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Competing Interests: Competing interests: None declared.

Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9 . FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3 H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1-FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.

Objective: Decompressive craniectomy (DC) is the definitive neurosurgical treatment for managing refractory malignant cerebral edema and intracranial hypertension due to combat-related severe traumatic brain injury (TBI). To date, the long-term outcomes and sequelae of this procedure on host-country national (HCN) populations during Operation Iraqi Freedom (Iraq, 2003-2011), Operation Enduring Freedom (Afghanistan, 2001-2014), and Operation Freedom's Sentinel (Afghanistan, 2015-2021) have not been described, specifically the process and results of delayed custom synthetic cranioplasty. The Joint Trauma System's Clinical Practice Guidelines (JTS-CPG) for severe head injury counsels surgeons to discard the cranial osseous explant when treating coalition service members. Ongoing political and healthcare system instabilities often preclude opportunities for delayed cranioplasty by host-country assets. Various surgical options (such as hinge craniectomy) are inadequate in the setting of complicated cranial comminution from blast or missile injuries, severe cerebral edema, grossly contaminated wounds, complex polytrauma, and tissue devitalization. Delayed cranioplasty with a custom synthetic implant is a viable but logistically challenging alternative. In this retrospective review, the authors present the first patient series describing delayed custom synthetic cranioplasty in an HCN population performed during active military conflict., Methods: Patients were identified through the Joint Trauma System/Theater Medical Data Store, and subgroup analyses were performed to include mechanisms of injury, surgical complications, and clinical outcomes., Results: Twenty-five patients underwent DC between 2012 and 2020 to treat penetrating, blast, and high-energy closed head injuries per JTS-CPG criteria. The average time from injury to surgery was 1.4 days, although 6 patients received delayed care (3-6 days) due to protracted evacuation from local hospitals. Delayed care correlated with an increased rate of intracranial abscess and empyema. The average time to cranioplasty was 134 days due to a lack of robust mechanisms for patient follow-up, tracking, and access to NATO hospitals. HCN patients who recovered from DC demonstrated overall benefit from custom synthetic cranioplasty, although formal statistical analysis was impeded by a lack of long-term follow-up., Conclusions: This review demonstrates that cranioplasty with a custom synthetic implant is a safe and feasible treatment for vulnerable HCN patients who survive their index DC surgery. This unique paradigm of care highlights the capabilities of deployed neurosurgical healthcare teams working in partnership with the prosthetics laboratory at Walter Reed National Military Medical Center.

Background: The kickstand rod has been described for the treatment of severe coronal imbalance. We present a modified description that combines an asymmetric pedicle subtraction osteotomy (PSO) for correction of severe kyphoscoliosis., Objective: To describe the use of a temporary kickstand rod., Methods: Type 1 osteotomies were performed across the main and fractional curves. An asymmetric PSO was performed at the apex of the main curve, and a kickstand rod placed on the concavity anchored from the ilium to a temporary connector above the main curve. Distraction was applied across the kickstand rod because the PSO was closed on the convexity. A permanent rod was placed contralateral to the kickstand, followed by replacement of the kickstand with a permanent rod and bilateral accessory rods., Results: A 66-year-old man presented with kyphoscoliosis causing severe coronal and sagittal imbalance. He underwent L4-S1 anterior lumbar interbody fusion followed by T4-pelvis instrumented fusion the following day. Type 1 osteotomies were performed from T6-T12 to L3-S1 and an asymmetric PSO at L2. A temporary kickstand rod was used to distract across the concavity because the PSO was closed on the convexity. The patient achieved excellent clinical and radiographical results., Conclusion: When used in conjunction with appropriate osteotomies, the kickstand rod can aid in correction of severe coronal imbalance. Use of a temporary kickstand rod is technically easier and allows for correction of the main and fractional curves when used with an asymmetric PSO., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases., Competing Interests: Competing interest statement: A patent related to small molecule guanylyl cyclase A receptor enhancers has been filed by the Mayo Foundation for Medical Education and Research and Sanford Burnham Prebys Medical Discovery Institute, of which S.J.S., S. Peddibhotla, P.M.H., H.E.S., P.R.M., S.M., and J.C.B. are listed as inventors, and this technology has been licensed to AlloRock. A patent for the ex vivo human therapeutic potency assay has been also filed by the Mayo Foundation for Medical Education and Research, of which S.J.S., Y.Z., and J.C.B. are listed as inventors. This research is being conducted in compliance with Mayo Clinic conflict of interest policies.

Objective: Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are well-recognized complications of long-segment spinal fusion. Previous studies have suggested that ligament augmentation can decrease rates of PJF by reducing junctional stress and strengthening upper instrumented vertebrae (UIVs) and adjacent segments. However, there is a paucity of long-term data on the efficacy of ligament augmentation in preventing PJF. In this study, the authors sought to determine the effect of ligament augmentation on rates of PJF in a cohort of adult spinal deformity patients with at least 1 year of follow-up., Methods: They conducted a retrospective analysis of ligament augmentation in a consecutive series of surgical patients with adult spinal deformity. Data on patient demographics, surgical characteristics, and surgery for PJF were collected. The minimum follow-up was 12 months. Univariate and multivariate analyses were performed to identify factors associated with reoperation for PJF., Results: The authors identified a total of 242 patients (166 women [68.6%]) with ligament augmentation whose mean age was 66 years. The mean number of fused levels was 10, with a UIV distribution as follows: 90 upper thoracic UIVs (37.2%) and 152 lower thoracic UIVs (62.8%). Compared to a historical cohort of 77 patients treated before implementation of ligament augmentation, reoperation for PJF was significantly lower with ligament augmentation (15.6% vs 3.3%, p < 0.001). In a multivariate model, only ligament augmentation (OR 0.184, 95% CI 0.071-0.478, p = 0.001) and number of fused levels (OR 0.762, 95% CI 0.620-0.937, p = 0.010) were associated with reductions in reoperation for PJF., Conclusions: Ligament augmentation was associated with significant reductions in the rate of reoperation for PJF at 12 months in a cohort of adult spinal deformity patients. The most dramatic reduction was seen among patients with lower thoracic UIV. These data suggest that in appropriately selected patients, ligament augmentation may be a valuable adjunct for PJF reduction; however, long-term follow-up is needed.

NAD + is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD + have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD + is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD + salvage pathway. We previously showed that NAMPT activators increase NAD + levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The sitting or semisitting position in neurosurgery allows for several technical advantages, including improved visualization of the surgical field. However, it has also been associated with an increased risk of venous air embolisms and positioning-related complications that limit its commonplace adoption. The authors report a large, single-center series of cervical spine procedures performed with patients in the sitting or prone position in order to assess the perceived risk of intraoperative and postoperative complications associated with the sitting position., Methods: Noninstrumented, single-level posterior cervical spine procedures performed with patients in the sitting/semisitting or prone position from 2000 to 2016 at a single institution were reviewed. Institutional abstraction tools (DataMart and Chart Plus) were used to collect data from the medical records. The two positions were compared with regard to preoperative factors, intraoperative variables, and postoperative outcomes. Multivariable logistic regression models were fitted for 30-day readmission, 30-day return to the operating room, and complication rates., Results: A total of 750 patients (sitting, n = 480; prone, n = 270) were analyzed. The median age was 53 years for those who underwent surgery in the prone position and 50 years for those who underwent surgery in the sitting position (IQRs 45-62 years and 43-60 years, respectively), and 35% of the patients were female. Sitting cases were associated with significantly longer anesthetic times (221 minutes [range 199-252 minutes] vs 205 minutes [range 179-254 minutes]) and operative times (126 minutes [range 101-163 minutes] vs 149 minutes [120-181 minutes]). Cardiorespiratory events in the postanesthesia care unit (PACU) were comparable between the two groups, with the exception of episodes of apnea (2.6% vs 0.6%, p = 0.041) and hypoventilation (4.4% vs 0.8%, p < 0.003), which were more frequent in the prone-position cohort. On multivariable analysis, the effect of the sitting versus the prone position was not significant for 30-day readmission (OR 0.77, 95% CI 0.34-1.71, p = 0.52) or reoperation (OR 0.71, 95% CI 0.31-1.60, p = 0.40). The sitting position was associated with lower odds of developing any complication (OR 0.31, 95% CI 0.16-0.62, p < 0.001)., Conclusions: Based on the intraoperative and postoperative complications chosen in this study, the sitting position confers a similar safety profile to the prone position. This can be explained by a more anatomic positioning accounting for reduced temporary neurological deficits and reduced PACU-associated hypoventilation noted in this series. Nevertheless, the findings may also reflect institutional familiarity, experience, and mastery of this position type, and outcomes may not reflect practices in general.

The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC 50  = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Autograft harvesting for spine arthrodesis has been associated with longer operative times and increased blood loss. Allograft compared to autograft in spinal fusions has not been studied in a multicenter cohort., Methods: Patients enrolled in the ACS-NSQIP registry between 2012 and 2013 who underwent cervical or lumbar spinal fusion with either allograft or autograft through a separate incision were included for analysis. The primary outcomes of interest were operative time, length of stay, blood transfusion, and surgical site infection (SSI)., Results: A total of 6790 and 6718 patients received a cervical or lumbar spinal fusion, respectively. On unadjusted analysis in both cervical and lumbar cohorts, autograft was associated with increased rates of blood transfusion (cervical: 2.9% vs. 1.0%, P<0.001; and lumbar: 21.0% vs. 15.7%, P<0.001) and increased operative time (cervical: 167 vs. 128 minutes, P<0.001; and lumbar: 226 vs. 204 minutes, P<0.001) relative to allograft. On multivariable analysis in both the cervical and lumbar cohorts, autograft was associated with increased odds of blood transfusion (cervical: OR=2.3, 95% CI: 1.0-5.1; and lumbar: OR=1.3, 95% CI: 1.1-1.6) and longer operative times (cervical: 27.8 minutes, 95% CI: 20.7-35.0; and lumbar: 25.4 minutes, 95% CI: 17.7-33.1) relative to allograft. Autograft was not associated with either length of stay or SSI., Conclusions: In a multicenter cohort of patients undergoing cervical or lumbar spinal fusion, autograft was associated with increased rates of blood transfusion and increased operative time relative to allograft.

We report a case of a middle-aged woman with a diffuse, nonenhancing, progressively atrophic T2-hyperintense lesion involving the left frontotemporal lobes and insula found to be synchronous high-grade sinonasal neuroendocrine carcinoma (SNEC) after initial endonasal resection. In 2014, a 47-year old woman underwent resection of a left-sided high-grade ethmoidal neuroendocrine carcinoma after presentation with weight gain and increased levels of serum and urine cortisol. Concurrent with the initial presentation, she was noted to have a nonenhancing, hyperintense signal change on T2-weighted images on the left frontotemporal lobes and insula thought to be paraneoplastic. Moreover, low titer antibodies to voltage-gated potassium channels were present, raising concern for limbic encephalitis. However, the patient was asymptomatic. A little more than a year after initial presentation, she noted excessive fatigue, daytime somnolence, and cognitive decline. Imaging revealed a gradually progressive, nonenhancing, T2-hyperintense signal abnormality with progressive atrophy in the left anteroinferior frontal lobe, anteromedial temporal lobe, insula bilateral cingulate gyri, and bilateral thalami. Given the progressive nature of the abnormality, stereotactic biopsy was performed, which confirmed the lesion to be metastatic, infiltrative SNEC. In summary, this is a rare case of a synchronous presentation of a high-grade SNEC with an unusual appearance that diffusely infiltrated the brain, likely directly involving the left olfactory nerve and spreading along olfactory projections. This case draws physicians' attention to the possibility that although paraneoplastic syndromes are most likely benign, dissemination of the primary cancer is a diagnostic possibility.

Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic., Competing Interests: A patent covering the use of the compounds for pathological angiogenesis was submitted to the USPTO (“4-aminoquinoline compounds for the treatment of angiogenesis”; filed March 6, 2018; application number 62/639,291). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Plasmacytomas, considered to be the solitary counterparts of multiple myeloma, are neoplastic monoclonal plasma cell proliferations within soft tissue or bone. Plasmacytomas often present as a collection of findings known as POEMS-syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-Protein spike, and Skin changes)., Case Description: We present a report of a 47 yo male diagnosed with POEMS-syndrome secondary to a skull base plasmacytoma. The mass resulted in marked instability of the cranio-cervical junction due to bony erosion. Following an induction course of chemotherapy, he showed clinical improvement with a marked reduction in tumor size and underwent an autologous peripheral blood stem cell transplant for systemic treatment of his POEMS-syndrome. Following completion of systemic treatment, he then underwent a definitive occipital-cervical fusion without complications. His neurologic exam upon dismissal was stable with subjective improvement in left upper extremity strength. Postoperative radiographs confirmed spinal alignment and pathological examination of a small biopsy from C1 revealed benign fibrous tissue., Conclusion: To the best of our knowledge, this is the first report of a skull-base plasmacytoma associated with POEMS-syndrome, causing cranio-cervical instability. The approach of systemic therapy combined with temporary external fixation, followed by definitive occipital cervical fusion resulted in a good outcome for this patient., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

OBJECTIVE The mechanism by which greater institutional case volume translates into improved outcomes after surgical clipping of unruptured intracranial aneurysms (UIAs) is not well established. The authors thus aimed to assess the effect of case volume on the rate of various types of complications after clipping of UIAs. METHODS Using information on the outcomes of inpatient admissions for surgical clipping of UIAs collected within a national database, the relationship of institutional case volume to the incidence of different types of complications after clipping was investigated. Complications were subdivided into different categories, which included all complications, ischemic stroke, intracerebral hemorrhage, medical complications, infectious complications, complications related to anesthesia, and wound complications. The relationship of case volume to different types of complications was assessed using linear regression analysis. The relationships between case volume and overall complication and stroke rates were fit with both linear and quadratic equations. The numerical cutoff for institutional case volume above and below which the authors found the greatest differences in mean overall complication and stroke rate was determined using classification and regression tree (CART) analysis. RESULTS Between October 2012 and September 2015, 125 health care institutions reported patient outcomes from a total of 6040 cases of clipping of UIAs. On linear regression analysis, increasing case volume was negatively correlated to both overall complications (r 2 = 0.046, p = 0.0234) and stroke (r 2 = 0.029, p = 0.0557) rate, although the relationship of case volume to the complication (r 2 = 0.092) and stroke (r 2 = 0.067) rate was better fit with a quadratic equation. On CART analysis, the cutoff for the case number that yielded the greatest difference in overall complications and stroke rate between higher- or lower-volume centers was 6 cases/year and 3 cases/year, respectively. CONCLUSIONS Although the authors confirm that increasing case volume is associated with reduced complications after clipping of UIAs, their results suggest that the relationship between case volume and complications is not necessarily linear. Moreover, these results indicate that the effect of case volume on outcome is most evident between very-low-volume centers relative to centers with a medium-to-high volume.

Background: Patients recovering from decompressive laminectomy without fusion may require assistance with activities of daily living and physical/occupational therapy upon hospital discharge., Objective: To examine comorbidities and perioperative characteristics of patients undergoing lumbar decompression for associations with discharge status using a multicenter database., Methods: A multicenter database was used for this retrospective cohort analysis. Patients admitted from home with degenerative spine disease for lumbar decompression without fusion were included. Thirty-day outcomes and operative characteristics were compared as a function of patient discharge using chi-square and Wilcoxon Rank Sum tests. Multivariable logistic regression was used to determine factors associated with discharge to a nonhome facility., Results: Of the 8627 patients included for analysis, 9.7% were discharged to a nonhome facility. On multivariable analysis, age (85+ vs <65, odds ratio [OR] 13.59), number of levels of decompression (3+ vs 1, OR 1.75), African American race vs Non-Hispanic or Hispanic White (OR 1.87), female vs male gender (OR 1.97), body mass index (BMI) (40+ vs 18.5-24.9, OR 1.74), American Society of Anesthesiologists physical classification status (4 vs 1 or 2, OR 2.35), hypertension (OR 1.29), dependent functional status (OR 3.92), diabetes (OR 1.47), smoking (OR 1.40), hematocrit (<35 vs 35+, OR 1.76), international normalized ratio (≥1.3 vs <1.3, OR 2.32), and operative time (3+ h vs <1 h, OR 5.34) were significantly associated with an increased odds of discharge to nonhome facilities., Conclusion: Preoperative status and operative course variables can influence discharge disposition in lumbar decompression patients. Identifying specific factors that contribute to a greater likelihood of dismissal to skilled facility or rehabilitation unit can further inform both surgeons and patients during preoperative counseling and disposition planning., (Copyright © 2017 by the Congress of Neurological Surgeons)

Background: This study retrospectively analyzed outcomes for patients undergoing gamma knife radiosurgery (GKR) for uveal melanoma (UM) and intraocular metastases., Methods: Patients who underwent GKR for UM or intraocular metastases between 1/1/1990 and 6/1/2015 at Mayo Clinic, Rochester, MN, USA, were retrospectively analyzed., Results: Eleven patients (11 eyes) had UM while seven patients (7 eyes) had intraocular metastases. Patients with UM were followed for a median of 19.74 ± 10.4 months. Visual acuity (VA) logMAR 0.30 ± 0.53 (Snellen 20/40) versus 0.40 ± 0.97 (Snellen 20/50), tumor thickness (5.30 ± 2.17 vs. 3.60 ± 2.32 mm), were not significantly different between preoperative and postoperative measurements, respectively. Nine percent (1/11) patients required enucleation. Subsequently, no patients experienced metastases. Patients with intraocular metastases were followed for a median of 6.03 ± 6.32 months. They did not have significant changes in VA (logMAR 0.30 ± 0.59 vs. 0.30 ± 1.57; Snellen 20/40 vs. 20/40) or tumor thickness (3.50 ± 1.36 vs. 1.30 ± 0.76 mm) postoperatively. Fourteen percent (1/7 patients) required enucleation. Complications experienced by patients with UM include radiation retinopathy (2/11), papillopathy (1/11), cystoid macular edema (1/11), vitreomacular traction (1/11), exudative retinal detachment (1/11). Patients with metastases had treatment complicated by recurrence (2/7). Dose to the margin, maximum dose of radiation, and clinical target volume did not correlate with post-procedural VA, risk of enucleation, or death in patients with either UM or patients with intraocular metastases., Conclusions: Visual outcomes were satisfactory for patients undergoing GKR without significant morbidity and without significant risk of enucleation or metastases.

OBJECTIVE With improving medical therapies for chronic conditions, elderly patients increasingly present as candidates for operative intervention for degenerative diseases of the spine. To date, there is a paucity of studies examining complications in lumbar decompression, without fusion, that include patients older than 80 years. Using a multicenter national database, the authors of this study evaluated lumbar decompression in the elderly, including octogenarians, to evaluate for associations between age and patient outcomes. METHODS The 2011-2013 American College of Surgeons' National Surgical Quality Improvement Program data set was queried for patients 65 years and older with diagnosis and procedure codes inclusive of degenerative spine disease and lumbar decompression without fusion. Morbidity and mortality within the 30-day postoperative period were the primary outcomes. Secondary outcomes of interest included unplanned readmission within 30 days or discharge to a nonhome facility. Outcomes and operative characteristics were compared using chi-square tests, Kruskal-Wallis tests, and multivariable logistic regression models. RESULTS A total of 8744 patients were identified; of these patients 4573 (52.30%) were 65 years and older. Elderly patients were stratified into 3 age categories: 85 years or older (n = 314), 75-84 years (n = 1663), and 65-74 years (n = 2596). Univariate analysis showed that, compared with age younger than 65 years, increased age was associated with the number of levels (≥ 3), readmissions within 30 days, nonhome discharge, any complication, length of stay, and blood transfusion (all p < 0.001). On multivariable analysis and with younger than 65 years as the reference, increased age was associated with any minor complication (p < 0.001; ≥ 85 years: OR 3.47, 95% CI 1.69-7.13; 75-84 years: OR 2.34, 95% CI 1.45-3.78; and 65-74 years: OR 1.44, 95% CI 0.94-2.20), as well as discharge location other than home (p < 0.001; ≥ 85 years: OR 13.59, 95% CI 9.47-19.49; 75-84 years: OR 5.64, 95% CI 4.33-7.34; and 65-74 years: OR 2.61, 95% CI 2.05-3.32). CONCLUSIONS The authors' high-powered, multicenter analysis of lumbar decompression without fusion in the elderly, specifically including patients older than 80 years, demonstrates that increased age is associated with more extensive operations, resulting in longer hospital stays, increased rates of nonhome discharge, and minor complications.

Objectives: The purpose of this study was to systematically compare the effectiveness and safety of full-endoscopic discectomy (FED) and micro-endoscopic discectomy (MED) with open discectomy (OD) for the treatment of symptomatic lumbar disc herniation., Methods: Electronic searches were performed using six databases from their inception to February 2016, identifying all relevant randomized controlled trials and comparative observational studies comparing either FED or MED with OD. Data were extracted and analyzed according to predefined clinical endpoints., Results: Twenty three studies were selected for analysis, including 421 FED, 6914 MED, and 21,152 OD cases. No significant difference was found between FED and OD in regards to postoperative visual analog scale (VAS) leg pain scores (WMD 0.03, P=0.93). Similar results were obtained for MED vs OD (WMD 0.09, P=0.18). In terms of postoperative Oswestry disability index (ODI), both FED and MED were similar to OD (WMD -2.60, P=0.32 and WMD -1.00, P=0.21, respectively). FED had a significantly shorter operative duration compared to OD (54.6 vs 102.6min, P=0.0001). MED alone and endoscopic approaches overall (including MED and FED) demonstrated significantly lower estimated blood loss (44.3 vs 194.4mL, P=0.03 and 38.2 vs 203.5mL, respectively, both p<0.05). FED alone demonstrated a trend towards lower estimated blood loss in comparison to OD (3.3 vs 244.9mL, P=0.07). No difference was found in overall complications, recurrence or reoperation rates, dural tears, root injury, wound infections, and spondylodiscitis between FED vs OD, or MED vs OD., Conclusions: Based on this meta-analysis, FED and MED appear to be safe and efficacious alternatives to traditional approaches, but these results require further investigation and validation by prospective randomized studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Split cord malformation (SCM) is a rare abnormality of notochord development. The majority of cases occur in the thoracolumbar region, with more than 30 cases of cervical SCM reported. The clinical impact of SCMs involving the cervical cord is therefore largely unknown. In addition, the concomitant finding of brainstem involvement is presumably incompatible with life in the majority of patients, resulting in a paucity of data regarding this clinical scenario. In this paper the authors present the first case, to their knowledge, of an incomplete cervical SCM involving the brainstem and discuss its clinical impact, diagnosis, and management.

Objective: This study moves beyond previous cohort studies and benchmark data by studying a population of elective spine surgery from a multicenter registry in an effort to validate, disprove, and/or identify novel risk factors for dural tears., Methods: A retrospective cohort analysis queried a multicenter registry for patients with degenerative spinal diagnoses undergoing elective spinal surgery from 2010-2014. Multivariable logistic regression analysis interrogated for independent risk factors of dural tears., Results: Of 104,930 patients, a dural tear requiring repair occurred in 0.6% of cases. On adjusted analysis, the following factors were independently associated with increased likelihood of a dural tear: ankylosing spondylitis vs. intervertebral disc disorders, greater than two levels, combined surgical approach and posterior approach vs. anterior approach, decompression only vs. fusion and decompression, age groups 85+, 75-84 and 65-74 vs. <65, obesity (BMI ≥30), corticosteroid use and preoperative platelet count <150,000., Conclusions: This multicenter study identifies novel risk factors for dural tears in the elective spine surgery population, including corticosteroids, thrombocytopenia, and ankylosing spondylitis. The results of this analysis provide further information for surgeons to use both in operative planning and in preoperative counseling when discussing the risk of dural tears.

Background: Diabetes mellitus (DM) is a known risk factor for post-surgical complications. However, few reports specifically study lumbar spine surgical outcomes in diabetics. The purpose of this study was to assess 30-day outcomes in patients with DM undergoing single-level open lumbar microdiscectomy (oLMD)., Methods: A retrospective case control study on patients with DM undergoing between 2001 and 2012. Patients who underwent a minimally invasive approach, repeat discectomy, or multilevel surgery were excluded. One hundred and twenty-six patients were age-matched with 126 non-diabetic controls. Outcomes assessed included length of stay (LOS), postoperative urinary retention (UR), total morbidity, infection, postoperative radiculitis, 30-day re-admissions and emergency department visits, and pain status at discharge and at 30 days. Categorical variables were evaluated with Pearson's χ2 tests. Student's t-tests were used to evaluate continuous variables. Univariate logistic regression was used to evaluate strength of association of DM with outcome variables., Results: Mean LOS was significantly higher in diabetic patients (1.9 vs. 1.4 days, P<0.0001). DM was associated with increased morbidity (P=0.009, OR=3.3, CI: 1.3-9.5) and UR (P<0.0001, OR=8.2, CI: 3.4-24.8). No differences were found in 30-day readmission rates or emergency department visits, pain status at discharge and at 30 days, or postoperative radiculitis., Conclusions: Overall, short-term outcomes are worse in patients with DM. Following single-level oLMD, DM is associated with longer hospital stays, UR, and increased morbidity. These short term outcomes consequently lead to an overall increase in hospital costs.

The aim of this study was to test the hypothesis that diabetes mellitus (DM) is associated with an increased prevalence of chronic low back pain (CLBP) in the general population. We analyzed data for 5106 adults (4591 without DM & 515 with diagnosed DM), who were part of the National Health and Nutrition Examination Survey (NHANES) from 2009 through 2010. Adults with DM were older (mean age 54.2years' vs. 42.1years), more likely to be obese (BMI>30, 69.5% vs. 33.3%), less educated (college or above 44.4% vs. 57.3%), had a lower annual income (<$20,000, 16.8% vs. 13.4%), were more likely to be a former smoker (31.5% vs. 20.9%), less physically active (43.5% vs. 59.4%). The prevalence of CLBP was 19.8% in adults with DM vs. 12.9% in adults without DM (age-adjusted OR 1.46; 95% CI, 1.00-1.94, P=.050). After the adjustments for CLBP's known risk factors, the association remained significant (OR 1.39; 95% CI, 1.02-1.92, P=.041). Adults with DM have a higher prevalence of CLBP. Further research is needed to examine the association and pathophysiology of DM and CLBP as well as the role of shared risk factors., Summary: Adults with diabetes have higher prevalence of chronic low back pain (CLBP), and higher odds of CLBP after adjusting for LBP risk factors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Large-scale studies examining the incidence and predictors of perioperative complications after surgical clipping of unruptured intracranial aneurysms (UIA) using nationally representative prospectively collected data are lacking in the literature., Methods: Using the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) dataset, we conducted a retrospective analysis of the complications experienced by patients that underwent surgical management of a UIA between the years of 2007 and 2013. The primary outcomes of interest were mortality within the 30-day perioperative period and adverse discharge disposition to a location other than home. Predictors of morbidity and mortality were elucidated using multivariable logistic regression analyses controlling for available patient demographic, comorbidity, and operative characteristics., Results: 662 patients were identified in the ACS-NSQIP dataset for operative management of an unruptured aneurysm. The observed rates of 30-day mortality and adverse discharge disposition were 2.27% and 19.47%, respectively. A hundred and eight (16.31%) patients developed at least one major complication. On multivariable analysis, death within 30days was significantly associated with increased operative time (OR 1.005 per minute, 95% CI 1.002-1.008) and chronic preoperative corticosteroid use (OR 28.4, 95% CI 1.68-480.42), whereas major complication development was associated with increased operative time (OR 1.004 per minute, 95% CI 1.002-1.006), age (OR 1.017 per year, 95% CI 1-1.034), preoperative dependency (OR 3.3, 95% CI 1.16-9.40) and diabetes mellitus (OR 2.89, 95% CI 1.45-5.75). Lastly, increasing age (OR 1.017 per year, 95% CI 1-1.034) as well as ASA Class 3 (OR 1.73, 95% CI 1.08-2.77) and 4 (OR 2.28, 95% CI 1.1-4.72) were independent predictors of discharge to a location other than home., Conclusion: Our study yields morbidity and mortality benchmarks for UIA surgery in a representative, national surgical registry. It will hopefully aid in recognizing those patients at greater risk for postoperative complications following surgical management, leading to appropriate changes in treatment strategies for this selected group of patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Obesity has been associated with increased risk for postoperative CSF leak in patients with benign cranial nerve tumors. Other measures of postoperative morbidity associated with obesity have not been well characterized., Methods: Patients enrolled in the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) from 2007 to 2013 with a diagnosis code of a benign neoplasm of a cranial nerve were included. The primary outcome of postoperative morbidity was analyzed as well as secondary outcomes of readmission and reoperation. The main covariate of interest was body mass index (BMI)., Results: A total of 561 patients underwent surgery for a benign cranial nerve neoplasm between 2007 and 2013. Readmission data, available for 2012-2013(n=353), revealed hydrocephalus, facial nerve injury, or CSF leak requiring readmission or reoperation occurred in 0.85%, 1.42%, and 3.12%, respectively. Composite morbidity included wound complications, infection, respiratory insufficiency, transfusion requirement, stroke, venous thromboembolism, coma and cardiac arrest. On multivariable analysis patients with class I (BMI 30-34.9) and II (BMI 35-39.9) obesity showed trends towards increasing return to operating room, though not significant, but there was no trend for composite complications in class I and II obesity patients. However, class III obesity, BMI≥40, was associated with increased odds of composite morbidity (OR 4.40, 95% CI 1.24-15.88) and return to the operating room (OR 5.97, 95% CI 1.20-29.6) relative to patients with a normal BMI, 18.5-25., Conclusions: Obesity is an independent and important risk factor for composite morbidity in resection of benign cranial nerve neoplasms, and as such, merits discussion during preoperative counseling., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Study Design: Retrospective study., Objective: This study reviews 1,768 consecutive cervical decompressions with or without instrumented fusion to identify patient-specific and procedural risk factors significantly correlated with the development of delayed cervical palsy (DCP)., Methods: Baseline demographic and procedural information was collected from the electronic medical record. Particular attention was devoted to reviewing each chart for recognized risk factors of postsurgical inflammatory neuropathy: autoimmune disease, blood transfusions, diabetes, and smoking., Results: Of 1,669 patients, 56 (3.4%) developed a DCP. Although 71% of the palsies involved C5, 55% of palsies were multimyotomal and 18% were bilateral. Significant risk factors on univariate analysis included age (p = 0.0061, odds ratio [OR] = 1.07, 95% confidence interval [CI] 1.008 to 1.050), posterior instrumented fusion (p < 0.0001, OR = 3.30, 95% CI 1.920 to 5.653), prone versus semisitting/sitting position (p = 0.0036, OR = 3.58, 95% CI 1.451 to 11.881), number of operative levels (p < 0.0001, OR = 1.42, 95% CI 1.247 to 1.605), intraoperative transfusions (p = 0.0231, OR = 2.57, 95% CI 1.152 to 5.132), and nonspecific autoimmune disease (p = 0.0107, OR = 3.83, 95% CI 1.418 to 8.730). On multivariate analysis, number of operative levels (p = 0.0053, OR = 1.27, 95% CI 1.075 to 1.496) and nonspecific autoimmune disease (p = 0.0416, OR 2.95, 95% CI 1.047 to 7.092) remained significant., Conclusions: Although this study partially supports a mechanical etiology in the pathogenesis of a DCP, we also describe a notable correlation with autoimmune risk factors. Bilateral and multimyotomal involvement provides additional support that some DCPs may result from an inflammatory response and thus an underlying multifactorial etiology for this complication.

Acute liver failure (ALF) has been associated with cerebral edema and elevated intracranial pressure (ICP), which may be managed utilizing an ICP monitor. The most feared complication of placement is catastrophic intracranial hemorrhage in the setting of severe coagulopathy. Previous studies reported hemorrhage rates between 3.8-22 % among various devices, with epidural catheters having lower hemorrhage rates and precision relative to subdural bolts and intraparenchymal catheters. We sought to identify institutional hemorrhagic rates of ICP monitoring in ALF and its associated factors in a modern series guided by protocol implantation. Patient records treated for ALF with ICP monitoring at Mayo Clinic in Rochester, MN from 1995 to 2014 were reviewed. Protocalized since 1995, epidural (EP) ICP monitors were first used followed by intraparenchymal (IP) for stage III-IV hepatic encephalopathy. The following variables and outcomes were collected: patient demographics, ICPs and treatment methods, laboratory data, imaging studies, number of days for ICP monitoring, radiographic and symptomatic hemorrhage rates, orthotopic liver transplantation rates, and death. A total of 20 ICP monitors were placed for ALF, 7 EP, and 13 IP. International normalized ratio (INR) at placement of an EP monitor was 2.4 (1.7-3.2) with maximum of 2.7 (2.0-3.6) over the following 2.3 (1-3) days. Mean EP ICP at placement was 36.3 (11-55) and maximum of 43.1 (20-70) mm Hg. INR at placement of an IP monitor was 1.3 (<0.8-3.0) with maximum value of 2.9 (1.6-5.4) over the following 4.2 (2-6) days. Mean IP ICP at placement was 9.9 (2-19) and maximum was 39.8 (11-100) mm Hg. There was one asymptomatic hemorrhage in the EP group (14.3 % hemorrhage rate) and two hemorrhages in the IP group (hemorrhage rate was 15.4 %), both of which were fatal. Overall mortality rate in the EP group was 71.4 % (5/7) with two patients receiving transplantation, and one death in the transplant group. Overall mortality in the IP group was 38.5 % (5/13) with nine liver transplantations; three of the transplanted patients died, including one of the fatal hemorrhages due to monitor placement. Intracranial hypertension is common in patients with ALF with severe hepatic encephalopathy. Monitored patients in both groups experienced elevations of ICP in the setting of intermittent coagulopathy. Severity of coagulopathy did not influence hemorrhage rate. Yet, hemorrhages related to IP monitoring can be catastrophic and may add to the overall mortality.

Pharmacological treatment for methamphetamine addiction will provide important societal benefits. Neurotensin receptor NTR1 and dopamine receptor distributions coincide in brain areas regulating methamphetamine-associated reward, and neurotensin peptides produce behaviors opposing psychostimulants. Therefore, undesirable methamphetamine-associated activities should be treatable with druggable NTR1 agonists, but no such FDA-approved therapeutics exist. We address this limitation with proof-of-concept data for ML314, a small-molecule, brain penetrant, β-arrestin biased, NTR1 agonist. ML314 attenuates amphetamine-like hyperlocomotion in dopamine transporter knockout mice, and in C57BL/6J mice it attenuates methamphetamine-induced hyperlocomotion, potentiates the psychostimulant inhibitory effects of a ghrelin antagonist, and reduces methamphetamine-associated conditioned place preference. In rats, ML314 blocks methamphetamine self-administration. ML314 acts as an allosteric enhancer of endogenous neurotensin, unmasking stoichiometric numbers of hidden NTR1 binding sites in transfected-cell membranes or mouse striatal membranes, while additionally supporting NTR1 endocytosis in cells in the absence of NT peptide. These results indicate ML314 is a viable, preclinical lead for methamphetamine abuse treatment and support an allosteric model of G protein-coupled receptor signaling.

Vesicular stomatitis virus (VSV) shows promise as a vaccine-vector and oncolytic virus. However, reports of neurotoxicity of VSV remain a concern. We compared 12 antiviral compounds to control infection of VSV-CT9-M51 and VSV-rp30 using murine and human brain cultures, and in vivo mouse models. Inhibition of replication, cytotoxicity and infectivity was strongest with ribavirin and IFN-α and to some extent with mycophenolic acid, chloroquine, and adenine 9-β-d-arabinofuranoside. To generate continuous IFN exposure, we made an adeno-associated virus vector expressing murine IFN; AAV-mIFN-β protected mouse brain cells from VSV, as did a combination of IFN, ribavirin and chloroquine. Intracranial AAV-mIFN-β protected the brain against VSV-CT9-M51. In SCID mice bearing human glioblastoma, AAV-mIFN-β moderately enhanced survival. VSV-CT9-M51 doubled median survival when administered after AAV-mIFN-β; some surviving mice showed complete tumor destruction. Together, these data suggest that AAV-IFN or IFN with ribavirin and chloroquine provide an optimal anti-virus combination against VSV in the brain., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Strokelike migraine attack after radiation therapy is a recently described clinical entity characterized by transient hemispheric dysfunction manifesting as, but not limited to, visuospatial deficits, confusion, hemisensory deficits, hemiparesis, aphasia, seizures, and, most prominently, headache in patients with a history of remote external beam radiation therapy to the brain. The radiographic hallmark on magnetic resonance imaging is the presence of transient, diffuse, unilateral gadolinium enhancement of the cortex with white matter sparing, usually corresponding to the previous radiation field., Case Description: We present a case of strokelike migraine attacks after radiation therapy syndrome diagnosed immediately following a craniotomy and temporal lobectomy for recurrent metastatic tumor resection after prior gamma knife radiosurgery and whole-brain radiation therapy., Conclusion: SMART syndrome should be considered in the differential diagnosis of postsurgical patients with remote history of cranial irradiation and significant, new transient neurologic deficits not explainable by any other mechanism. It is possible that manipulation of the trigeminal ganglion, or the dura of the Meckel cave, contributed to triggering the manifestations of this syndrome in our patient during the immediate postoperative period., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The neurotensin 1 receptor (NTR1) is an important therapeutic target for a range of disease states including addiction. A high throughput screening campaign, followed by medicinal chemistry optimization, led to the discovery of a non-peptidic β-arrestin biased agonist for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)- piperazin-1-yl)quinazoline, 32 ( ML314 ), exhibits full agonist behavior against NTR1 (EC 50 = 2.0 μM) in the primary assay and selectivity against NTR2. The effect of 32 is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound 32 has no significant response in a Ca 2+ mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional G q coupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound 32 displays good brain penetration in rodents, and studies examining its in vivo properties are underway.

Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts--that is, increased rates of star formation--in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ~5 (refs 2-4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A 'maximum starburst' converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.

The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10 μM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Gravitational lensing is a powerful astrophysical and cosmological probe and is particularly valuable at submillimeter wavelengths for the study of the statistical and individual properties of dusty star-forming galaxies. However, the identification of gravitational lenses is often time-intensive, involving the sifting of large volumes of imaging or spectroscopic data to find few candidates. We used early data from the Herschel Astrophysical Terahertz Large Area Survey to demonstrate that wide-area submillimeter surveys can simply and easily detect strong gravitational lensing events, with close to 100% efficiency.

We report the identification of substituted cis-bicyclo[3.3.0]-oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.

We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.

Recent studies have indicated that bile acids regulate the expression of several genes involved in bile acid and lipid metabolism as ligands for the farnesoid X receptor (FXR). We report here that bile acids are directly able to govern cholesterol metabolism by a novel mechanism. We show that chenodeoxycholic acid (CDCA) enhances low density lipoprotein (LDL) receptor gene expression in human cultured cell lines (HeLa, Hep G2, and Caco-2). The proteolytic activation of sterol regulatory element-binding protein-2 (SREBP-2), a major regulator for LDL receptor gene expression, is not affected by CDCA. Both deoxycholic acid and lithocholic acid as well as CDCA, but not ursodeoxycholic acid, increase the mRNA level for the LDL receptor, even when Hep G2 cells are cultured with 25-hydroxycholesterol, a potent suppressor of gene expression for the LDL receptor. Although it seems possible that FXR might be involved in genetic regulation, both reporter assays with a reporter gene containing the LDL receptor promoter as well as Northern blot analysis reveal that FXR is not involved in the process. On the other hand, inhibition of mitogen-activated protein (MAP) kinase activities, which are found to be induced by CDCA, abolishes the CDCA-mediated up-regulation of LDL receptor gene expression. We further demonstrate that CDCA stabilizes LDL receptor mRNA and that the MAP kinase inhibitors accelerate its turnover. Taken together, these results indicate that bile acids increase LDL uptake and the intracellular cholesterol levels through the activation of MAP kinase cascades in conjunction with a down-regulation of bile acid biosynthesis by FXR. This work opens up a new avenue for developing pharmaceutical interventions that lower plasma LDL by stabilizing LDL receptor mRNA.

A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

We examine the suggestion that half of the galaxies observed by the Hubble Space Telescope Key Project and the Type Ia Supernova Calibration Team have had their distances systematically underestimated, by 0.1-0.3 mag in the distance modulus, because of the underappreciated influence of stellar profile blending on the Wide Field Camera chips. The signature of such an effect would be a systematic trend in (1) the Type Ia supernova-corrected peak luminosity and (2) the Tully-Fisher residuals, with increasing calibrator distance, and (3) a differential offset between Planetary Camera and Wide Field Camera distance moduli, within the same galaxy. The absence of a trend would be expected if blending were negligible (as has been inherently assumed in the analyses of the aforementioned teams). We adopt a functional form for the predicted influence of blending that is consistent with the models of Mochejska et al. and Stanek & Udalski, and we demonstrate that the expected correlation with distance predicted by these studies is not supported by the data. We conclude that the Cepheid-based extragalactic distance scale has not been severely compromised by the neglect of blending.

A series of substituted phenethyl derivatives of 3-benzisothiazolylpiperazine incorporating potent D2 and 5-HT2A antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT2A/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.