Selective Inhibition of Acetylcholinesterase in the Cerebellum and Hippocampus of Mice Following an Acute Treatment with Malathion

Adult male ICR mice were treated by intraperitoneal injection with 250?mg/kg of bodyweight of commercial malathion (a dose corresponding to 1/12 the LD50). After 6?h, acetylcholinesterase (AChE) activity in blood, liver, and six brain regions was determined. A statistically significant inhibition was observed in whole blood (23%), liver (21%), and, in particular, the central nervous system; the greatest degree of AChE inhibition was observed in the cerebellum (45%), followed by the hippocampus (29%). There was no significant change in AChE activity in the caudate putamen, frontal cortex, midbrain, or pons medulla. These results demonstrate that the magnitude of AChE inhibition in peripheral tissues does not accurately reflect the central-inhibitory effects of malathion on AChE activity in specific brain regions.     

Inhibition of acetylcholinesterase by two arylderivatives: 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-Acetoxy-phenylisomaleimide

Two arylderivatives, 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione 3 and cis-N-p-Acetoxy-phenylisomaleimide 4, were synthesized from anthranilic acid and para-aminophenol, respectively. The inhibitory effects of these compounds on acetylcholinesterase (AChE) activity were evaluated in vitro as well as by docking simulations. Both compounds showed inhibition of AChE activity (K_i = 4.72 ± 2.3 μM for 3 and 3.6 ± 1.8 μM for 4) in in vitro studies. Moreover, they behaved as irreversible inhibitors and made π–π interaction with W84 and hydrogen bonded with S200 and Y337 according to experimental data and docking calculations. The docking calculations showed ΔG bind (kcal/mol) of ? 9.22 for 3 and ? 8.58 for 4. These two compounds that can be use as leads for a new family of anti-Alzheimer disease drugs.     

Hidden areas of endemism: Small units in the South-eastern Neotropics

This study aimed to establish if the Lower Río de la Plata Basin (LRPB) wetlands can be considered a biogeographic unit. The species of this area were compiled and segregated according to the habitat, selecting only 87 endemic taxa restricted to the LRPB and linked to wetlands. Distributional data of species obtained from the literature, web databases, biological collections, and field trips were georeferenced. The areas of endemism were established as those areas where the distribution of two or more taxa overlaps in groups of rivers’ sections with geographic continuity and were tested with a cluster analysis. This congruence is due to ecological, geomorphological, and historical factors. Four areas of endemism were found: a broad area that comprises the whole study area (Riverine district), which is divided into three nested smaller areas (Paraguay–Paraná Flooding Valleys, Uruguay Basin, and Paraná Delta subdistricts). Then, we analysed 170 taxa distributions to evaluate the relationship between the study area and the neighbouring biogeographic units. According to the results, the study area belongs to the Paraná biogeographic province. Some areas of endemism are hidden inside broader areas and are hardly detected with the currently used biogeographic grid-methods. We propose to combine the information about ecological requirements of each taxon with its georeferenced records to estimate their areas of distribution as a primary step for searching areas of endemism in intracontinental studies.     

Molecular phylogenetic diversity in the widespread lizard Cercosaura ocellata (Reptilia: Gymnophthalmidae) in South America

For a long time, Cercosaura ocellata was considered polytypic, with three subspecies: C. ocellata ocellata, C. ocellata petersi and C. ocellata bassleri. Recently, C. ocellata bassleri was elevated to full species, based on analysis of a few molecular samples from Peru. This species complex is widely distributed in South America, occurring in Amazonia, Cerrado, Atlantic forest and Pampa biomes. The monophyly and species diversity of C. ocellata are still unstudied. Here, we infer phylogenetic relationships and species diversity of this group analysing 2326 base pairs of three mitochondrial (12S, 16S, and ND4) and one nuclear (c-mos) genes. Our taxon sampling of 115 specimens includes 72 samples of C. ocellata and sequences of other Cercosaura species and closely related Cercosaurinae. Maximum likelihood phylogenetic analysis recovered the monophyly of Cercosaura and that of C. ocellata with strong support. Our analyses suggest that C. ocellata is a complex of cryptic species, which possibly started diversifying in Amazonia.     

Inhibition of Fatty Acid Amidohydrolase,the Enzyme Responsible for the Metabolism of the Endocannabinoid Anandamide,by Analogues of Arachidonoyl-serotonin

Arachidonoyl-serotonin inhibits in a mixed-type manner the metabolism of the endocannabinoid anandamide by the enzyme fatty acid amidohydrolase. In the present study, compounds related to arachidonoyl-serotonin have been synthesised and investigated for their ability to inhibit anandamide hydrolysis by this enzyme in rat brain homogenates. Removal of the 5-hydroxy from the serotonin head group of arachidonoyl-serotonin produced a compound (N-arachidonoyltryptamine) that was a 2.3-fold weaker inhibitor of anandamide hydrolysis, but which also produced its inhibition by a mixed-type manner (K_i(slope) 1.3 µM; K_i(intercept) 44 µM). Replacement of the amide linkage in this compound by an ester group further reduced the potency. In contrast, replacement of the arachidonoyl side chain by a linolenoyl side chain did not affect the observed potency. N-(Fur-3-ylmethyl) arachidonamide (UCM707), N-(fur-3-ylmethyl)linolenamide and N-(fur-3-ylmethyl)oleamide inhibited anandamide hydrolysis with pI50 values of 4.53, 5.36 and 5.25, respectively. The linolenamide derivative was also found to be a mixed-type inhibitor. It is concluded that the 5-hydroxy group of arachidonoyl-serotonin contributes to, but is not essential for, inhibitory potency at fatty acid amidohydrolase.     

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

Introduction

The T allele of a single nucleotide polymorphism (SNP: rs2544390) in lipoprotein receptor-related protein 2 (LRP2) is associated with higher serum urate and risk of gout in Japanese individuals. SNP rs2544390 also interacts with alcohol consumption in determining hyperuricemia in this population. We investigated the association of rs2544390 with gout, and interaction with all types of alcohol consumption in European and New Zealand (NZ) Māori and Pacific subjects, and a Māori study cohort from the East Coast region of NZ’s North Island.

Methods

Rs2544390 was genotyped by Taqman®. From NZ a total of 1205 controls and 1431 gout cases clinically ascertained were used. Publicly available genotype and serum urate data were utilized from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS). Alcohol consumption data were obtained by consumption frequency questions in all study cohorts. Multivariate adjusted logistic regression was done using STATA.

Results

The T allele of rs2544390 was associated with increased risk of gout in the combined Māori and Pacific Island cohort (OR = 1.20, P = 0.009), and associated with gout in the European subjects, but with a protective effect (OR = 0.79, P_Unadjusted = 0.02). Alcohol consumption was positively associated with risk of gout in Māori and Pacific subjects (0.2% increased risk/g/week, P = 0.004). There was a non-additive interaction between any alcohol intake and the risk of gout in the combined Māori and Pacific cohorts (P_Interaction = 0.001), where any alcohol intake was associated with a 4.18-fold increased risk in the CC genotype group (P = 6.6x10^-5), compared with a 1.14-fold increased risk in the CT/TT genotype group (P = 0.40). These effects were not observed in European subjects.

Conclusions

Association of the T-allele with gout risk in the Māori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals. The non-additive interaction in the Māori and Pacific subjects showed that alcohol consumption over-rides any protective effect conferred by the CC genotype. Further exploration of the mechanism underlying this interaction should generate new understanding of the biological role of alcohol in gout, in addition to strengthening the evidence base for reduction of alcohol consumption in the management of gout.     

SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis

Introduction

Our objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA).

Methods

A series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+).

Results

We included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+.

Conclusions

Neither of these two function charts was useful in estimating CV risk in Spanish RA patients.