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Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: Epilepsy is the most common major neurological disorder that affects people of all ages. The prevalence varies from one country to another and even between different areas, due to a lack of access to medical care for reasons related to limited resources., Objective: Epilepsy is a worldwide public health problem that affects more deeply populations living in developing countries such as Mexico, where more aggressive health policies based on epidemiological data are needed; however, this information is scarce and the evolution of this data over time remains unclear. The aim of the present study is to provide an overview of the epidemiology of epilepsy in Mexico from 1970 to 2020., Methods: We searched descriptive epidemiological studies on epilepsy in rural and urban regions of Mexico from 1970 to 2020. Available data on the sociodemographic characteristics, prevalence, and incidence data were extracted. Finally, the abstract, full-text review, and data abstraction were conducted in duplicate and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Descriptive statistics was also used., Results: Overall, 11 underrepresented and heterogeneous epidemiological studies were included. In total, the prevalence of epilepsy in Mexico is 3.9 to 41:1,000 inhabitants; 3.9 to 41 per 1,000 persons in rural regions, and 3.49 to 44.3 per 1,000 persons in urban regions. None of these studies addressed the incidence of epilepsy. The prevalence of epilepsy in Mexico has remained unchanged during the last 5 decades., Conclusions: Our results confirm a high prevalence of epilepsy in both urban and rural settings in Mexico that remain unchanged during the last 5 decades. All studies included in the present review showed multiple methodological limitations. New and robust epidemiological studies are needed to delineate the epidemiological profile of epilepsy in Mexico., Competing Interests: The authors have no conflict of interests to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

In socially monogamous titi monkeys, involuntary separation from a pair mate can produce behavioral distress and increased cortisol production. The neuropeptide oxytocin (OXT) is thought to play an important role in the separation response of pair-bonded species. Previous studies from our lab have shown that chronic intranasal oxytocin (IN OXT) during development can have long-term effects on adult social behavior. In the current study, we examined the chronic and acute effects of IN OXT or Saline (SAL) on the subjects' response to a brief separation from their pair mates. Subjects with a history of chronic IN OXT or SAL treatment during development received a single dose of OXT or SAL as adults 30 min before being separated from their pair mate. Chronic treatment consisted of a daily dose of IN OXT (0.8 IU/kg) or SAL (control) from 12 to 18 months of age. Subjects ( N = 29) were introduced to a pair mate at 30 months of age. After the pairs had cohabitated for 5 months, pairs underwent two "Brief Separation" (OXT and SAL) and two "Non-Separation" (OXT and SAL) test sessions. Vocalizations and locomotion were measured as behavioral indices of agitation or distress during the Brief Separation and Non-Separation periods (30 min each). We collected blood samples after the Brief Separation and Non-Separation periods to measure cortisol levels. Our results showed subjects treated with chronic OXT had a reduction in long call and peep vocalizations compared to subjects treated with chronic SAL. Subjects treated with chronic SAL and acute OXT produced more peeps and long calls compared to animals treated with acute SAL; however, patterns in this response depended on sex. Cortisol and locomotion were significantly higher during the Brief Separation period compared to the Non-Separation period; however, we did not find any treatment or sex effects. We conclude that chronic IN OXT given during development blunts the separation response, while acute OXT in chronic SAL subjects had sexually dimorphic effects, which could reflect increased partner seeking behaviors in males and increased anxiety in females., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arias del Razo, Velasco Vazquez, Turcanu, Legrand, Lau, Weinstein, Goetze and Bales.)

Intranasal oxytocin (IN OXT) administration has been proposed as a pharmacological treatment for a range of biomedical conditions including neurodevelopmental disorders. However, studies evaluating the potential long-lasting effects of chronic IN OXT during development are still scarce. Here we conducted a follow-up study of a cohort of adult titi monkeys that received intranasal oxytocin 0.8 IU/kg (n = 15) or saline (n = 14) daily for six months during their juvenile period (12 to 18 months of age), with the goal of evaluating the potential long-lasting behavioral and neural effects one year post-treatment. Subjects were paired with an opposite-sex mate at 30 months of age (one year post-treatment). We examined pair affiliative behavior in the home cage during the first four months and tested for behavioral components of pair bonding at one week and four months post-pairing. We assessed long-term changes in brain glucose uptake using 18 FDG positron emission tomography (PET) scans. Our results showed that OXT-treated animals were more affiliative across a number of measures, including tail twining, compared to SAL treated subjects (tail twining is considered the "highest" type of affiliation in titi monkeys). Neuroimaging showed no treatment differences in glucose uptake between SAL and OXT-treated animals; however, females showed higher glucose uptake in whole brain at 23 months, and in both the whole brain and the social salience network at 33 months of age compared to males. Our results suggest that chronic IN OXT administration during development can have long-term effects on adult social behavior., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Respiratory infections (RIs) are an important cause of morbidity and excessive antibiotic prescriptions in children attending day care centers (DCCs). We aimed to assess the effectiveness of an educational and hand hygiene program in DCCs and homes in reducing RI incidence and antibiotic prescriptions in children., Methods: A cluster, randomized, controlled, and open study of 911 children aged 0 to 3 years attending 24 DCCs in Almería (Spain) with an 8-month follow-up. Two intervention groups of DCC families performed educational and hand hygiene measures, 1 with soap and water (SWG; n = 274), another with hand sanitizer (HSG; n = 339), and the control group (CG; n = 298) followed usual hand-washing procedures. RI episode rates were compared through multilevel Poisson regression models. The percentage of days missed were compared with Poisson exact tests., Results: There were 5211 RI episodes registered. Children in the HSG had less risk of RI episodes (incidence rate ratio [IRR]: 0.77; 95% confidence interval [CI]: 0.68-0.88) and antibiotic prescriptions (IRR: 0.69; 95% CI: 0.57-0.84) compared with the those in the CG. Children in the SWG had a higher risk of RI episodes (IRR: 1.21; 95% CI: 1.06-1.39) and antibiotic prescriptions (IRR: 1.31; 95% CI: 1.08-1.56) than those in the HSG. Pupils missed 5186 DCC days because of RIs, and the percentage of days absent was significantly lower in the HSG compared with the CG ( P < .001) and the SWG ( P < .001)., Conclusions: Hand hygiene programs that include hand sanitizer and educational measures for DCC staff, children, and parents, reduce absent days, RIs, and antibiotic prescriptions for these infections in children at DCCs., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

This study reports the introduction of egfp or mCherry markers to the Sp245, Sp7, and M40 wild-type strains of Azospirillum brasilense and the hhkB (encoding for a putative hybrid histidine kinase) minus mutant an isogenic strain of A. brasilense Sp245 to monitor colonization of wheat (Triticum aestivum). Two plasmids were constructed: (1) the pJMS-2 suicide plasmid derived from pSUP202 and harboring the mCherry gene expressed under the constitutive kanamycin resistance promoter to create a cis tag and (2) the broad-range plasmid pMP2449-5 that carries the mCherry gene under the lac promoter, which is derived from the plasmid pMP2444; to create the in trans tag. The stability of the plasmids encoding egfp and mCherry were confirmed in vitro for seven days of bacterial growth, and then, the A. brasilense strains harboring the plasmids were studied under nonselective conditions for adherence to seeds and, at seven or 14 days post-inoculation, for wheat root colonization. The utility of the labeled strains was proven by observation, using fluorescence microscopy and confocal laser scanning microscopy (CLSM) in wheat plants inoculated with the labeled strains and compared with the CFU g -1 for seed and wheat root. The method was suitable for observation of the in situ formation of mini-colonies, enabled visualization of bacterial colonization sites on large root fragments, and showed adherence to germinated seeds and root colonization of all strains by cell counts and direct microscopic examination. Thus, we are able to quantify the structures of the biofilms formed by each strain., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Aims: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842., Methods: This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842., Results: Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t ½ 2.8-5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus kinase signalling inhibition., Conclusions: These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases., (© 2018 The British Pharmacological Society.)

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Background: We assessed the effectiveness of a handwashing program using hand sanitizer to prevent school absenteeism due to upper respiratory infections (URIs)., Methods: This was a randomized, controlled, and open study on a sample of 1341 children 4-12 years old, attending 5 state schools in Almería (Spain), with an 8-month follow-up. The experimental group (EG) washed their hands with soap and water, together with using hand sanitizer, and the control group followed their usual handwashing procedures. Absenteeism rates due to URIs were compared between the 2 groups through a multivariate Poisson regression analysis. The percent of days missed in both groups were compared with a z test., Results: Overall, 1271 cases of school absenteeism due to URIs were registered. Schoolchildren from the EG had a 38% lower risk of absenteeism due to URIs, incidence rate ratio: 0.62, 95% confidence interval: 0.55-0.70, and a decrease in absenteeism of 0.45 episodes/child/academic year, p < .001. Pupils missed 2734 school days due to URIs and the percentage of days absent was significantly lower in the EG, p < .001., Conclusions: Use of hand sanitizer plus handwashing with soap accompanied by educational support is an effective measure to reduce absenteeism due to URIs., (© 2016, American School Health Association.)

Crystals of phosphorylated JAK1 kinase domain were initially generated in complex with nucleotide (ADP) and magnesium. The tightly bound Mg 2+ -ADP at the ATP-binding site proved recalcitrant to ligand displacement. Addition of a molar excess of EDTA helped to dislodge the divalent metal ion, promoting the release of ADP and allowing facile exchange with ATP-competitive small-molecule ligands. Many kinases require the presence of a stabilizing ligand in the ATP site for crystallization. This procedure could be useful for developing co-crystallization systems with an exchangeable ligand to enable structure-based drug design of other protein kinases.

Background: School absenteeism because of infections is one of the most important problems facing both public and private primary schools. The aim of the study was to assess the impact of infections on school absenteeism and their reduction with a handwashing program using hand sanitizer., Methods: The study was an 8-month-long, randomized, controlled open study (N = 1,609 children, aged 4-12 years old) at 5 state schools in Almeria (Spain). The experimental group (EG) washed their hands with soap and water, complemented with the use of hand sanitizer, and the control group (CG) followed the usual handwashing procedure. The total number of episodes and days missed as well as those because of upper respiratory infections and gastrointestinal infections were compared in both groups with a Z-test., Results: The students were absent 12,386 days in 7,945 episodes. The incidence of total absent episodes and percent of missed days, including those because of upper respiratory infections and gastrointestinal infections, were significantly lower in the EG than the CG (P < .001), and this was maintained through the flu pandemic period., Conclusion: School absenteeism because of infections in schools is reduced when a hand hygiene program utilizing sanitizing gels is properly carried out, especially during the flu season., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Acute gastroenteritis (AGE) is one of the most common diseases among children and an important cause of school absenteeism. The aim of this study was to assess the effectiveness of a handwashing program using hand sanitizers for the prevention of school absenteeism due to AGE., Methods: A randomized, controlled and open study of a sample of 1341 children between 4 and 12 years of age, attending 5 state schools in Almería (Spain), with an 8-month follow up (academic year). The experimental group (EG) washed their hands with soap and water, complementing this with the use of a hand sanitizer, and the control group (CG) followed the usual handwashing procedure. Absenteeism rates due GI were compared between the 2 groups through the multivariate Poisson regression analysis. Percent days absent in both groups were compared with a Z-test., Results: 446 cases of school absenteeism due to AGE were registered. The school children from the EG had a 36% lower risk of absenteeism due to AGE (IRR: 0.64, 95% confidence interval: 0.52-0.78) and a decrease in absenteeism of 0.13 episodes/child/academic year (0.27 of EG vs 0.40 CG/episodes/child/academic year, P < 0.001). Pupils missed 725 school days due to AGE and absent days was significantly lower in the EG (EG: 0.31%, 95% confidence interval: 0.28-0.35 vs. CG: 0.44%, 95% confidence interval: 0.40-0.48, P < 0.001)., Conclusions: The use of hand sanitizer as a complement to handwashing with soap is an efficient measure to reduce absent days and the number of school absenteeism cases due to AGE.

The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na(+) intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na(+) intake (NSI) or low Na(+) intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg(-1)·day(-1) PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg(-1)·day(-1)) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na(+) intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Elastofibroma dorsi (ED) is a benign soft tissue tumor that classically presents as an ill-defined mass at the inferior pole of the scapula. Several studies have indicated the benefits of using magnetic resonance imaging (MRI) to identify ED. In this study, we calculate the sensitivity and positive predictive value (PPV) of MRI in the diagnosis of ED using histopathology as the gold standard diagnostic method. Clinical characteristics of ED and radiologic features of MRI as well as treatment options are discussed., Materials and Methods: A systematic retrospective review was performed of all ED patients treated in our center between 1999 and 2009. MRI and histopathology samples were performed in all cases. The MRI sensitivity and PPV in the diagnosis of ED were calculated., Results: A total of 15 patients who were treated within the study period were reviewed; of these, were 14 (3 men, 11 women) true ED cases. MRI scan results matched the histopathology in 14 of 15 patients; 1 false-positive patient was observed, and no false-negative patients (negative MRI and positive histopathology) were noted. The PPV and sensitivity of MRI scan in the diagnosis of ED were 93.3% (95% confidence interval, 68.0%-100.0%) and 100% (95% confidence interval, 75.2%-100.0%) respectively., Conclusions: MRI is a useful tool for assessment of ED and can potentially help avoid the need for unnecessary biopsy and surgery, especially in the asymptomatic patient., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.)

Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE(2) synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC(50)=16.5+/-3.8nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE(2) synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE(2) synthesis (IC(50) in the range of 0.5-5 microM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF(1alpha) (PGF(1alpha)) and PGF(2alpha). In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE(2), PGF(1alpha) and PGF(2alpha) synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention., (2010 Elsevier Inc. All rights reserved.)

Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway, constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure-function relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1. The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer, including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic pi-stacking (F82-F103-F106), all contributing to the overall stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1 structure. Possible binding site for the substrate, prostaglandin H(2) (PGH(2)), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced fit docking of PGH(2) in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool for structure-guided design of inhibitors for this emergently important therapeutic target.

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.

The use of the voltammetry of microparticles at paraffin-impregnated graphite electrodes allows for the characterization of different types of Maya Blue (MB) used in wall paintings from different archaeological sites of Campeche and YucatAn (Mexico). Using voltammetric signals for electron-transfer processes involving palygorskite-associated indigo and quinone functionalities generated by scratching the graphite surface, voltammograms provide information on the composition and texture of MB samples. Application of hierarchical cluster analysis and other chemometric methods allows us to characterize samples from different archaeological sites and to distinguish between samples proceeding from different chronological periods. Comparison between microscopic, spectroscopic, and electrochemical examination of genuine MB samples and synthetic specimens indicated that the preparation procedure of the pigment evolved in time via successive steps anticipating modern synthetic procedures, namely, hybrid organic-inorganic synthesis, temperature control of chemical reactivity, and template-like synthesis.

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.

Assessment of the left ventricular mass (LVM) from electrocardiograms may be improved by the addition of clinical variables into a multivariate equation. As the heart-thorax distance may affect the results, its relationships with electrocardiographic and clinical data have been evaluated in a group of 220 subjects (53 +/- 15 years, 126 female, 175 without demonstrated heart disease) who were assessed for echocardiographic LVM and heart-thorax distance. Sokolow, Cornell, and total QRS voltage indexes were obtained. Multiple regression equations with LVM as the dependent variable were fit, with an ECG index, body mass index (BMI), age, and gender as the independent predictors. Each of the 3 ECG indexes, BMI, age, and sex was shown to be independent predictors of LVM, with the ECG and BMI contributing with most of the explanatory power. When added to the model, the distance from the interventricular septum to the precordium (septal-LVD) was not a predictor of LVM, but when BMI was withdrawn, septal-LVD became an independent predictor of LVM (P < .001). This was not observed when septal-LVD was substituted for any other clinical or ECG variable, thus suggesting that septal-LVD accounts for information contained in BMI but not in the remaining variables. In addition, the distance from the center of LV to the precordium (mid-LVD) achieved significance as an independent LVM predictor, although the coefficient of multiple determination (R) practically did not change. Almost identical results are obtained when LVM is indexed for body surface area. Body mass index supplies virtually all the information contained in the heart-thorax distance.

The aim of any health care system is to help improve the people's health, and to do so as efficiently as possible. In order to improve the efficiency and equity of health services provision, many countries around the world have implemented reforms, including several Latin American nations. However similar the objectives may appear, the various ways societies implement such reforms reflect different values and concepts. This article analyzes the egalitarian and neoliberal values underlying different concepts of equity in health care. The authors develop criteria to interpret selected health services funding and provision strategies in Latin American health system reforms. These criteria are then applied to health care financing and delivery policies under the reforms currently being implemented in Colombia and Costa Rica.

A polymer-bound calcium sulfonate resin is prepared and used to sequester tetrabutylammonium fluoride. The simultaneous use of the calcium sulfonate resin with a sulfonic acid resin is used for the quenching and purification of desilylating reactions involving tetrabutylammonium fluoride as the reagent. Employment of this resin workup technique eliminates the need for a liquid-phase extractive protocol allowing the procedure to be easily automated.

This study examined the kinetics of sperm nuclear decondensation induced by the action of physiological concentrations of heparin and glutathione in hamster sperm nuclei as a chromatin model that contains protamine P1 and P2. Sperm suspension was incubated at different temperatures (37, 40, 43, and 46 degrees C) in media, keeping constant the concentration of either heparin or GSH and increasing concentrations of the other reagent. Spermatozoa nuclei without any treatment, incubated for 72 h, appear densely condensed. Swelling of hamster spermatozoa nuclei was observed after 30 min of incubation in the presence of efficient concentrations of heparin-GSH. The extent of this time lag was significantly reduced at higher temperatures. DNA presence was verified by the use of ethidium bromide, acridine orange, and Feulgen stain. Phase-contrast microscopy shows that nuclear decondensation begins at the equatorial levels, with DNA highly condensed at the acrosome pole, and the basal pole as the DNA attachment point. Electron microscopy observations showed that hamster sperm nuclei initiates its decompaction at the peripheral regions and this behavior remains until late stages of decondensation, nevertheless, the chromatin is organized into "hub-like" nuclear bodies that measured 10-100 nm in diameter, joined by a network of chromatin fibers with apparent reduction in number. At the decondensation full stage, the network seems to be wide open with a reduced number of hub-like nuclear bodies present in the interlace. DNA is not organized into topologically constrained loop domains and is attached to the basal plate instead of to the nuclear matrix or any other structure.

Histiocytic cytophagic panniculitis (HCP) is the name given to the hemophagocytic syndrome when subcutaneous fat is involved. Histologically, it is characterized by phagocytosis of blood elements by histiocytes that appear to be benign. We report this rare skin disease in a 46-year-old patient that occurred 32 months after an allogeneic bone marrow transplantation. This skin disease could be a manifestation of graft-versus-host disease, although the connection remains speculative.

A household interview survey combined with a serological survey on the incidence of malaria attacks and prevalence of antibodies has been carried out in rural and urban areas of the pacific coast of Colombia. Additional information on people's knowledge, attitudes and behaviour towards malaria was collected by means of participant observation and informal interviews. The results show that people incorporate modern and traditional elements into their concepts of the disease and treatment strategies. The deficiencies of the official control programmes are shown from the people's point of view. Some human factors which influence malaria transmission are discussed and an estimate of the accuracy of self-diagnosis presented.

(+/-)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-D-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-D-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki greater than 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 microgram) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.

A mechanism previously proposed for inactivation of monoamine oxidase (MAO) by N-cyclopropylbenzylamine (N-CBA) [Silverman, R. B., & Hoffman, S. J. (1980) J. Am. Chem. Soc. 102, 884-886] is revised. Inactivation of MAO by N-[1-3H]CBA results in incorporation of about 3 equiv of tritium into the enzyme and release of [3H]acrolein. Treatment of inactivated enzyme with benzylamine, a reactivator for N-CBA-inactivated MAO, releases only 1 equiv of tritium as [3H]acrolein concomitant with reactivation of the enzyme. Even after MAO is inactivated by N-[1-3H]CBA, the reaction continues. At pH 7.2, a linear release of [3H]acrolein is observed for 70 h, which produces 55 equiv of [3H]acrolein while 2.3 equiv of tritium is incorporated into the enzyme. At pH 9, only 3.5 equiv of [3H]acrolein is detected in solution after 96 h, but 40 equiv of tritium is incorporated into the enzyme, presumably as a result of greater ionization of protein nucleophiles at the higher pH. N-[1-3H]Cyclopropyl-alpha-methylbenzylamine (N-C alpha MBA) produces the same adduct as N-CBA but gives only 1-1.35 equiv of tritium bound after inactivation of the enzyme. Denaturation of labeled enzyme results in reoxidation of the flavin without release of tritium, indicating attachment is not to the flavin but rather to an amino acid residue. Enzyme inactivated with N-[1-3H]C alpha MBA is reactivated by benzylamine with the release of 1 equiv of [3H]acrolein, which must have come from an adduct attached to an active site amino acid residue.(ABSTRACT TRUNCATED AT 250 WORDS)

[1-3H]Allylamine was synthesized by sodium boro[3H]hydride reduction of acrolein followed by direct conversion of the [1-3H]allyl alcohol to N-allylphthalimide with triphenylphosphine, diethylazodicarboxylate, and phthalimide. The protecting group was removed with hydrazine. Inactivation of beef liver mitochondrial monoamine oxidase with [1-3H]allylamine led to incorporation of 1-6 eq of inactivator/active site depending upon the length of incubation time. Inactivation and radioactivity incorporation coincided; however, after 1 eq of tritium was incorporated and 5% enzyme activity remained, additional radioactivity continued to become incorporated into the enzyme. The optical spectrum of the FAD coenzyme changed during inactivation from that of oxidized to reduced flavin. Following dialysis of the inactivated enzyme, the spectrum remained reduced, but denaturation in urea rapidly resulted in reoxidation of the flavin. Under these same denaturing conditions, 96% of the radioactivity associated with the enzyme remained bound, therefore indicating that allylamine attachment is not to the flavin coenzyme but rather to an active site amino acid residue. The adduct also was stable to base and, to a lesser degree, acid treatment. Although allylamine and N-cyclopropylbenzylamine appear to be oxidized by monoamine oxidase to give 3-(amino acid residue) propanal adducts, two different amino acids seem to be involved because of a difference in stability of the adducts. The mechanisms for inactivation of monoamine oxidase by allylamine and reactivation by benzylamine are discussed in relation to previously reported results.

Treatment with praziquantel for neurocysticercosis frequently induces adverse reactions due to acute destruction of parasites; these reactions are suppressed by dexamethasone therapy. However, there is controversy about the most appropriate regimen with praziquantel and dexamethasone. We studied plasma levels of praziquantel in eight patients given the drug alone or with dexamethasone. Plasma levels of praziquantel were 50% lower in the same patient when dexamethasone was given simultaneously. Dexamethasone should not be added to praziquantel therapy as preventive treatment, but should be reserved for transient therapy of adverse reactions.