Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.

Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. In bacteria, disulfide bonds are catalyzed by DsbA and DsbB/VKOR enzymes. First, DsbA, a periplasmic disulfide oxidoreductase, introduces disulfide bonds into substrate proteins. Then, the membrane enzyme, either DsbB or VKOR, regenerate DsbA's activity by the formation of de novo disulfide bonds which reduce quinone. We have previously performed a high-throughput chemical screen and identified a family of warfarin analogs that target either bacterial DsbB or VKOR. In this work, we expressed functional human VKORc1 in Escherichia coli and performed a structure-activity-relationship analysis to study drug selectivity between bacterial and mammalian enzymes. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants using bacteria. We also found one warfarin analog capable of inhibiting both bacterial DsbB and VKOR and a second one antagonized only the mammalian enzymes when expressed in E. coli. The difference in the warfarin structure suggests that substituents at positions three and six in the coumarin ring can provide selectivity between the bacterial and mammalian enzymes. Finally, we identified the two amino acid residues responsible for drug binding. One of these is also essential for de novo disulfide bond formation in both DsbB and VKOR enzymes. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.

Long-term Efficacy of Corticosteroid Injection for Carpal Tunnel Syndrome: A Systematic Review.

Carpal tunnel syndrome (CTS) is a debilitating condition that can cause significant morbidity. Corticosteroid injection (CI) is a popular treatment for CTS. Short-term benefits of CI for CTS have been reported, but there is little evidence on long-term outcomes. We performed a systematic review in the PubMed/MEDLINE and Cochrane Library databases to identify studies which reported outcomes of CI for CTS with at least 1-year follow-up. We identified 20 total studies and extracted data on outcomes such as number of patients needing eventual surgery or reinjection, complications, and functional scores. In included studies, 41.6% of patients underwent eventual carpal tunnel release surgery (CTRS), 29% underwent reinjection, there were no major and approximately 34/1133 (3.0%) minor complications, and median/mean time from CI to eventual CTRS ranged from 128 to 446 days. There was disparity on the long-term efficacy of CI for functional outcomes. The evidence indicates that CI is a very low risk procedure that has potential to improve symptoms enough to either prevent or, in most cases, delay the need for further reintervention. However, our conclusions are limited by the heterogeneity of available studies. There is a need for further, high-quality research on this topic.

Resultados de una cohorte de pacientes tratados con osteopatía en un hospital polivalente / Results of a cohort of patients treated with osteopathy in a polivalent hospital

Introducción: la osteopatía aborda al paciente de manera global y aplica técnicas de tratamiento manual. Se realizó una evaluación retrospectiva sobre 447 pacientes para conocer los resultados del tratamiento del dolor lumbar y cervical. Material y métodos: fueron incluidos en este estudio 447 pacientes con diagnóstico de lumbalgia y cervicalgia (77,4% de sexo femenino). Los pacientes atendidos ya habían realizado tratamientos convencionales sin haber conseguido resultados satisfactorios. Se evaluó a los pacientes con la escala de valor numérico de dolor (EVN), y los puntajes (scores) de Oswestry (ODI) y el índice de discapacidad de la región cervical (NDI). Los 4 osteópatas intervinientes son profesionales certificados en esta disciplina. Resultados: el 42,8% de los pacientes fueron derivados por el Servicio de Traumatología y el 41,3% por el Servicio de Medicina Familiar. El 34,2% tuvieron diagnóstico de dolor lumbar y al 20,81% se le diagnosticó dolor cervical. Tanto en la valoración del dolor como en los scores utilizados se encontraron diferencias estadísticamente significativas entre la primera y la última sesión. Discusión: en pacientes con diagnóstico de lumbalgia y cervicalgia que no habían obtenido resultados satisfactorios con tratamientos convencionales previos, el tratamiento osteopático derivó en mejoras significativas en todos los parámetros estudiados. (AU)

Introduction: osteopathy addresses the patient globally and applies manual treatment techniques. A retrospective evaluation was carried out on 447 patients to know the results of the treatment of lumbar and cervical pain. Material and methods: 447 patients with a diagnosis of low back pain and cervical pain (77.4% female) were included in this study. The patients already had undergone conventional treatments without having achieved satisfactory results. The patients were evaluated with the numerical value of pain scale (VNS), and Oswestry scores (ODI) and the index of disability of the cervical region (NDI). The 4 intervening osteopaths are certified professionals in this discipline. Results: 42.8% of the patients were referred by the Traumatology Service and 41.3% by the Family Medicine Service. 34.2% had a diagnosis of lumbar pain and 20.8% were diagnosed with neck pain. Statistically significant differences were found between the first and last sessions in both the pain assessment and the scores used. Discussion: in patients with low back pain and neck pain who had not obtained satisfactory results with previous conventional treatments, osteopathic treatment resulted in significant improvements in all the parameters evaluated. (AU)