summary, we demonstrate for the first time that D3T confers protection against ischemic stroke, which is mediated through suppression of MG activation and inhibition of CNS peripheral cell infiltration, and that the protective effect of D3T in ischemic stroke is dependent on the activation of Nrf2.

3H-1,2-dithiole-3-thione as a novel therapeutic agent for the treatment of experimental autoimmune encephalomyelitis.

3H-1,2-dithiole-3-thione (D3T), the simplest member of the sulfur-containing dithiolethiones, is found in cruciferous vegetables, and has been previously reported to be a potent inducer of antioxidant genes and glutathione biosynthesis by activation of the transcription factor Nrf2. D3T is a cancer chemopreventive agent and possesses anti-inflammatory properties. Although D3T has been shown to protect against neoplasia, the effect of D3T in the autoimmune inflammatory disease multiple sclerosis/experimental autoimmune encephalomyelitis (EAE) is unknown. The present study is the first report of the therapeutic effect of D3T in EAE. Our results show D3T, administered post immunization, not only delays disease onset but also dramatically reduces disease severity in EAE. Strikingly, D3T, administered post disease onset of EAE, effectively prevents disease progression and exacerbation. Mechanistic studies revealed that D3T suppresses dendritic cell activation and cytokine production, inhibits pathogenic Th1 and Th17 differentiation, represses microglia activation and inflammatory cytokine expression, and promotes microglia phase II enzyme induction. In summary, these results indicate that D3T affects both innate and adaptive immune cells, and the protective effect of D3T in EAE might be attributed to its effects on modulating dendritic cell and microglia activation and pathogenic Th1/Th17 cell differentiation.

Synthesis and structure-activity relationships study of dithiolethiones as inducers of glutathione in the SH-SY5Y neuroblastoma cell line.

Parkinson's disease is a neurodegenerative disorder that involves the degeneration of nigrostriatal dopaminergic neurons. Elevated levels of reactive oxygen species have been shown to deplete cellular levels of the ubiquitous antioxidant glutathione, leading to oxidative stress and eventual neuronal cell death. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, have been shown to induce cellular production of glutathione in a variety of tissues, but have not been extensively evaluated in neurons. Herein, we report the synthesis and preliminary structure-activity relationships study of several substituted dithiolethiones. Three molecules were identified (D3T, CPDT, and 2d) that potently induced cellular glutathione in the SH-SY5Y neuroblastoma cell line. Furthermore, these compounds were found to provide neuroprotection in the 6-hydroxydopamine model of neurotoxicity. This study suggests that dithiolethione-mediated neuroprotection may have potential as a disease-modifying antiparkinsonian therapy.

Targeting Nrf2 with 3 H-1,2-dithiole-3-thione to moderate OXPHOS-driven oxidative stress attenuates IL-17A-induced psoriasis.

Psoriasis, a chronic autoimmune disease characterized by the hyperproliferation of keratinocytes in the epidermis and parakeratosis, significantly impacts quality of life. Interleukin (IL)- 17A dominates the pathogenesis of psoriasis and facilitates reactive oxygen species (ROS) accumulation, which exacerbates local psoriatic lesions. Biologic treatment provides remarkable clinical efficacy, but its high cost and unignorable side effects limit its applications. 3 H-1,2-Dithiole-3-thione (D3T) possesses compelling antioxidative capacities against several diseases through the nuclear factor erythroid 2-related factor 2 (Nrf2) cascade. Hence, we aimed to evaluate the effect and mechanism of D3T in psoriasis. We found that D3T attenuates skin thickening and scaling by inhibiting IL-17A-secreting γδT cells in imiquimod (IMQ)-induced psoriatic mice. Interleukin-17A markedly enhanced IL-6 and IL-8 expression, lipid peroxidation, the contents of nitric oxide and hydrogen peroxide, oxidative phosphorylation and the MAPK/NF-κB pathways in keratinocytes. IL-17A also inhibited the Nrf2-NQO1-HO-1 axis and the activities of superoxide dismutase and glutathione peroxidase. D3T significantly reversed these parameters in IL-17A-treated keratinocytes. ML-385, a Nrf2 neutralizer, failed to improve D3T-induced anti-inflammatory and antioxidative effects in IL-17A-treated keratinocytes. We conclude that targeting Nrf2 with D3T to diminish oxidative and inflammatory damage in keratinocytes may attenuate psoriasis.

4-Ethylguaiacol Modulates Neuroinflammation and Promotes Heme Oxygenase-1 Expression to Ameliorate Brain Injury in Ischemic Stroke.

Ischemic stroke is caused by a sudden reduction in cerebral blood flow that subsequently induces a complex cascade of pathophysiological responses, leading to brain inflammation and irreversible infarction. 4-ethylguaiacol (4-EG) is reported to suppress inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects in ischemic stroke remains unexplored. We evaluated the therapeutic potential of 4-EG and examined the cellular and molecular mechanisms underlying the protective effects of 4-EG in ischemic stroke. The effect of 4-EG in ischemic stroke was determined by using a transient middle cerebral artery occlusion (MCAO) animal model followed by exploring the infarct size, neurological deficits, microglia activation, inflammatory cytokine production, blood-brain barrier (BBB) disruption, brain endothelial cell adhesion molecule expression, and microglial heme oxygenase-1 (HO-1) expression. Nrf2-/- and HO-1 inhibitor ZnPP-treated mice were also subjected to MCAO to evaluate the role of the Nrf2/HO-1 pathway in 4-EG-mediated protection in ischemic stroke. We found that 4-EG attenuated infarct size and neurological deficits, and lessened BBB disruption in ischemic stroke. Further investigation revealed that 4-EG suppressed microglial activation, peripheral inflammatory immune cell infiltration, and brain endothelial cell adhesion molecule upregulation in the ischemic brain. Finally, we identified that the protective effect of 4-EG in ischemic stroke was abolished in Nrf2-/- and ZnPP-treated MCAO mice. Our results identified that 4-EG confers protection against ischemic stroke and reveal that the protective effect of 4-EG in ischemic stroke is mediated through the induction of the Nrf2/HO1 pathway. Thus, our findings suggest that 4-EG could be developed as a novel therapeutic agent for the treatment of ischemic stroke.

Design, Synthesis, and Anti-Neuroinflammatory Activity of Amide- Containing Dithiolethiones.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination of neurons and neurodegeneration. Current MS therapies ameliorate inflammatory damage but are unable to address the degenerative aspects of the disease. OBJECTIVE: In this report, we evaluate the ability of amide-based dithiolethiones (DTTs) to suppress neuroinflammation in microglia and increase anti-oxidant capacity in neuron-like cells. METHODS: A series of amide-containing DTTs were designed, synthesized, and assayed for the ability to suppress pro-neuroinflammatory cytokines IL-12p40 and IL-23p19 induced by LPS in the BV2 microglial cell line. Lead analog 2c was identified and further characterized. RESULTS: Structure-activity data revealed tolerance towards a variety of amides. Morpholine analog 2c dose-dependently reduced various other inflammatory cytokines and mediators, including TNF, IL-6, IL-1ß, NOS2, and COX2. Additionally, 2c elevated cellular levels of glutathione in SH-SH5Y neuronal cell line. Furthermore, mechanistic studies showed that 2c increased the expression of antiinflammatory Nrf2 and HMOX proteins. CONCLUSION: The combination of anti-neuroinflammatory and anti-oxidant activities of amide-based DTTs suggests that they are promising agents for the treatment of both demyelination and neurodegeneration in MS.

Perinatal factors in students admitted to the University of the West Indies data from the Jamaican Perinatal Study.

OBJECTIVE: To compare perinatal and social factors in students admitted to The University of the West Indies (UWI), Kingston, Jamaica, at age 18 years with those in the rest of the Jamaican Perinatal Cohort. METHOD: The Jamaican Perinatal Survey recorded demographic and perinatal details in 10 527 or 97% of births in Jamaica in September and October 1986. Eighteen years later 140 of these were admitted to the UWI in Kingston, Jamaica. The perinatal features of these UWI students have been compared with the rest of the Perinatal Survey Cohort. RESULTS: Mothers of UWI students were older (p < 0.001), more likely to be married at the time of birth (p < 0.001), had earlier and more complete antenatal care (p < 0.05) and greater educational achievement at time of pregnancy (p < 0.001). These mothers of UWI students were also more likely to have diabetes (p < 0.01), operative deliveries (p < 0.01) and to attend private hospitals (p < 0.01). The UWI students had fewer siblings by their mothers (p < 0.05), were less likely to be low birthweight babies (p = 0.035) and more likely to be full-term (37-42 weeks) than lower gestational age (p = 0.005). Differences in Apgar scores did not reach statistical significance. CONCLUSIONS: The students of the University of the West Indies were more likely to come from smaller families with features indicative of a better quality of life. They were also of higher birthweight and tended to be full-term. The lack of association of Apgar scores with educational attainment is noteworthy.

Investigation of various N-heterocyclic substituted piperazine versions of 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: effect on affinity and selectivity for dopamine D3 receptor.

Here we report on the design and synthesis of several heterocyclic analogues belonging to the 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol series of molecules. Compounds were subjected to [(3)H]spiperone binding assays, carried out with HEK-293 cells expressing either D2 or D3 dopamine receptors, in order to evaluate their inhibition constant (K(i)) at these receptors. Results indicate that N-substitution on the piperazine ring can accommodate various substituted indole rings. The results also show that in order to maintain high affinity and selectivity for the D3 receptor the heterocyclic ring does not need to be connected directly to the piperazine ring as the majority of compounds included here are linked either via an amide or a methylene linker to the heterocyclic moiety. The enantiomers of the most potent racemic compound 10e exhibited differential activity with (-)-10e (K(i); D2=47.5 nM, D3=0.57 nM) displaying higher affinity at both D2 and D3 receptors compared to its enantiomer (+)-10e (K(i); D2=113 nM, D3=3.73 nM). Additionally, compound (-)-10e was more potent and selective for the D3 receptor compared to either 7-OH-DPAT or 5-OH-DPAT. Among the bioisosteric derivatives, the indazole derivative 10g and benzo[b]thiophene derivative 10i exhibited the highest affinity for D2 and D3 receptors. In the functional GTPgammaS binding study, one of the lead molecules, (-)-15, exhibited potent agonist activity at both D2 and D3 receptors with preferential affinity at D3.

Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles.

Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF-κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α-methylene-γ-butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties. To determine the individual contributions of the Michael acceptors toward NF-κB inhibition, we synthesized a small library of helenalin-based analogues containing various combinations of α-methylene-γ-butyrolactones and cyclopentenones. The kinetics of thiol addition to a subset of the analogues was measured to determine the relative thiol reactivities of the embedded electrophiles. Additionally, the cellular NF-κB inhibitory activities of the analogues were determined to elucidate the contributions of each Michael acceptor to biological potency. Our studies suggest the α-methylene-γ-butyrolactone contributes most significantly to the NF-κB inhibition of our simplified helenalin analogues.

Further structure-activity relationships study of substituted dithiolethiones as glutathione-inducing neuroprotective agents.

BACKGROUND: Parkinson's disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective approach to limit the oxidative damage that characterizes Parkinson's disease pathophysiology. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited information is available regarding the influence of dithiolethione structure on activity. Herein, we report the design, synthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell line. RESULTS: Our structure-activity relationships data show that dithiolethione electronic properties, given as Hammett σp constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer identified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective effects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance of glutathione in the protective activities of 6a. CONCLUSIONS: The results of this study further delineate the relationship between dithiolethione chemical structure and glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential antiparkinsonian agents.

Anastomotic leak or organ space surgical site infection: What are we missing in our quality improvement programs?

BACKGROUND: Expert panels of colorectal surgeons consistently rank anastomotic leak as among the most important quality metrics for colectomies. Nonetheless, most administrative and clinical databases do not collect data on anastomotic leaks and rely on reported organ space surgical site infections (OSI) as a proxy for identifying anastomotic leaks. This study questions the validity of using OSI as a surrogate for anastomotic leak. METHODS: The Upstate New York Surgical Quality Initiative (UNYSQI) is a collaboration of 12 hospitals that prospectively collects colectomy-specific metrics, including anastomotic leak, in addition to standard National Surgical Quality Improvement Program (NSQIP) data, including OSIs. Cases with an organ space infection and/or anastomotic leak were selected from the 2010-2011 UNYSQI database. Patient characteristics and outcomes were compared for cases with organ space infections and anastomotic leaks. RESULTS: Overall, 3% of colectomies had a reported organ space infection and 4% had an anastomotic leak. Among cases having anastomotic leaks, only 25% were also coded as having an organ space infection, leaving 75% of anastomotic leaks not captured by the NSQIP database (κ = 0.272; P ≤ .001). CONCLUSION: Organ space infection is a poor surrogate for anastomotic leak, resulting in grossly underestimated leak rates and seemingly represents different postoperative courses. Procedure-specific quality measures for colorectal surgery should include data collection on anastomotic leaks to provide accurate data for use in improving patient care.

Structurally constrained hybrid derivatives containing octahydrobenzo[g or f]quinoline moieties for dopamine D2 and D3 receptors: binding characterization at D2/D3 receptors and elucidation of a pharmacophore model.

A series of structurally constrained analogues based on hybrid compounds containing octahydrobenzo[g or f]quinoline moieties were designed, synthesized, and characterized for their binding to dopamine D2 and D3 receptors expressed in HEK-293 cells. Among the newly developed constrained molecules, trans-octahydrobenzo[f]quinolin-7-ol (8) exhibited the highest affinity for D2 and D3 receptors, the (-)-isomer being the eutomer. Interestingly, this hybrid constrained version 8 showed significant affinity over the corresponding nonhybrid version 1 (representing a constrained version of the aminotetralin structure only) when assayed under same conditions (K(i) of 49.1 and 14.9 nM for 8 vs 380 and 96.0 nM for 1 at D2 and D3, respectively). Similar results were found with other lead hybrid compounds, indicating a contribution of the piperazine moiety in the observed enhanced affinity. On the basis of the data of new lead constrained derivatives and other lead hybrid derivatives developed by us, a unique pharmacophore model was proposed consisting of three pharmacophoric centers, two with aromatic/hydrophobic and one with cationic features.

Perinatal factors in students admitted to the university of the West Indies data from the jamaican perinatal study / Factores perinatales en estudiantes de nuevo ingreso en la Universidad de West Indies datos del estudio perinatal de Jamaica

OBJECTIVE: To compare perinatal and social factors in students admitted to The University of the West Indies (UWI), Kingston, Jamaica, at age 18 years with those in the rest of the Jamaican Perinatal Cohort. METHODS: The Jamaican Perinatal Survey recorded demographic and perinatal details in 10 527 or 97% of births in Jamaica in September and October 1986. Eighteen years later, 140 of these were admitted to the UWI in Kingston, Jamaica. The perinatal features of these UWI students have been compared with the rest ofthe Perinatal Survey Cohort. RESULTS: Mothers of UWI students were older (p < 0.001), more likely to be married at the time of birth (p < 0.001), had earlier and more complete antenatal care (p < 0.05) and greater educational achievement at time of pregnancy (p < 0.001). These mothers of UWI students were also more likely to have diabetes (p < 0.01), operative deliveries (p < 0.01) and to attend private hospitals (p < 0.01). The UWI students had fewer siblings by their mothers (p < 0.05), were less likely to be low birthweight babies (p = 0.035) and more likely to be full term (37-42 weeks) than lower gestational age (p = 0.005). Differences in Apgar scores did not reach statistical significance. CONCLUSIONS: The students of the University of the West Indies were more likely to come from smaller families with features indicative of a better quality of life. They were also of higher birthweight and tended to be full term. The lack of association of Apgar scores with educational attainment is noteworthy.

OBJETIVO: Comparar los factores perinatales y sociales en estudiantes aceptados para sus estudios en la Universidad de West Indies (UWI), Kingston, Jamaica, a la edad 18 años, con los del resto de la Cohorte Perinatal de Jamaica. . MÉTODO: El Estudio Perinatal de Jamaica registró los detalles demográficos y perinatales en el caso de 10 527 o 97% de nacimientos en Jamaica en septiembre y octubre de 1986. Dieciocho años después, 140 de ellos ingresaron a UWI en Kingston, Jamaica. Las características perinatales de estos estudiantes de UWI con el resto de la Cohorte del Estudio Perinatal. RESULTADOS: Las madres de los estudiantes de UWI eran de mayor edad (p < 0.001), presentaban una mayor probabilidad de estar casadas al momento del nacimiento (p < 0.001), tuvieron cuidados prenatales más completos y más tempranos (p < 0.05), así como mayores logros en su educación al momento del embarazo (p < 0.001). Estas madres de estudiantes de UWI presentaban también una probabilidad mayor de diabetes (p < 0.01), partos operativos (p < 0.01) y asistencia a hospitales privados (p < 0.01). Los estudiantes de UWI tenían menos hermanos y hermanas por parte de sus madres (p < 0.05), tenían una menor probabilidad de ser bebés de bajo peso al nacer (p = 0.035) y una mayor probabilidad de ser bebés de término completo (37-42 semanas) que tener una edad gestacional menor (p = 0.005). Las diferencias en puntuación de Apgar no alcanzaron a tener importancia estadística. CONCLUSIONES: Los estudiantes de la Universidad de West Indies, presentaban una mayor probabilidad de provenir de familias más pequeñas con rasgos que indicaban una mayor calidad de vida. También poseían mayor peso al nacer y tendencia a término completo. La falta de correspondencia entre la puntuación de Apgar con los logros educacionales, fue cuestión de interés.