Citations

Background The 3-hour window for treating stroke with intravenous tissue plasminogen activator (t-PA) requires well-organized, integrated efforts by emergency physicians and stroke neurologists. Objective To evaluate attitudes and knowledge of emergency physicians about intravenous t-PA for acute ischemic stroke, particularly in primary stroke centers (PSCs) with stroke neurology teams. Methods A 15-question pilot Internet survey administered by the Arizona College of Emergency Physicians. Results Between March and August 2005, 100 emergency physicians responded: 71 in Arizona and 29 in Missouri. Forty-eight percent practiced at PSCs; 48% thought t-PA was effective, 20% did not, and 32% were uncertain. PSC or non-PSC location of practice did not influence endorsement (odds ratio, 0.96; 95% confidence interval, 0.27–1.64). Of those opposing t-PA, 87% cited risk of hemorrhage. Conclusions Most emergency physicians did not endorse t-PA. Improved collaboration between emergency physicians and stroke neurologists is needed.

Objective We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. Methods We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry–based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM. Results A large proportion of acinar cells gained CD133 expression during the 2-dimensional culture and showed down-regulation of acinar markers and up-regulation of ductal markers, assuming an ADM phenotype. In a serum-free culture condition, ADM induction was mainly dependent on transforming growth factor β (TGF-β) secreted from cultured ductal cells. Human acinar cells when cultured alone for a week in a serum-free condition do not undergo ADM. However, serum may contain other factors besides TGF-β to induce ADM in human acinar cells. In addition, we found that TGF-β cannot induce ADM of murine acinar cells. Conclusions Ductal cells are the major source of TGF-β that induces ADM in cultured human exocrine pancreatic tissues. This culture system might be a useful model to investigate the mechanism of ADM in human cells.

Study Objective The extended‐release ( ER ) form of venlafaxine is preferred because of improved patient adherence, but the immediate‐release (IR) form is frequently used after Roux‐en‐Y gastric bypass ( RYGB ) surgery because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB . Design Prospective nonblinded single‐dose pharmacokinetic study. Setting Clinical research unit at a large tertiary care medical practice. Patients Ten adult pre–bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls. Interventions Patients were administered one venlafaxine ER 75‐mg capsule at two visits—the first visit at least 1 week before undergoing RYGB and the second visit 3–4 months after RYGB . Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured. Measurements and Main Results Plasma levels of venlafaxine and its primary metabolite, O ‐desmethylvenlafaxine ( ODV ), were compared at baseline and 3–4 months after RYGB . The areas under the serum concentration–time curves from 0–24 hours ( AUC 0–24 ) for venlafaxine (mean ± SD 734 ± 602 vs 630 ± 553 ng·hr/ml, p=0.22) and ODV (mean ± SD 894 ± 899 vs 1083 ± 972 ng·hr/ml, p=0.07) were similar before and after RYGB . Using a bioequivalence approach, differences in pre‐ RYGB and post‐ RYGB values of AUC 0–24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV. Conclusion This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV , absorbed from a venlafaxine ER capsule or the time over which it is absorbed.

OBJECTIVEThe subspecialization of neurosurgical practice is an ongoing trend in modern neurosurgery. However, it remains unclear whether the degree of surgeon specialization is associated with improved patient outcomes. The authors hypothesized that a trend toward increased neurosurgeon specialization was associated with improved patient morbidity and mortality rates.METHODSThe Nationwide Inpatient Sample (NIS) was used (1998–2009). Patients were included in a spinal analysis cohort for instrumented spine surgery involving the cervical spine (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 81.31–81.33, 81.01–81.03, 84.61–84.62, and 84.66) or lumbar spine (codes 81.04–81.08, 81.34–81.38, 84.64–84.65, and 84.68). A cranial analysis cohort consisted of patients receiving a parenchymal excision or lobectomy operation (codes 01.53 and 01.59). Surgeon specialization was measured using unique surgeon identifiers in the NIS and defined as the proportion of a surgeon’s total practice dedicated to cranial or spinal cases.RESULTSA total of 46,029 and 231,875 patients were identified in the cranial and spinal analysis cohorts, respectively. On multivariate analysis in the cranial analysis cohort (after controlling for overall surgeon volume, patient demographic data/comorbidities, hospital characteristics, and admitting source), each percentage-point increase in a surgeon’s cranial specialization (that is, the proportion of cranial cases) was associated with a 0.0060 reduction in the log odds of patient mortality (95% CI 0.0034–0.0086) and a 0.0042 reduction in the log odds of morbidity (95% CI 0.0032–0.0052). This resulted in a 15% difference in the predicted probability of mortality for neurosurgeons at the 75th versus the 25th percentile of cranial specialization. In the spinal analysis cohort, each percentage-point increase in a surgeon’s spinal specialization was associated with a 0.0122 reduction in the log odds of mortality (95% CI 0.0074–0.0170) and a 0.0058 reduction in the log odds of morbidity (95% CI 0.0049–0.0067). This resulted in a 26.8% difference in the predicted probability of mortality for neurosurgeons at the 75th versus the 25th percentile of spinal specialization.CONCLUSIONSFor both spinal and cranial surgery patient cohorts derived from the NIS database, increased surgeon specialization was significantly and independently associated with improved mortality and morbidity rates, even after controlling for overall case volume.

Purpose This study compared orofacial strength between adults with dysarthria and neurologically normal (NN) matched controls. In addition, orofacial muscle weakness was examined for potential relationships to speech impairments in adults with dysarthria. Method Matched groups of 55 adults with dysarthria and 55 NN adults generated maximum pressure (P max ) against an air-filled bulb during lingual elevation, protrusion and lateralization, and buccodental and labial compressions. These orofacial strength measures were compared with speech intelligibility, perceptual ratings of speech, articulation rate, and fast syllable-repetition rate. Results The dysarthria group demonstrated significantly lower orofacial strength than the NN group on all tasks. Lingual strength correlated moderately and buccal strength correlated weakly with most ratings of speech deficits. Speech intelligibility was not sensitive to dysarthria severity. Individuals with severely reduced anterior lingual elevation P max (< 18 kPa) had normal to profoundly impaired sentence intelligibility (99%–6%) and moderately to severely impaired speech (26%–94% articulatory imprecision; 33%–94% overall severity). Conclusions Results support the presence of orofacial muscle weakness in adults with dysarthrias of varying etiologies but reinforce tenuous links between orofacial strength and speech production disorders. By examining individual data, preliminary evidence emerges to suggest that speech, but not necessarily intelligibility, is likely to be impaired when lingual weakness is severe.

Abstract Prostate cancer is the most frequently diagnosed male cancer. For prostate cancer that has progressed to an advanced or metastatic stage, androgen deprivation therapy (ADT) is the standard of care. ADT inhibits activity of the androgen receptor (AR), a master regulator transcription factor in normal and cancerous prostate cells. The major limitation of ADT is the development of castration-resistant prostate cancer (CRPC), which is almost invariably due to transcriptional re-activation of the AR. One mechanism of AR transcriptional re-activation is expression of AR-V7, a truncated, constitutively active AR variant (AR-V) arising from alternative AR pre-mRNA splicing. Noteworthy, AR-V7 is being developed as a predictive biomarker of primary resistance to androgen receptor (AR)-targeted therapies in CRPC. Multiple additional AR-V species are expressed in clinical CRPC, but the extent to which these may be co-expressed with AR-V7 or predict resistance is not known. Here we utilized long read sequencing to identify and quantify AR isoforms expressed in CRPC. To unambiguously characterize all AR isoforms, we prepared Iso-Seq™ libraries via 3’ rapid amplification of cDNA ends (RACE) with RNA isolated from prostate cancer cell lines and xenograft tissues using a forward primer anchored in AR exon 1. 3’RACE reactions were subjected to single molecule, real-time (SMRT®) long-read sequencing with a Pacific Biosciences RSII System. Our work identified AR-V9 as a truncated isoform that is frequently co-expressed with AR-V7 in CRPC. Mechanistically, our work re-annotated AR-V7 and AR-V9 mRNAs, showing these two species shared a common 3’ terminal exon containing separate splice acceptor sites. Taking into account this new information, novel siRNAs and antibodies which could distinguish between AR-V7 and AR-V9 were designed, validated and used to measure the relative expression of these two AR isoforms in CRPC cells with a view to determining the potential of AR-V9 as a predictive biomarker of primary resistance to AR-targeted therapies. Citation Format: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson A. Clark, Liguo Wang, Kevin Silverstein, Liewei Wang, Scott M. Dehm. SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2017-425