A new genus of caponiid spiders with its phylogenetic placement within Nopinae and the description of a new species of Orthonops Chamberlin, 1924 from Eastern Mexico (Araneae: Synspermiata, Caponiidae).

A new caponiid genus, Aamunops gen. n., is described and its phylogenetic placement within Nopinae tested using a published morphological data matrix. This genus includes four species collected during three standardized inventories in the state of Veracruz, Mexico. All specimens were collected inside plots of oak forests and tropical wet forests fragments, from leaf litter using active searching, sifted litter processed with Berlese funnels and pitfall traps. Aamunops gen. n. was recovered monophyletic under equal and implied weighting schemes including the following species: Aamunops olmeca sp. n., A. chimpa sp. n., A. misi sp. n. and A. noono sp. n. An additional character for females and two new characters states for males were added to the published dataset. In addition, Orthonops confuso sp. n. is described and its phylogenetic affinities discussed. More information regarding these inventories and additional images for the described species can be found online at http://www.unamfcaracnolab.com.

Reversible focal intracranial hypertension swine model with continuous multimodal neuromonitoring.

BACKGROUND: Intracranial hypertension (HI) is associated with worse neurological outcomes and higher mortality. Although there are several experimental models of HI, in this article we present a reproducible, reversible, and reliable model of intracranial hypertension, with continuous multimodal monitoring. NEW METHOD: A reversible intracranial hypertension model in swine with multimodal monitoring including intracranial pressure, arterial blood pressure, heart rate variation, brain tissue oxygenation, and electroencephalogram is developed to understand the relationship of ICP and EEG. By inflating and deflating a balloon, located 20 mm anterior to the coronal suture and a 15 mm sagittal suture, we generate intracranial hypertension events and simultaneously measure intracranial pressure and oxygenation in the contralateral hemisphere and the EEG, simulating the usual configuration in humans. RESULTS: We completed 5 experiments and in all of them, we were able to complete at least 6 events of intracranial hypertension in a stable and safe way. For events of 20-40 mmHg of ICP we need an median (IQR) of 4.2 (3.64) ml of saline solution into the Foley balloon, a median (IQR) infusion time of 226 (185) second in each event and for events of 40-50 mmHg of ICP we need a median (IQR) of 5.1 (4.66) ml of saline solution, a median (IQR) infusion time of 280 (48) seconds and a median (IQR). The median (IQR) maintenance time was 352 (77) seconds and 392 (166) seconds for 20-40 mmHg and 40-50 mmHg of ICP, respectively. COMPARISON WITH EXISTING METHOD(S): Existing methods do not include EEG measures and do not present the reversibility of intracranial hypertension. CONCLUSIONS: Our model is fully reproducible, it is capable of generating reversible focal intracranial hypertension through strict control of the injected volume, it is possible to generate different infusion rates of the volume in the balloon, in order to generate different scenarios, the data obtained are sufficient to determine the brain complacency in real time. and useful for understanding the pathophysiology of ICP and the relationship between ICP (CPP) and EEG.

Outcomes of Heart Transplant Recipients with Class II Obesity: A United Network for Organ Sharing Database Analysis.

BACKGROUND: In the 2016 ISHLT listing criteria guidelines for heart transplantation, recipients were recommended to have a body mass index (BMI) <35 kg/m². However, outcomes data for subgroups of transplant recipients with a BMI >35 kg/m² are limited. We examined the outcomes of heart transplant recipients who had a BMI of 35 to 39.9 kg/m² or ≥40 kg/m² and compared their outcomes with recipients who had a BMI <35 kg/m2. METHODS: Using data from the United Network for Organ Sharing database, we performed a retrospective cohort analysis of 23,009 adults who underwent cardiac transplantation between 2009 and 2018. Transplant recipients were stratified by BMI categories (<35 kg/m², 35-39.9 kg/m², and ≥40 kg/m²). Patient survival was depicted by Kaplan-Meier curves. Cox proportional-hazards modeling was used to determine the prognostic factors associated with mortality within 90 days, 1 year, and 5 years after transplantation. RESULTS: Survival at 90 days, 1 year, and 5 years after transplantation was better in recipients who had a BMI <35 kg/m² than in those who had a BMI of 35 to 39.9 kg/m² (P values ranged from 0.01 to < 0.001) or ≥40 kg/m² (P < 0.001). Additionally, survival at 90 days (P < 0.001) and 1 year (P = 0.002) was significantly better in recipients who had a BMI of 35 to 39.9 kg/m² than in those who had a BMI ≥40 kg/m². In multivariate analysis, a BMI of 35 to 39.9 was significantly associated with increased 90-day mortality (HR = 1.53; 95% CI 1.12, 2.08; P = 0.01) but not increased 1-year (HR = 1.28; 95% CI 0.99, 1.66; P = 0.06) or 5-year mortality (HR = 1.11; 95% CI 0.91, 1.36; P = 0.29). CONCLUSIONS: Although heart transplant recipients with class II obesity (BMI 35-39.9 kg/m²) may have suboptimal survival compared with those who have a BMI <35 kg/m², these patients have better outcomes than do those with class III obesity (BMI ≥40 kg/m²). Thus, contrary to current guidelines, selected patients with class II obesity should be considered for transplantation.

A protocol for online documentation of spider biodiversity inventories applied to a Mexican tropical wet forest (Araneae, Araneomorphae).

Spider community inventories have relatively well-established standardized collecting protocols. Such protocols set rules for the orderly acquisition of samples to estimate community parameters and to establish comparisons between areas. These methods have been tested worldwide, providing useful data for inventory planning and optimal sampling allocation efforts. The taxonomic counterpart of biodiversity inventories has received considerably less attention. Species lists and their relative abundances are the only link between the community parameters resulting from a biotic inventory and the biology of the species that live there. However, this connection is lost or speculative at best for species only partially identified (e. g., to genus but not to species). This link is particularly important for diverse tropical regions were many taxa are undescribed or little known such as spiders. One approach to this problem has been the development of biodiversity inventory websites that document the morphology of the species with digital images organized as standard views. Their main contributions are the dissemination of phenotypic data for species difficult to identify or new with the assignment of species codes, allowing species comparisons between areas regardless of their taxonomic status. The present paper describes a protocol to produce these websites almost automatically. This protocol was successfully applied to 237 species from a tropical primary forest in Mexico. The time and infrastructure required for the documentation of these species are discussed. Taxonomic information in terms of identification challenges, possible new species, and potential nomenclatural issues is described. In addition, the conventional community parameters (e. g., inventory completeness, species richness estimations, sampling intensity) are also calculated and compared through time and between methods. An optimized version for sampling allocation effort per season is presented and compared with protocols optimized for other tropical forests.

Programa de Simulación Neuroquirúrgica / Neurosurgical Simulation Program

Objetivo: Describir un programa de entrenamiento básico para implementar en la residencia de Neurocirugía con una metodología estructurada, diferentes niveles de complejidad y elementos de fácil adquisición. Introducción: La simulación se define como el uso de modelos para imitar experiencias de la vida real. Debido a la complejidad del aprendizaje en Neurocirugía, el programa de la Residencia debería incluir entrenamiento básico mediante simulación que permita al residente entrenarse en habilidades básicas fuera del quirófano, o bien, desarrollar y complejizar las ya aprendidas. Materiales y Métodos: Se realizó un programa de entrenamiento básico a desarrollar en el Centro de Simulación Quirúrgica del Hospital italiano, dividido en tres niveles de complejidad quirúrgica. Se idearon distintos ejercicios con materiales accesibles, de bajo costo y replicables. El programa se diseñó para ser llevarse a cabo con una frecuencia de una vez por semana durante cinco horas. Discusión: Los modelos propuestos presentan fácil acceso y alta disponibilidad; y permitieron el desarrollo de habilidades microquirúrgicas desde etapas muy tempranas de la residencia, abarcando la utilización del instrumental microquirúrgico y la magnificación microscópica, y simulando distintas técnicas quirúrgicas en materiales biológicos y sintéticos realistas; enmarcado por un programa basado en objetivos sin límites de repeticiones. La evaluación con un neurocirujano Senior permitió brindar un espacio relajado de enseñanza y debate, sin ser influenciado por las presiones propias de la cirugía. El aprendizaje de técnicas quirúrgicas se basa en la repetición de maniobras específicas, por lo que el desarrollo de habilidades quirúrgicas en ámbitos académicos no asistenciales es fundamental en cualquier aprendizaje quirúrgico. Conclusión: La simulación en el entrenamiento neuroquirúrgico sigue siendo un campo de estudio que requiere mayor investigación y validación en su implementación. En nuestra experiencia resulta una herramienta sumamente favorable para su posterior aplicación en procedimientos quirúrgicos reales, que podría mejorar y homogeneizar la enseñanza en programas de formación quirúrgica

Objective: To describe a basic training program to implement at neurosurgery residency with a structured methodology, different complexity levels, and easily acquired elements. Introduction: Simulation is defined as use of models to imitate real life experiences. Due to complexity of neurosurgery learning, residency program should include simulation training that allows the resident learning basic skills outside the operating room and develop practices learned. Materials and methods: A training program was developed at Centro de Simulación Quirúrgica del Hospital Italiano, divided into three surgical complexity levels. Different exercises were designed with accessible, low cost and replicable materials. This program is carried out with a frequency of once a week, five hours each. Discussion: The proposed models have easy acquisition and high availability, allowing the development of microsurgical skills since early stages in residency, including the use of microsurgical instruments and microscopic magnification, surgical techniques in realistic biological and synthetic materials, based on a program with objectives without repetition limits. The evaluation with a senior neurosurgeon allowed providing a relaxed teaching space, without pressures of surgery. Learning of surgical techniques is based on repetition, so the development of surgical skills in non-assistance academic fields is fundamental in any surgical learning. Conclusion: Simulation in neurosurgical training remains a field that requires further investigation and validation in its implementation. In our experience, it is an extremely favorable tool because its subsequent application in real life procedures, which could improve and standardize surgical programs teaching

Description of five new Wulfila (Araneae, Anyphaenidae) species from Mexico with comments on the taxonomy of the genus.

The genus Wulfila O. Pickard-Cambridge 1895 belongs to the family Anyphaenidae Bertkau, 1878, commonly called ghost spiders. Wulfila is endemic to the Americas and currently has 43 valid species; here we describe five new: Wulfila conchamonile spec. nov., W. xilitlensis spec. nov., W. luisi spec. nov., W. unguis spec. nov. and W. phantasma spec. nov. Specimens were collected in Mexico as part of three biological inventories developed in Xilitla, San Luis Potosí, and Atotonilco and Xamaticpac, Veracruz, between 2011 and 2014. In addition, we provide an overview of Wulfila taxonomic literature with a discussion on the genus taxonomy, diagnostic characters, species placement, and novel genital characters.

New species of the orb-weaving spider genus Chrysometa (Araneae, Tetragnathidae) from oak forests near of the Pico de Orizaba National Park (Veracruz, Mexico).

Seven new species of the genus Chrysometa Simon are described: C. citlaltepetl n. sp., C. triangulosa n. sp., C. rosarium n. sp., C. atotonilco n. sp., C. xamaticpac n. sp. C. puya n. sp. and C. sagicuta n. sp. Species identities were evaluated and sexes for each species matched with a fragment of the cytochrome c oxidase subunit I. These data were analyzed with maximum likelihood and the resulting cladograms separated all species with high support values (95-100) and an average distance of 0.093 %. The genetic signal also agreed with the diagnostic morphological features used to separate these taxa. The sex matching results discovered that the female of C. chipinque Levi actually belongs to C. puya n. sp.; the correct female of C. chipinque is here described for the first time. A redescription of the male of C. chipinque and the female of C. puya is also provided. All species were collected as part of a faunistic inventory from two oak forests near Pico de Orizaba Volcano National Park. A total of 399 adult specimens, 209 females and 195 males, were sorted and identified. Most individuals were collected from medium height vegetation by beating trays and from high vegetation by direct collecting at night. High resolution images for all species are available at www.unamfcaracnolab.com. Finally, the functional anatomy of the epigynum for the species described here is discussed.

[Action of Calendula officinalis essence on bone preservation after the extraction]. / Acción del extracto de Calendula officinalis en la preservación ósea posterior a extracción.

BACKGROUND: Calendula officinalis is a phytodrug used as analgesic, antiseptic and wound-healing agent due to its collagenogenic effect, which is why it is a convenient and affordable treatment that promotes alveolar bone preservation after tooth extraction in vivo. The aim of this study was to use Calendula officinalis during and after tooth extraction to determine its ability to preserve bone after this procedure. METHODS: We established two groups matched by age, gender and position of the third molar. We used with patients on the experimental group Calendula officinalis diluted 10% as an irrigant during surgical extraction of third molars. We performed the conventional way with the control group irrigating with saline solution. Subsequently, both groups continued to make mouthwash for a week with the irrigating agent. Every week for a month, each patient underwent periapical radiography, out of which we took measurements of alveolar ridges and depth of alveolar bone, which were compared. CONCLUSIONS: There is statistically significant evidence to state that Calendula officinalis favorably affects bone preservation after extraction.

INTRODUCCIÓN: la Calendula officinalis es un fitofármaco al que se le atribuyen múltiples usos, entre los que destacan el de analgésico, antiséptico y cicatrizante por su efecto colagenogénico, lo que lo hace un tratamiento conveniente y económico que favorece la preservación ósea alveolar después de la extracción dental in vivo. El objetivo del presente estudio fue utilizar la Calendula officinalis durante y después de la extracción dental para determinar si tiene capacidad de preservación ósea después de la extracción. MÉTODOS: se seleccionaron dos grupos pareados por edad, género y posición del tercer molar. A un grupo experimental se le aplicó Calendula officinalis diluida al 10% en solución fisiológica como agente irrigante durante la extracción quirúrgica del tercer molar. Al grupo control se le realizó el procedimiento de manera convencional irrigando con solución fisiológica. Posteriormente ambos grupos continuaron realizando colutorios durante una semana con el agente irrigante. Durante un mes a cada paciente se le realizó semanalmente la toma de radiografía periapical con radiovisiógrafo a la cual se le tomaron medidas de crestas alveolares y profundidad alveolar que fueron comparadas. CONCLUSIONES: existe evidencia estadísticamente significativa para afirmar que la Calendula officinalis influye favorablemente en la preservación ósea posterior a la extracción.

The spider tree of life: phylogeny of Araneae based on target-gene analyses from an extensive taxon sampling.

We present a phylogenetic analysis of spiders using a dataset of 932 spider species, representing 115 families (only the family Synaphridae is unrepresented), 700 known genera, and additional representatives of 26 unidentified or undescribed genera. Eleven genera of the orders Amblypygi, Palpigradi, Schizomida and Uropygi are included as outgroups. The dataset includes six markers from the mitochondrial (12S, 16S, COI) and nuclear (histone H3, 18S, 28S) genomes, and was analysed by multiple methods, including constrained analyses using a highly supported backbone tree from transcriptomic data. We recover most of the higher-level structure of the spider tree with good support, including Mesothelae, Opisthothelae, Mygalomorphae and Araneomorphae. Several of our analyses recover Hypochilidae and Filistatidae as sister groups, as suggested by previous transcriptomic analyses. The Synspermiata are robustly supported, and the families Trogloraptoridae and Caponiidae are found as sister to the Dysderoidea. Our results support the Lost Tracheae clade, including Pholcidae, Tetrablemmidae, Diguetidae, Plectreuridae and the family Pacullidae (restored status) separate from Tetrablemmidae. The Scytodoidea include Ochyroceratidae along with Sicariidae, Scytodidae, Drymusidae and Periegopidae; our results are inconclusive about the separation of these last two families. We did not recover monophyletic Austrochiloidea and Leptonetidae, but our data suggest that both groups are more closely related to the Cylindrical Gland Spigot clade rather than to Synspermiata. Palpimanoidea is not recovered by our analyses, but also not strongly contradicted. We find support for Entelegynae and Oecobioidea (Oecobiidae plus Hersiliidae), and ambiguous placement of cribellate orb-weavers, compatible with their non-monophyly. Nicodamoidea (Nicodamidae plus Megadictynidae) and Araneoidea composition and relationships are consistent with recent analyses. We did not obtain resolution for the titanoecoids (Titanoecidae and Phyxelididae), but the Retrolateral Tibial Apophysis clade is well supported. Penestomidae, and probably Homalonychidae, are part of Zodarioidea, although the latter family was set apart by recent transcriptomic analyses. Our data support a large group that we call the marronoid clade (including the families Amaurobiidae, Desidae, Dictynidae, Hahniidae, Stiphidiidae, Agelenidae and Toxopidae). The circumscription of most marronoid families is redefined here. Amaurobiidae include the Amaurobiinae and provisionally Macrobuninae. We transfer Malenellinae (Malenella, from Anyphaenidae), Chummidae (Chumma) (new syn.) and Tasmarubriinae (Tasmarubrius, Tasmabrochus and Teeatta, from Amphinectidae) to Macrobuninae. Cybaeidae are redefined to include Calymmaria, Cryphoeca, Ethobuella and Willisius (transferred from Hahniidae), and Blabomma and Yorima (transferred from Dictynidae). Cycloctenidae are redefined to include Orepukia (transferred from Agelenidae) and Pakeha and Paravoca (transferred from Amaurobiidae). Desidae are redefined to include five subfamilies: Amphinectinae, with Amphinecta, Mamoea, Maniho, Paramamoea and Rangitata (transferred from Amphinectidae); Ischaleinae, with Bakala and Manjala (transferred from Amaurobiidae) and Ischalea (transferred from Stiphidiidae); Metaltellinae, with Austmusia, Buyina, Calacadia, Cunnawarra, Jalkaraburra, Keera, Magua, Metaltella, Penaoola and Quemusia; Porteriinae (new rank), with Baiami, Cambridgea, Corasoides and Nanocambridgea (transferred from Stiphidiidae); and Desinae, with Desis, and provisionally Poaka (transferred from Amaurobiidae) and Barahna (transferred from Stiphidiidae). Argyroneta is transferred from Cybaeidae to Dictynidae. Cicurina is transferred from Dictynidae to Hahniidae. The genera Neoramia (from Agelenidae) and Aorangia, Marplesia and Neolana (from Amphinectidae) are transferred to Stiphidiidae. The family Toxopidae (restored status) includes two subfamilies: Myroinae, with Gasparia, Gohia, Hulua, Neomyro, Myro, Ommatauxesis and Otagoa (transferred from Desidae); and Toxopinae, with Midgee and Jamara, formerly Midgeeinae, new syn. (transferred from Amaurobiidae) and Hapona, Laestrygones, Lamina, Toxops and Toxopsoides (transferred from Desidae). We obtain a monophyletic Oval Calamistrum clade and Dionycha; Sparassidae, however, are not dionychans, but probably the sister group of those two clades. The composition of the Oval Calamistrum clade is confirmed (including Zoropsidae, Udubidae, Ctenidae, Oxyopidae, Senoculidae, Pisauridae, Trechaleidae, Lycosidae, Psechridae and Thomisidae), affirming previous findings on the uncertain relationships of the "ctenids" Ancylometes and Cupiennius, although a core group of Ctenidae are well supported. Our data were ambiguous as to the monophyly of Oxyopidae. In Dionycha, we found a first split of core Prodidomidae, excluding the Australian Molycriinae, which fall distantly from core prodidomids, among gnaphosoids. The rest of the dionychans form two main groups, Dionycha part A and part B. The former includes much of the Oblique Median Tapetum clade (Trochanteriidae, Gnaphosidae, Gallieniellidae, Phrurolithidae, Trachelidae, Gnaphosidae, Ammoxenidae, Lamponidae and the Molycriinae), and also Anyphaenidae and Clubionidae. Orthobula is transferred from Phrurolithidae to Trachelidae. Our data did not allow for complete resolution for the gnaphosoid families. Dionycha part B includes the families Salticidae, Eutichuridae, Miturgidae, Philodromidae, Viridasiidae, Selenopidae, Corinnidae and Xenoctenidae (new fam., including Xenoctenus, Paravulsor and Odo, transferred from Miturgidae, as well as Incasoctenus from Ctenidae). We confirm the inclusion of Zora (formerly Zoridae) within Miturgidae.

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Three new species of the genus Trachelas (Araneae: Trachelidae) from an oak forest inside the Mesoamerican biodiversity hotspot in Mexico.

Three new species of the spider genus Trachelas L. Koch, 1872 are described and included in the speciosus group based on the following features: embolus as a separate sclerite from the tegulum with no basal coils, legs with a conspicuous fringe of long trichobothria and narrow copulatory ducts coiled irregularly. The new species described are: T. crassus sp. n., T. ductonuda sp. n. and T. odoreus sp. n. A total of 46 specimens were collected in an oak forest near Pico de Orizaba Volcano, Mexico. Most individuals were collected on low vegetation using beating trays and direct collecting at night. Additional images are available at www.unamfcaracnolab.com.

Description of a novel mating plug mechanism in spiders and the description of the new species Maeotasetastrobilaris (Araneae, Salticidae).

Reproduction in arthropods is an interesting area of research where intrasexual and intersexual mechanisms have evolved structures with several functions. The mating plugs usually produced by males are good examples of these structures where the main function is to obstruct the female genitalia against new sperm depositions. In spiders several types of mating plugs have been documented, the most common ones include solidified secretions, parts of the bulb or in some extraordinary cases the mutilation of the entire palpal bulb. Here, we describe the first case of modified setae, which are located on the cymbial dorsal base, used directly as a mating plug for the Order Araneae in the species Maeotasetastrobilaris sp. n. In addition the taxonomic description of Maeotasetastrobilaris sp. n. is provided and based on our findings the geographic distribution of this genus is extended to the Northern hemisphere.

Complejo de deformidades amnióticas, adhesiones, mutilación: interminable debate / Complex of amniotic deformities, adhesions, mutilations: Endless debate

El complejo de deformidades amnióticas, adhesiones, mutilaciones (cADAM) es un amplio espectro heterogéneo de anomalías congénitas. Se caracteriza por la presencia de anillos de constricción o amputación de dedos o extremidades y la presencia de bridas amnióticas; no obstante, puede involucrar disrupciones craneofaciales, en órganos internos y defectos de pared. El objetivo de esta revisión fue presentar los datos que se encontraron del cADAM, desde los antecedentes históricos, hasta las manifestaciones clínicas, estudios epidemiológicos y demás; se dirigió especial interés en mostrar las distintas teorías de la etiopatogenia, las contradicciones entre ellas y otros argumentos y conceptos difusos que envuelven a esta entidad. La búsqueda se realizó en las bases de datos de Pubmed, EBSCO host, Ovid, SpringerLink, Scopus, nature.com, JAMA y ScienceDirect con las siguientes palabras clave: "amniotic band syndrome", "sequence amniotic band", "Streeter syndrome", "ADAM complex". Se tomaron en cuenta 22 artículos. Los pacientes con cADAM requieren de una evaluación prenatal y postnatal completa para la integración del diagnóstico, la toma de decisiones y un tratamiento oportuno. De ahí la importancia del conocimiento de esta entidad por parte de clínicos y cirujanos, y la necesidad de replantear interrogantes para nuevas investigaciones y lograr establecer bases nosológicas.

Amniotic deformities, adhesions, mutilations (ADAM) complex is a broad heterogeneous spectrum of congenital anomalies. ADAM complex is characterized by constriction rings, amputation of fingers or limbs and the presence of the amniotic band. However, it may also involve craniofacial disruptions, body wall defects and internal organ abnormalities. The aim of this review is to present the results found in regard to ADAM complex from its historical background, clinical manifestations, epidemiology, etc. In particular, our attention was focused on demonstrating the varying etiopathogenesis theories of ADAM complex and their contradictions. The study was conducted using the databases of PubMed, EBSCO host, Ovid, SpringerLink, Scopus, nature.com, JAMA and ScienceDirect with the following keywords for the search: "amniotic band syndrome", "amniotic band sequence", "Streeter dysplasia", "ADAM complex". In this study we used 22 full-text articles. Patients with ADAM complex require a complete pre- and postnatal evaluation to integrate the diagnosis and to decide on timely treatment. It is important for clinicians and surgeons to possess knowledge of this entity. Further research is necessary to establish a nosological basis.

The male of Megacormusgranosus (Gervais, 1844) with comments on its hemispermatophore (Scorpiones, Euscorpiidae).

The male of Megacormusgranosus is described for the first time and the female redescribed. A homology scheme proposed recently is applied to hemispermatophore structures. The specimens were collected in an oak forest from Pico de Orizaba Volcano at an average altitude of 2340 m. All adult males were collected by pitfall traps, whereas all adult females and both sex immatures were collected using Berlese funnels, suggesting that males are comparatively more mobile within the leaf litter layer, probably due to mating season.

[Complex of amniotic deformities, adhesions, mutilations: Endless debate]. / Complejo de deformidades amnióticas, adhesiones, mutilación: interminable debate.

Amniotic deformities, adhesions, mutilations (ADAM) complex is a broad heterogeneous spectrum of congenital anomalies. ADAM complex is characterized by constriction rings, amputation of fingers or limbs and the presence of the amniotic band. However, it may also involve craniofacial disruptions, body wall defects and internal organ abnormalities. The aim of this review is to present the results found in regard to ADAM complex from its historical background, clinical manifestations, epidemiology, etc. In particular, our attention was focused on demonstrating the varying etiopathogenesis theories of ADAM complex and their contradictions. The study was conducted using the databases of PubMed, EBSCO host, Ovid, SpringerLink, Scopus, nature.com, JAMA and ScienceDirect with the following keywords for the search: "amniotic band syndrome", "amniotic band sequence", "Streeter dysplasia", "ADAM complex". In this study we used 22 full-text articles. Patients with ADAM complex require a complete pre- and postnatal evaluation to integrate the diagnosis and to decide on timely treatment. It is important for clinicians and surgeons to possess knowledge of this entity. Further research is necessary to establish a nosological basis.

Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.

We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.

Rational design of highly selective spleen tyrosine kinase inhibitors.

A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.

Discovery of novel PI3-kinase δ specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition.

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.