A-ring-fused pyrazoles of dihydrotestosterone targeting prostate cancer cells via the downregulation of the androgen receptor.

High expression of the androgen receptor (AR) and the disruption of its regulation are strongly responsible for the development of prostate cancer (PCa). Therapeutically relevant non-steroidal or steroidal antiandrogens are able to block the AR effect by eliminating AR-mediated signalling. Herein we report the synthesis of novel steroidal pyrazoles derived from the natural sex hormone 5α-dihydrotestosterone (DHT). 2-Ethylidene or 2-(hetero)arylidene derivatives of DHT obtained by regioselective Claisen-Schmidt condensation with acetaldehyde or (hetero)aromatic aldehydes in alkaline ethanol were reacted with monosubstituted hydrazines to give A-ring-fused 1,5-disubstituted pyrazoles as main or exclusive products, depending on the reaction conditions applied. Spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the primarily formed pyrazolines resulted in the desired products in moderate to good yields, while 17-oxidation also occurred by using the Jones reagent as a strong oxidant. Transcriptional activity of the AR in a reporter cell line was examined for all novel compounds, and several previously synthesized similar DHT-based pyrazoles with differently substituted heteroring were also included to obtain information about the structure-activity relationship. Two specific regioisomeric groups of derivatives significantly diminished the transcriptional activity of the AR in reporter cell line in 10 µM concentration, and displayed reasonable antiproliferative activity in AR-positive PCa cell lines. Lead compound (3d) was found to be a potent AR antagonist (IC50 = 1.18 µM), it generally suppressed AR signalling in time and dose dependent manner, moreover, it also led to a sharp decrease in wt-AR protein level probably caused by proteasomal degradation. We confirmed the antiproliferative activity of 3d in AR-positive PCa cell lines (with GI50 in low micromolar ranges), and its cellular, biochemical and in silico binding in AR ligand-binding domain. Moreover, compound 3d was shown to be potent even ex vivo in patient-derived tissues, which highlights the therapeutic potential of A-ring-fused pyrazoles.

Anesthesia and Analgesia in the Patient with an Unstable Shoulder.

INTRODUCTION: The patient with an unstable shoulder represents a challenge for the anesthesiologist. Most patients will be young individuals in good health but both shoulder dislocation reduction, a procedure that is usually performed under specific analgesia in an urgent setting, and instability surgery anesthesia and postoperative management present certain peculiarities. MATERIAL AND METHODS: For the purpose of the article, 78 references including clinical trials and reviews were included. The review was organized considering the patient that presents an acute shoulder dislocation and the patient with chronic shoulder instability that requires surgery. In both cases the aspects like general or regional anesthesia, surgical positions and postoperative pain management were analyzed. CONCLUSION: The patient with an acutely dislocated shoulder is usually managed in the emergency room. Although reduction without analgesia is often performed in non-medical settings, an appropriate level of analgesia will ease the reduction procedure avoiding further complications. Intravenous analgesia and sedation is considered the gold standard but requires appropriate monitorization and airway control. Intraarticular local analgesic injection is considered also a safe and effective procedure. General anesthesia or nerve blocks can also be considered. The surgical management of the patient with shoulder instability requires a proper anesthetic management. This should start with an exhaustive preoperative evaluation that should be focused in identifying potential respiratory problems that might be complicated by local nerve blocks. Intraoperative management can be challenging, especially for patients operated in beach chair position, for the relationship with problems related to cerebral hypoperfusion, a situation related to hypotension events directly linked to patient positioning. Different nerve blocks will help attaining excellent analgesia both during and after the surgical procedure. An interescalene nerve block should be considered the best technique, but in certain cases, other blocks can be considered.

Effects of the Hypnotic Agent on Primary Graft Dysfunction After Liver Transplantation.

BACKGROUND: Morbidity and mortality rates in orthotopic liver transplantation have decreased in the past few years. Risk factors related to severe postoperative complications, such as primary graft dysfunction, still need to be analyzed. We evaluated the influence of the hypnotic agent used during anesthesia on primary graft dysfunction. METHODS: We performed a retrospective analysis of 419 consecutive patients who received a liver transplant between 2005 and 2013 in a single center. We analyzed the incidence of primary graft dysfunction (defined as alanine aminotransferase or aspartate aminotransferase levels higher than 1500 IU/L on the first 3 days after surgery) and if the hypnotic agent was associated with this event. RESULTS: The incidence of primary graft dysfunction was 42.2% (114 patients), similar in both groups (propofol group, 89 patients, 43.2% and sevoflurane group, 25 patients, 39.1%). In the multivariate analysis, we did not find any relationship between the hypnotic agent (propofol or sevoflurane) and early graft dysfunction. CONCLUSIONS: In our patients, we found no differences in the incidence of liver graft dysfunction according to the hypnotic used during transplantation. We can suggest that both drugs (sevoflurane and propofol) are equally safe in orthotopic liver transplantation.

Mobile Phones As Surveillance Tools: Implementing and Evaluating a Large-Scale Intersectoral Surveillance System for Rabies in Tanzania.

Katie Hampson and colleagues describe their experience of developing and deploying a large-scale rabies surveillance system based on mobile phones in southern Tanzania.

Effect of VEGF-A165 addition on the integration of a cortical allograft in a tibial segmental defect in rabbits.

PURPOSE: Long-bone segmental defects caused by infection, fracture, or tumour are a challenge for orthopaedic surgeons. Structural allografts are sometimes used in their treatment but their poor biological characteristics are a liability. The objective of this study was to determine whether the addition of recombinant vascular endothelial growth factor-A (VEGF) to a structural allograft improved its integration into a rabbit tibial segmental defect in a non-union model. METHODS: Tibial segmental defects were filled with heat sterilized allogenic tubular tibiae sections and then stabilized with a screw plate. In the VEGF treatment group (n = 6 tibiae), 2 µg of VEGF added to a 50 µl matrigel solution was inserted into the allograft cavity. In the control group (n = 6 tibiae), only matrigel was added. After 12 weeks, macroscopic and microscopic analysis, radiographs, and computerized micro-tomography (micro-CT) were performed. If allograft consolidation was present, a torsional resistance analysis was performed. RESULTS: Addition of VEGF to the allograft decreased the rate of osteosynthesis failure compared with the control group (1/6 vs. 5/6, p = 0.08), increased trabecular continuity evaluated by micro-CT in the bone-allograft interphases (8/12 vs. 2/12, p = 0.036) and histological trabecular continuity (7/12 vs. 0/12, p = 0.0046). Full consolidation was observed in three tibiae of the VEGF group and one in the control group (differences not significant); however, torsional resistance showed no significant differences (n.s.). CONCLUSION: Addition of VEGF to a structural allograph inserted into a rabbit tibial segmental defect increased allograft integration rate. Further research in this direction might help clinicians in dealing with large bone defects.

Repair of meniscal tears associated with tibial plateau fractures: a review of 15 cases.

BACKGROUND: Tibial plateau fractures are frequently associated with meniscal tears. Little is known about the results of meniscal repair in this group of patients. PURPOSE: To determine the results of repair of meniscal tears found during arthroscopically assisted reduction and internal fixation (ARIF) of tibial plateau fractures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In a cohort of 51 tibial plateau fractures treated with ARIF, 15 associated meniscal tears (15 knees) in 14 patients were repaired. There were 12 peripheral longitudinal tears of the lateral meniscus, 1 longitudinal peripheral tear of the medial meniscus, 1 full-thickness radial tear of the lateral meniscus, and 1 bird-beak tear of the lateral meniscus. Repairs were performed using an outside-in technique for the anterior horn and all-inside repair for the body and posterior horn lesions. Mean (SD) age at operation was 47.3 (14.0) years. Patients were followed for a mean (SD) of 4.83 (1.01) years and evaluated using the Rasmussen, Honkonen, Lysholm, Tegner, and International Knee Documentation Committee (IKDC) scores. A second-look arthroscopy was performed in 13 knees a mean (SD) of 14.2 (10.1) months after the initial surgery. RESULTS: The mean (SD) Rasmussen score was 29.1 (0.96). Thirteen of 15 patients scored good or excellent results in all Honkonen sections. The mean (SD) Lysholm score was 88.6 (12.4). The mean (SD) IKDC score was 79.3 (19.3). There was a small decrease of the activity level according to the Tegner score when compared with the preoperative situation (1.20 [1.82], P = .022). There were not any meniscal symptoms in any case. Of the 13 menisci evaluated with second-look arthroscopy, 12 had healed completely and a radial tear had healed partially in the vascular zone. In one of the cases that healed, a new tear was found in a different location. CONCLUSION: Meniscal repair of tears associated with tibial plateau fractures has good results. All patients had good or excellent clinical results. Second-look arthroscopy confirmed complete healing in 92% of meniscal tears when performed.

Las nuevas guías de profilaxis de enfermedad tromboembólica venosa en artroplastia de cadera y rodilla electivas / The new guidelines for deep venous thromboembolic disease prophylaxis in elective hip and knee replacement surgery. Are we nearer or further away from a consensus?

La profilaxis de eventos tromboembólicos venosos (ETV) tras artroplastia electiva de cadera o rodilla es un tema controvertido. Recientemente, 3 guías clínicas sobre este tema (las guías NICE, ACCP y AAOS) han sido actualizadas. Las guías presentan puntos en común: es necesario de hacer profilaxis; es recomendable asociar profilaxis mecánica y farmacológica en los pacientes que han sufrido un ETV previo; las medidas mecánicas aisladas son efectivas y las heparinas de bajo peso molecular, los nuevos anticoagulantes orales y el fondaparinux son fármacos eficaces. Hay cierto consenso en recomendar la anestesia regional, en desaconsejar estudios ecográficos en pacientes asintomáticos y en promover la movilización precoz del paciente. Hay discrepancias sobre la terapia farmacológica más adecuada y, el momento de inicio y duración de esta, sobre los filtros de vena cava, los antiagregantes y los factores de riesgo de ETV o sangrado (AU)

Venous thromboembolism events (VTE) prophylaxis after elective hip or knee replacement surgery is a subject of controversy. Three sets of guidelines (NICE, ACCP and AAOS) on this topic have recently been updated. The guidelines have points in common: prophylaxis is necessary, it is recommended to combine mechanical and pharmacological prophylaxis in patients who have suffered a previous VTE, isolated mechanical measures and low molecular weight heparins are effective, the new oral anticoagulants and fondaparinux are effective drugs. There is some consensus in recommending regional anaesthesia, in advising against echography studies in asymptomatic patients, and in the promotion of early mobilisation of the patient. There is controversy over the most suitable pharmacological treatment and the time of starting, and the duration of this, as well as on vena cava filters, antiplatelet drugs, and VTE or bleeding risk factors (AU)

[The new guidelines for deep venous thromboembolic disease prophylaxis in elective hip and knee replacement surgery. Are we nearer or further away from a consensus?]. / Las nuevas guías de profilaxis de enfermedad tromboembólica venosa en artroplastia de cadera y rodilla electivas: ¿nos acercamos o nos alejamos del consenso?

Venous thromboembolism events (VTE) prophylaxis after elective hip or knee replacement surgery is a subject of controversy. Three sets of guidelines (NICE, ACCP and AAOS) on this topic have recently been updated. The guidelines have points in common: prophylaxis is necessary, it is recommended to combine mechanical and pharmacological prophylaxis in patients who have suffered a previous VTE, isolated mechanical measures and low molecular weight heparins are effective, the new oral anticoagulants and fondaparinux are effective drugs. There is some consensus in recommending regional anaesthesia, in advising against echography studies in asymptomatic patients, and in the promotion of early mobilisation of the patient. There is controversy over the most suitable pharmacological treatment and the time of starting, and the duration of this, as well as on vena cava filters, antiplatelet drugs, and VTE or bleeding risk factors.

The effect of the addition of adipose-derived mesenchymal stem cells to a meniscal repair in the avascular zone: an experimental study in rabbits.

PURPOSE: To determine whether adipose-derived mesenchymal stem cells (ASCs) affect the healing rate of meniscal lesions sutured in the avascular zone in rabbits. METHODS: Four groups were used. In group A (n = 12) a short, 5-mm-long longitudinal lesion in the avascular zone of the anterior horn of the medial meniscus was created and immediately sutured. In group B (n = 8) the same short lesion was created but suture was delayed 3 weeks. In group C (n = 12) a larger, 15-mm-long lesion that spanned the whole meniscus was created and sutured immediately. In group D (n = 8) the same large lesion was sutured 3 weeks later. Both knees in each rabbit were used: 1 served as the control, and in the other, 1 × 10(5) allogeneic ASCs marked with bromodeoxyuridine were placed in the lesion immediately before suturing. The animals were killed at 12 weeks. RESULTS: In group A (short lesion, acute repair) 6 of 12 ASC-treated menisci and 0 of 12 controls had some healing (P = .014). In group B (short lesion, delayed repair) 2 of 8 ASC-treated menisci and 1 of 8 controls had some healing (P = .5). In group C (long lesion, acute repair) 6 of 12 ASC-treated menisci and 0 of 12 controls had some healing (P = .014). In group D (long lesion, delayed repair) 4 of 8 ASC-treated menisci and 0 of 8 controls had some healing (P = .07). The addition of ASCs increased the healing rate (odds ratio, 32 [range, 3.69 to 277]; P = .002). The histologic analysis of the healed zones identified well-formed meniscal fibrocartilage with persistence of cells derived from the ASCs (immunolocated with anti-bromodeoxyuridine antibodies). CONCLUSIONS: Adding ASCs to a repair in the avascular zone of rabbit menisci increases the chances of healing. Healing is improved in small and larger lesions. When suture is delayed, the effect is not as evident. CLINICAL RELEVANCE: In the future, ASCs might help in meniscal repair in the avascular zone.

Predicting acute renal failure after cardiac surgery: external validation of two new clinical scores.

BACKGROUND AND OBJECTIVES: Different scores to predict acute kidney injury after cardiac surgery have been developed recently. The purpose of this study was to validate externally two clinical scores developed at Cleveland and Toronto. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective analysis was conducted of a prospectively maintained database of all cardiac surgeries performed during a 5-yr period (2002 to 2006) at a University Hospital in Madrid, Spain. Acute kidney injury was defined as the need for renal replacement therapy. For evaluation of the performance of both models, discrimination and calibration were measured. RESULTS: Frequency of acute kidney injury after cardiac surgery was 3.7% in the cohort used to validate the Cleveland score and 3.8% in the cohort used to validate the Toronto score. Discrimination of both models was excellent, with values for the areas under the receiving operator characteristics curves of 0.86 (95% confidence interval 0.81 to 0.9) and 0.82 (95% confidence interval 0.76 to 0.87), respectively. Calibration was poor, with underestimation of the risk for acute kidney injury except for patients within the very-low-risk category. The performance of both models clearly improved after recalibration. CONCLUSIONS: Both models were found to be very useful to discriminate between patients who will and will not develop acute kidney injury after cardiac surgery; however, before using the scores to estimate risk probabilities at a specific center, recalibration may be needed.

Inclinación pélvica en el plano sagital. Descripción y validación de un nuevo sistema de medida. Valores normales en 75 sujetos / Pelvic tilt in the sagittal plane. Description and validation of a new measurement method. Normal values in 75 subjects

Las alteraciones de la inclinación pélvica en el plano sagital en bipedestación son importantes en el dolor lumbar crónico y la espondilolistesis. Los métodos habituales que se usan para medir este parámetro necesitan de la realización de radiografías o requieren de aparataje complejo. Se describe un nuevo sistema de medida rápido y fácil de utilizar. El sistema determina la altura respecto al suelo de las espinas ilíacas anterosuperiores y posterosuperiores y las distancias entre sí, y calcula la inclinación del plano que pasa por estos cuatro puntos. Se analizó la reproducibilidad del sistema midiendo de manera repetida un grupo de 12 sujetos. El coeficiente de correlación intraclase intraobservador fue de 0,90 y el interobservador fue de 0,80, por lo que el sistema tiene una buena reproducibilidad. Se analizó la validez del método comparando las medidas obtenidas con las realizadas sobreradiografías laterales de pelvis en 27 sujetos. Se observaron errores medios de 1,3° con una gran correlación entre ambos datos (R2 = 0,68; p < 0,001) por lo que el sistema se considera válido. Se realizaron medidas sobre 75 voluntarios sanos. La inclinación pélvica media fue de 9,88° (desviación estándar [DE]: 5,43°). El análisis de regresión lineal multivariante observó una inclinación pélvica menor en los hombres que en las mujeres (p = 0,044) y que la edad se relaciona inversamente con la inclinación pélvica (p = 0,004)

Variations in pelvic tilt in the sagittal planeare important in chronic lumbar pain and spondylo listhesis. The current methods used to measure this parameter require the use of roentgenograms or need complex instruments. A new method is described that is quick an easy to use. The system determines the height from the floor of the posterior superior and anterior superior iliac spines and the distances between them, and calculates the inclination of the plane that traverses these four points. The reproducibility of the system was assessed with repeated measurements in a group of 12 subjects. The intraobserverintra class correlation coefficient was 0.90 and the interobserver coefficient was 0.80, implicating a good reproducibility. The validity of the system was assessed comparing the measurements with those obtained over lateral pelvic roentgenograms in 27 subjects. Mean error was 1.3° with a high correlation between measurements (R2 = 0,68, p < 0,001)so the system is valid. Seventy-five healthy volunteers were measured. Mean pelvic tilt was 9.88° (standard deviation 5.43°). Multivariate linear regression analysis appreciated less pelvic tilt in males than in females (p = 0.044) and that age was inversely related to pelvic tilt (p = 0.004)

[Intestinal transplantation in adults: present situation and future prospects]. / Trasplante intestinal del adulto. Situación actual y perspectivas de futuro.

Intestinal transplantation is becoming more firmly established as a treatment for intestinal failure in patients whose home parenteral nutrition regimens have caused serious side effects. Outcomes have improved spectacularly over recent years thanks to the refinement of surgical techniques and the introduction of new immunosuppressants, and also to greater experience in anesthetic and postoperative management of intestinal transplant patients. The main causes of high morbidity and mortality continue to be sepsis and acute rejection of the graft. Both graft and patient survival have improved with the advent of the immunosuppressant regimens based on Tacrolimus, although survival rates are still far below those reported for other solid organ transplants. The first intestinal transplant performed in Spain took place in July 2002 in our hospital and the results were promising. Given this new challenge for anesthesiologists, we decided to review current trends in the perioperative management of patients receiving isolated intestinal transplants, the main complications that arise, treatment strategies, and future prospects.