Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A

Emergency vaccination of rabies under limited resources – combating or containing?

BACKGROUND: Rabies is the most important viral zoonosis from a global perspective. Worldwide efforts to combat the disease by oral vaccination of reservoirs have managed to eradicate wildlife rabies in large areas of central Europe and North-America. Thus, repeated vaccination has been discontinued recently on a geographical scale. However, as rabies has not yet been eradicated globally, a serious risk of re-introduction remains. What is the best spatial design for an emergency vaccination program – particularly if resources are limited? Either, we treat a circular area around the detected case and run the risk of infected hosts leaving the limited control area, because a sufficient immunisation level has not yet been built up. Or, initially concentrate the SAME resources in order to establish a protective ring which is more distant from the infected local area, and which then holds out against the challenge of the approaching epidemic. METHODS: We developed a simulation model to contrast the two strategies for emergency vaccination. The spatial-explicit model is based on fox group home-ranges, which facilitates the simulation of rabies spread to larger areas relevant to management. We used individual-based fox groups to follow up the effects of vaccination in a detailed manner. Thus, regionally – bait distribution orientates itself to standard schemes of oral immunisation programs and locally – baits are assigned to individual foxes. RESULTS: Surprisingly, putting the controlled area ring-like around the outbreak does not outperform the circular area of the same size centred on the outbreak. Only during the very first baitings, does the ring area result in fewer breakouts. But then as rabies is eliminated within the circle area, the respective ring area fails, due to the non-controlled inner part. We attempt to take advantage of the initially fewer breakouts beyond the ring when applying a mixed strategy. Therefore, after a certain number of baitings, the area under control was increased for both strategies towards the same larger circular area. The circle-circle strategy still outperforms the ring-circle strategy and analysis of the spatial-temporal disease spread reveals why: improving control efficacy by means of a mixed strategy is impossible in the field, due to the build-up time of population immunity. CONCLUSION: For practical emergency management of a new outbreak of rabies, the ring-like application of oral vaccination is not a favourable strategy at all. Even if initial resources are substantially low and there is a serious risk of rabies cases outside the limited control area, our results suggest circular application instead of ring vaccination

The weekend effect on the provision of Emergency Surgery before and during the COVID-19 pandemic: case–control analysis of a retrospective multicentre database

Introduction: The concept of “weekend effect”, that is, substandard healthcare during weekends, has never been fully demonstrated, and the different outcomes of emergency surgical patients admitted during weekends may be due to different conditions at admission and/or different therapeutic approaches. Aim of this international audit was to identify any change of pattern of emergency surgical admissions and treatments during weekends. Furthermore, we aimed at investigating the impact of the COVID-19 pandemic on the alleged “weekend effect”. Methods: The database of the CovidICE-International Study was interrogated, and 6263 patients were selected for analysis. Non-trauma, 18+ yo patients admitted to 45 emergency surgery units in Europe in the months of March–April 2019 and March–April 2020 were included. Demographic and clinical data were anonymised by the referring centre and centrally collected and analysed with a statistical package. This study was endorsed by the Association of Italian Hospital Surgeons (ACOI) and the World Society of Emergency Surgery (WSES). Results: Three-quarters of patients have been admitted during workdays and only 25.7% during weekends. There was no difference in the distribution of gender, age, ASA class and diagnosis during weekends with respect to workdays. The first wave of the COVID pandemic caused a one-third reduction of emergency surgical admission both during workdays and weekends but did not change the relation between workdays and weekends. The treatment was more often surgical for patients admitted during weekends, with no difference between 2019 and 2020, and procedures were more often performed by open surgery. However, patients admitted during weekends had a threefold increased risk of laparoscopy-to-laparotomy conversion (1% vs. 3.4%). Hospital stay was longer in patients admitted during weekends, but those patients had a lower risk of readmission. There was no difference of the rate of rescue surgery between weekends and workdays. Subgroup analysis revealed that interventional procedures for hot gallbladder were less frequently performed on patients admitted during weekends. Conclusions: Our analysis revealed that demographic and clinical profiles of patients admitted during weekends do not differ significantly from workdays, but the therapeutic strategy may be different probably due to lack of availability of services and skillsets during weekends. The first wave of the COVID-19 pandemic did not impact on this difference

Efficient And Practical Procedure For The Esterification Of The Free α-carboxylic Acid Of Amino Acid Residues With β-(trimethylsilyl)ethoxymethyl Chloride And Triisopropylsilyl Chloride

An efficient and practical procedure for the free α-carboxylic acid esterification of amino acid residues with β-(trimethylsilyl)ethoxymethyl chloride and triisopropylsilyl chloride is described. The reaction takes place under mild conditions and the expected protected amino acids are obtained in good to excellent yields. Our method provides a useful alternative for the C-terminal carboxylic acid protection of amino acids and peptides. Moreover, the removal of such protection was also achieved under mild conditions, without affecting either the other protecting groups at the α-amino moiety and side chains or the optical integrity at the α-position of the amino acid residues. Examples of their use in peptide synthesis are also illustrated.462230753084Barany, G., Merrifield, R.B., (1977) J. Am. Chem. Soc., 99, p. 7363Barany, G., Albericio, F., (1985) J. Am. Chem. Soc., 107, p. 4936Isidro-Llobet, A., Álvarez, M., Albericio, F., (2009) Chem. Rev., 109, p. 2455. , references cited thereinArrieta, A., Garcia, T., Palomo, C., (1982) Synth. Commun., 12, p. 1139Balasubramaniyan, V., Bhatia, V.G., Wagh, S.B., (1983) Tetrahedron, 39, p. 1475Widmer, U., (1983) Synthesis, p. 135Brook, M.A., Chan, T.H., (1996) Synthesis, p. 201Arai, I., Muramatsu, I., (1983) J. Org. Chem., 48, p. 121Koåodziejczyk, A.M., Slebjoda, M., (1984) Synthesis, p. 866Lalezari, I., Lalezari, P., (2014), U.S. Pat. Appl. PublSieber, P., (1977) Helv. Chim. Acta, 60, p. 2711Sieber, P., Andreatta, R.H., Eisler, K., Kamber, B., Riniker, B., Rink, H., (1977) Peptides, Proceedings of the 5th American Peptide Symposium, p. 543. , Goodman M. Meienhofer J. Wiley New YorkSchmidt, U., Zäh, M., Lieberknecht, A., (1991) J. Chem. Soc., Chem. Commun., p. 1002. , With DCCFécourt, F., Sapi, J., Bourguet, E., (2010) Synlett, p. 399. , With DICBoger, D.L., Yohannes, D., (1990) J. Org. Chem., 55, p. 6000Wang, T., Danishefsky, S.J., (2012) J. Am. Chem. Soc., 134, p. 13244Banala, S., Ensle, P., Süssmuth, R.D., (2013) Angew. Chem. Int. Ed., 52, p. 9518Schnabel, E., Klostermeyer, H., Berndt, H., (1971) Justus Liebigs Ann. Chem., 749, p. 90Akaji, K., Fujii, N., Yajima, H., (1985) Chem. Pharm. Bull., 33, p. 173Huffman, G.W., Gesellchen, P.D., Turner, J.R., Rothenberger, R.B., Osborne, H.E., Miller, F.D., Chapman, J.L., Queener, S.W., (1992) J. Med. Chem., 35, p. 1897Bachi, M.D., Breiman, R., (1980) J. Chem. Soc., Perkin Trans. 1, p. 11Pfizenmayer, A.J., Ramanjulu, J.M., Vera, M.D., Ding, X., Xiao, D., Chen, W.-C., Joullié, M.M., (1999) Tetrahedron, 55, p. 313See also ref. 12For one example of chemoselective OBn ether deprotection, see ref. 13Coste, J., Le-Nguyen, D., Castro, B., (1990) Tetrahedron Lett., 31, p. 205Frérot, E., Coste, J., Pantaloni, A., Dufour, M.-N., Jouin, P., (1991) Tetrahedron, 47, p. 259Campagne, J.-M., Coste, J., Jouin, P., (1993) Tetrahedron Lett., 34, p. 674

Clinical epidemiology: health information

Clinical epidemiology is the application of epidemiological methods and tools with a clinical purpose: to design health information. From the beginning, it has played a central role in the generation of evidence, its critical appraisal, the efficient storage and retrieval of data, in evidence-based medicine and evidence synthesis. The increase in the use of electronic medical records in veterinary medicine offers the opportunity to use a large volume of data and new technologies allow the data set management and processing. The objective of this work was to carry out a synthesis on the evolution of clinical epidemiology and its application in Veterinary Sciences. The application of Clinical Epidemiology is presented at the veterinary teaching hospital of the Facultad de Ciencias Veterinarias ? Universidad de Buenos Aires, where it began to transform the daily medical practice data into valid information. From the collection, classification and coding of the data present in the electronic medical records, several research lines emerged: to observe changes in the epidemiological patterns of companion animals? diseases, another line is about canine monocytic ehrlichiosis with the aim of advancing in the knowledge of clinical and diagnostic aspects. Among the prevalent diseases, Toxoplasma gondii and Neospora caninum through a case-control study. Another research line seeks to know which non-traditional animal species require medical attention and the most frequent diseases. Also, as an emergent situation, the antimicrobial use at the clinic. Knowledge advances and it must be incorporated into the profession efficiently. Clinical Epidemiology and informatics offer new possibilities within veterinary medicine and between veterinary medicine and human medicine and contributing to ?One Health? initiatives.Fil: López, C. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: López, C. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Loiza, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Loiza, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Sierra, M.F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Sierra, M.F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Cornero, F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Cornero, F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Safar, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Safar, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE).Buenos Aires, ArgentinaFil: Sanz, R. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Gallardo, M.D. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Suppo, J. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Suraniti, A. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaLa epidemiologia clínica es la aplicación de métodos y herramientas epidemiológicas con una finalidad clínica: diseñar información en salud. Desde sus inicios ha jugado un papel central en la generación de evidencia, su valoración crítica, el eficiente almacenamiento y recuperación de datos, en la medicina basada en evidencia y la síntesis de evidencia. El incremento en el uso de historias clínicas electrónicas en medicina veterinaria ofrece la oportunidad de utilizar un gran volumen de datos de pacientes y las nuevas tecnologías permiten la gestión y procesamiento del conjunto de datos. El objetivo del presente trabajo fue realizar una síntesis sobre la evolución de la epidemiología clínica y su aplicación en las Ciencias Veterinarias. Se presenta la aplicación de la epidemiología clínica en el Hospital Escuela de la Facultad de Ciencias Veterinarias de la Universidad de Buenos Aires donde se comenzó a transformar los datos que surgen de la práctica médica diaria en información válida. A partir de la recolección, clasificación y codificación de los datos presentes en las Historias Clínicas Electrónicas (HCE), surgieron diversas líneas de investigación: observar los cambios en los patrones epidemiológicos de las enfermedades de los animales de compañía, otra línea está dirigida a la ehrlichiosis monocítica canina con el objetivo de avanzar en el conocimiento de aspectos clínicos y de diagnóstico. Dentro de las enfermedades prevalentes, Toxoplasma gondii y Neospora caninum a través de un estudio de casos y controles. Otra línea de investigación busca conocer qué especies de animales no tradicionales requieren atención y las patologías más frecuentes. Como situación emergente, el uso de antimicrobianos en la clínica. El conocimiento avanza y debe ser incorporado a la profesión de manera eficiente. La epidemiologia clínica y la informática brindan nuevas posibilidades dentro de la medicina veterinaria y entre la medicina veterinaria y la medicina humana, aportando a las iniciativas de ?Una Salud?

Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition

Modifications at the bridgehead position of englerin A were made to explore the effects of variation at this site on the molecule for biological activity, as judged by the NCI 60 screen, in which englerin A is highly potent and selective for renal cancer cells. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 as well as for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A

Proactive management of extreme prematurity: disagreement between obstetricians and neonatologists

Objective: To verify, in extremely preterm infants, if disagreement between obstetricians and neonatologists regarding proactive management is associated with early death. Study Design: Prospective cohort of 484 infants with 23(0/7) to 26(6/7) weeks, without malformations, born from January 2006 to December 2009 in eight Brazilian hospitals. Pro-active management was defined as indication of >= 1 dose of antenatal steroid or cesarean section (obstetrician) and resuscitation at birth according to the international guidelines (neonatologist). Main outcome was neonatal death in the first 24 h of life. Result: Obstetricians and neonatologists disagreed in 115 (24%) patients: only neonatologists were proactive in 107 of them. Disagreement between professionals increased 2.39 times the chance of death in the first day (95% confidence interval 1.40 to 4.09), adjusted for center and maternal/neonatal clinical conditions. Conclusion: In infants with 23 to 26 weeks of gestation, disagreement between obstetricians and neonatologists, translated as lack of antenatal steroids and/or vaginal delivery, despite resuscitation procedures, increases the odds of death in the first day. Journal of Perinatology (2012) 32, 913-919; doi:10.1038/jp.2012.28; published online 29 March 20123212913919Ministry of Health of Brazil [MS/VIGISUS 1755/2000, MS/FNS 274, FIOCRUZ/PDTSP