BACKGROUND CONTEXT:The indications for surgical intervention of axial back pain without leg pain for degenerative lumbar disorders have been limited in the literature, as most study designs allow some degree of leg symptoms in the inclusion criteria. PURPOSE:To determine the outcome of surgery (decompression only vs. fusion) for pure axial back pain without leg pain. STUDY DESIGN/SETTING:Prospectively collected data in the Michigan Spine Surgery Improvement Collaborative (MSSIC). PATIENT SAMPLE:Patients with pure axial back pain without leg pain underwent lumbar spine surgery for primary diagnoses of lumbar disc herniation, lumbar stenosis, and isthmic or degenerative spondylolisthesis ≤ grade II. OUTCOME MEASURES:Minimally clinically important difference (MCID) for back pain, Numeric Rating Scale of back pain, Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), MCID of PROMIS-PF, and patient satisfaction on the North American Spine Surgery Patient Satisfaction Index were collected at 90 days, 1 year, and 2 years after surgery. METHODS:Log-Poisson generalized estimating equation models were constructed with patient-reported outcomes as the independent variable, reporting adjusted risk ratios (RRadj). RESULTS:Of the 388 patients at 90 days, multi-level versus single level lumbar surgery decreased the likelihood of obtaining a MCID in back pain by 15% (RRadj=0.85, p=.038). For every one-unit increase in preoperative back pain, the likelihood for a favorable outcome increased by 8% (RRadj=1.08, p<.001). Of the 326 patients at 1 year, symptom duration > 1 year decreased the likelihood of a MCID in back pain by 16% (RRadj=0.84, p=.041). The probability of obtaining a MCID in back pain increased by 9% (RRadj=1.09, p<.001) for every 1-unit increase in baseline back pain score and by 14% for fusions versus decompression alone (RRadj=1.14, p=.0362). Of the 283 patients at 2 years, the likelihood of obtaining MCID in back pain decreased by 30% for patients with depression (RRadj=0.70, p<.001) and increased by 8% with every one-unit increase in baseline back pain score (RRadj=1.08, p<.001). CONCLUSIONS:Only the severity of preoperative back pain was associated with improvement in MCID in back pain at all time points, suggesting that surgery should be considered for selected patients with severe axial pain without leg pain. Fusion surgery versus decompression alone was associated with improved patient-reported outcomes at 1 year only, but not at the other time points.

In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.

BACKGROUND: The Michigan Spine Surgery improvement Collaborative is a statewide multicenter quality improvement registry. Because missing data can affect registry results, we used MSSIC to find demographic and surgical characteristics that affect the completion of patient-reported outcomes (PROs) at 90 days and 1 year. METHODS: A total of 24,404 patients who had lumbar surgery (17,813 patients) or cervical surgery (6591 patients) were included. Multivariate logistic regression models of patient disease were constructed to identify risk factors for failure to complete scheduled PRO surveys. RESULTS: Patients >= 65 years old and female patients were both more likely to respond at 90 days and 1 year. Increasing education was associated with greater response rate at 90 days and 1 year. Whites and African Americans had no differences in response rates. Calling provided the highest response rate at 90 days and 1 year. For cervical spine patients, only discharge to rehabilitation increased completion rates, at 90 days but not 1 year. For lumbar spine patients, spondylolisthesis or stenosis (vs. herniated disc) had a greater response rate at 1 year. Patients with leg (vs. back) pain had a greater response only at 1 year. Patients with multilevel surgery had an increased response at 1 year. Patients who underwent fusion were more likely to respond at 90 days, but not 1 year. Discharge to rehabilitation increased response at 90 days and 1 year. CONCLUSIONS: A multivariate analysis from a multi-center prospective database identified surgical factors that affect PRO follow-up, up to 1 year. This information can be helpful for imputing missing PRO data and could be used to strengthen data derived from large prospective databases.

Background: Postoperative urinary retention (POUR) is common in neurosurgical patients. The use of alpha-blockade therapy, such as tamsulosin, has benefited many patients with a history of obstructive uropathy by decreasing lower urinary tract symptoms such as distension, infections, and stricture formation, as well as the incidence of POUR. For this study, we targeted patients who had undergone spinal surgery to examine the prophylactic effects of tamsulosin. Increased understanding of this therapy will assist in minimizing the morbidity of spinal surgery. Methods: We enrolled 95 male patients undergoing spine surgery in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to receive either preoperative tamsulosin (N = 49) or a placebo (N = 46) and then followed-up prospectively for the development of POUR after removal of an indwelling urinary catheter (IUC). They were also followed-up for the incidence of IUC reinsertions. Results: The rate of developing POUR was similar in both the groups. Of the 49 patients given tamsulosin, 16 (36%) developed POUR compared to 13 (28%) from the control group (P = 0.455). In the control group, 5 (11%) patients had IUC re-inserted postoperatively, whereas 7 (14%) patients in the tamsulosin group had IUC re-inserted postoperatively (P = 0.616). In patients suffering from axial-type symptoms (i.e., mechanical back pain), 63% who received tamsulosin and 18% from the control group (P = 0.048) developed POUR. Conclusion: Overall, there was no statistically significant difference in the rates of developing POUR among patients in either group. POUR is caused by a variety of factors, and further studies are needed to shed light on its etiology.

A toxicological evaluation of N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6] thiadiazin-5-yl) oxy)-2-methylpropan- 2-yl)-2,6-dimethylisonicotinamide (S2218; CAS 1622458-34-7), a flavour with modifying properties, was completed for the purpose of assessing its safety for use in food and beverage applications. S2218 exhibited minimal oxidative metabolism in vitro, and in rat pharmacokinetic studies, the compound was poorly orally bioavailable and rapidly eliminated. S2218 was not found to be mutagenic in an in vitro bacterial reverse mutation assay, and was found to be neither clastogenic nor aneugenic in an in vitro mammalian cell micronucleus assay. In subchronic oral toxicity studies in male and female rats, the NOAEL was 140 mg/kg bw/day (highest dose tested) for S2218 sulfate salt (S8069) when administered as a food ad-mix for 13 consecutive weeks. Furthermore, S2218 sulfate salt demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg bw/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

Toxicological evaluations of two N-alkyl benzamide umami flavour compounds, N-(heptan-4-yl)benzo[d][1,3]dioxole-5-carboxamide (S807, CAS 745047-51-2) and (R)-N-(1-methoxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (S9229, CAS 851669-60-8), were completed for the purpose of assessing their safety for use in food and beverage applications. Both S807 and S9229 undergo rapid oxidative metabolism by both rat and human liver microsomes in vitro. In pharmacokinetic studies in rats, the systemic exposure to S9229 on oral administration is very low at all doses (% F < 1%), while that of S807 demonstrated a non-linear dose dependence. In metabolism studies in rats, hydroxylation of the C-4 aryl methyl group was found to be the dominant metabolic pathway for S9229. The dominant metabolic pathway for S807 in the rat involved oxidative scission of the methylenedioxy moiety to produce the corresponding 3,4-dihydroxybenamide which is further converted by Phase II metabolic enzymes to the 3- and 4-O-methyl ethers as well as their corresponding glucuronides. Both S807 and S9229 were not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in polychromatic erythrocytes in vivo. In a subchronic oral toxicity study in rats, the no-observed-effect-level (NOEL) for S807 was 20 mg/kg bw/day when administered in the diet for 13 weeks. The no-observed-adverse-effect-level (NOAEL) for S9229 in rats was 100 mg/kg bw/day (highest dose tested) when administered in the diet for 28 consecutive days.

BACKGROUND: Arteriovenous malformations (AVMs) are hypothesized to be static, congenital lesions developing as early as 4 weeks of fetal life. New literature has shown that AVMs may represent dynamic and reactive vascular lesions arising from cerebral infarction, inflammation, or trauma. A literature search reveals 17 previously reported cases of new AVM formation after previous negative imaging studies. This reactive development or "second hit" theory suggests that at a molecular level, growth factors may play a vital role in aberrant angiogenesis and maturation of an arteriovenous fistula into an AVM.CASE DESCRIPTION: A 52-year-old female presented with a ruptured left frontal AVM demonstrated by computed tomography angiography and digital subtraction angiography. The patient had suffered an acute ischemic stroke in the similar cerebral vascular territory 8 years prior due to left internal carotid artery occlusion. Detailed neuroimaging at that time failed to reveal any vascular malformation, suggesting that the AVM might have developed in response to initial vascular insult.CONCLUSIONS: We believe that there might exist a subset of AVMs that display dynamic characteristics and could potentially appear, grow, or resolve spontaneously without intervention, especially in the presence of local growth factors and molecular signaling cascades. When combined with a previous cerebral insult such as stroke, trauma, or inflammation, de novo AVM formation may represent a "second hit" with abnormal angiogenesis and vessel formation.

A toxicological evaluation of a umami flavour compound, 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine (S3643; CAS 902136-79-2), was completed for the purpose of assessing its safety for use in food and beverage applications. S3643 undergoes extensive oxidative metabolism in vitro with rat microsomes producing the S3643-sulfoxide and 4′-hydroxy-S3643 as the major metabolites. In incubations with human microsomes, the O-demethyl-S3643 and S3643-sulfoxide were produced as the major metabolites. In pharmacokinetic studies in rats, the S3643-sulfoxide represents the dominant biotransformation product. S3643 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in CHO-WBL cells. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S3643 was 100mg/kg bw/day (highest dose tested) when administered in the diet for 90 consecutive days.

A toxicological evaluation of two novel bitter modifying flavour compounds, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (S6821, CAS 1119831-25-2) and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (S7958, CAS 1217341-48-4), were completed for the purpose of assessing their safety for use in food and beverage applications. S6821 undergoes oxidative metabolism in vitro, and in rat pharmacokinetic studies both S6821 and S7958 are rapidly converted to the corresponding O-sulfate and O-glucuronide conjugates. S6821 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in bone marrow polychromatic erythrocytes in vivo. S7958, a close structural analog of S6821, was also found to be non-mutagenic in vitro. In short term and subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for both S7958 and S6821 was 100mg/kg bw/day (highest dose tested) when administered as a food ad-mix for either 28 or 90 consecutive days, respectively. Furthermore, S6821 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000mg/kg bw/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

A toxicological evaluation of a novel cooling agent, 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(2-thienylmethyl) acetamide (S2227; CAS 1374760-95-8), was completed for the purpose of assessing its safety for use in food and beverage applications. S2227 undergoes rapid oxidative metabolism in vitro, and in rat and dog pharmacokinetic studies is rapidly converted to its component carboxylic acid and secondary amine. S2227 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in polychromatic erythrocytes in vivo. The secondary amine hydrolysis product, N-(2-thienylmethyl)-1H-pyrazol-3-amine (M179), was also evaluated for genotoxicity. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S2227 was 100 mg/kg/day (highest dose tested) when administered by oral gavage for 90 consecutive days. Furthermore, S2227 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

A toxicological evaluation of two structurally related flavors with modifying properties, 3-((4-amino-2,2-dioxido-1H- benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-N-propylpropanamide (S6973; CAS 1093200-92-0) and (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one (S617; CAS 1469426-64-9), was completed for the purpose of assessing their safety for use in food and beverage applications. Both compounds exhibited minimal oxidative metabolism in vitro, and in rat pharmacokinetic studies, were poorly absorbed and rapidly eliminated. Neither compound exhibited genotoxic concerns. S6973 and S617 were not found to be mutagenic or clastogenic, and did not induce micronuclei in vitro or in vivo. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-levels (NOAELs) were 20 mg/kg/day and 100 mg/kg/day (highest doses tested) for S6973 and S617, respectively, when administered as a food ad-mix for 90 consecutive days. Furthermore, S617 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

A toxicological evaluation of 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid(S9632; CAS 1359963-68-0), a flavour with modifying properties,was completed for the purpose of assessing its safety for use in food and beverage applications. No Phase I biotransformations of S9632 were observed in rat or human microsomes in vitro, and in rat pharmacokinetic studies, the compound was poorly orally bioavailable and rapidly eliminated. S9632 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei or indicate interactions with the mitotic spindle in an in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. In subchronic oral toxicity studies in rats, the NOEL was 100 mg/kg/day (highest dose tested) for S9632 when administered as a food ad-mix for 90 consecutive days. Furthermore, S9632 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOEL of 1000 mg/kg/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.

BACKGROUND:Postoperative urinary retention (POUR) is a common problem in adult neurosurgical patients. The incidence of POUR is unknown and the etiology has not been well established. POUR can lead to urogenital damage, prolonged hospital stay, higher cost, and infection. This study elucidates several risk factors that contribute to POUR in a variety of neurosurgical patients in one institution.METHODS:A total of 137 neurosurgical patients were prospectively followed up for the development of POUR, which we defined as initial postvoid residual (PVR1) >250 ml 6 hours after removal of an indwelling urinary catheter (IUC). For patients with PVR >250 ml on the third check, IUCs were reinserted and kept in for 5-7 days.RESULTS:Of the 137 patients, 68 (50%) were male, 41% (56/137) were 60 years or older, 86% (118/137) underwent spinal surgery, and 54% (74/137) had anesthesia over 200 minutes. Overall incidence of clinical POUR was 39.4% (54/137). Significantly higher rates of PVR1 >250 were noted in males, patients older than 60 years, and those who underwent spine surgery. When considering all patient characteristics (except selective alpha blockers), only gender, surgery time, and surgery type remained significant. In addition, PVR1 >250 was positively associated with longer length of stay. Of all patients, 24 (18%) had IUCs reinserted postoperatively or should have had one (5 refused and 2 had a third PVR). The association of IUC reinsertion with male gender was significant.CONCLUSION:Male gender, time of anesthesia >200 minutes, older age, and spinal surgery are the most significant risk factors associated with POUR in neurosurgical patients.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.