RESUMEN
ABSTRACT: Selective motion blindness, also known as akinetopsia, is infrequently reported in the literature. Hence, little is known about the condition including its causes, time course, pathophysiology, and current diagnostic methods. In this investigation, we comprehensively surveyed the literature using a systematic review to identify each reported case of the condition. The purpose of this study was to provide an exhaustive catalog of every published occurrence to date to identify and discuss trends, commonalities, and differences among them. Our results revealed distinct characteristics for the various etiologies of this phenomenon in addition to a shared pathophysiologic pathway among them.
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Atrofia Óptica Hereditaria de Leber , Deficiencia de Vitamina B 12 , Humanos , Atrofia Óptica Hereditaria de Leber/diagnóstico , Atrofia Óptica Hereditaria de Leber/genética , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/diagnóstico , Deficiencia de Vitamina B 12/genética , Mutación , Mitocondrias/genética , ADN Mitocondrial/genéticaRESUMEN
Temozolomide (TMZ) is a newly approved alkylating agent for the treatment of malignant gliomas. To investigate resistance mechanisms in a multidrug therapeutic approach, a TMZ-resistant human glioma cell line, SF188/TR, was established by stepwise exposure of human SF188 parental cells to TMZ for approximately 6 months. SF188/TR showed 6-fold resistance to TMZ and cross-resistance to a broad spectrum of other anticancer agents that included 3-5-fold resistance to melphalan (MEL), gemcitabine (GEM), paclitaxel (PAC), methotrexate (MTX), and doxorubicin (DOX), and 1.6-2-fold resistance to cisplatin (CDDP) and topotecan (TPT). Alkylguanine alkyltransferase (AGT) activity was increased significantly in the resistant cell line compared with the parental cell line (P<0.05), whereas no significant differences occurred in the cellular uptake of TMZ and PAC between resistant and parental cells. Depletion of AGT by O(6)-benzylguanine significantly increased the cytotoxicity of TMZ in both the sensitive and resistant cell lines, but did not influence the cytotoxicity of the other drugs tested. Treatment with TMZ caused SF188 cells to accumulate in S phase, whereas SF188/TR cells were unaffected. Expression of Bcl-2 family members in SF188/TR cells compared with SF188 cells indicated that the pro-apoptotic proteins (i.e. Bad, Bax, Bcl-X(S)) were reduced 2-4-fold in the resistant cell line, whereas the anti-apoptotic proteins Bcl-2 and Bcl-X(L) were expressed at similar levels in both cell lines. In conclusion, the mechanism of resistance of SF188/TR cells to TMZ involved increased activity of AGT, a primary resistance mechanism, whereas the broad cross-resistance pattern to other anticancer drugs was due to a common secondary resistance mechanism related to alterations in the relative expression of the pro-apoptotic and anti-apoptotic proteins.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Enzimas Reparadoras del ADN , Dacarbazina/farmacología , Resistencia a Múltiples Medicamentos/fisiología , Glioma/patología , Guanina/análogos & derivados , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adenosina Trifosfatasas/biosíntesis , Antineoplásicos Fitogénicos/farmacología , Proteínas Portadoras , Ciclo Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Proteínas de Unión al ADN/biosíntesis , Dacarbazina/análogos & derivados , Doxorrubicina/farmacología , Interacciones Farmacológicas , Ensayos de Selección de Medicamentos Antitumorales , Guanina/farmacología , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteínas de Neoplasias/biosíntesis , Proteínas Nucleares , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Paclitaxel/farmacología , Fenotipo , Temozolomida , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
OBJECTIVES: To evaluate the effects of a collaborative pharmacy benefits manager (PBM)/ health plan-administered drug therapy management (DTM) program on healthcare utilization and costs in patients with diabetes treated with polypharmacy. STUDY DESIGN: Retrospective quasi-experimental design with comparison group. METHODS: This DTM program was a collaborative effort between the PBM, PerformRx, and the care management departments of Keystone First (KF) and AmeriHealth Caritas Pennsylvania (ACP) care management departments, targeting patients with diabetes using >15 medications. Pharmacists reviewed member profiles and made evidencebased prescriber and patient interventions, working directly with prescribers and indirectly with members, via care managers. Care managers provided additional services not otherwise within the scope of DTM. The study group consisted of 954 DTM participants reviewed by a pharmacist between November 1, 2010, and July 31, 2011. The control group consisted of 810 matched DTM participants not reviewed by a pharmacist. RESULTS: Intervention acceptance rates for KF and ACP were 33% and 26%, respectively. The study group demonstrated lower inpatient admissions and emergency department utilization rates, although only the KF study group inpatient admission rate achieved statistical significance (76.4%; P = .0002). The study groups realized statistically significant total cost savings (pharmacy + medical) compared with their corresponding control groups (47.8% KF, P = .0039; 50.7% ACP, P = .0497) despite non-statistically significant increases in pharmacy costs. CONCLUSIONS: A collaborative pharmacist-driven DTM program with a care manager-executed patient outreach component results in reduced hospital utilization and significant healthcare cost savings.