Retrospective case series with one year follow-up after radial nerve palsy associated with humeral fractures.

PURPOSE: The purpose of this study was to assess recovery and clinical outcome in patients with primary or secondary radial nerve palsy following humeral shaft fracture. METHODS: We retrospectively assessed 102 patients (45 female and 57 male) with humeral shaft fracture and concomitant radial nerve palsy, who were followed up for 12 months. Patients were divided into two groups with primary or secondary radial nerve palsy depending on the onset. Muscle function was measured according to Daniels classification and degree of nerve damage was assessed by the Sunderland classification. RESULTS: The average time for onset of recovery after primary RNP was 10.5 ± 3.31 weeks, in the case of secondary RNP it was 8.9 ± 7.98 weeks (p < 0.05). Full recovery or significant improvement was achieved with average of 26.7 ± 8.86 weeks and 23.9 ± 6.04 weeks respectively (p < 0.05). Trauma mechanism and type of treatment had no significant influence on time of onset of recovery or time to full recovery (p < 0.904). CONCLUSION: Secondary RNP shows tendency for earlier recovery and is more commonly associated with ORIF.

Targeting RAS oncogenesis with SOS1 inhibitors.

RAS proteins play major roles in many human cancers, but programs to develop direct RAS inhibitors so far have only been successful for the oncogenic KRAS mutant G12C. As an alternative approach, inhibitors for the RAS guanine nucleotide exchange factor SOS1 have been investigated by several academic groups and companies, and major progress has been achieved in recent years in the optimization of small molecule activators and inhibitors of SOS1. Here, we review the discovery and development of small molecule modulators of SOS1 and their molecular binding modes and modes of action. As targeting the RAS pathway is expected to result in the development of resistance mechanisms, SOS1 inhibitors will most likely be best applied in vertical combination approaches where two nodes of the RAS signaling pathway are hit simultaneously. We summarize the current understanding of which combination partners may be most beneficial for patients with RAS driven tumors.

Bone-on-Bone Anatomic Patellar Tendon Graft Anterior Cruciate Ligament Reconstruction: A Reproducible Technique Combining Press-Fit and Extracortical Fixation.

Scientific interest in optimizing outcomes after anterior cruciate ligament (ACL) reconstruction is ongoing, and some recent developments have focused on graft shape as one of the most important factors of anatomic graft placement. The double-bundle or fanlike structure of the native ACL seems to more closely restore normal function and control of rotational stability of the knee with implant-free or press-fit techniques, creating a favorable situation in terms of direct graft-tunnel healing. The ACL reconstruction technique presented in this article enables safe, reproducible, and anatomic fixation of the patellar tendon autograft, providing the biological and biomechanical benefits of direct bony integration of the ribbonlike bone-patellar tendon-bone graft. Because press-fit fixation represents a technically challenging surgical procedure, the goal of the described technique is to enable direct bone-to-bone healing by using secondary extracortical femoral and tibial fixation without the need for a true press-fit situation. Safe and anatomic femoral tunnel drilling is achieved with an outside-in technique (retrograde drilling), hence providing advantages in the routine clinical setting in terms of applicability and time effort. To reduce donor-site morbidity caused by bone block harvesting, refilling of the harvest sites with autologous material is performed.

Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor.

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.

Contaminación bacteriana de esponja de lavado y bachas de cocina de Cantinas de Escuelas de Asunción y Gran Asunción

RESUMEN Introducción: Las esponjas y el fregadero constituyen un medio favorable para el crecimiento de microorganismos. Objetivo: Evaluar la presencia de microorganismos en esponjas de lavado y bachas de cocina de cantinas de escuelas y colegios de Asunción y gran Asunción. Materiales y Métodos: estudio fue observacional descriptivo de corte transversal. Se tomó muestras de esponjas de lavado e hisopado de bachas de cocina de 25 cantinas de escuelas y colegios públicos y privados de Asunción y gran Asunción. Se utilizo medios de cultivo para bacterias aerobias mesófilas y coliformes fecales, Staphylococcus aureus y Salmonella spp. Se considero contaminación la presencia de ≥100UFC para las bacterias aerobias mesófilas y cualquier crecimiento de bacterias patógenas. El análisis se realizó en Micorsoft Excell utilizando estadísticas descriptivas. Resultados: Fueron incluidas 11 instituciones privadas y 14 públicas. El 88% (22/25 de las esponjas presentaron alta contaminación con bacterias aerobias mesófilas; 20 (80%) con coliformes fecales y 1 (4%) estéril. Hisopados de bachas, 21 (84%) presentaron alta contaminación las mesófilas y 20 (80%) con coliformes fecales, 1 (4%). No se aisló Salmonella spp. ni Staphylococcus aureus. No hubo diferencias en la contaminación de bachas entre instituciones públicas o privadas, pero si en las esponjas 14/14 vs 6/11 en las públicas y privadas respectivamente p=0.008 (T Fisher). Conclusión: esponjas de cocina y las bachas de las escuelas de Asunción y gran Asunción estudiadas, presentaron alto porcentaje de contaminación bacteriana tanto con bacterias aerobias mesófilas como con coliformes fecales. No se aisló Staphylococcus aureus ni Salmonella spp.

ABSTRACT Introduction: Sponges and the sink are a favorable medium for microorganism growth. Objective: To evaluate the presence of microorganisms in washing sponges and kitchen sinks in school cafeterias in Asunción and Greater Asunción. Materials and Methods: This was a descriptive, observational and cross-sectional study. Samples were taken by swabbing from washing sponges and kitchen sinks from 25 public and private school cafeterias in Asunción and the Greater Asunción area. Culture media were used for aerobic mesophilic and fecal coliform bacteria, Staphylococcus aureus and Salmonella species. The presence of ≥100 CFU for mesophilic aerobic bacteria and any growth of pathogenic bacteria was considered contamination. The analysis was performed with Microsoft Excel using descriptive statistics. Results: 11 private and 14 public institutions were included. 88% (22/25 of the sponges presented high contamination with aerobic mesophilic bacteria; 20 (80%) with fecal coliforms and 1 (4%) was sterile. Sink swabs: 21 (84%) presented high contamination with mesophylls and 20 (80%) with fecal coliforms, 1 (4%) was sterile. No Salmonella species or Staphylococcus aureus was isolated. There were no differences in the contamination of sinks between public or private institutions, but in sponges, 14/14 (public) were contaminated vs 6/11 (private), p = 0.008 (T Fisher). Conclusions: kitchen sponges and sinks from the schools of Asuncion and Greater Asuncion area in this study presented a high percentage of bacterial contamination with both aerobic mesophilic bacteria and fecal coliforms. No Staphylococcus aureus or Salmonella species were isolated.

Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin.

As a key regulator of mitosis, the Ser/Thr protein polo-like kinase-1 (Plk-1) is a well validated drug target in cancer therapy. In order to enable structure-guided drug design, determination of the crystal structure of the kinase domain of Plk-1 was attempted. Using a multi-parallel cloning and expression approach, a set of length variants were identified which could be expressed in large amounts from insect cells and which could be purified to high purity. However, all attempts to crystallize these constructs failed. Crystals were ultimately obtained by generating designed ankyrin-repeat proteins (DARPins) selective for Plk-1 and using them for cocrystallization. Here, the first crystal structure of the kinase domain of wild-type apo Plk-1, in complex with DARPin 3H10, is presented, underlining the power of selective DARPins as crystallization tools. The structure was refined to 2.3 A resolution and shows the active conformation of Plk-1. It broadens the basis for modelling and cocrystallization studies for drug design. The binding epitope of 3H10 is rich in arginine, glutamine and lysine residues, suggesting that the DARPin enabled crystallization by masking a surface patch which is unfavourable for crystal contact formation. Based on the packing observed in the crystal, a truncated DARPin variant was designed which showed improved binding characteristics.

Detecting and overcoming hemihedral twinning during the MIR structure determination of Rna1p.

The structure of Rna1p was originally solved to 2.7 A resolution by MIRAS from crystals with partial hemihedral twinning in space group I4(1) [Hillig et al. (1999), Mol. Cell, 3, 781-791] by finding a low-twinned native crystal (twin fraction alpha=0.06) and after twin correction of all data sets. Rna1p crystals have now been used to examine how far twinning and twin correction affect MIR phasing with a higher resolution but highly twinned native data set. Even high hemihedral twinning [alphanative=0.39, alphaderivative=0.24] would not have hindered heavy-atom site identification of strong derivatives using difference Patterson maps. However, a weaker derivative could have been missed and refinement would have stalled at high R values had twinning not been identified and accounted for. Twin correction improved both site identification, experimental phasing statistics and MIR map quality. Different strategies were tested for refinement against twinned data. Using uncorrected twinned data and TWIN-CNS, Rna1p has now been refined to 2.2 A resolution (final twinned R and Rfree were 0.165 and 0.218, respectively). The increased resolution enabled release of the NCS restraints and allowed new conclusions to be drawn on the flexibility of the two molecules in the asymmetric unit. In the case of Rna1p, twinned crystal growth was possible owing to the presence of a twofold NCS axis almost parallel to the twin operator.