Carboxylesterase catalyzed 18O-labeling of carboxylic acid and its potential application in LC-MS/MS based quantification of drug metabolites

LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel ¹⁸O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H₂¹⁸O in the presence of the enzyme, generating singly- and doubly-¹⁸O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

A Novel Nomogram to Identify Candidates for Extended Pelvic Lymph Node Dissection Among Patients with Clinically Localized Prostate Cancer Diagnosed with Magnetic Resonance Imaging-targeted and Systematic Biopsies

Background

Available models for predicting lymph node invasion (LNI) in prostate cancer (PCa) patients undergoing radical prostatectomy (RP) might not be applicable to men diagnosed via magnetic resonance imaging (MRI)-targeted biopsies.

Psychosocial mechanisms of a behavioral treatment for urinary incontinence of prostate cancer survivors

Abstract

Purpose: We examined underlying psychosocial processes of a behavioral treatment for urinary incontinence (UI) of prostate cancer survivors.

Design: Secondary analysis of data collected from a clinical trial.

Sample: Two hundred forty-four prostate cancer survivors who participated in a clinical trial of behavioral intervention to UI as intervention or control subjects.

Methods: The participants had a 3-month behavioral intervention or usual care and were followed up for an additional 3?months. They were assessed at baseline, 3, and 6?months. Latent growth curve models were performed to examine trajectories of each study variable and relationships among the variables.

Findings: Increasing self-efficacy and social support were significantly and independently associated with more reduction of urinary leakage frequency over time.

Implications for psychosocial oncology: Providing problem-solving skills and social support, including peer support, are essential for empowering patients to reduce UI.     

Clinical outcomes of bypass-first versus endovascular-first strategy in patients with chronic limb-threatening ischemia due to infrageniculate arterial disease

Background

Chronic limb-threatening ischemia (CLTI), defined as ischemic rest pain or tissue loss secondary to arterial insufficiency, is caused by multilevel arterial disease with frequent, severe infrageniculate disease. The rise in CLTI is in part the result of increasing worldwide prevalence of diabetes, renal insufficiency, and advanced aging of the population. The aim of this study was to compare a bypass-first with an endovascular-first revascularization strategy in patients with CLTI due to infrageniculate arterial disease.

Minimal-invasive Adrenalektomie beim Phäochromozytom

ZusammenfassungHintergrund Bedingt durch die intraoperative Katecholaminsekretion mit hämodynamischen Veränderungen, einem größeren Tumordurchmesser und einer deutlichen Neovaskularisation ist die Adrenalektomie beim Phäochromozytom im Vergleich zu anderen Nebennierenerkrankungen schwieriger und potenziell komplikationsträchtiger. Ziel unserer Studie war die Frage, ob das Risiko intraoperativer kardiovaskulärer Komplikationen durch das minimal-invasive Vorgehen potenziert wird.Patienten und Methodik Im Zeitraum zwischen Februar 1992 und Mai 2005 wurden in unserer Klinik 82 Eingriffe wegen eines Phäochromozytoms bei 71 Patienten durchgeführt. Davon wurden 8 (1) Patient(en) bi-(tri-)lateral adrenalektomiert und bei 2 Patienten erfolgte eine ipsilaterale Rezidivoperation. Eingeschlossen sind 5 weitere Patienten mit Rezidiv nach Erstoperation vor 1992. Sechsunddreißig Eingriffe erfolgten konventionell (transperitoneal n=35, retroperitoneal n=1) und 46 Operationen endoskopisch (transperitoneal n=28, retroperitoneal n=18), davon keine Konversion zum offenen Vorgehen.Ergebnisse Das mediane Alter zum Zeitpunkt der Operation betrug 45 (24–75) Jahre bei einer Anamnesedauer von 12 (0–180) Monaten. Die offen operierten Phäochromozytome waren mit 5,5 (1–19) cm vs. 3,5 (0,5–8) cm (endoskopisch) signifikant größer (p=0,0011). Patienten mit endoskopischer, insbesondere mit retroperitoneoskopischer Adrenalektomie hatten im Vergleich zum konventionellen Vorgehen intraoperativ höhere systolische und diastolische maximale Blutdruckwerte sowie Spitzen über 200 mmHg (statistisch nicht signifikant). Faktoren mit möglichem Einfluss auf intraoperative hämodynamische Veränderungen waren in der multivariaten Analyse das Geschlecht (p=0,0107), der operative Zugangsweg (p=0,0153), das Patientenalter (p=0,0364) und die Tumorgröße (p=0,0484). Die postoperative stationäre Verweildauer war nach endoskopischer Operation signifikant kürzer (p<0,0001).Schlussfolgerung Die endoskopische Adrenalektomie beim Phäochromozytom ist in der Routine ohne vermehrtes Risiko kardiovaskulärer Komplikationen die Methode der Wahl. Das offene Vorgehen sollte extraadrenalen Befunden oder sehr großen Tumoren mit Malignitätsverdacht vorbehalten bleiben.      

EQUAL FREQUENCY OF TEL/AML1 ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN WITH AND WITHOUT DOWN SYNDROME

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposing factor.     

肿胀法超声抽吸术治疗腋臭83例疗效观察

目的观察肿胀法超声抽吸术治疗液臭的效果,寻找一种治疗腋臭的新方法。方法在腋窝毛发区皮下注入肿胀液80~100ml,经5mm大小切口将超声探头在腋部皮下组织快速移动,直到皮肤发红发热为止,再用负压抽吸被乳化的皮下组织加压包扎。结果83例受术者,术后6~12个月随访,效果良好者76例(91.5%),有效5例(6.25%),无效2例(2.25%)。结论肿胀法超声抽吸术治疗腋臭,操作简单,不留瘢痕,安全有效,是目前治疗腋臭较为理想的方法。     

机械通气治疗小儿急性肺损伤

目的：探讨小儿急性肺损伤(ALI)的临床治疗。方法：对本院综合ICU1998年4月至2002年4月发生的22例小儿ALI的临床治疗情况进行回顾性分析。结果：本组22例小儿ALI采用呼吸末正压机械通气(PEEP)联合大剂量甲基强的松龙冲击治疗，有效率为86．36％；3例死亡，死亡率为13．64％，死于多器官功能不全综合征(MODS)。结论：机械通气治疗小儿ALI应选择最佳PEEP，动态监测动脉血气指标和X线胸片，在综合治疗基础上加用大剂量甲基强的松龙冲击治疗能收到较好的疗效。     

1例射频消融术后并发肺栓塞的抢救配合及护理

总结1例射频消融术后并发肺栓塞的抢救配合及护理体会，认为肺栓塞患者一旦发生晕厥，应立即行心肺复苏，以确保有效的循环和呼吸，尽早溶栓，改善临床症状。积极的抢救、熟练的配合、良好的护理是此患者康复的关键，同时术后早期生命体征的监测、并发症的预防、合理饮食、适当活动及休息对预防肺栓塞的发生也是很重要的。