Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.

Approximate reduction of linear population models governed by stochastic differential equations: application to multiregional models.

In this work we develop approximate aggregation techniques in the context of slow-fast linear population models governed by stochastic differential equations and apply the results to the treatment of populations with spatial heterogeneity. Approximate aggregation techniques allow one to transform a complex system involving many coupled variables and in which there are processes with different time scales, by a simpler reduced model with a fewer number of 'global' variables, in such a way that the dynamics of the former can be approximated by that of the latter. In our model we contemplate a linear fast deterministic process together with a linear slow process in which the parameters are affected by additive noise, and give conditions for the solutions corresponding to positive initial conditions to remain positive for all times. By letting the fast process reach equilibrium we build a reduced system with a lesser number of variables, and provide results relating the asymptotic behaviour of the first- and second-order moments of the population vector for the original and the reduced system. The general technique is illustrated by analysing a multiregional stochastic system in which dispersal is deterministic and the rate growth of the populations in each patch is affected by additive noise.

Minimally invasive clamp-assisted reduction and cephalomedullary nailing without cerclage cables for subtrochanteric femur fractures in the elderly: Surgical technique and results.

INTRODUCTION: The treatment of subtrochanteric fractures in the elderly remains technically challenging, due to instability and osteoporosis, with high reoperation rates. Even if intramedullary nailing is the most reliable treatment, reduction is difficult and cerclage wiring remains controversial. The purpose of this study was to evaluate 26 consecutive subtrochanteric fractures in elderly patients treated with a minimally invasive clamp-assisted reduction and cephalomedullary nailing without cerclage wiring. PATIENTS AND METHODS: A retrospective analysis was conducted between January 2010 and September 2013. Data obtained from the medical records included patient's age, sex, classification of the fracture, the quality of reduction after surgery, and the presence of postoperative complications, especially fracture displacement and delayed union or nonunion. RESULTS: Twenty-six patients had adequate radiographic and clinical follow-up. Mean age was 84.4 (range 75-96) years. The mean duration of follow-up was 7.6 months (6-14 months). Mean surgical time was 74.42 min (range 45-115 min). Twenty-four (92.3%) showed acceptable varus/valgus alignment, and no sagittal plane malunions were noted. The tip-apex distance was <25 mm in all cases. Distraction at the fracture was <10mm in 21 fractures. Three patients had limb length discrepancy of 1cm. All fractures healed uneventfully. DISCUSSION: Reducing the fracture before nailing is mandatory to achieve good results. Minimally invasive clamp reduction without cerclage wires, even if challenging, has proven to be a safe, reproducible, and effective surgical technique, with at least the same results as other series.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I.

A knowledge-based design strategy led to the discovery of several new series of potent and orally bioavailable CRTh2 antagonists where a bicyclic heteroaromatic ring serves as the central core. Structure-kinetic relationships (SKR) opened up the possibility of long receptor residence times.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.

Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: the role of a hydrogen-bond acceptor in long receptor residence times.

The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ≠ H) gives access to compounds with dissociation half-lives of ⩾ 24h.

Pyrazine-based Syk kinase inhibitors.

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.

Discovery of potent and selective bicyclic A(2B) adenosine receptor antagonists via bioisosteric amide replacement.

Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.

Approximating the distribution of population size in stochastic multiregional matrix models with fast migration.

In this work we deal with a multiregional model in discrete time for an age-structured population which lives in an environment that changes randomly with time and is distributed in different spatial patches. In addition, and as is often the case in applications, we assume that migration is fast with respect to demography. Using approximate aggregation techniques we make use of the existence of different time scales in the model and reduce the dimension of the system obtaining a stochastic Leslie model in which the variables are the total population in each age class. Literature shows that, under reasonable conditions, the distribution of population size in matrix models with environmental stochasticity is asymptotically lognormal, and is characterized by two parameters, stochastic growth rate (s.g.r.) and scaled logarithmic variance (s.l.v.), that, in most practical cases, cannot be computed exactly. We show that the s.g.r. and the s.l.v. of the original multiregional model can be approximated by those corresponding to the reduced stochastic Leslie model, therefore simplifying its analysis. Moreover, we illustrate the usefulness of the reduction procedure by presenting some practical cases in which, although the explicit computation of the s.g.r. and the s.l.v. of the original multiregional model is not feasible, we can calculate its analogues for the reduced model.

Reduction of supercritical multiregional stochastic models with fast migration.

In this work we study the behavior of a time discrete multiregional stochastic model for a population structured in age classes and spread out in different spatial patches between which individuals can migrate. The dynamics of the population is controlled both by reproduction-survival and by migration. These processes take place at different time scales in the sense of the latter being much faster than the former. We incorporate the effect of demographic stochasticity into the population, which results in both dynamics being modelled by multitype Bienaymé-Galton-Watson branching processes. We present a multitype global model that incorporates the effect of both processes and, making use of the existence of different time scales for demography and migration, build a reduced model in which the variables correspond to the total population in each age class. We extend previous results that relate the behavior of the original and the reduced model showing that, given a large enough separation of time scales between demography and migration, we can obtain information about the behavior of the multitype global model through the study of the simpler reduced model. We concentrate on the case where the two systems are supercritical and therefore the expected number of individuals grows to infinity, and show that we can approximate the asymptotic structure of the population vector and the asymptotic population size of the original system through the study of the reduced model.

Thrombosed iliac venous aneurysm: a rare form of presentation of a congenital anomaly of the inferior vena cava.

Aneurysms of the iliac veins are extremely rare. We report a case of a 51-year-old male who was admitted for swelling of the lower right limb. Sonography and ascending phlebogram showed a complete occlusion of the right femoropopliteal veins, both iliacs and the inferior vena cava (IVC). A large collateral circulation throughout the paravertebral plexus and azygos system was also observed. The CT scan revealed a 5 x 9 cm thrombosed aneurysm of the right external iliac vein and a congenital hypoplasia of the infrarenal IVC. Anticoagulant treatment and compression with elastic stocking was started. The 3-month follow-up showed mild residual edema of the right lower limb. The literature on this pathology is extensively reviewed.

Aneurisma micótico por Salmonella en un paciente con síndrome de inmunodeficiencia adquirida y riñón en herradura / Mycotic aneurysm due to Salmonella in a patient with acquired immunodeficiency syndrome and horseshoe kidney

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Pseudoaneurisma tras autotrasplante renal. Corrección endovascular / Pseudoaneurysm following kidney autotransplantation. Endovascular correction

Introducción. Los pseudoaneurismas son una rara complicación después de un trasplante renal y prácticamente son excepcionales tras cirugía de banco y autotrasplante. En presencia de dichas lesiones se considera obligatoria su corrección con objeto de evitar el riesgo potencial de complicaciones mortales asociadas a la ruptura diferida del pseudoaneurisma. La reparación convencional es un procedimiento complejo que puede verse dificultado por los problemas inherentes asociados a una redirección. Caso clínico. Mujer de 52 años con un pseudoaneurisma de arteria ilíaca desarrollado tras cirugía ex vivo y autotrasplante renal por aneurisma de arteria renal. Las pruebas de imagen pusieron de manifiesto la lesión arterial en la ubicación de un bypass ilíacorrenal concomitante a la cirugía previa. La corrección endovascular del pseudoaneurisma se llevó a cabo mediante la liberación de un stent cubierto. La arteriografía de control mostró la completa exclusión del pseudoaneurisma de arteria ilíaca y la preservación completa del flujo en la arteria renal reconstruida. Conclusión. La exclusión del pseudoaneurisma con preservación completa del flujo del riñón trasplantado pone de relieve la potencial utilidad del tratamiento endovascular en pacientes seleccionados

Introduction. Pseudoaneurysms are a rare complication after a kidney transplant and are practically unknown following bench surgery and autotransplantation. Such lesions must be corrected in order to avoid the potential risk of fatal complications that are associated with the delayed rupture of a pseudoaneurysm. Conventional repair is a complex procedure that can be further complicated by the problems inherent to any intervention involving redirection. Case report. A 52-year-old female with a pseudoaneurysm in the iliac artery that developed after ex vivo surgery and kidney autotransplantation due to an aneurysm in the renal artery. Imaging tests showed the arterial lesion to be situated at the site of an iliac-renal bypass that had been carried out during the previous intervention. Endovascular correction of the pseudoaneurysm was performed by deploying a covered stent. The control arteriography showed the complete exclusion of the pseudoaneurysm in the iliac artery and full preservation of blood flow in the reconstructed renal artery. Conclusion. The exclusion of the pseudoaneurysm with full preservation of flow in the transplanted kidney highlights the potential value of endovascular treatment in selected patients